P2P Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention – Day 2

P2P Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention – Day 2


OUR FIRST SESSION BEGINS THIS MORNING WITH DR. FINK’S PRESENTATION ON DRUG HOLIDAYS. HOWARD?>>THANK YOU. OKAY. THANK YOU FOR COMING BACK. THIS IS — I’M HOWARD FINK FROM — ANYBODY WHO WASN’T HERE YESTERDAY, FROM THE MINNEAPOLIS V.A. AND MINNESOTA EVIDENCE-BASED PRACTICE CENTER. THIS IS PART 3 OF OUR — FROM OUR EVIDENCE REPORT. THIS SESSION IS ON DRUG HOLIDAYS. MY DISCLAIMERS ARE, AGAIN, THE SAME AS THEY WERE YESTERDAY. THIS IS BASED ON AN EVIDENCE REPORT. WE’VE CONTRACTED WITH AHRQ, I HAVE NO FINANCIAL INTERESTS TO DECLARE, AND THIS IS BASED ON A PEER REVIEWED DRAFT REPORT. THE DRAFT REPORT WAS POSTED PUBLICLY YESTERDAY FOR PUBLIC COMMENT, AND I THINK WE’RE GOING TO TRY TO GET THE LINK UP FOR PEOPLE WHO ARE INTERESTED IN PROVIDING CONSTRUCTIVE FEEDBACK SO THAT WE CAN MAKE THE FINAL REPORT EVEN BETTER. THE GOALS OF OUR SYSTEMATIC REVIEW ARE TO REVIEW THE EVIDENCE ON THE BENEFITS AND HARMS OF LONG TERM OSTEOPOROSIS DRUG THERAPY AND ON OSTEOPOROSIS DRUG TREATMENT HOLIDAYS AND FACTORS THAT MAY MODIFY THESE EFFECTS. THIS THIRD PART WE’RE TALKING ABOUT DRUG HOLIDAYS. SO THE KEY QUESTION FOR THIS PART OF THE EVIDENCE REPORT WAS AMONG MEN AND POST-MENOPAUSAL WOMEN AGED 50 OR OLDER WITH OSTEOPOROSIS OR OSTEOPENIA. WHAT ARE THE BENEFITS, AND THESE ARE PEOPLE WHO ARE BEING TREATED WITH OSTEOPOROSIS DRUG THERAPY, WHAT ARE THE BENEFITS AND HARMS OF DRUG HOLIDAYS AND DO THE BENEFITS AND HARMS VARY BY PATIENT BONE OR DRUG TREATMENT CHARACTERISTICS. THE METHODS ARE SIMILAR, LARGELY THE SAME AS WHAT I DESCRIBED YESTERDAY FOR THE LONG TERM BENEFITS AND HARMS. WE DID AN ELECTRONIC THROUGH JUNE OF 2018, REFERENCED SOME SYSTEMATIC REVIEWS FOR THE POPULATIONS THAT WE INCLUDED WERE ADULTS WITH PAST TREATMENT HERE FOR OSTEOPOROSIS OR OH OSTEOPENIA, TO PREVENT FRACTURES. IN THE DRUG HOLIDAY PORTION OF THE REPORT, I’M TALKING ABOUT BOTH THE EFFECTS ON FRACTURES AND HARM, SO FOR HARMS, WE INCLUDED PARTICIPANTS REGARDLESS OF THEIR OSTEOPOROSIS STATUS, AND FOR OUR SEARCH, WE DEFINE DRUG HOLIDAY AS PEOPLE WHO HAD STOPPED THEIR OSTEOPOROSIS DRUG TREAT THEMENT FOR AT TREATMENT AFTER PRIOR TREATMENT FOR AT LEAST A YEAR. AGAIN, WE LIMITED OUR SCOPE TO TREATMENTS THAT WERE FDA-APPROVED FOR TREATMENT OR PREVENTION OF OSTEOPOROSIS, FOR EFFECTS ON FRACTURES, WE LIMITED OUR REVIEW TO RANDOMIZED CONTROL TRIALS AND CONTROLLED CLINICAL TRIALS, AND FOR HARMS, WE INCLUDED BOTH THE TRIALS AND OBSERVATIONAL DATA. THE EFFICACY OUTCOMES SAME AT YESTERDAY, PRIMARILY INCIDENT CLINICAL FRACTURES, SECONDARILY INCIDENT RADIOGRAPHIC VERTEBRAL FRACTURES AND THIRD, CHANGE IN BMD BUT WE’RE NOT ADDRESSING THE CHANGE IN BMD OUTCOME IN THIS PRESENTATION. HARMS OUTCOMES, SAME AS YESTERDAY: ATYPICAL FEMORAL FRACTURES WITH RADIOGRAPHIC CONFIRMATION OF AFF FEATURES, AND THEN SUBTROA CAN TAIRK/FEMORAL SHAFT FRACTURES WHICH THE RADIOGRAPHIC FEATURES AFF HAVE NOT BEEN CONFIRMED, ONJ, SERIOUS ADVERSE EVENTS. POSSIBLE EFFECT MODIFIERS, AGAIN, SAME APPROACH AS YESTERDAY, PATIENT, BONE AND DRUG TREATMENT CHARACTERISTICS. SO THE SLIDES ARE ORGANIZED BY TREATMENT, AND SO FOR ALENDRONATE, THERE WERE WOULD STUDIES THAT WE THOUGHT PROVIDED SOME DATA ON THIS. THE FIRST ONE WAS A STUDY THAT ENROLLED INDIVIDUALS WITH — OR THEY WERE ALL IN POST-MENOPAUSAL WOMEN,, THEY HAD ENROLLED PATIENTS WITH EITHER OS PENA, OSTEOPOROSIS OR JUST OSTEOPOROSIS. THE FIRST STUDY, THE FIRST TWO LINES, IT’S A COMPLICATED STUDY BUT THE PART THAT’S RELEVANT FOR THE DRUG HOLIDAY QUESTION IS, THE PARTICIPANTS WHO HAD HAD FIVE YEARS OF ALLEN DROA NATE WERE COMPAREED, THEY EITHER HAD TWO MORE YEARS OND PLACEBO, THIS IS A CONTROLLED CLINICAL TRIAL, NOT A RANDOMIZED TRIAL, AND THEY FOUND NO DIFFERENCE BETWEEN TREATMENT GROUPS IN NON-VERTEBRAL OR CLINICAL VERTEBRAL FRACTURE. THEN OF THE PEOPLE WHO HAD SEVEN YEARS OF ALENDRONATE, THEY WERE EITHER CONTINUED ON IT OR PLACEBO AND IN THAT COMPARISON, THERE WAS NO DIFFERENCE IN NON-VERTEBRAL FRACTURE. THE MAIN STUDY THAT PROVIDES EVIDENCE FOR THIS QUESTION, THOUGH, IS THE FIT LONG TERM EXTENSION OR FLEX STUDY IN WHICH PARTICIPANTS WHO HAD RECEIVED ALENDRONATE IN THE — OR IN FIT, EITHER FIT 1 OR FIT THE 2, AND THEN CONTINUED ON SOME DURING A GAP BETWEEN THE END OF FIT AND THE START OF FLEX, SO THEY’D BEEN ON IT FOR AN AVERAGE OF FIVE YEARS, WERE RANDOMIZED TO ANOTHER FIVE YEARS OF ALENDRONATE VERSUS PLA PLACEBO,
AND THE PRIMARY OUTCOME WAS CHANGE IN BMD BUT THE REPORTED FRACTURE OUTCOMES AND THIS STUDY FOUND APPROXIMATELY A HALING OF THE RISK OF INCIDENT CLINICAL VERTEBRAL FRACTURES. HAZARD RATIO OF .45, THAT LOOKED AT OTHER FRACTURES AND THERE WAS NO SIGNIFICANT DIFFERENCE IN RISK OF CLINICAL FRACTURE, NON-VERTEBRAL FRACTURE, HIP FRACTURE OR RADIOGRAPHIC VERTEBRAL FRACTURE. IN LOOKING TO SEE WHETHER THE EFFECTS OF TREATMENT ON RISK OF FRACTURE VARIED AS A FUNCTION OF OTHER CHARACTERISTICS, PATIENT CHARACTERISTICS, THEY EVALUATED BOTH BASELINE RADIOGRAPHIC VERTEBRAL FRACTURE AND BASELINE FEMORAL NECK BMD MEASURED AT THE TIME PEOPLE RANDOMIZED TO PLACEBO OR ANOTHER FIVE YEARS OF ALENDRONATE AND FOUND THAT THE RESULTS DIDN’T VARY AS A FUNCTION OF EITHER OF THESE FACTORS. SO FOR ZOLEDRONATE, THERE ARE TWO STUDIES. THE FIRST ONE RANDOMIZED PATIENTS WITH POST-MENOPAUSAL WOMEN WITH OSTEOPENIA TO ZOLENDRONATE FOR TWO YEARS VERSUS FOR ONE YEAR AND PLACEBO FOR ONE YEAR. THEY REPORTED — AGAIN THE PRIMARY OUTCOME WAS NOT INCIDENT FRACTURE, IT WAS A BONE DENSITY CHANGE. THEY REPORTED ON CLINICAL FRACTURE YOU CAN SEE THE HAZARD RATIO IS 1.37, THE CONFIDENCE RULES ARE VERY WIDE. SO THIS DIDN’T REALLY PROVIDE SUFFICIENT EVIDENCE TO DRAW ANY CONCLUSIONS FOR THIS TREATMENT COMPARISON. THEN THERE WAS THE HORIZON EXTENSION IN WHICH POST-MENOPAUSAL WOMEN WHO HAD BEEN ASSIGNED — ACID FOR THREE YEARS FOR HAVING OSTEOPOROSIS BY EITHER BMD OR RADIOGRAPHIC VERTEBRAL FRACTURE WERE RANDOMIZED EITHER ANOTHER THREE YEARS OF ZOLEDRONATE OR PLACEBO, AND WHAT THIS STUDY FOUND WAS APPROXIMATELY 50% RELATIVE REDUCTION OF RADIOGRAPHIC VERTEBRAL FRACTURE, AND NO SIGNIFICANT DIFFERENCE IN CLINICAL VERTEBRAL FRACTURE. WHICH IS THE FLIP OF THE FLEX STUDY. AND THEN SIMILAR TO THE FLEX STUDY IN THAT IT FOUND NO REDUCTION IN RISK OF ANY NON-VERTEBRAL FRACTURE, SO NO DIFFERENCE IN RISK OF CLINICAL FRACTURE, NON-VERTEBRAL FRACTURE OR HIP FRACTURE. THE PEOPLE WHO HAD THEN SIX YEARS OF ZOLEDRONIC ACID, SOME WERE RANDOMIZED TO ANOTHER THREE YEARS VERSUS PLACEBO, SMALL NUMBER, AND THE HAZARD RATIO FOR RADIOGRAPHIC VERTEBRAL FRACTURE WAS SIMILAR IN MAGNITUDE, BUT THE CONFIDENCE RULES WERE VERY WIDE, AND THERE WAS NO SIGNIFICANT DIFFERENCE IN RISK FOR CLINICAL FRACTURE. WITH THE SMALL NUMBER OF FRACTURE AND THE WIDE CONFIDENCE RULES, WE FOUND EVIDENCE WAS INSUFFICIENT TO DRAW ANY CONCLUSION ABOUT THIS COMPARISON, NINE YEARS VERSUS SIX YEARS. THE STUDY DEPARTMENT REPORT ANY INFORMATION ABOUT WHETHER DIFFERENCES IN RISK OF FRACTURE BETWEEN CONTINUING ZOLEDRONIC ACID VERSUS DRUG HOLIDAY VARIED BY PATIENT, BONE OR DRUG CHARACTERISTICS. THERE WAS A DENOSUMAB STUDY I TALKED ABOUT YESTERDAY, I WOULD LIKE TO HAVE HAD THIS FIGURE AVAILABLE TO ILLUSTRATE IT YESTERDAY, BUT BASICALLY IT WAS A PHASE 2 TRIAL IN 365 POST-MENOPAUSAL WOMEN WHO HAD A — I THINK A T SCORE OF MINUS 1.8 OR WORSE, AND THERE WERE — IT WAS A DOSE FINDING STUDY. THERE WERE EIGHT ARMS, THERE WAS AN ARM WHERE DENOSUMAN WAS GIVEN FOR TWO YEARS AND THEN PLACEBO FOR TWO YEARS, WHAT I HAVE IT LISTED IS ARM 7, 2 YEARS THEN PLACEBO FOR A YEAR. FINALLY THE LAST ARM WAS PLACEBO FOR EIGHT YEARS. THIS TRIAL WOULD HAVE THE POSSIBILITY, IF DATA WERE AVAILABLE, OF PROVIDING SOME INFORMATION ABOUT DENOSUMAB DRUG RESULTS ONLY WITH ALL THE ARMS IN WHICH SOMEBODY RECEIVED DENOSUMAB POOLED TOGETHER, AND COMPARED THEM TO PLACEBO AND DID THAT FOR BOTH FRACTURE OUTCOMES AND HARMS. AND SO IT WASN’T POSSIBLE TO CONCLUDE ANYTHING ABOUT THE EFFECT OF DENOSUMAB DRUG HOLIDAY FROM THIS — WHAT THEY REPORTED. AND THEN THEY REPORTED NO INFORMATION ABOUT WHETHER RESULTS DIFFERED AS A FUNCTION OF PATIENT BONE OR DRUG CHARACTERISTICS. SO FOR HARMS, SO THAT WAS THE EFFECT OF DRUG HOLIDAYS ON EFFICACY ON FRACTURES. SO IN THIS SLIDE, I HAVE THE FLEX STUDY RESULTS HIGHER UP ON THE TABLE, BUT THERE WERE NO SIGNIFICANT DIFFERENCES BETWEEN TREATMENT GROUPS IN SERIOUS ADVERSE EVENTS, THERE WAS JUST A STATEMENT, THERE WERE NO DATA PROVIDED. THE STUDY REPORTED NO STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN 10 YEARS VERSUS FIVE YEARS OF ALENDRONATE IN SUBTROCHANTERIC OR FEMORAL SHAFT FRABTS, BUT FRACTURES, BUT
YOU CAN S EE THE CONFIDENCE INTERVALS ARE VERY WIDE, SO VERY FEW CASES. AND SO IT’S NOT REALLY CONCLUSIVE. ONJ, THEY REPORTED THERE WERE NO CASES. THE STUDY THAT LOOKED AT ALENDRONATE FIVE YEARS VERSUS SEVEN YEARS AND THEN 10 YEARS VERSUS SEVEN YEARS REPORTED SERIOUS ADVERSE EVENTS AS BEING NOT STATISTICALLY SIGNIFICANTLY DIFFERENT BETWEEN TREATMENT GROUPS. FOR ZOLEDRONIC ACID, THE STUDY THAT COMPARED TWO YEARS VERSUS ONE YEAR ZOLEDRONIC ACID REPORTED THAT THERE WAS NO DIFFERENCE IN SERIOUS ADVERSE EVENTS, BUT DIDN’T PROVIDE ANY NUMERICAL DATA, AND THEY REPORTED THAT THERE WERE NO CASES OF ONJ OR ATRIAL FIBRILLATION. I DON’T BELIEVE THEY REPORTED ANY INFORMATION ABOUT AFF OR SUBTROCHANTERIC OR FEMORAL SHAFT FRACTURES. IN THE HORIZON EXTENSION COMPARING SIX YEARS VERSUS THREE YEARS, THE STUDY REPORTED NO DIFFERENCE BETWEEN TREATMENT GROUPS IN SERIOUS ADVERSE EVENTS, REPORTED THAT THERE WERE NO CASES OF AFF, ONE CASE OF ONJ, SO NOT ENOUGH INFORMATION TO DRAW ANY CONCLUSION ABOUT THE DIFFERENCE IN — A DIFFERENCE IN RISK BETWEEN THE TREATMENT GROUPS, AND FOR ATRIAL FIBRILLATION, I THINK IT WAS 3.4% VERSUS 2.1% BETWEEN THE GROUPS. IT WASN’T STATISTICALLY SIGNIFICANTLY DIFFERENT, BUT NUMERICALLY, IT LOOKED LIKE MORE — POSSIBLY MORE CASES OF ATRIAL FIBRILLATION IN THE CONTINUATION GROUP THAN. THEN FOR THE NINE YEARS VERSUS SIX YEARS, NO DIFFERENCE IN SERIOUS ADVERSE EVENTS BETWEEN THE TREATMENT GROUPS, NO CASES OF AFF AND ONJ DURING THIS THREE-YEAR FOLLOW-UP PERIOD, AND THEN FOR ATRIAL FIBRILLATION, AGAIN, WHILE THE RESULTS WERE NOT STATISTICALLY SIGNIFICANTLY DIFFERENT BETWEEN THE GROUPS, IT’S 5% IN THE CONTINUATION GROUP VERSUS 1% IN THE DISCONTINUATION GROUP. FOR DENOSUMAB, AGAIN, THEY REPORTED THAT THERE WERE NO CASES OF ONJ OR ATRIAL FIBRILLATION IN THE STUDY, AND THEN DIDN’T REPORT DATA IN A WAY THAT YOU COULD COMPARE ANY OUTCOMES BETWEEN THE DENOSUMAB CONTINUATION VERSUS HOLIDAY GROUPS. LOOKING AT WHETHER DIFFERENCES IN RISK OF HARMS BETWEEN OSTEOPOROSIS DRUG TREATMENT CONTINUATION AND DRUG HOLIDAY DIFFERED AS A FUNCTION OF PATIENT BONE AND DRUG CHARACTERISTICS, WE FOUND NO DATA REPORTED. SO LIMITATIONS OF EVIDENCE ON DRUG HOLIDAY, THERE WERE A FEW TRIALS, NONE OF THEM HAD INCIDENT FRACTURES AS PRIMARY OUTCOME. THE TRIALS THAT EXISTED HAD RELATIVELY FEW CLINICAL FRACTURE EVENTS, ESPECIALLY FOR HIP FRACTURE. NO TRIALS DIRECTLY COMPARE DRUG HOLIDAYS OF DIFFERENT DURATIONS AND AT THE SAME TIME PROVIDED USABLE DATA. THE TRIALS WERE GENERALLY IN HEALTHY, LARGELY WHITE, POST-MENOPAUSAL WOMEN WITHOUT INFORMATION PROVIDED ONCOMORBIDDITIES. SO THE GENERALIZABILITY OF THE RESULTS TO OTHER POPULATIONS IS UNCLEAR. THERE WERE MINIMAL DATA — NO DATA ON POSSIBLE DRUG HOLIDAY EFFECT MODIFIERS. IDEALLY, THOUGH NOT EVERYTHING HERE MAY BE FEASIBLE, BUT FUTURE DRUG HOLIDAY STUDIES SHOULD BE POWERED TO ASSESS CLINICAL FRACTURE END POINTS, THAT IT WOULD BE USEFUL TO HAVE COMPARISONS OF DIFFERENT DURATIONS OF DRUG HOLIDAYS, WITH OR WITHOUT RESTARTING OSTEOPOROSIS DRUG TREATMENT, AND INCLUDING A CONTINUOUS OSTEOPOROSIS DRUG THERAPY COMPARISON GROUP. THE PARTICULARS WOULD VARY DEPENDING ON WHICH AGENTS WE’RE TALKING ABOUT, BUT THIS IS JUST A BROADER STATEMENT. IT WOULD BE USEFUL FOR STUDIES TO INCLUDE HIGH RISK, NON-OSTEOPOROTIC POPULATIONS TO INCLUDE MEN, NON-WHITES AND INDIVIDUALS WITH COMORBIDITIES. HARMS KAY TA HARMS DATA SHOULD BE SYSTEMATICALLY COLLECTED AND REPORTED, AND THE STUDIES SHOULD SPECIFY FACTORS IN ADVANCE TO LOOK AT TO SEE IF TREATMENT — TREATMENT EFFECTS DIFFER TO HELP INDIVIDUALIZE WHICH PATIENTS MAY HAVE A MORE OR LESS FAVORABLE BENEFITS TO HARMS RATIO FOR CONTINUATION VERSUS DRUG HOLIDAY HOLIDAY. AND THAT’S IT. [APPLAUSE]>>GOOD MORNING EVERYONE. IT’S A REAL PLEASURE TO BE HERE. THANK YOU FOR COMING OUT. I’M DOLORES SHOBACK FROM THE UNIVERSITY OF CALIFORNIA SAN FRANCISCO AND I WANTED TO EXPRESS MY APPRECIATION FOR
THE OPPORTUNITY TO BE HERE TODAY. MY TOPIC IS CLINICAL PERSPECTIVES REGARDING DRUG HOLIDAYS FOLLOWING B BISPHOSPHONATE THERAPY. MY PRESENTATION HAS BEEN REVIEWED TO ENSURE THERE’S NO BIAS, AND WE WILL NOT BE DISCUSSING UNLABELED USE OR ANY INVESTIGATIONAL PRODUCTS IN THIS DISCUSSION. SO I THOUGHT WHAT I WOULD DO IS FRAME THIS DISCUSSION OVER THE NEXT 20 MINUTES IN TERMS OF THREE TYPICAL PATIENTS THAT I OFTEN WILL ENCOUNTER IN MY CLINICAL PRACTICE. SO THE FIRST IS A 60-YEAR-OLD FEMALE, CAN SEE SHE HAD EARLY MENOPAUSE AT THE AGE OF 42, SHE’S TAKEN WEEKLY RISEDRONAE
ATE FOR THE LAST TWO YEARS, CURRENTLY AND THE QUESTION IS IS SHE A GOOD CANDIDATE FOR A DRUG HOLIDAY. HER CURRENT BMD IS NEG NEGATIVE 2.4 TR SPINE AND NEGATIVE 1.8 AT THE HIP. MY SECOND PATIENT IS A 66-YEAR-OLD ASIAN FEMALE WHO HAD A RADIUS FRACTURE AT THE AGE OF 60 TRYING TO GET ON TO THE CABLE CAR IN SAN FRANCISCO. SHE’S BEEN ON WEEKLY ALENDRONATE FOR THE PAST FIVE YEARS. HER INITIAL BONE DENSITY AT THE SPINE NEGATIVE 2.9, NOW IT’S NEGATIVE 2.4, AT THE HIP, NEGATIVE 2.1, NOW IT’S NEGATIVE 1.8. THIS THIRD PATIENT, 75 YEARS OLD CURRENTLY, WHEN WE SAW HER IN THE OFFICE, SHE’D REPORTED TWO FALLS OVER THE PRIOR 18 MONTHS. AT INITIATION OF THERAPY AT THE AGE OF 72, SHE’D HAD ONE MILD AND ONE MODERATE VERTEBRAL FRACTURE CONFIRMED ON IMAGING. SHE’S BEEN ON I.V. ZOLEDRONIC ACID YEARLY FOR THE LAST THREE YEARS. YOU CAN SEE HER BONE DENSITY, NEGATIVE 3.2 AT THE SPINE, NEGATIVE 2.7 AT THE HIP, AND NEGATIVE 2.8 NOW AFTER THREE YEARS OF THERAPY, NEGATIVE 2.5 AT THE HIP. AND SHE’S HAD NO WORSENING OF HER BASELINE LUMBAR SPINE FRACTURES AND NO NEW FRACTURES IN THAT TIME. SO LET’S THINK ABOUT THOSE THREE WOMEN AS WE GO THROUGH THESE SLIDES. WHEN I THINK IN TERMS OF CLINICAL CONSIDERATIONS, EMPHASIZING THIS IS A TREATMENT INTERRUPTION AND THAT PATIENTS NEED TO BE FOLLOWED CHRONICALLY, I LIKE TO UPDATE THE CURRENT FRACTURE RISK PROFILE FOR THAT PATIENT. A LOT OF THIS INFORMATION IS VERY NICELY SUMMARIZED BY DR. ADLER. I THINK ABOUT THE CURRENT AGE OF THE PATIENT, WAS THERE A PRIOR OSTEOPOROTIC FRACTURE WHEN TREATMENT WAS INITIATED OR DID ONE OCCUR WHILE THE PATIENT WAS ON THERAPY. I THINK ABOUT ANY NEW DIAGNOSES THAT THEY’VE ACQUIRED IN THE TIME SINCE THEY’VE BEEN TREATED, ARE THEY ON NEW MEDICATIONS THAT ARE ASSOCIATED WITH BONE LOSS NOW LIKE GLUCOCORTICOIDED, AND SO FORTH, SO WHAT’S GOING ON WITH THE PATIENT. I LIKE TO HAVE A CURRENT BONE MINERAL DENSITY PARTICULARLY FOCUSING ON THE HIP SITES IN THAT PARTICULAR INDIVIDUAL AND THEN THE PATIENT CHARACTERISTICS AND I’M ALWAYS THINKING ABOUT THAT PARTICULAR PATIENT IN VIEW OF THE ONES THAT SEEM TO BE AT GREATEST RISK FOR SOME OF THE RARE COMPLICATIONS THAT WE’VE TALKED SO MUCH ABOUT IN THIS CONFERENCE. THEN OF COURSE ONE NEEDS TO ALWAYS THINK ABOUT AND EXPLORE PATIENT PREFERENCES. SO WHEN I THINK ABOUT THE RARE COMPLICATION OF ATYPICAL FEMUR FRACTURES, I ALWAYS THINK BACK TO THESE VERY IMPORTANT TASK FORCE REPORTS LED BY DR. SHANE IN TERMS OF THINKING ABOUT WHO IS THAT PATIENT WHO’S MOST AT RISK FOR THIS RARE COMPLICATION. AND THESE TASK FORCE REPORTS LOOKED AT OVER 300 CASES. SOME OF THE FEATURES ONE GETS FROM THAT IS THE MEDIAN EXPOSURE WITH SEVEN YEARS IN THESE PATIENTS, BUT THE RANGE WAS REALLY QUITE WIDE. PATIENTS WERE AT GREATER RISK IF THEY WERE RECEIVING SOME OTHER ANTIRESORPATIVE DURING THAT TIME. PROTON PUMP INHIBITORS ARE IMPORTANT, GLUCOCORTICOID — CON FIR FERS A VERY SIGNIFICANT INCREASED RISK FOR THESE ATYPICAL FEMUR FRACTURES AND HYPOPHOSPHATA SI. A, OFASIA. THAT ADDS AGAIN A VERY SIGNIFICANT ADDITIONAL RISK FOR THAT INDIVIDUAL ON LONG TERM BISPHOSPHONATES HAVING BEEN ON GLUCOCORTICOIDS. THESE PATIENTS TEND TO BE YOUNGER, UNDER THE AGE OF 65. YOU CAN SEE THAT ADD SOME ADDITIONAL RISK, THEN WHICH BISPHOSPHONATE THEY’RE TAKING, WE DIDN’T HAVE INFORMATION FROM THAT SERIES ON ALL OF THE PATIENTS BUT WE THIS IN ABOUT 189, AND IN THOSE, THE VAST, VAST MAJORITY HAD BEEN ON ALENDRONATE MONO THERAPY PRIOR TO BEING REPORTED WITH ONE OF THESE FRACTURES. NOW THE KIE KAISER SERIES
REPORTED BY DR. LOWE IN 2012 IN BONE INCLUDED 38 WOMEN WITH ATYPICAL FEMUR FRACTURES, AND IN THAT SERIES, 50% OF THEM WERE ASIAN WOMEN, COMPARED TO THE FACT THAT ONLY 12% OF WOMEN OVER THE AGE OF 60 IN THE KAISER HEALTH PLAN WERE ASIAN WOMEN. SO CERTAINLY ETHNICITY FIGURES IN TO MY THINKING, AND THESE PATIENTS TENDED TO BE YOUNGER, AVERAGE AGE 74 FOR THE AFFs IN THIS SERIES VERSUS 81 FOR YOUR TYPICAL HIP FRACTURE. SO THOSE ARE SOME OF THE CHARACTERISTICS THAT COME TO MIND WHEN I’M THINKING ABOUT THAT RARE RISK, WHICH IS FOREMOST AS YOU KNOW ON THE MIND OF OUR PATIENTS. I ALSO THINK ABOUT THE EVIDENCE FOR WHO MIGHT BENEFIT FROM A LONGER COURSE OF THERAPY BEYOND THAT INITIAL COURSE, AND AS HAS BEEN VERY NICELY REVIEWED ALREADY. WE THINK ABOUT THE FLEX — DATA FROM THE FLEX STUDY AND DATA EXTENSION, AND AGAIN, WE WON’T GO INTO THE DETAILS SINCE THIS HAS BEEN VERY WELL REVIEWED ALREADY, BUT WHAT I THINK ABOUT THERE IS CERTAINLY FROM FLEX, THEY SAW FEWER CLINICAL VERTEBRAL FRACTURES IN PATIENTS TAKING 10 YEARS OF THERAPY VERSUS 5 YEARS OF THERAPY. SO CLINICAL VERTEBRAL FRACTURES REDUCED, AND MORPHOMETRIC VERTEBRAL FRACTURES WITH SIX VERSUS THREE YEARS OF ZOLEDRONIC ACID SO I’M THINKING ABOUT THAT PATIENT AND RISK OF VERTEBRAL FRACTURES. ADDITIONALLY A NUMBER OF SUBGROUP ANALYSES HAVE BEEN DONE ON ALL OF THESE DATA, LOOKING AT WHO IS AT HIGHEST RISK AND WHO MIGHT BENEFIT FROM LONGER TERM THERAPY. AND THE FOCUS REALLY HAS BEEN ON HIP BMDT SCORES ON FLEX AND HORIZON AND WHEN THROWS GET INTO THE RANGE OF NEGATIVE 2.5 OR LOWER OVER TIME, THERE ARE FEWER CLINICAL VERTEBRAL FRACTURES AND FEWER NON-SPINE FRACTURES IN THAT HIGHEST RISK GROUP OF PATIENTS. AND AS WELL IN HORIZON, FEWER MORPHOMETRIC VERTEBRAL FRACTURES SO THAT APPEARS TO BE A HIGH RISK CLINICAL GROUP OF PATIENTS. SUBGROUP ANALYSES HAVE ALSO LOOKED AT CLINICAL CHARACTERISTICS. IT’S KIND OF TRY TO FIGURE OUT WHICH GROUP MIGHT BE AT GREATEST RISK OF FRACTURE, CONSIDERING A SHORTER TERM VERSUS EXTENDED THERAPY. AND IN SOME OF THESE ANALYSES, THE AGE OVER 75 OR THE WEIGHT LESS THAN 60 KILOGRAMS WAS ACTUALLY NOT PREDICTIVE, BUT THE HIGHER RISK PATIENT SEEMED TO BE THOSE WHO’D HAD A MAJOR OSTEOPOROTIC FRACTURE THAT LED TO THE INITIATION OF THERAPY, AND THEN PATIENTS WHO FRACTURED WHILE ON THERAPY. AND DATA FROM HORIZON, I’VE LISTED HERE, SO IF HAD AN INCIDENT VERTEBRAL FRACTURE DURING THE TRIAL, THAT WAS — YOU CAN SEE AND HERE’S THE ODDS RATIO — A PREDICTER OF HAVING AN ADDITIONAL NEW VERTEBRAL FRACTURE DURING THE DISCONTINUATION PHASE, FOUR TO SIX YEARS OF BEING ON PLACEBO, ALMOST FIVE FOLD GREATER RISK. AND IF YOU HAD AN INCIDENT NON-VERTEBRAL FRACTURE DURING THE TRIAL, AGAIN, THAT ABOUT TWO TO THREE FOLD INCREASED YOUR RISK OF HAVING A NON-VERTEBRAL FRACTURE DURING THE THREE YEARS OF DISCONTINUATION. SO IN ADDITION TO THOSE CLINICAL CHARACTERISTICS, I LIKE TO THINK ABOUT WHICH BISPHOSPHONATE THE PATIENT HAS BEEN TAKING. I THINK THAT’S AN IMPORTANT CONSIDERATION AND PEOPLE HAVE ALREADY MENTIONED THAT DURING THIS SESSION. SO ALENDRONATE WE KNOW HAS A TIGHTER ADHERENCE OR TIGHTER AFFINITY TO THE BONE MATRIX, FOR EXAMPLE, THAN RISEDRONATE AND A ABANDRONATE. SO IN SUCH INDIVIDUALS WHO HAVE BEEN ON ALENDRONATE, ONE THINKS MAYBE WE CAN RE-ASSESS AFTER A DRUG HOLIDAY TWO TO THREE YEARS AFTER THE INITIATION OF THAT HOLIDAY. IF THE PATIENT HAS BEEN ON RISEDRONATE OR IBANDRONATE, THAT’S A SHORTER BIOLOGIC HALF-LIFE SO YOU MAY CONSIDER RE-ASSESSING THAT PATIENT AT ONE TO TWO YEARS AFT INITIATION OF THE DRUG HOLIDAY. AND FINALLY WITH INTRAVENOUS ZOLEDRONIC ACID, LONGEST HALF-LIFE IN BONE, ONE MIGHT CONSIDER RE-ASSESSING MAYBE THREE YEARS AFT INITIATION OF THE HOLIDAY. AND THESE ARE JUST ROUGH NUMBERS THAT ONE TAKES FROM THE LITERATURE, NOT VERY DATA-DRIVEN, IF YOU WILL, BUT AT LEAST THIS IS A CONSIDERATION IN THE CLINICAL APPLICATION, IF YOU WILL, OF A DRUG HOLIDAY. SO WITH THIS BACKGROUND IN MIND, THERE’S NOT A LOT OF DATA IN THIS AREA AS YOU CAN APPRECIATE, I’LL TALK ABOUT THREE SMALL CLINICAL STUDIES, I’VE LISTED THEM HERE, AS WELL AS A COHORT STUDY OUT OF KAISER THAT DR. BLACK HAS ALREADY MENTIONED TO YOU. SO THIS FIRST ONE REPORTED ON ABOUT 200 PATIENTS WHO WERE FOLLOWED DURING A BISPHOSPHONATE DRUG HOLIDAY. THESE PATIENTS ON INITIATION OF THE HOLIDAY WERE 67 YEARS OLD AS YOU CAN SEE, THE MEAN BMI WAS 24. THE TREATMENT DURATION PRIOR TO THE INITIATION OF THE HOLIDAY WAS FIVE YEARS, AND PATIENTS WERE FOLLOWED ON AVERAGE ABOUT THREE YEARS AFTER THE INITIATION OF THE HOLIDAY. EVERYBODY WHO GOT INTO THIS CASE STUDY HAD OSTEOPOROSIS AT INITIATION OF THERAPY, EITHER BY VIRTUE OF HAVING A FRACTURE OR A T SCORE BELOW NEGATIVE 2.5, SO THEY HAD THE DISEASE, AND YOU CAN SEE THE BREAKDOWN IN TERMS OF ALENDRONATE VERSUS RISEDRONATE, 60 ON RISEDRONATE FOR 4 1/2 YEARS. YOU CAN SEE THE DEMOGRAPHICS DOWN HERE, THE MAJORITY, AGAIN, WERE CAUCASIAN FEMALE WITH A FEW ASIAN WOMEN INCLUDED HERE. SO WHAT THEY SAW OVER TIME, AND THESE ARE THE BONE MINERAL DENSITY RESULTS FROM THE FOLLOW-UP OF THESE PATIENTS, PANEL A IS YOUR LUMBAR SPINE BONE DENSITY, PANEL D IS THE FEMORAL NECK BONE DENSITY AND PANEL C IS THE TOTAL HIP, AND WHAT THEY SAW THAT BONE DENSITY OVER TIME DID DECLINE, AT THE SPINE IT WAS STABLE AND THE FEMORAL NECK WAS STABLE FOR THE FIRST TWO YEARS OF THE DRUG HOLIDAY, BUT THEN HERE AT THE THREE-YEAR TIME POINT, THIS WAS A STATISTICALLY SIGNIFICANT REDUCTION IN BMD AT BOTH THE FEMORAL NECK AND THE SPINE. THE HIP IN CONTRAST FELL SIGNIFICANTLY BY THE FIRST YEAR AFTER THE INITIATION OF THE DRUG HOLIDAY. AND THEY REALLY DIDN’T FIND ANY CLINICAL CHARACTERISTICS EXCEPT PERHAPS FOR THE BODY MASS INDEX AT THE START OF THE HOLIDAY AND A CHANGE IN BODY WEIGHT THAT WERE SIGNIFICANT PREDICTERS OF THE FALL IN BMD IN THESE PATIENTS. THEY ALSO LOOKED AT — THEY MADE A COMPARISON BETWEEN ALENDRONATE AND RISEDRONATE IN THEIR POPULATION, AND ALENDRONATE, AGAIN, THIS IS THE LUMBAR SPINE ON YOUR LEFT, AND THE TOTAL HIP ON YOUR RIGHT. AND ALENDRONATE IS SHOWN IN THE STRAIGHT LINE, THE NON-BROKEN LINE, AND RISEDRONATE IS IN THE DOTTED LINE SHOWN HERE. SO I THINK WHAT YOU CAN APPRECIATE IS THAT BONE MINERAL DENSITY FELL OVER TIME, PARTICULARLY IN PATIENTS WHO WERE ON A HOLIDAY AFTER BEING ON RISEDRONATE THERAPY. IT FELL IN A MORE NEGATIVE DIRECTION IN THE SPINE, AND ALSO FELL IN THE TOTAL HIP IN A MORE NEGATIVE DIRECTION, AND THE NEGATIVE TRENDS WERE STATISTICALLY SIGNIFICANT AT BOTH OF THESE SITES IN PATIENTS ON RISEDRONATE. THIS WASN’T TRUE FOR THE FEMORAL NECK, BUT THESE TWO SITES, CERTAINLY IT WAS TRUE. DURING THE HOLIDAY, THERE WERE 22 OUT OF THE 208 PATIENTS, ABOUT 10%, THAT HAD A CLINICAL FRACTURE DURING THE DRUG HOLIDAY, AND YOU CAN SEE THEM LISTED HERE. FIVE SPINE FRACTURES, FOUR WRIST FRACTURES, AND THESE OTHER SITES WERE ALSO INCLUDED, ONE DISTAL FEMUR FRACTURE. THERE WERE NO HIP FRACTURES, NO FEMORAL NECK FRACTURES AND NO ATYPICAL — FRACTURES IN THIS SERIES. THEY COULDN’T COME UP WITH ANY CLINICAL, DEMOGRAPHIC OR BMD DIFFERENCES THAT ALLOWED THEM TO PREDICT WHO WERE GOING TO BE THOSE INDIVIDUALS WHO WOULD FRACTURE DURING THERAPY. BUT CERTAINLY I THINK THIS STUDY IS VALUABLE FOR AT LEAST CONFIRMING OUR CONCERNS THAT THE CHANGE IN BONE MINERAL DENSITY WITH RISEDRONATE VERSUS ALENDRONATE IS PROBABLY GOING TO BE DIFFERENT. IN THIS SECOND STUDY, 166 POST-MENOPAUSAL WOMEN WITH OSTEOPOROSIS WERE FOLLOWED FOR UP TO THREE YEARS. IN THIS STUDY, ALL OF THEM HAD TAKEN THREE TO FIVE YEARS OF AN INITIAL FIRST LINE THERAPY, AND YOU CAN SEE THE THERAPIES HERE. THE MAJORITY ON ALENDRONATE AND RISEDRONATE AND A FEW OTHERS ON ZOLEDRONIC ACID AND IBANDRONATE. THESE WERE ALL INITIALLY TREATMENT-NAIVE PATIENTS PLACED ON BISPHOSPHONATE, BUT THEY ALL WERE SIGNIFICANTLY OSTEOPOROTIC AND ABOUT 50% HAD A FRACTURE AT BASELINE. SO THIS WAS A FAIRLY HIGH RISK PATIENT POPULATION. OF THE 166, 31 WENT ON TO A DRUG HOLIDAY AND THE OTHER 135, BASED ON THE DECISION BY THEIR CLINICIAN, CONTINUED THERAPY. SO OVER THAT THREE-YEAR PERIOD, THERE WERE FIVE CLINICAL FRACTURES IN THE PATIENTS ON THE DRUG HOLIDAY, THE 31, AND 16 IN THE GROUP THAT CONTINUED THERAPY, AND YOU CAN SEE THE PERCENTAGE DIFFERENCE IN PATIENTS WHO UNDERWENT DRUG HOLIDAY VERSUS CONTINUED THERAPY. AND AFTER ADJUSTING FOR ALL THE VARIABLES THAT THEY CHOSE TO ADJUST FOR, THERE WAS ABOUT A 40% INCREASE IN THE RISK OF HAVING A FRACTURE IF YOU WERE A PATIENT ON A DRUG HOLIDAY INN THIS STUDY COMPARED TO THOSE WHO CONTINUED BISPHOSPHONATE THERAPY. AND WHEN THEY EXPRESSED THEIR DATA AS THE PERCENT OF PATIENTS WITHOUT NEW FRACTURES AND THE BLUE WERE THE CONTINUOUS TREATMENT THE GROUP AND THE GREEN WERE THE DRUG HOLIDAY, YOU CAN SEE THAT BEING ON A DRUG HOLIDAY RAISED YOUR RATE OF HAVING A NEW FRACTURE SO THE PERCENTAGE WITHOUT A NEW FRACTURE WAS LOWER AND THIS WAS ACTUALLY QUITE STATISTICALLY SIGNIFICANT. OF COURSE THE STUDY OF THIS SIZE HAS LIMITATIONS, VERY SMALL NUMBERS, BUT IN FACT IT WAS THE SAME CLINICIANS MAKING DECISIONS ABOUT INITIATING THE DRUG HOLIDAY INN THIS ENTIRE GROUP OF PATIENTS AND THE HOLIDAY WAS INITIATED CONSCIOUSLY, WHICH MEANS IT WASN’T JUST A FIGUREMENT FIGMENT OF BEING NON-ADHERENT OR CHANGING THE OVERALL CLINICAL OUTLOOK FOR A PATIENT THAT LED TO THEIR COMING OFF THERAPY. THEY FURTHER LOOKED AT THE FRAX SCORES IN THESE PATIENTS, AND FRAX WASN’T PREDICTIVE OF WHO WAS GOING TO FRACTURE. BUT THE BEST PREDICT TER, IN FACT, IN THIS STUDY WAS ACTUALLY THE AGE OF THE PATIENT. THOSE WHO FRACTURED AVERAGED AGE 71 VERSUS THOSE WHO DID NOT — SO AGE TURNED OUT TO BE AN IMPORTANT CLINICAL CHARACTERISTIC IN THIS SMALL STUDY. THE FINAL SMALL STUDY TO TELL YOU ABOUT IS ONE WITH 134 PATIENTS IN IT, 10% OF THEM BEING MEN, WHO INITIATED A HOLIDAY AFTER ABOUT SIX YEARS OF BISPHOSPHONATE THERAPY. THE FLAN IN THIS STUDY WAS TO DO FOLLOW-UP AT 12 TO 18 MONTHS AFTER THE HOLIDAY, AND 24 TO 30 MONTHS AFTER THE INITIATION OF THE DRUG HOLIDAY. AND ROUGHLY THE GUIDELINES BY NOG WERE FOLLOWED BY THE CLINICIANS IN THIS STUDY DECIDING WHEN AND WHO TO DISCONTINUE BISPHOSPHONATE THERAPY. I’LL POINT OUT TO YOU THESE WERE NOT PARTICULARLY LOW RISK PATIENTS. SO 55% OF THE ONES ON ORAL BISPHOSPHONATES HAD HAD A PRIOR FRACTURE, AND OF THOSE ON I.V. BISPHOSPHONATES, ALMOST 75% WITH PRIOR FRACTURE. THERE WERE SOME MEN IN HERE AS I SAID AND ABOUT 30% OF THE INDIVIDUALS HERE HAD SOME FORM OF SECONDARY OSTEOPOROSIS. AND YOU CAN SEE 97 ON ORAL BISPHOSPHONATES, 37 ON I.V. BISPHOSPHONATES WITH A TREATMENT DURATION HERE OF 6 1/2 YEARS FOR THE ORALS AND ABOUT 3 1/2 YEARS FOR THE I.V. BISPHOSPHONATES. SO WHAT HAPPENED OVER TIME? SO AGAIN, THE FIRST TIME POINT FOR MAKING A BMD MEASUREMENT WAS 12 TO 18 18 MONTHS AND THAT’S
SHOWN IN THE WHITE BARS FOR THE SPINE, THE TOTAL HIP AND THE FEMORAL NECK. AND AT THE THIS VERY EARLY TIME POINT, THESE CHANGES IN SPINE BONE DENSITY BUT PARTICULARLY AT THE HIP, ABOUT 1 1/2 OF TO 2% DECREMENTS IN THE HIPBONE MINERAL DENSITY AT THIS TIME POINT. THIS WAS — CLINICAL DECISIONS DROVE THIS STUDY, PATIENTS 42% OF THEM WERE RE-STARTED ON THEIR BISPHOSPHONATE THERAPY. AND THOSE THAT CONTINUED ON THE DRUG HOLIDAY, YOU CAN SEE 2 1/2 TO 3% CHANGES AT THE FEMORAL NECK AND THE TOTAL HIP AT THE 2 AND 2 1/2-YEAR TIME POINT AFTER DRUG HOLIDAY. SO THEY ALSO LOOKED AT BONE TURNOVER MARKERS. SERUM CTX AND SERUM P1NP. AND AT THE ONE-YEAR TIME POINT, THERE WAS ABOUT A 90% INCREASE IN CTX AND ABOUT A 90% INCREASE IN P1NP IN THESE PATIENTS, AND THOSE CHANGES PERSISTED AT THE SECOND TIME POINT OF MEASUREMENT, WHICH WAS 2 TO 2 1/2 YEARS. THEY DIDN’T SEE DIFFERENCES BETWEEN HAVING BEEN ON ORAL BISPHOSPHONATES VERSUS I.V. BISPHOSPHONATES IN THE MARKER CHANGES, AND THEY SAW NO CORRELATION BETWEEN THE CHANGES IN THE MARKERS AND THE B MD CHANGES IN THIS POPULATION. AND THEY ALSO DID ONE OTHER, I THINK, INTERESTING THING, WHICH WAS TO CALCULATE FRAX SCORES. SO AT THE 12 TO 18 MONTH TIME POINT, THOSE IN WHOM THEY FELT THEY NEEDED TO REINITIATE THERAPY ON CLINICAL GROUND HAD A MAJOR OSTEOPOROTIC FRACTURE RISK FOR YEARS OF 21%, AND AT THE HIP OF ALMOST 8%, AND THOSE WHO CONTINUED THE HOLIDAY, THOSE NUMBERS WERE LOWER. AND THEY ALSO LOOKED AT FRAX SCORES OVER 25% AND UNDER 25%, THAT’S SHOWN HERE, AND THE RATE OF FEMORAL NECK BONE LOSS. AND IT WAS ALMOST 3.7% IN THIS 12 TO 18 MONTH TIME POINT IF YOUR FRAX SCORE WAS OVER 25, AND IT WAS QUITE A BIT LOWER, IT DIDN’T QUITE MAKE STATISTICAL SIGNIFICANCE, IT WAS QUITE A BIT LOWER IF YOUR FRAX SCORE WAS UNDER 25. AND THESE ARE THE THREE FRACTURES THAT WERE REPORTED DURING THAT STUDY. SO THE CONCLUSION OF THESE AUTHORS WAS THAT EXPERIENCE IN CLINICAL PRACTICE IS QUITE DIFFERENT FROM CLINICAL TRIAL EXPERIENCE. THE FINAL STUDY TO SQUIGGLY SUMMARIZE TO YOU IS A RETROSPECTIVE COHORT OUT OF THE KAISER DATASET ON ALMOST 40,000 WOMEN, AND DR. BLACK HAS ALREADY INTRODUCED THIS STUDY TO YOU, BUT THESE WOMEN RECEIVED BISPHOSPHONATES FOR ON AVERAGE FIVE YEARS AND YOU CAN SEE THE VAST MAJORITY RECEIVED ALENDRONATE, AND WHEN THEY LOOKED AT THIS GROUP OF ALMOST 40,000 WOMEN, THEY BROKE THEM DOWN INTO THOSE WHO HAD TAKEN A DRUG HOLIDAY AND THAT WAS DEFINED AS OVER 12 MONTHS OFF THERAPY, THOSE THAT WERE PERSISTENT USERS, AND THEY DEFINE THAT AS 50% OR BETTER ADHERENCE, AND THEN NON-PERSISTENT USERS, LESS THAN 50% ADHERENCE. AND SO IN THIS COHORT STUDY, THE AVERAGE DRUG HOLIDAY, YOU CAN SEE WAS THREE YEARS, AND THEY HAD PLENTY OF FRACTURES THAT OCCURRED DURING THAT TIME TO EXAMINE. AND SO IN THE PATIENTS ON THE DRUG HOLIDAY FROM THIS BIG COHORT, THEY SAW NO DIFFERENCES IN FRACTURE RISK IN THE HOLIDAY PATIENTS VERSUS THE PERSISTENT USER, HERE’S THE HAZARD RATIO, AND THEY SAW NO DIFFERENCE IN HIP FRACTURE RISK, HERE’S THE HAZARD RATIO, AND VERTEBRAL FRACTURE RISK ACTUALLY MIGHT HAVE EVEN BEEN SLIGHTLY LOWER, BUT CERTAINLY THESE PISHTS ON THE DRUG HOLIDAY ON THE BASIS OF THIS STUDY WERE OKAY, THEY WERE PROTECTED FROM HARM, PARTICULARLY COMPARED TO THE NON-PERSISTENT USER. SO WITH THE DATA THAT I’VE REVIEWED AND THE THOUGHTS I’VE PUT FORWARD HERE, LET’S COME BACK TO THESE THREE WOMEN. THE 60-YEAR-OLD WITH THE EARLY MENOPAUSE AND FIVE YEARS OF RISEDRONATE THERAPY WHO’S HAD AN IMPROVEMENT IN HER BMD, AM I GOING TO INITIATE A DRUG HOLIDAY? I THINK YES, AND WITH THE RISEDRONATE, I’M PROBABLY GOING TO DO YEARLY CLINICAL FOLLOW- UP AND PROBABLY A BMD AT THE ONE-YEAR TIME POINT. IN MY 66-YEAR-OLD ASIAN FEMALE WITH THE RADIUS FRACTURE FIVE YEARS OF ALENDRONATE WHO’S IMPROVED HER BMD, I THINK I’M GOING TO INITIATE A DRUG HOLIDAY HERE, DO YEARLY FOLLOW-UP AND PERHAPS A BMD AT THE TWO-YEAR TIME POINT, ALTHOUGH THIS IS ALL UP TO CLINICAL JUDGMENT. NOW TO MY 75-YEAR-OLD WOMAN, REPORTING SOME FALLS AND QUITE SIGNIFICANT SPINAL DISEASE, WHO’S HAD AN IMPROVEMENT IN HER BMD AFTER THREE YEARS OF ZOLEDRONIC ACID. WHAT AM I GOING TO DO HERE? WELL, SHE’S 75 YEARS OLD. SHE’S FALLING, SHE HAS PREVALENT VERTEBRAL FRACTURES, AND HER HIPBONE DENSITY IS STILL IN THAT NEGATIVE 2.5 RANGE. SO FOR HER, I’M THINKING I’M GOING TO CONTINUE TREATMENT. I’M PROBABLY GOING TO CONTINUE TREATMENT WITH I.V. ZOLEDRONIC ACID, BUT WE HAVE LITTLE GUIDANCE AS TO WHETHER THERE MIGHT BE SOME OTHER THERAPY THAT MIGHT BE BETTER FOR SOMEONE LIKE HER. BUT I FEEL THAT WITH ENOUGH CLINICAL RISK FACTORS, I WOULD CONTINUE THERAPY. SO IF I CAN SUMMARIZE THE EVIDENCE I’VE REVIEWED WITH YOU, BMD OF FEMORAL NECK AND TOTAL HIP, NEGATIVE 2.5 OR LOWER, AT THE END OF AN INITIAL TREATMENT COURSE, SEEMS LIKE A GOOD MARKER FOR POST-MENOPAUSAL WOMEN WHO ARE AT GREATER RISK DURING A TREATMENT INTERRUPTION OR A DRUG HOLIDAY. WOMEN IN THE OLD OHER AGE OLDER
AGE GROUP, AGE GREATER THAN 70, THIS MAY IDENTIFY THEM AS A GROUP TO BE CAUTIOUS ABOUT IN INITIATING A DRUG HOLIDAY, ALTHOUGH THE DATA ARE SOMEWHAT INCONSISTENT. WE HAVE NO GUIDELINES CURRENTLY ON HOW TO MANAGE THIS TREATMENT INTERRUPTION, WHO IS THE RIGHT PATIENT, WHAT’S THE RIGHT DURATION, HOW SHOULD RISK FACTORS BE WEIGHED IN OUR DECISION-MAKING, AND HOW WE SHOULD MONITOR THEM. AND FINALLY, IN PRACTICE, THE CONSEQUENCES TO A TREATMENT INTERRUPTION ARE VERY INDIVIDUAL, AND PATIENTS REALLY NEED TO BE COUNSELED INDIVIDUALLY. BONE DENSITY MAY BE LOST DURING THAT TIME AND FRACTURES MAY OCCUR. SO SOME KEY RECOMMENDATIONS THAT I WOULD MAKE. I THINK IT WOULD BE EXTREMELY VALUABLE TO HAVE MORE REAL WORLD EXPERIENCE, AND I’D LOVE TO SEE A PROGRAM THAT PROSPECTIVELY ASSESSES TREATMENT INTERRUPTION IN REAL WORLD CLINICAL SETTINGS, LOOKING AT BMD, LOOKING AT MARKERS, LOOKING AT CLINICAL CHARACTERISTICS, FRAX SCORES, ANYTHING THAT WE CAN USE AT THE POINT OF CARE TO HELP US MAKE THESE DECISIONS. I THINK IT WOULD BE GREAT IF WE KNEW WHEN TO USE ANABOLIC THERAPY, WHEN IS THE RIGHT TIME TO INTRODUCE IT IN A PATIENT THAT WE’RE LOOKING AT THE LONG TERM SEQUENCE OF CARE. AND THEN FINALLY, I THINK IT WILL BE CRITICAL TO CLOSE THE GENDER GAP, AND CERTAINLY THE ETHNICITY GAP. WE NEED TO HAVE SUF SUFFICIENT NUMBERS OF MEN WITH OSTEOPOROSIS IN THESE STUDIES TO REALLY BETTER UNDERSTAND THE CONSEQUENCES OF DRUG HOLIDAYS IN MEN. SO WITH THAT, I’LL CLOSE AND THANK YOU FOR YOUR ATTENTION. [APPLAUSE]>>GOOD MORNING, EVERYBODY. I’M GRATEFUL FOR THE INVITATION TO COME AND PRESENT HERE. MY NAME IS RICHARD EASTELL FROM THE UNIVERSITY OF SHEFFIELD, DIRECTOR OF THE MELLANBY CENTRE FOR BONE RESEARCH. MY TOPIC THIS MORNING CONCERNS TOOLS TO GUIDE DECISIONS REGARDING LONG TERM TREATMENT. SO OVER THE PAST DAY OR SO, WE’VE HEARD ABOUT INDIVIDUALIZING TREATMENT AND PERSONALIZED MEDICINE, AND HOPEFULLY THAT’S WHAT I’LL GET TO. SO THESE ARE THE DISCLOSURES THAT I HAVE ABOUT MY CONSUL TAN SEES AND GRAND FUNDING FROM ROCHE AND A NITTOBO. THESE ARE THE SUMMARY OF MY FINDINGS, AND THEY’RE GOING TO BE CONCERNING BONE TURNOVER MARKERS, BONE MINERAL DENSITY AND SPINE IMAGING AND I’M GOING TO BE POINTING OUT THAT BONE MARKERS CAN BE USED TO IDENTIFY RESPONSE IN THE INDIVIDUAL PATIENT TO TREATMENT AND ALLOW US TOOFFSET INDIVIDUALS. BONE DENSITY, USEFUL IN IDENTIFYING PATIENTS WHO HAVE REACHED A GOAL AND READY FOR DRUG HOLIDAY, AND SPINE IMAGING USEFUL FOR IDENTIFYING PATIENTS WHERE YOU SHOULD SWITCH TREATMENTS AND PEOPLE IN WHOM WE SHOULD AVOID A DRUG HOLIDAY. SO THE THREE MAIN TOOLS THEN, BONE TURNOVER MARKERS, BONE MINERAL DENSITY AND VERTEBRAL FRACTURE ASSESSMENT. WE HAVE A NUMBER OF DECISION WE HAVE TO MAKE WHEN WE’RE TREATING PATIENTS IN THE LONG TERM. I’VE PUT FOUR OF THESE DECISIONS JUST HERE. BUT THE IMPORTANT THING I WANT TO MAKE IS THAT WHEN WE’RE THINKING ABOUT THE INDIVIDUAL AND N EQUALS 1, WE NEED TO HAVE THE STATISTICS THAT ARE APPROPRIATE TO INDIVIDUAL PATIENTS. AND SO I’M GOING TO BE TALKING PARTICULARLY ABOUT THE LEAST SIGNIFICANT CHANGE AND ALSO ABOUT THE USE OF THRESHOLDS. BY USING THESE, WE CAN THEN IDENTIFY PEOPLE WHO DO AND DON’T RESPOND TO OUR TREATMENTS. SO MY FIRST SECTION THEN, I’M GOING TO TALK ABOUT BONE TURNOVER MARKERS, AND HOW THESE MIGHT BE USED. THERE ARE A NUMBER OF THEM, BUT THE INTERNATIONAL OSTEOPOROSIS FOUNDATION RECOMMENDED THAT WE FOCUS AS REFERENCE MARKERS OF THE BONE RESORPTION MARKER CTX, AND THE BONE FORMATION MARKER PRO COLLAGEN ONE AND PRO PEPTIDE. SO MUCH OF MY TALK, I WILL DO THAT. IN ORDER TO USE BONE TURNOVER MARKERS, WE NEED TO KNOW ABOUT THE SOURCES OF VARIABILITY. THESE ARE LISTED HERE AS PROPOSED BY THE NBHA IN OUR RECENT REVIEW OF THESE SOURCES. SO WHEN WE SAY CONTROLLABLE, WE MEAN THE PHYSICIAN CAN CONTROL THEM, SO KNOWING ABOUT THE CIRCADIAN RHYTHM MEANS THAT WE CAN TAKE THE SAMPLE FOR A BONE RESORPTION MARKER FIRST THING IN THE MORNING. SIMILARLY WHEN WE HAVE UNCONTROL CAUSES LIKE AGE AND GENDER, WE CAN MAKE SURE THAT WE USE REFERENCE RANGES WHICH ARE APPROPRIATE TO A PERSON’S AGE AND GENDER. NOW PEOPLE HAVE PROPOSED A NUMBER OF USES OF BONE TURNOVER MARKER AND I’M LISTING SOME OF THEM HERE. THEY CAN BE USED FOR RISK ASSESSMENT, AND IT’S THE CASE THAT HIGHER BONE TURNOVER IN THE OLD PERSON IS ASSOCIATED WITH HIGHER RATES OF BONE LOSS AND OF FRACTURE RISK. BUT TODAY I’M GOING TO FOCUS MUCH MORE ON TREATMENT EFFECTS, AND MONITORING THE RESPONSE, MONITORING THE OFFSET. NOW I COULD TALK ABOUT ALL OF THE ANTI-RESORPTIVE TREATMENTS BUT I DON’T HAVE TIME. BECAUSE THE MOST COMMON TREATMENT WE USE IN CLINICAL PRACTICE ARE ORAL BISPHOSPHONATES, I’M GOING TO FOCUS ON THESE. I COULD HAVE TALKED ABOUT PARENTERAL ANTI-RESORPTIVE THERAPIES AND I COULD HAVE ALSO TALKED ABOUT ANABOLIC DRUGS, BUT THE PRINCIPLES I’M GOING TO ENUNCIATE WILL ACTUALLY BE APPLICABLE IN THE MAIN TO THESE TREATMENTS TOO. SO WE DESIGNED A STUDY ABOUT 10 YEARS AGO THAT WE CALLED THE TREE OWE STUDY, AND IT WAS GOING TO BE COMPARING THE THREE COMMONLY USED ORAL BISPHOSPHONATES AT THEIR LICENSE DOSES. THE TRIAL WASN’T TO SEE THE RELATIVE EFFICACY, IT WAS TO SEE HOW WE COULD USE TOOLS TO MONITOR THE INDIVIDUAL PATIENT, SO WE DESIGNED THE TRIAL SO THAT WE COULD DO THAT. SO WE COULD CALCULATE THE BIOLOGICAL VARIABILITY WHICH ALLOWS US TO ESTIMATE THE LEAST SIGNIFICANT CHANGE. WE ALSO RECRUITED A GROUP OF HEALTHY YOUNG WOMEN SO WE COULD HAVE A REFERENCE RANGE. SO THAT ALLOWS US TO TAKE TWO APPROACHES THAT WE’RE GOING TO BE USING FOR IDENTIFYING RESPONSE. THIS IS THE BASELINE DATA FROM THAT TRIO STUDY, JUST SHOWING THESE 172 POST-MENOPAUSAL WOMEN WITH THE BONE RESORPTION MARKER CTX. AND I WANT TO MAKE TWO POINTS HERE. THE FIRST ONE RELATES TO THE REFERENCE INTERVAL. YOU’LL NOTICE THE AVERAGE VALUE ISN’T IN THE MIDDLE, IT’S TOWARDS THE LOWER END BECAUSE THE DISTRIBUTION IS SKEWED, SO THIS IS OUR GEOMETRIC MEAN FOR HEALTHY YOUNG WOMEN. YOU CAN SEE THAT WITH OSTEOPOROSIS, ALMOST NOBODY FALLS BELOW IT, SO THEY’RE EITHER IN THE THE UPPER HALF OF THE REFERENCE RANGE OR THEY’RE HIGH. HIGHER BONE TURNOVER MARKER IS ASSOCIATED WITH FASTER BONE LOSS AND FRACTURE SO THESE PEOPLE PROBABLY ARE MORE AT RISK OF TO RESPOND BETTER TO ANTI-RESORPTIVE TREATMENT AND WHEN THEY STOP TREATMENT, ON A DRUG HOLIDAY, THEY TEND TO BOUNCE BACK QUICKER. SO I’M GOING TO COME BACK TO THIS CONCEPT OF THE GEOMETRIC MEAN IN A FEW MINUTES. NOW WHAT HAPPENS WHEN WE GIVE THE ORAL BISPHOSPHONATES? I’M SHOWING HERE ALENDRONATE, MOST COMMONLY USED TODAY IN MOST COUNTRIES, AND I’M SHOWING TWO MARKERS TO MAKE THE POINT THAT THE CHANGE IS VERY LARGE AND IT’S VERY EARLY, SO BY 12 WEEKS, THE MAXIMUM RESPONSES HAVE OCCURRED AND WILL STAY DOWN — THE CTX WILL STAY DOWN THERE FOR AS MANY YEARS AS YOU GIVE THE DRUG, AND ALSO YOU CAN SEE — IS MUCH LESS — SO THE CTX, IT EMPHASIZES THE VALUE OF THIS MARKER FOR MONITORING THERAPY AND BEING ABLE TO DO SO AT THE VERY EARLY TIME POINT. BONE FORMATION MARKERS, THEY SHOW THE SAME PATTERN WITH EXCEPTION, THAT IS THE FIRST FOUR WEEKS, THERE’S NO CHANGE, BUT THEN AFTER THAT, BY 12 WEEKS, WE ALMOST HAVE MAXIMUM SUPPRESSION, WITH THE P1NP SHOWING THE GREATEST REDUCTION. SO WE HAVE HERE A PARADOX THAT SOME PEOPLE FIND DIFFICULT TO UNDERSTAND THAT ACTUALLY BONE FORMATION GOES DOWN WHEN YOU GIVE A DRUG THAT BENEFITS BONE. BUT IT MEANS THAT IT IS A USEFUL MARKER FOR IDENTIFYING RESPONSE. LATER THIS MORNING DR. BAUER IS GOING TO TALK ALL ABOUT THE FNIH STUDY BUT I WANTED TO SHOW THIS TO MAKE THE POINT THAT ACTUALLY WHEN YOU DO HAVE THE GREATER REDUCTION IN BONE TURNOVER, AS SHOWN HERE OR HERE WITH P1NP, THEN YOU HAVE THE LOWEST RISK OF HAVING A VERTEBRAL FRACTURE AS WE’VE PUBLISHED. SO IT DOES SEEM THAT THE BONE TURNOVER MARKER RESPONSE IS RELEVANT TO THE FRACTURE BENEFIT. BUT I WANT TO FOCUS ON THE INDIVIDUAL AND SO HERE I’M SHOWING YOU THE LEAST SIGNIFICANT CHANGE CONCEPT, AND THIS HAS BEEN USED IN THE 30 OR SO YEARS THAT WE’VE HAD DEXA, THIS HAS BEEN USED TO IDENTIFY WHETHER PATIENTS ARE RESPONDING TO TREATMENT. SO HERE WE’RE TALK SCIOING LUMBAR SPINE DENSITY THE, SO WE GET THE BIOLOGICAL VARIABILITY AND WE CAN CALCULATE THE LEAST SIGNIFICANT CHANGE, WHICH IS THE LIKELY LIKELIHOOD OF SOMEBODY EXCEEDING THE USUAL VARIABILITY, SO IT’S ABOUT 4% IN THIS STUDY, SO YOU CAN SEE THE AVERAGE PERSON GIVING ALENDRONATE WOULD HAVE ABOUT A 4% INCREASE BY THE 48-WEEK TIME POINT AND ABOUT 6% BY THE 96-WEEK TIME POINT. SO ABOUT TWO THIRDS OF THE PEOPLE TWO YEARS WOULD BE RESPONDERS, WHEREAS P1NP, THE RESPONSE IS MUCH, MUCH GREATER AND MUCH EARLIER, SO BY 12 WEEKS, AS WE’LL SEE IN A MOMENT, ABOUT 90% OF PEOPLE ARE RESPONDING. SO THE ADVANTAGES OF USING BONE TURNOVER MARKERS IS THAT THE RESPONSE IS LARGE, AND IT’S EARLY. AND LEAST SIGNIFICANT CHANGES AND SOMETHING WHICH JUST THE BONE COMMUNITY USE IN THE FIELD OF CLINICAL CHEMISTRY IT’S WIDELY USED, IT’S JUST CALLED SOMETHING DIFFERENT, CALLED REFERENCE CHANGE VALUE IN OUR PARTICULAR FIELD. SO IN THE TRIO STUDY, WE LOOK AT THE THREE DIFFERENT BISPHOSPHONATES AND WE PUT IN A THRESHOLD FOR LEAST SIGNIFICANT CHANGE FOR CTX, WE CAN SEE THAT JUST ABOUT EVERYBODY RESPONDED. WE HAD ADHERENCE INFORMATION ON ALL THESE PATIENTS. ELECTRONIC CAPS THAT ALLOW YOU TO CALCULATE — SO THESE PEOPLE WERE PRETTY ADHERENT AND THEY WERE PRETTY RESPONSIVE. IT WASN’T QUITE THE SAME WITH RIEZ BUT RISEDRONATE BUT THAT’S A LESS POTENT BISPHOSPHONATE SO I WOULDN’T EXPECT SUCH A HIGH RESPONSE RATE. SO THIS INFORMATION MEANS THAT ACTUALLY IF PEOPLE ARE ADHERENT, THEY’RE VERY LIKELY TO RESPOND IF THEY’RE GETTING ALENDRONATE WHEN YOU MEASURE CTX. WE DO THE SAME THING WITH P1NP BECAUSE IT, TOO, GOES DOWN, AND P1NP HAS THE ADVANTAGE THAT WE DON’T HAVE TO MEASURE IN THE FASTING STATE AND ET CETERA LESS VARIABLE, AGAIN WE HAVE THE THRESHOLD HERE. SO AGAIN, MOST PEOPLE ARE RESPONDERS WITH ALENDRONATE BUT NOW IT’S MORE LIKE 80% RATHER THAN 95%. SO THIS INFORMATION HAS BEEN USED BY THE INTERNATIONAL OSTEOPOROSIS FOUNDATION AS A WAY OF IDENTIFYING PATIENTS WHO ARE NOT RESPONDING TO TREATMENT FOR WHATEVER REASON, PARTICULARLY POOR ADHERENCE. SO WHEN THE IOF PUT OUT ITS POOR ADHERENCE GUIDELINE, THEN THEY PROPOSED THAT WE SHOULD MEASURE BONE TURNOVER MARKERS AT THE START OF TREATMENT AND THEN AGAIN THREE MONTHS LATER, AND IF A BONE MARKER EXCEEDS THE LEAST SIGNIFICANT CHANGE, THEN PROBABLY SOMETHING GOOD HAS HAPPENED AND WE CAN CONTINUE THE TREATMENT. AND IF IT HASN’T EXCEEDED THAT, THEN WE SHOULD RE-ASSESS WHAT’S HAPPENING. USUALLY IT’S THE ADHERENCE THAT’S POOR AND WE SHOULD REINFORCE THE IMPORTANCE OF TAKING THE MEDICINE CORRECTLY. NOW, WE DON’T ALWAYS A HAVE A BASELINE BONE TURNOVER MARKER. QUITE OFTEN THE PATIENT IS SENT TO US WHEN THEY’RE ALREADY ON TREATMENT. SO WE NEED TO HAVE AN ALTERNATIVE APPROACH TO IDENTIFYING RESPONSE. SO THE ALTERNATIVE APPROACH WE PROPOSED, HERE I’M SHOWING THE CTX IN THE TRIO STUDY, POINTING OUT AS I SHOWED YOU EARLIER THAT IF WE HAVE THE GEOMETRIC MEAN FOR HEALTHY YOUNG WOMEN HERE, JUST ABOUT EVERYBODY WITH OSTEOPOROSIS IS ABOVE THAT, WHEREAS WHEN THEY GET ALENDRONATE BY 12 WEEKS, JUST ABOUT EVERYBODY IS BELOW THAT. SO KNOWING WHETHER THE PERSON IS ABOVE OR BELOW THE GEOMETRIC MEAN IS A VERY GOOD WAY OF KNOWING WHETHER THEY’RE TAKING& THE MEDICINE OR NOT, AND SO IF WE TALK ABOUT RESPONDERS, THEN IT MEANS WE FIND 96% OF PEOPLE RESPONDERS IN THIS WAY, AND THE P1NP IS A SIMILAR VALUE. SO SO MUCH FOR BONE TURNOVER MARKERS FOR THE TRIO STUDY. WE’VE TAKEN THIS DATA AND APPLIED THIS IN CLINICAL PRACTICE, AND WE TELL THE GENERAL PRACTITIONERS, THE PRIMARY CARE DOCTORS TO HAVE TWO TARGETS, GREATER THANT LEAST SIGNIFICANT CHANGE WHICH IS THE STATISTICAL APPROACH I’VE DESCRIBED AND WE BELOW THE MEAN
FOR HEALTHY YOUNG WOMEN, WHICH IS THE BIOLOGICAL VALUE, AND WE FOUND IT USEFUL TO GIVE THE BONE MARKER CHANGE IN ABSOLUTE UNITS BECAUSE THAT’S EASIER TO MANAGE IN GENERAL PRACTICE. SO WE’VE IMPLEMENTED THIS AND WE USE IT ON A REGULAR BASIS. WHAT HAPPENS WHEN YOU STOP TREATMENT? SO WE’VE HEARD ALREADY FROM DOLORES SOME TRIALS WHICH ARE OBSERVATIONAL, OURS IS A RANDOMIZED TRIAL BECAUSE OF COURSE THE TRIO STUDY, PEOPLE WERE RANDOMIZED WITH THE THREE BISPHOSPHONATES, SO WE DON’T HAVE THE BIAS, WE USUALLY PUT RISEDRONATE ON MILDER CASES, 57 OF THE WOMEN AFTER TWO YEARS OF BEING GIVEN THE DRUG, THEY MET THE CRITERIA OF STOPPING BECAUSE THEIR FEMORAL NECK BMDT STORE WAS ABOVE MINUS 2.5 SO AT THIS POINT WE STOPPED THE DRUG SO WE CAN SEE THE RISEDRONATE, IBANDRONATE AND ALENDRONATE, THEY ALL RESOLVED AND WITHIN THE FIRST SIX MONTHS, WE SAW QUITE A LOT OF RESOLUTION OF THE BONE TURNOVER, NOT BACK TO BASELINE BUT TOWARDS BASELINE, PERHAPS HALF RESOLUTION. BY THE END OF THE TWO YEARS OFF, ALL THREE BEISTS THREE
BISPHOSPHONATES ARE THE SAME AND BY THE END OF THE TWO YEARS OFFSET, ALL THE SAME. SO THE IDEA THAT THE DRUGS MIGHT BE DIFFERENT, I THINK WAS A MISCONCEPTION BASED ON THEORETICAL GROUNDS BUT WHEN WE DO THE RANDOMIZED TRIAL, THEY’RE ALL THE SAME. SO WE CAN USE THE MARKERS TO MONITOR OFFSET AND WE NEED TO DO MORE RESEARCH ON THIS BECAUSE THERE ISN’T VERY MUCH LOOKING AT INDIVIDUAL, BUT MY PROPOSAL IS THAT WE SHOULD DO THE SAME APPROACH THAT WE DO FOR ONSET OF TREATMENT, WE SHOULD USE THE LEAST SIGNIFICANT CHANGE APPROACH AND WE SHOULD SEE WHETHER PATIENTS EXCEED THE THRESHOLD. SO THIS IS AN ACTIVE AREA OF RESEARCH AT THE MOMENT. SO HERE I SUMMARIZE BONE TURNOVER MARKERS AS A TOOL FOR LONG TERM THERAPY, AND HOW THE THEY MIGHT BE USED, WHAT THE STRENGTHS ARE AND WHAT THE LIMITATIONS ARE. SO I WON’T READ THROUGH ALL THESE BECAUSE I’VE JUST SPOKEN THEM ALL AND YOU CAN READ FASTER THAN I CAN TALK. SO I’M GOING TO MOVE NOW FROM BONE TURNOVER MARKERS AND I’M GOING TO GO ON TO THE NEXT TOPIC, WHICH IS BONE MINERAL DENSITY. SO HERE WE’RE ASKING QUESTIONS ABOUT WHETHER TREATMENT SHOULD BE STOPPED, WHETHER DRUG HOLIDAY SHOULD BE TERMINATED. SO BONE DENSITY, THE TEST HAS BEEN AROUND FOR ABOUT 30 YEARS NOW, AND IT’S THE WORLDWIDE ISSUES, THE TEST FOR DIAGNOSING OSTEOPOROSIS, AND USUALLY FOR MAKING DECISIONS ABOUT WHETHER WE START TREATMENT. SO VERY IMPORTANT TEST. TODAY I’M GOING TO BE TALKING ABOUT HOW IT MIGHT BE USED TO IDENTIFY WHETHER A CHANGE IN THERAPY MIGHT BE REQUIRED, OR WHETHER WE SHOULD BE STOPPING TREATMENT OR RESTARTING AFTER A DRUG HOLIDAY, AND I’LL USE SOME SIMILAR CONCEPTS OF LEAST SIGNIFICANT CHANGE THRESHOLDS THAT I’VE USED FOR BONE TURNOVER MARKERS. SO WHEN IT COMES TO THRESHOLDS, ONE OF THE EXCITING IDEAS OF THE LAST FEW YEARS IS THAT WE SHOULD LEARN FROM OTHER THERAPY — AND USE A GOAL TREATMENT FOR BONE DENSITY WHICH SEEMS TO ME TO BE POSSIBLE, SO THIS IS MIKE LEWIECKI WRITING ABOUT THIS TOPIC. HE WAS COMPARING THE CURRENT PARADIGM OF HOW WE MANAGE OSTEOPOROSIS VERSUS IF WE USE A TRARGT TARGET TO TREAT PARADIGM. SO YOU MIGHT CHOOSE YOUR TREATMENT BASED ON WILL YOU BE ABLE TO REACH YOUR DESIRABLE LEVEL OF BONE DENSITY. SO WHEREAS WITH THE CURRENT PARADIGM, YOU MIGHT GIVE EVERYBODY AN ORAL BISPHOSPHONATE, IF YOU HAVE SOMEONE WITH VERY LOW BONE DENSITY TO BEGIN WITH, YOU MIGHT START OUT WITH A MORE POTENT DRUG. SO THIS APPROACH DOES LEAD TO DIFFERENT FORMS OF PRACTICE SH AND SIMILARLY WHEN YOU’RE LOOKING TO SEE WHETHER OR NOT YOU’VE HAD A GOOD SUCCESS, THEN YOU NEED TO ATTAIN A PARTICULAR VALUE WHICH MIGHT BE A T OF, LET’S SAY, MINUS 2.5. AND IF YOU DON’T REACH THAT TARGET, THEN YOU HAVE TO MAKE A CHANGE TO YOUR TREATMENT, WHEREAS WITH THE CURRENT PARADIGM, WE’RE JUST INTERESTED IN CHANGING BONE TURNOVER TO BEYOND THE LEAST SIGNIFICANT CHANGE. SO THIS IS A CHANGE OF A WAY OF THINKING ABOUT HOW WE MIGHT MANAGE THE DISORDER USING THE GOAL OF THERAPY APPROACH. NOW WE’VE ALREADY HEARD ABOUT DR. ADLER’S REVIEW ABOUT WHEN WE SHOULD STOP — WOMEN SHOULD BEGIN A DRUG HOLIDAY, AND HOW BONE DENSITY REALLY CAN BE SO USEFUL IN MAKING THAT DECISION. SO THIS IS BASED ON THE TWO KEY TRIALS, THE FLEX TRIAL AND THE HORIZON TRIAL, SO IN MAKING THE DECISION WHETHER A PERSON HAS HAD FIVE YEARS OF ORAL BISPHOSPHONATE OR THREE YEARS OF INVA INTRAVENOUS BISPHOSPHONATE, WHETHER THERE’S A
HIGH FRABT RISING, WHETHER THEY’VE HAD A FRACTURE OR NOT, SO IF THEY’VE NOT HAD A FRACTURE IN THE FIRST THREE TO FIVE YEARS, AND IF THAT BONE DENSITY IS ABOVE MINUS 2.5, THAT’S WHEN WE CONSIDER A DRUG HOLIDAY. SO THAT’S A REALLY GOOD USE, THEN, FOR THE BONE DENSITY TEST IN THIS PARTICULAR SETTING. WHAT ABOUT OOS EUSING BONE DENSITY FOR THE DRUG HOLIDAY ABOUT WHEN THEY SHOULD STOP? SO WE LOOK TO THIS IN THE FLEX STUDY, HERE I’M SHOWING THE DISTRIBUTION IN THE MOST RELIABLE BONE DENSITY MEASUREMENT IN THE OLDER PERSON, NAMELY TOTAL HIP, AND I’M PUTTING IN THE ESTIMATE OF LEAST SIGNIFICANT CHANGE FROM THE IOF’S REPORT, JUST ILL STRAIGHTING ILT STRAIGHTING THAT EVEN AFTER FIVE YEARS OF STOPPING ALENDRONATE, OF THE PEOPLE WOULD ACTUALLY EXCEED THE LEAST SIGNIFICANT CHANGE BECAUSE THEY CONSIDERED IT A FAST LOSER WHEREAS BECAUSE OF THE BONE TURNOVER MARKERS, EVEN AFTER THE FIRST SIX MONTHS OH, ABOUT A THIRD OF THE PEOPLE CAN SEEN TO EXCEEDING THE THRESHOLD FOR PERHAPS RESTARTING TREATMENT. SO I DON’T THINK IT’S SUCH A GOOD WAY OF MONITORING BUT DON’T KNOW SO IT NEEDS TO BE FURTHER INVESTIGATED. SO WHEN IT COMES TO THINKING ABOUT BONE DENSITY AS A TOOL, IT HAS ITS STRENGTHS, LIMITATIONS, AND I’VE LISTED THOSE HERE THAT REALLY IS A VERY USEFUL TEST AND IT CAN HELP US TO MAKE SOME DECISIONS. NOW THOSE ARE MY TWO MAJOR TOOLS THAT I USE IN CLINICAL PRACTICE BUT MY THIRD TOOL, I CAN’T POSSIBLY LEAVE WITHOUT SAYING A LITTLE BIT ABOUT IT. THE THIRD TOOL IS IDENTIFYING VERTEBRAL FRACTURES AND THIS IS GOING TO BE TALKED ABOUT MORE IN THE NEXT PRESENTATION WITH DR. MILLER, BUT JUST TO MAKE THE POINT THAT IT IS A REALLY, REALLY IMPORTANT PART OF OUR PRACTICE TO IDENTIFY VERTEBRAL FRACTURES BECAUSE THEY’RE SO OFTEN ASYMPTOM ASYMPTOMATIC. SO THE ISCD CAME UP WITH GUIDELINES WHEN WE SHOULD BE DOING IMAGING OF THE SPINE TO IDENTIFY VERTEBRAL FRACTURES. I’VE SPENT THE LAST 35 YEARS OF MY CAREER TRYING TO WORK OUT HOW YOU SHOULD SPOT A FRACTURE, AND THIS IS FINALLY THE ALGORITHM THAT WE CAME UP WITH WHICH WE THINK IS THE BEST WITH WAY OF IDENTIFYING VERTEBRAL FRACTURES. IN THIS ALGORITHM, THE QUALITATIVE APROAP, WE IDENTIFY VERTEBRAL FRACTURES, OSTEOPOROTIC VERTEBRAL FRACTURES OR VERTEBRA BEING NORMAL OR NON-FRACTURE DEFORMITY. SO WE SPENT YEARS WORKING OUT THIS ALGORITHM, WE NOW HAVE TRAINING COURSES WHERE WE TEACH PEOPLE HOW TO RECOGNIZE VERTEBRAL FRACTURE BECAUSE THIS IS SUCH AN IMPORTANT PART OF WHAT WE DO. BUT AUTOMATING THIS APPROACH IS AN AREA FOR THE RESEARCH AGENDA, ABOUT TO DO THIS IN A WIDESPREAD WAY. SO I’M SUMMARIZING HERE WHAT ARE THE STRENGTHS AND WHAT ARE THE LIMITATIONS OF VERTEBRAL FRACTURE ANALYSIS. WE USE OUR DXA MACHINE USUALLY, WE CAN USE REGULAR RADIOGRAPHS, AND OF COURSE WE CAN RECONSTRUCT THE CT IMAGE OR MRI TO SPOT VERTEBRAL FRACTURE. SO THESE ARE ALL APPROACHES THAT WE CAN USE AND IS PROVEN TO BE A VERY USEFUL TOOL IN OUR EVERY DAY WORK. SO WHAT ARE THE RESEARCH GAPS? WHEN IT COMES TO BONE TURNOVER MARKERS, WE NEED TO HAVE MORE INFORMATION ABOUT THE EFFECTS OF STOPPING TREATMENT, AND WE NEED TO HAVE MORE ANALYSES AMONG CHANGE IN THRESHOLDS AND WE NEED TO HAVE BIGGER STUDIES. BONE DENSITY, MAYBE WE SHOULD BE ALSO EVALUATING FURTHER OTHER TESTS BESIDES DXA LIKE QCT AND IMAGING, WE NEED TO AUTOMATE THE APPROACHES. MY RECOMMENDATIONS, THAT WE NEED TO CHARACTERIZE BETTER THE CHANGES IN BONE TURNOVER MARKERS AFTER STOPPING LICENSED TREATMENTS, WE NEED TO RELATE THESE CHANGES TO HARM, WHAT’S THE RATIO BETWEEN BURN TURNOVER ON TREATMENT AND HARM SUCH AS AFF, THE RELATIONSHIP BETWEEN CHANGES IN BONE TURNOVER MARKERS, CHANGES IN BMD AND RISK AND FINALLY, OTHER FORMS OF SPINE IMAGING. SO WITH THAT, I WILL STOP. THANK YOU VERY MUCH. [APPLAUSE] WE’RE GOING TO HAVE A BRIEF DISCUSSION SECTION HERE GOING INTO THE NEXT SESSION WHICH STARTS AT 10:15 BEFORE WE HAVE A BREAK LATER IN THE MORNING. SO AS WE DID YESTERDAY, WE START WITH QUESTIONS FROM THE PANEL.>>THANK YOU. SO GIVEN THE RELATIVE DEARTH OF INFORMATION WE HAVE ABOUT DRUG HOLIDAYS COMING FROM A VERY FEW CLINICAL TRIALS, AND GOING BACK TO THE CONVERSATION FROM YESTERDAY ABOUT WHETHER IT’S REASONABLE TO EXPECT LONG TERM TRIALS 10 YEARS OR MORE FOR ODT, IS IT REASONABLE TO EXPECT THAT WE WILL BE ABLE TO LEARN ANYTHING ABOUT — OR UNDERSTAND ANYTHING ABOUT APPROPRIATE LENGTH OR INITIATION OF DRUG HOLIDAYS FROM THESE EXTENDED TRIALS, OR DO WE NEED TO BE THINKING ABOUT ALTERNATIVE SOURCES OF INFORMATION ABOUT DRUG HOLIDAY OR OTHER STUDY DESIGNS AND WHAT MIGHT THOSE — [INAUDIBLE]>>JUST A COMMENT ON THAT, BECAUSE I THOUGHT A LOT ABOUT THIS, AND THESE STUDIES ARE EXTREMELY HARD. YOU SAW MY STUDY WAS TWO YEARS PLUS TWO YEARS, AND I’D LOVED TO HAVE DONE FIVE YEARS PLUS FIVE YEARS, BUT EVENTUALLY I’M GOING TO RETIRE. THE — IS SO LONG, AND ALSO ONE OF THE CHALLENGES ABOUT DOING TRIALS IS THE STATE OF ECK ECK
WHICH EQUIPOISE, SO RECRUITING PATIENTS TO A TRIAL IS OFTEN QUITE CHALLENGING. SO DOING FURTHER TRIALS IS ACTUALLY QUITE CHALLENGING IN THIS AREA, BUT THERE ARE OPPORTUNITIES OF TAKING THE DATA FROM THE FLEX, FROM THE HORIZON AND SO FORTH, SOME OF THE QUESTIONS ABOUT — OF THE INDIVIDUAL, AND THERE ARE OPPORTUNITIES OF LOOKING AT REGISTERS AND LOOKING AT BONE DENSITY CHANGE IN PEOPLE WHO HAVE STOPPED TREATMENT JUST LIKE DOLORES HAD SPOKEN ABOUT. SO THERE ARE FURTHER OPPORTUNITIES FOR GETTING INFORMATION. BUT STARTING OFF NEW TRIALS IS A BIT OF A CHALLENGE.>>THANK YOU FOR YOUR PRESENTATIONS, AGAIN, I LEARNED QUITE A BIT. ONE OF THE THINGS THAT MIGHT BE HELPFUL IS IF YOU COULD SAY SOMETHING ABOUT HOW THESE DIFFERENT ODTs MAY VARY ON DIFFERENT BONES IN THE BODY, BECAUSE WE SEE A LOT OF EVIDENCE ABOUT VERTEBRAE, SOME ABOUT HIP, BUT DR. SHOW BECK DR. SHOBACK
SHOWED US TH INGS ABOUT ANKLES, WRISTS, WE DON’T HEAR A LOT ABOUT THAT. SO WHY DON’T YOU SAY SOMETHING ABOUT WHY THESE THERAPIES MAY WORK BETTER IN CERTAIN BONES THAN OTHERS OR SOMETHING ALONG THAT LINE SO WE COULD UNDERSTAND THE DIFFERENCES?>>I WILL GO, IF IT’S ALL RIGHT?>>GO AHEAD.>>ALL I WAS GOING TO SAY IS, WHEN WE SEE THE BONE TURNOVER MARKERS COME UP, OFTEN THE FRACTURE THAT BONE TURNOVER MARKERS RELATE TO MOST STRONGLY IS VERTEBRAL FRACTURE, SO IN THE TRIALS THAT WE HEARD FROM PARTICULARLY EARLIER ON, THE FLEX AND THE HORIZON, WHEN WE SAW THE FRACTURE THAT REALLY MADE A DIFFERENCE IF YOU CONTINUE TREATMENT WAS VERTEBRAL FRACTURE, SO THAT DOESN’T SURPRISE ME AT ALL, BECAUSE VERTEBRAL FRACTURE IS VERY SENSITIVE TO CHANGES IN BONE TURNOVER. SO I THINK THERE ARE VERY MUCH DIFFERENCES DEPENDING ON WHICH FRACTURE TYPE, BUT IT MEANS VERTEBRAL FRACTURE VERSUS ALL THE REST. VERTEBRAL FRACTURE IS THE CLASSICAL FRACTURE THAT GOES ALONG WITH HIGHER BONE TURNOVER AND, THEREFORE, WE DO SEE DIFFERENCES BETWEEN THE DIFFERENT FRACTURE TYPES AND THAT’S THE MAJOR DISTINCTION IN MY MIND.>>I’LL MAKE ONE COMMENT ON THAT WHICH IS CERTAINLY WE KNOW SPINAL BONE DENSITY, BECAUSE OF THE TYPE OF BONE THAT’S THERE, IS MORE RESPONSIVE TO THE TYPICAL THERAPIES WE’RE TALKING ABOUT, BISPHOSPHONATES AND ANTI-RESORPTIVE THERAPIES, YOU SEE THE BIGGEST CHANGES IN BMD, THE MOST RAPID CHANGE IN FRACTURE REDUCTION AND SO FORTH. IN THE STUDIES I PRESENTED AND TRIED TO REVIEW HERE, REALLY NO ONE HAD SYSTEMATICALLY — THEY COLLECTED CLINICAL FRACTURES AS PATIENT-REPORTED OUTCOMES AND ADVERSE EVENTS SO TO SPEAK, BUT REALLY VERTEBRAL FRACTURES, MORPHOMETRIC WERE NOT LOOKED FOR SPECIFICALLY, AND WE KNOW THAT WHAT WE SEE CLINICALLY IS A VERY SMALL TOP OF THE ICEBERG AND THERE’S A LOT MORE THAT GOES ON THERE. SO REALLY, THE REAL WORLD CLINICAL EXPERIENCE WITH OTHER FRACTURE TYPES, PARTICULARLY VERTEBRAL THAT ARE RADIOGRAPHIC, WE HAVE VERY LITTLE INFORMATION ABOUT. EXCEPT FROM THE EXTENSION TRIALS THAT HAVE BEEN DONE.>>SO I HAVE A QUESTION ABOUT THE BONE — THE TURNOVER. IT SEEMS LIKE BONE MINERAL DENSITY THE IS, AS YOU SAID, THE MAJORITY OF PEOPLE AFTER FIVE YEARS, YOU SEE A LOT LESS CHANGE AND YOU SEE THE TURNOVER A LOT FASTER, AND SO I WAS JUST WONDERING IF WHEN YOU’RE TRYING TO WEIGH BOTH THE FACTORS OF THE TURNOVER VERSUS MINERAL DENSITY, GIVEN THE DIFFERENT TIME COURSES, IS THE TURNOVER MORE RIGHT NOW IN KIND OF THE RESEARCH STAGE WHERE THE BMD IS MORE OF THE KIND OF CLINICAL PRACTICE STAGE, DO YOU SEE THAT OR DO YOU SEE THE TURNOVER BEING USED MORE AND MORE IN THE CLINICAL DECISIONS?>>SO BONE TURNOVER MARKERS ARE USED IN A PATCHY WAY, SO WE USE THEM ALL THE TIME, AND HAVE BEEN FOR THE LAST 20 YEARS, BUT NOT ALL PHYSICIANS USE THEM AND IT’S PARTLY BECAUSE NOT ALL PHYSICIANS FEEL COMFORTABLE ABOUT THIS ISSUE OF VARIABILITY AND BEING ABLE TO CONTROL FOR THAT, BUT IT’S PARTLY BECAUSE IN THIS COUNTRY BONE MARKERS — YOU PAY ABOUT 10 TIMES MORE FOR YOUR BONE MARKERS FOR ME IN MY PRACTICE SO FOR ME, IT’S VERY EASY TO USE THEM. THE DRUGS WE’RE USING, THE PRIMARY WAY THEY’RE WORKING IS THROUGH THE CELL AND THROUGH CHANGING THE CELLULAR ACTIVITY, SO WHEN WE’RE MEASURING BONE TURNOVER MARKERS, WHETHER IT’S RESORPTION OR FORMATION, WE’RE OBSERVING THE PRIMARY PEESKTS AND WHEN WE’RE LOOKING AT BONE DENSITY, IT’S A SECONDARY EFFECT. AND SO WHEN I WAS SAYING THAT WHEN THEY HAVE THE OFFSET PERIOD, WE SEE EARLY CHANGES IN BONE MARKERS AND LATER CHANGES IN BMD, THAT’S JUST WHAT WE’D EXPECT, IS THAT THEY OCCUR EARLIER. SO IF THE QUESTION IS, IN MY PATIENT, HAS THE BISPHOSPHONATE WORN OFF, YOU’LL PICK IT UP EARLIER IF YOU MEASURE THE BONE MARKER. SO THAT’S AN ADVANTAGE. SO THEY’RE BOTH GOOD TEST, IT’S JUST THAT IF YOU WANT AN EARLY SIGNAL, THE BONE MARKERS TELL YOU EASILY.>>IT WOULD BE FAIR SO SAY, HOWEVER, IN THE U.S., FOR EXAMPLE, THE USE OF THESE TURNOVER MARKERS IN ACTUAL PRACTICE IS VERY, VERY LOW. FOR THE REASONS THAT RICHARD HAS TALKED ABOUT AND THE CTX WHICH MAY BE THE MOST SENSITIVE NEEDS TO BE COLLECTED UNDER CONDITIONS AS HE DESCRIBED, FASTING AND FIRST THING IN THE MORNING AND IT’S A BIT INCONVENIENT, SO THE UPTAKE IS NOT THEN HUGE.>>DR. FINK, YOU WERE SHARING WITH US A REVIEW WHERE YOU WERE LOOKING AT — SHOWING A TEST OF DIFFERENCES AMONG PEOPLE WHO HAD SOME SORT OF CESSATION OR DRUG HOLIDAY. CAN YOU GIVE US YOUR POINT OF VIEW ON WHETHER YOU REALLY WANT TO TEST FOR DIFFERENCES OR YOU WANT TO TEST FOR EQUIVALENCIES?>>I GUESS THAT’S REALLY A CLINICAL QUESTION. IF YOU’RE — I MEAN, WHAT WE WERE REPORTING IN EVIDENCE REPORTING — PRIMARY STUDIES REPORTED. I DON’T RECALL THAT THEY STATISTICALLY LOOKED TO SEE WHETHER THE RESULTS WERE EQUIVALENT THAT THEY WERE DESIGNED AS EQUIVALENCY STUDIES, THAT THEY WERE DESIGNED TO LOOK TO SEE WHETHER RESULTS ON FRACTURE OUTCOMES DIFFERED BETWEEN THE TWO TREATMENT ASSIGNMENTS. BUT IF YOU’RE JUST LOOKING TO SEE WHETHER — I MEAN, YOU COULD ASK THAT QUESTION WHETHER RISK OF FRACTURE STAYED THE SAME EVEN AFTER YOU STOPPED TREATMENT.>>AND SO I’D LIKE TO ASK THE CLINICIANS, ARE YOUR PATIENTS ASKING YOU WILL IT BE THE SAME IF I TAKE A BREAK OR ARE THEY ASKING IF IT’S GOING TO BE DIFFERENT?>>SO I SEE YOUR POINT ACTUALLY. I WAS PART OF THE CLINICAL TRIALS, WE DID TEST WHETHER THEY WERE DIFFERENT AS HOWARD JUST SAID, BUT YOU COULD ARGUE THAT THE PATIENT WOULD WANT TO KNOW, I’VE GOT TWO CHOICES HERE, I CAN STOP OR I CAN KEEP GOING, IS IT GOING TO BE THE SAME, SEEMS TO ME LIKE A REASONABLE QUESTION.>>JUST A FOLLOW- UP ON THAT, JUST CURIOUS IN TERMS OF THE PATIENT, WHEN THEY ARE ON THIS DRUG HOLIDAY, ARE THERE ANY TYPICAL SIDE EFFECTS? I MEAN, GIVEN THAT THEY’RE COMING OFF A DRUG, I DON’T KNOW, ARE THERE HEADACHES, DIARRHEA OR ANYTHING LIKE THAT THAT A PATIENT WOULD UNDERGO?>>NO, THEY’RE HAPPY TO BE RELIEVED OF HAVING TO TAKE THE MEDICINE FOR A FEW YEARS USUALLY, BUT I’VE NOT SEEN ANYBODY COMPLAINING OF ANYTHING, BECAUSE TO BE HONEST, THESE DRUGS, ESPECIALLY THE ORAL BISPHOSPHONATES, ARE REALLY SAFE. WE’VE TALKED A LOT ABOUT ALL OF THE CHALLENGES YOU GET IN TERMS OF ATYPICAL FRACTURE BUT THESE ARE ALL REALLY, REALLY, REALLY RARE, SO MOST PATIENTS WE SEE, THEY’RE USUALLY PRETTY HAPPY WITH THE MEDICINES THAT THEY’RE TAKING SO WHEN THEY STOP THEM, THEY’RE ALSO PRETTY HAPPY. IT’S ACTUALLY VERY RARE TO ENCOUNTER ANY PROBLEMS.>>LET ME OPEN THIS TO QUESTIONS FROM THE AUDIENCE. WHY DON’T WE START OVER HERE.>>SAAG, U.A.B. HOWARD, THANKS AGAIN FOR ANOTHER EXCELLENT UPDATE ON THE META-ANALYSIS. THE CLINICAL QUESTION THAT REALLY IS ON EVERYBODY’S MINE RIGHT NOW AND, IN FACT, IS APPROACHING THE BISPHOSPHONATE DRUG HOLIDAY ISSUE IS WHAT TO DO WITH LONG TERM DENOSUMAB. YOU PROVIDED A LITTLE BIT OF DATA ON THAT. I’M WONDERING, THOUGH, IF YOUR META-ANALYSIS INCLUDED A RECENT PAPER PUBLISHED BY STEVE CUMMINGS IN JBMR THAT SHOWED AN INCREASE IN FRACTURES AFTER STOPPING DENOSUMAB AND HAD A TREND TOWARDS AN INCREASE IN MULTIPLE FRACTURES. THIS HAS REALLY BEEN A VERY IMPORTANT PAPER THAT’S INFLUENCING PRACTICE THESE DAYS.>>IS THIS THE STUDY WITH THE VIRTUAL CONTROL GROUP?>>NO, ACTUALLY THEY HAD A — IT’S AN AD HOC –>>IN THE FREEDOM TRIAL, I WAS A CO-AUTHOR ON THE PAPER. IN THE FREEDOM TRIAL, WE HAD A NUMBER OF PEOPLE WHO ACTUALLY STOPPED THE TREATMENT BUT WERE FOLLOWED FOR AN AVERAGE ABOUT SEVEN MONTHS, SO WE LOOKED AT THEIR FRACTURE RATES AND SO — AND WE REPORTED THAT TO THE GENERAL — JUST RECENTLY IN THE LAST FEW MONTHS.>>OKAY. WELL, I MEAN, I THINK I’VE HEARD OF THE STUDY BUT — SO THIS WAS JUST PUBLISHED AFTER JUNE?>>I CAN’T TELL YOU –>>OKAY. WELL, I’LL LOOK IT UP.>>THE EVIDENCE REPORTS IN COMMENT PERIOD SO GOOD THING TO BRING UP.>>HI. DOUG — FROM SAN FRANCISCO. SO FOR THE PANEL MEMBER THAT WAS ASKING ABOUT THE USE OF BONE TURNOVER MARKERS IN THE U.S., I JUST WANTED TO ADD A QUICK COMMENT TO THE BEAUTIFUL PRESENTATION, WE HAVE ANOTHER PROBLEM BESIDE THE REALLY EXORBITANT COST, AND THAT IS THAT AT LEAST ONE OF THE MARKERS CANNOT BE MEASURED ON AN AUTOMATED PLATFORM WHICH IS P1NP. THE FDA HAS ONLY APPROVED THE IMMUNOASSAY HERE AND NOT THE MUCH MORE REPRODUCIBLE PLATFORM-BASED ASSAY. SO THAT WAS ONE PROBLEM. THE OTHER PROBLEM IS THAT FOR PRIMARY CARE DOCTORS LIKE ME, WHEN I SEND OFF A BONE TURNOVER MARKER, I ACTUALLY DON’T KNOW WHERE IT GOES. MY HOSPITAL SENDS IT OUT TO THE LOWEST COMMERCIAL LAB WITH THE LOWEST PRICE, AND WE’VE JUST CON A DONE A COMPARABILITY STUDY WHERE WE SENT BLINDED SPECIMENS AND EVEN WITH CTX, THERE WAS A LOT OF VARIABILITY, SO I’M VERY OPTIMISTIC AND HOPEFUL BUT THERE’S STILL SOME KINKS TO BE WORKED OUT IN THE U.S.>>I SYMPATHIZE WITH EVERYTHING YOU SAY. ONE THING WE ARE TRYING TO DO THROUGH A COMMITTEE OF THE IOF IS TO STANDARDIZE AND HARMONIZE THE BONE DENSITY TESTING, WHETHER IT’S CTX OR P1NP AND WE’RE IN THE PROCESS, BUT IT ALL TAKES TIME AND I APPRECIATE ALL OF THE POINTS YOU’RE MAKING.>>ROB BLANK, WISCONSIN. THIS IS DIRECTED PRIMARILY TO DR. EASTELL. I WOULD LIKE TO FOLLOW UP ON THE CONCEPT OF LEAST SIGNIFICANT CHANGE. BOTH FOR TURNOVER MARKERS AND FOR DXA. AND THE CHALLENGE THAT EXISTS IS THAT A LOT OF PATIENTS CHANGE FACILITIES AND THERE IS NO COMPARABLE WAY TO MEASURE LEAST SIGNIFICANT CHANGE IF YOU’RE GOING TO A DIFFERENT FACILITY. CAN YOU COMMENT FIRST ON INTERSITE LEAST SIGNIFICANT CHANGE WITH MARKERS AND SECOND, WHAT YOU MIGHT PROPOSE. HAVE YOU THOUGHT ABOUT THE POSSIBILITY OF RESEARCH NEEDS IN TERMS OF ESTABLISHING A CROSS FACILITY KIND OF DXA LEAST SIGNIFICANT CHANGE? AND FOLLOWING UP ON THAT, ALSO, THERE IS BIG ISSUE IN THE UNITED STATES IN TERMS OF QUALITY OF DXA PERFORMANCE, SO THERE IS EXTREME VARIABILITY, I CAN TELL YOU FROM MY OWN PRACTICE AND I’M SURE OTHERS CAN ECHO THIS, THAT WE GET REFERRALS OF PATIENTS WHO HAVE VERY POOR QUALITY DXA STUDIES DONE AHEAD OF TIME. IN OUR ACADEMIC CENTERS, WE DO BET ARE BUT NOTTER BUT NOT
NECESSARILY WEL L. THIS, TOO, IS A CHALLENGE TO USING THE TOOLS EFFECTIVELY.>>THANK YOU VERY MUCH FOR THAT. SO THERE ARE SEVERAL COMPONENTS TO YOUR QUESTION THERE. THE FIRST ONE IS THIS ISSUE ABOUT LEAST SIGNIFICANT CHANGE FOR BONE TURNOVER MARKERS. SO INTERESTINGLY, ALMOST ALL THE VARIABILITY, LET’S SAY 80 OR 90% OF THE VARIABILITY, IS WITHIN THE PERSON RATHER THAN WITHIN THE ASSAY, BECAUSE NOW DAYS, WHEN WE MEASURE BONE TURNOVER MARKERS, WE DO USE THE AUTOMATED ANALYZERS AND THE C.V. OF THE ASSAYS RUN ABOUT 2% SO IT’S REALLY SMALL, WHERE AS THE PERSON, THE SUBJECT IS MORE LIKE 10 OR 15%. SO IT’S A MUCH BIGGER COMPONENT, SO THEREFORE IT DOESN’T REALLY MATTER WHETHER YOU MAKE THE BONE TURNOVER MEASUREMENT OR WHETHER I MAKE IT, IT WILL HAVE THE SIMILAR LEAST SIGNIFICANT CHANGE. NOW, DXA, I APPRECIATE, IS DIFFERENT, BECAUSE THEN THERE’S A LOT OF THE OPERATOR — THERE’S COMPONENT, RATHER, OF THE OPERATOR WHERE IT DOES CONTRIBUTE TO THE OVERALL. SO THERE IS A CHALLENGE AND I APPRECIATE THAT. BUT THERE’S ANOTHER ASPECT ABOUT LEAST SIGNIFICANT CHANGE WHICH IS, WE ALL OF US HAVE A DIFFERENT LSC. WE COULD ACTUALLY CALCULATE THE LSC FOR YOU AND FOR ME AND ACTUALLY IT WILL BE DIFFERENT BECAUSE SOME PEOPLE ARE VARIABLE PEOPLE AND SOME PEOPLE ARE VERY STEADY, PROBABLY RELATES TO THE WAY WE LIVE. SO THERE ARE SOME TO LEAST SIGNIFICANT CHANGE WHICH I GLOSSED OVER IN MY TALK AND I’D BE HAPPY TO SPEAK TO ARE NOW ABOUT.>>SO ONE MORE QUESTION WHICH IS IS, CAN YOU TELL US WHETHER THERE IS ANY RESEARCH ONGOING RIGHT NOW, BECAUSE I BELIEVE IT’S A NEED, AND IT’S ALLUDED TO BY DR. ADLER’S TALK YESTERDAY, OF DEVELOPING MARKERS FOR POST TRANSLATIONAL MODIFICATIONS OF PROTEINS SUCH AS ADVANCED GLIECATION CHANGES THAT HAPPEN WITH DURATION OF RESIDENCE IN THE TISSUE THAT MIGHT BE USEFUL IN TERMS OF MONITORING PATIENTS OVER TIME?>>THE IDEA ABOUT BIOCHEMICAL MARKERS THAT TELL US INFORMATION OTHER THAN JUST REMODELING — THIS MORNING I JUST FOCUSED ON REMODELING MARKERS BUT THERE ARE THE AGES THAT HE TALKED ABOUT WHICH RELATE TO THE DAMAGE YOU CAN GET FROM GLYCOSYLATION OF PROTEINS, AND THERE ARE ASSAYS FOR THAT. THE BEST ASSAYS CURRENTLY ARE USEING TANDEM MASS SPEC AND THEY’RE NOT SO WIDELY AVAILABLE BUT THAT’S A VERY INTERESTING AREA, WHERE THEY COULD BE VALUABLE, AND THEN THERE ARE ALSO SOME ISOFORMS OF THE CTX, WHICH I DIDN’T TALK ABOUT, THE ALPHA AND THE BETA, WHICH ALSO TELL US ABOUT THE AGING OF THE BONE, WHICH ALSO CAN BE INFORMATIVE. SO THESE ARE ALL IN THE RESEARCH AGENDA, AND ARE INTERESTING AND COULD BE USEFUL IN
THE FUTURE.>>GOOD. BARRING ANY QUESTIONS FROM PUBLIC COMMENT, I THINK WE ARE GOING TO PLOW AHEAD AND LET ME THANK OUR SPEAKERS FOR THIS SESSION. WE HAVE DR. MILLER NEXT AND FOLLOWED BY DR. HOCHBERG AND THEN A BREAK. MY NAME IS PAUL MILLER, AND I HAVE BEEN IN THIS FIELD A LONG TIME, AND I’M A VERY ACTIVE PRACTITIONER, I’M A NEPHROLOGIST BY FORMAL TRAINING AND, BUT I
SEE ABOUT 80 PATIENTS A WEEK. I’M A VERY ACTIVE PRACTITIONER, A LOT OF COMPLICATED PEOPLE. I’M WITH A GROUP NOW OF WONDERFUL BIG OR THE ORTHOPEDIC SURGEONS THAT ARE LEARNING METABOLIC BONE DISEASE AND HOW TO INCORPORATE ALL OF THE THINGS THAT WE’RE TEACHING THEM HERE FOO THIS AND THEY GIVE ME A LOT OF SUPPORT, I WANTED TO THANK THEM FOR MY RESEARCH AND THE SUPPORT THAT THEY HAVE. THESE ARE MY DISCLOSURES. SO THE SUMMARY OF THE FINDINGS, I WAS ASKED TO PRESENT THIS, CLINICAL APPROACH, I THINK ARE CRITICAL AND DON’T GET ADDRESSED. ASKING PATIENTS IF THEY’VE EVER HAD A LOW TRAUMA FRACTURE IS AN IMPORTANT COMPONENT OF THE MEDICAL HISTORY. FREQUENTLY WE DON’T ASK. HEIGHT MEASUREMENTS AND SPINE X-RAYS, THE LOSS OF HEIGHT OF MORE THAN AN INCH AND A HALF SHOULD BECOME THE STANDARD OF CARE AND MAYBE SHOULD BE A QUALITY MEASURE FOR PAYMENT. THE DIAGNOSIS OF OSTEOPOROSIS BASED ON FRACTURE TRUMPS T SCORES. THAT’S NOT A POLITICAL COMMENT. IS ITS SIMPLY A FACT THAT REGARDLES OF WHAT THE BONE DENSITY IS, IT MAKES THE DIAGNOSIS REGARDLESS OF THE T SCORE. THAT IMPORTANT — THAT STATEMENT CANNOT BE OVEREMPHASIZED MORE BECAUSE OF THE FACT THAT WE HAVE A HUGE PROBLEM IN CLINICAL IMPLEMENTATION OF INSURANCE COMPANIES DENYING PAYMENT BECAUSE THE PATIENT DOESN’T HAVE OSTEOPOROSIS, THE T SCORES CERTAINLY DOES NOT TRUMP FRACTURES, FRACTURES MAKE THE DIAGNOSIS, PERIOD. AND THERE ARE MANY TEASES
DISEASES THAT WE TREAT THAT HAVE IMPAIRMENT OF BONE QUALITY WHICH IS THE OTHER HALF OF BONE STRENGTH THAT WE CAN’T MEASURE IN CLINICAL PRACTICE, SUCH AS DIABETES OR PEOPLE ON STEROID OR PEOPLE WITH MORE SEVERE CHRONIC KIDNEY FAILURE WHO FRACTURE BECAUSE THEY HAVE A BONE QUALITY ISSUE. FRACTURES DEMAND A SECONDARY WORKUP AND TREATMENT. NOT ALL KINDS OF FRACTURES ARE POST-MENOPAUSAL OR MALE OAP, WE HAVE TO THINK ABOUT OTHER DISEASES THAT CAN CAUSE FRACTURES, SOME OF THE RARE BONE DISEASES WE FOLLOW VERY CAREFULLY AS WELL SUCH AS T.I.O. OR HYPOFOS FA TAI SHA. THIS WAS THE NIH DEFINITION OF OSTEOPOROSIS THAT WAS PRINTED AND PUBLISHED IN 2000, AND TODAY HERE IN 2018, IT STILL STANDS FIRM. A SKELETAL DISORDER CHARACTERIZED BY COMPROMISED BONE STRENGTH PREDISPOSING TO AN INCREASED RISK FOR FRACTURE.& BONE STRENGTH IS A COMPOSITE OF BONE DENSITY, WHICH WE CAN MEASURE, AND BONE QUALITY, WHICH WE CAN’T MEASURE IN CLINICAL PRACTICE. IT GIVES US AN INDICATOR BUT IS CERTAINLY IMPERFECT. SO BRIDGING THE GAP, RESEARCH KNOWLEDGE TO PRACTICE, I’VE DIVIDED THIS INTO THE LEFT-HAND SIDE OF WHAT RESEARCH SHOWS AND ON THE RIGHT-HAND SIDE, WHERE THE GAPS ARE. ONE, RESEARCH HAS SHOWN DEFINITELY THAT SPECIFIC LOW TRAUMA FRACTURES IN PATIENTS 50 YEARS OF AGE AND OLDER IS THE SINGLE GREATEST RISK FACTOR FOR A SECOND FRACTURE. THE GAP, PRACTICE PHYSICIANS DON’T EVEN GRASP THIS MESSAGE. IT’S NOT IMPUNING THE BUSY PHYSICIAN WITH ALL THE PRIMARY CARE PROBLEMS THAT THEY DO, IT’S SIMPLY THAT THE MESSAGE HAS NOT GOTTEN THROUGH. THI DO NOT LOOKTHEY DO NOT LOOK
FOR THE ASYMPTOMATIC VERTEBRAL FRABT THEAND DON’T KNOW FRACTURES ARE THE KEY TO MAKING THE DIAGNOSIS ABOVE AND BEYOND WHATEVER BONE DENSITY NUMBER IS THERE. TWO, THE RESEARCH HAS SHOWN THAT TREATING 50 YEARS OF AGE OR OLDER WITH PHARMACOLOGICAL FACTOR INDEPENDENT OF THE BONE DENSITY NUMBER. A LOT OF THIS IS A ADDRESSING
THE PAYOR PROBLEMS. — EVEN FOR A HOSPITALIZED PATIENT WITH A HIP FRACTURE. HOPEFULLY FLS IMPLEMENTATION MAY ADDRESS THIS. THIS IS ONE OF MANY STUDIES TO SHOW THAT A LOW TRAUMA FRACTURE IN THIS PARTICULAR STUDY BY — VERTEBRAE AND HIP PREDICT FRACTURES AT OTHER SKELETAL SITES. WHETHER IT BE SOFT, WHETHER IT BE — DATA IN TERMS OF — FRACTURES. THE FRACTURE IS SYMBOLIC OF SYSTEMIC SKELETAL FRAGILITY. AND THAT’S HOW I CONVEY THAT TO PATIENTS. I ONLY HAD A WRIST FRACTURE, DOCTOR. BUT YES, YOU HAVE A HIGH RISK FOR HIP FRACTURES AS WELL. THAT IS A MESSAGE THAT NEEDS TO BE CONVEYED IN MORE — WITH GREATER ARTICULATION. RESEARCH — TREATMENT. RESEARCH IS UNEQUIVOCAL EVIDENCE THAT PHARMACOLOGICAL THERAPY WITH FDA AGENTS REDUCES THE RISK OF FRACTURE IN POST
POST-MENOPAUSAL WOMEN, IN MEN, AND IN GLUCOCOURT TOYED INDUCED OSTEOPOROSIS. FEAR. THIS HAS BEEN ADDRESSED MANY TIMES, ATYPICAL FEE MURL FRACTURE YOU’RE RESPONSIBLE MEDIA HYPE. IT WAS MARCH 10TH, 2010, HAS REALLY KILLED BISPHOSPHONATES. WITH FEAR TRICKLING OVER INTO ALL OTHER THERAPIES. THE PATIENTS THAT I WANT TO THINK ABOUT ASK ME IF THAT’S A SIMILAR COMPOUND AND DOESN’T DO THE SAME THINGS AND AFRAID TO TAKE IT. IT’S A CHALLENGE. I WAS IN SAN ANTONIO TEXAS AT THE ISC ANNUAL MEET WHG THIS CAME ON THE NEWS THAT NIGHT. I GOT HOME, 88 PHONE CALLS WAITING FOR ME MONDAY MORNING WONDERING ABOUT PATIENTS STOPPING THEIR BISPHOSPHONATES. IN ALL DUE RESPECT, OUR SCIENCE AND PROFESSIONAL SOCIETIES HAVE NOT BEEN SUCCESSFUL IN MITIGATING THIS FEAR. AND THAT’S A CHALLENGE FOR ALL OF US, NO MATTER WHAT ORGANIZATIONS THAT WE’RE DEVOTED TO AND MOST OF US ARE DEVOTED TO ALL THE ONES, ASBMR, AC ROOM, ISED AND GO ON, TO WORK TOGETHER TO ADDRESS THIS TERRIBLE ISSUE. RESEARCH AND GAPS, RESEARCH HAS SHOWN THAT EVEN ASYMPTOMATIC VERTEBRAL COMPRESSION FRACTURE IS ASSOCIATED WITH A HIGH RISK FOR CERTIFICATE BRAL AND
VERTEBRAL AND NON -VERTEBRAL FRACTURE IN PATIENTS. THEY DON’T MEASURE HEIGHT ACCURATELY OR LOOK BY X-RAY OR VFA EVEN IF PATIENTS HAVE LOST AN INCH AND A HALF OR MORE FROM WHAT THEY THOUGHT THEY WERE. I THINK THE GAP HERE, MOST PATIENTS ARE MEASURED BY THE MEDICAL ASSISTANT IN THE OFFICE AND THEY PUT DOWN — THEY MAY NOT KNOW HOW TO DO IT CORRECTLY. THEY PUT DOWN THE NUMBER ON A CHART THAT GETS BACK TO THE DOCTOR WITHOUT IT EVEN BEING HIGHLIGHTED THAT THIS MIGHT BE OF PARTICULAR CONCERN. I’D LIKE TO SEE THE ABILITY OF THE M.A. WHO MEASURES THE HEIGHT TO AUTOMATICALLY BE ABLE TO ORDER THE X-RAY. SO THEY CAN DO IT RIGHT THERE AS POINT OF CARE IF SOMEBODY HAS FULFILLED THAT CRITERIA. THAT WOULD BE A BIGGER MAJOR STEP FORWARD. RIGHT NOW IT’S NOT ALLOWED IN THE HEALTHCARE SYSTEM. THIS IS A PICTURE ON THE LEFT OF THE LATE BETSY MCCLUNG, DOING HER MEASUREMENTS ACCURATELY ON A PATIENT TOTALLY ASYMPTOMATIC, BUT HAD LOST 3 INCHES IN HEIGHT. AND THE X-RAY TO THE RIGHT SHOWS THE VERTEBRAL COMPRESSION FRACTURE. CHANGES THE DIAGNOSIS, CHANGES THE RISK, CHANGES THE MANAGEMENT IF THAT IS FOUND. SO I THINK RICHARD PROBABLY SHOWED SOME OF THESE FROM THE U.K., WE WORK VERY HARD WITH MULTIPLE ORGANIZATIONS TO GET MEDICARE TO COVER THESE CERTAIN INDICATIONS OF WHEN TO DO AN X-RAY OR V.F.A. CERTAINLY WITH A HEIGHT LOSS OUGHT TO BE NUMBER ONE. I MEAN, WE MISS THAT ALL THE TIME. THE STEROID STUFF, KEN CAN TALK ABOUT MORE LATER, BUT THESE ARE SOME OF THE INDICATIONS THAT ARE REIMBURSED CURRENTLY FOR WHEN TO DO THESE MEASUREMENTS. THIS IS FROM THE N.O.F. GUIDELINES, THOUGH OFTEN UNRECOGNIZED, THE IDENTIFICATION OF VERTEBRAL FRACTURES IS IMPORTANT. A VERTEBRAL FRACTURE, CLINICAL OR MORPHOMETRIC IS THE INDICATION FOR PHARMACOLOGICAL TREAT. ONCE THE WORKUP FOR SECONDARY CAUSES INCLUDING THINGS THAT WE SEE COMMONLY SILL YAK DISEASE AND OTHER KIND OF IK EUS ARE RULED OUT. THE CONSEQUENCES OF THESE FRACTURES ARE ENORMOUS. WE DEAL WITH THESE DAY IN AND DAY OUT. THEY HAVE AN INCREASED RISK FOR FALLS. THEY MAY HAVE NO PAIN BUT THEY’VE LOST BALANCE. THEY’RE GOING TO HAVE MORE FRACTURES IF THEY’RE UNTREATED. AND THERE’S A HIGH MORTALITY. THIS IS A SLIDE FROM THE DUBOS AUSTRALIAN POPULATION STUDIES LOOKING AT SURVIVAL BY TYPE OF FRACTURES IN WOMEN ON THE LEFT OVER A 10-YEAR PERIOD, ACTUALLY AT THE 20-YEAR PERIOD, UNDER THE AGE OF — FROM 50 TO 75, AND MEN ON THE RIGHT. AND THE DIFFERENT COLORS, THE DIFFERENT TYPES OF FRACTURES. THE BLUE BEING HIP FRACTURES, THE GREEN BEING VERTEBRAL FRACTURES. AND LOOK AT IT, THIS IS — NOT PICKING OUT — THE MEN. THE BLUE LINE SHOWS THEIR SURVIVAL AFTER A HIP FRACTURE. BUT LOOK AT THE GREEN LINE. IN THE EARLIER YEARS, IT’S EVEN FASTER AND MORE MORTALITY THAN HIP FRACTURES. AND THERE ARE MULTIPLE REASONS BEHIND THIS. IT MAY BE THE DISEASES THAT THEY ACCOMPANY, BUT THESE FRACTURES ARE SIGNIFICANT AND WE MISS THEM AND WE CAN’T TAKE THEM LIGHTLY. LOW BMD IS A STRONG BREE PREE DICTIONARIER FOR FUTURE FRACTURE, YET DXA ACCESSIBILITY IS DECLINING. DESPITE THE GREAT RECOMMENDATIONS OF THE EU.D STATES PREVENTION SERVICES TASK FORCE AND THE U.S. SURGEON GENERAL’S OFFICE, THAT ALL POST-MENOPAUSAL WOMEN OBTAIN A BMD AT AGE 65 REGARDLESS OF RISK FACTORS, THE NUMB DER NUMBER OF
DXA MACHINES HAS DECLINED BY NEARLY 50% IN FREE-STANDING FACILITIES. IN COLORADO, WE’VE LOST HALF. IF YOU DON’T HAVE THE MACHINE, YOU CAN’T TEST. YOU CAN’T MAKE A DIAGNOSIS, YOU’RE NOT GOING TO TREAT. ASSOCIATED WITH A LOWER ACCESSIBILITY OF DXA MACHINES, THE NUMBER OF PEOPLE BEING SCREENED FOR OSTEOPOROSIS HAS A CONSEQUENCE. THIS IS A RECOMMENDATION FOR LOP POPP LAITION OWE POPULATION SCREENING. THE NUMBER OF PEOPLE BEING TREATED HAS STEADILY DECLINED AND THE MAJOR REASON FOR DECLINE IN MOST OSTEOPOROSIS IS THE CUT THE IN DXA REUM BURSTMENT IN 2012 FROM MEDICARE. THIS HAS NEVER BEEN A CASH COW. IF WE COULD JUST GET IT TO BREAK EVEN, WE’D SEE THIS FIELD TURN AROUND TO SOME DEGREE AND MEMBERSHIP IN MANY SOCIETIES INCREASING. THIS IS THE SLIDE YOU’VE SEEN BEFORE FROM MIKE, AND IT JUST SHOWS THE TREND, IF YOU LOOK AT THE LIGHT BLUE BARS, MEDICARE REIMBURSEMENT STARTED TO GO DOWN, AND THEN WENT DOWN IN 2012 TO ABOUT $37, $38, FOR FREE-STANDING FACILITIES. HOSPITAL-BASED FACILITIES, THEY KEPT THE PRICE THE SAME. THIS WAS A BROAD RADIOLOGICAL CHANGE FOR ALL RADIOLOGICAL DEVICES WHERE REIMBURSEMENT FOR HOSPITAL-BASED FACILITIES WAS MAINTAINED, FOR FREE-STANDING FACILITIES, IT WAS CUT. TO ME, THAT’S DISCRIMINATION. BUT THE POINT IS, IS THAT IF YOU HAVE A MACHINE WITH A BREAK-EVEN, WE’VE CALCULATE THIS HAD AT ABOUT $90 AND YOU’RE PAYING THEM 37, YOU CAN’T KEEP IT OPEN. I’M BLESSED THAT I CAN KEEP MY MACHINES OPEN BECAUSE OF MY RESEARCH GRANTS. BUT I’M DIFFERENT AND I’M LUCKY. AND I’M BLESSED FOR THAT. BUT THIS IS WHAT’S HAPPENING. AND WITH THAT TREND, DIAGNOSIS GOING DOWN, NUMBER OF PEOPLE — DXA TESTING GOING DOWN, AND OF COURSE THE NUMBER OF PEOPLE BEING TREATED GOING DOWN. AGE AND RISK. THIS WAS THE FIRST STUDY, 1988. CONNIE JOHNSTON, UNIVERSITY OF INDIANA, THE GROUP, SHOWING THE RELATIONSHIP BETWEEN LOW BONE DENSITY, AGE AND FRACTURE RISK. SO THAT THE FRACTURE RISK DOUBLES BY DECADE OF AGE AT THE SAME BONE DENSITY. THIS WAS A GREAT LANDMARK STUDY. AND IT’S BEEN REPEATED MANY, MANY TIMES BY OTHER WORK. THERE’S A COUPLE OF POINTS IN HERE. FIRST OF ALL, IF YOU TAKE A LOOK AT THE 50 TO 59, IT’S PRETTY FLAT. IT’S A LITTLE INCREASED. AND OUR RECOMMENDATIONS ARE GUIDELINES, IF YOU’RE POST-MENOPAUSAL, WHERE THE AVERAGE AGE IS 51 AND YOU HAVE A T SCORE 2.5 TO TREAT. I THINK A HEALTHY PERSON DOESN’T WANT TO GET TREATED. AND THOSE GUIDELINES HAVE TO BE CHANGED. WE’RE OVERTREATING THE LOW RISK PEOPLE AND AS YOU KNOW, WE’RE UNDERTREATING THE HIGH RISK PEOPLE. SO FRACTURE RISK DOUBLED BY DECADE FROM — EVEN AT THE SAME T SCORE. THE REASON FOR THIS WELL DOCUMENTED RELATIONSHIP IS DUE IN PART TO INCREASED FALL RISK. AND ALSO DETERIORATION IN BONE QUALITY WITH AGE, WHICH IS HALF OF THE BONE STRENGTH. THERE ARE NO OFFICE-BASED BONE QUALITY MEASUREMENT TOOLS AND I WOULD LOVE TO SEE ALL THE GREAT SCIENTISTS THAT HAVE WORKED IN THIS AREA GET TOGETHER AND DEVELOP SOME AFFORDABLE OFFICE-BASED QUALITY MEASUREMENT. BUT THE LACK OF THE KNOWLEDGE OF THE AGE-RISK RELATIONSHIPS LEADS TO OVERTREATMENT OF LOW RISK PEOPLE AND UNDERTREATMENT OF HIGH RISK PEOPLE. FRAX. WE WERE ON THE FRAX COMMITTEE. IT’S A GREAT PIECE OF WORK. BUT AS WE LOOK BACK ON IT, TRY TO USE IT, I THINK SOME OF THE — ONE OF THE GREATEST FAULTS OF FRAX, IF I CAN USE THAT, IS THAT IT NEVER CAPTURED FALL DATA. IT’S A HEALTH ECONOMIC MODEL. IF ONE WAS TO RE-ASSESS FRAX WITH A DRUG PRICE OF $14, YOU’D TREAT EVERYONE, AND IF YOU TRY TO DO THIS HEALTH-ECONOMIC MODEL OF WHEN IT BECOMES COST-EFFECTIVE TO TREAT, BASED ON THE PRICE OF THE DRUG AT $3,200, YOU’D TREAT NO ONE. THE INSURANCE COMPANIES, AND I PUT HERE “NON-RESPONSIBLE” BUT I BETTER USE THE WORD NON-ACCOUNTABLE. I’M IN FRONT OF PATIENTS, WE’RE UNACCOUNTABLE. HERE’S MY FACE, HERE’S MY CARD, CALL ME. IF YOU DON’T LIKE ME, HAVE YOUR LAWYER CALL ME. BUT I’M ACCOUNT WILLABLE.
ACCOUNTABLE. THEN ALL OF A SUDDEN, WE GET DENIED OUR TREATMENT BY SOMEBODY WHO’S NOT ACCOUNTABLE. AND THERE NEEDS TO BE A CHANGE IN THAT. AN EXAMPLE OF THE IMPORTANCE OF FALLS, NOW I SPEND HALF OF MY TIME WITH PATIENTS, TEACHING THEM FALL METHODS. WE HAVE LITTLE BALANCE THINGS, I GET ON THEM AND SHOW THEM HOW TO DO THINGS, BECAUSE NON-VERTEBRAL FRACTURES OCCUR AFTER FALLS. IF WE REDUCE THE RISK OF FALLS, WE REDUCE THE RISK OF NON-VERTEBRAL FRACTURES. SO HERE’S FRAX DATA WHERE A PATIENT WHO IS 85, A T SCORE MINUS 2.5, 4 VERTEBRAL FRACTURES, FOUR FALLS, THAT’S THE FRAX NUMBER, OBVIOUSLY WITHOUT FALLS. THE DUBOS MODEL, GARVAN MODEL IS A MUCH SMALLER STUDY, I UNDERSTAND, YOU CAN SEE THE IMPACT OF THE FALLS ON THE HIP FRACTURES AND ANY OSTEOPOROTIC FRACTURES. VERTEBRAL FRACTURES OCCUR WHILE WE’RE WALKING AROUND WISCONSIN AVENUE. BUT NON-VERTEBRAL FRACTURES OCCUR AFTER FALLS. SO RESEARCH HAS SHOWN THAT MOST NON-VERTEBRAL FRACTURES OCCUR AFTER FALLS AND MOST PRACTITIONERS DO NOT APPRECIATE THE FALL ISSUE. RESEARCH HAS SHOWN THAT BALANCABILITY BEGINS TO DECLINE FROM AGE 65 ON, I CAN ATTRIBUTE TO THAT, AND THAT FALLS BEGIN TO INCREASE ALSO FROM AGE OF 65 ON AND THERE’S LOTS OF DATA ON THIS. MOST PROVIDERS DO NOT TEST FOR BALANCE IN THEIR OFFICE. IT TAKES TIME. OR CLINICAL SARCOPENIA, OR GRIP STRENGTH. WHEN I WALK INTO THE ROOM, MOST PATIENTS STAND UP. I DON’T KNOW IF THAT’S RESPECT OR WHETHER OR NOT I’M JUST GETTING OLDER, BUT THEY — AND I WATCH HOW THEY STAND UP AND SEE IF THEY CAN GET OUT OF A CHAIR WITHOUT USING THEIR HANDS. SIMPLE THINGS. OBSERVATIONS. THAT BEGIN TO FOCUS ON CERTAIN AREAS. AND WE DISCUSS ALL KIND OF FALL PREVENTION STRATEGIES AND GET PEOPLE INTO P.T., YOGA, TAI CHI, PILATES, ANYTHING AT ALL THAT WILL KEEP IN THEIR MIND THE FACT THAT THEY’VE GOT TO WORK ON THIS PARTICULAR ISSUE. WE DON’T SPEND ENOUGH TIME WITH THIS. ADVISE AGAINST THE RISKY BEHAVIOR OF FALL. THIS IS A SLIDE GIVEN TO ME BY NELSON WATT. WE DO THIS ALL THE TIME AND WE SEE PATIENTS DO THIS ALL THE TIME. AND AFTER YOU HAVE FALLEN AND YOU’VE BROKEN, YOU GO, BOY, THAT WAS A STUPID THING FOR ME TO DO. BUT THAT’S HUMAN BEHAVIOR. THE OTHER THING ABOUT THE STEPS THAT I WANTED TO POINT OUT IS THAT WE ALWAYS POINT OUT TO PATIENTS, WHAT’S THE MOST DANGEROUS STEP GOING DOWN? IT’S THE LAST STEP. THEY LOOK — THEY’RE LOOKING AHEAD. IT BLENDS IN TO THE FLOOR. WE SEE MORE LOWER EXTREMITY FRACTURES ON THE LAST STEP, I’M GOING TO WRITE A LITTLE PAPER CALLED “THE LAST STEP.” SO WE HAVE A LOT OF WORK TO DO WITH PATIENTS THAT DOESN’T COST A LOT OF MONEY. AND DOESN’T EXPOSE THEM TO MEDICATIONS. WHICH I USE A LOT. BUT THE FALL RISK IS IS SOMETHING THAT NEEDS TO HAVE A MAJOR EMPHASIS IN THIS PARTICULAR AREA. KEY RECOMMENDATION, EDUCATE, TRAIN, AND RE-TRAIN ALL PROVIDERS THAT A SINGLE LOW TRAUMA FRACTURE IN EITHER GENDER, AND YOU CAN INCLUDE THE OTHER MAJOR FRACTURES THAT WERE CAPTURED IN FRAX, FROM AGE 50 ON AND OLDER IS THE SINGLE MOST IMPORTANT RISK FACTOR FOR FUTURE FRACTURE INDEPENDENT OF THE PREVAILING BMD OR T SCORE. HEIGHT MEASUREMENTS AND ACTING ON SUBSTANTIAL HEIGHT LOSS SHOULD BECOME A PERFORMANCE MEASUREMENT FOR PAYMENT. MITIGATING FEAR OF ALL OF OUR FDA-APPROVED TREATMENTS FOR OSTEOPOROSIS IS A CONSTANT PHYSICIAN-PATIENT DIALOGUE. WE SPEND SO MUCH TIME AT THIS. INCREASE DXA REIMBURSEMENT TO AT LEAST A BREAK-EVEN AMOUNT. IT WOULD BE A HUGE STEP IN THE FIELD. AND FALL PREVENTION STRATEGIES THAT ARE MAINTAINED THROUGHOUT LIFE SHOULD BE DISCUSSED ANNUALLY FROM AGE 65 ON, AND WITH THAT, I’LL END AND SAY THANK YOU VERY, VERY MUCH FOR YOUR INVITING ME HERE. [APPLAUSE] GOOD MORNING, EVERYBODY. SO I’M MARC HOCHBERG, TRAINED AS A GENERAL INTERNIST, RHEUMATOLOGIST AND EPIDEMIOLOGIST, BUT I’M MOSTLY AN ADMINISTRATOR THESE DAYS, ALTHOUGH I DO SEE PATIENTS TWO HALF DAYS A WEEK AND ONE MONTH A YEAR ON GENERAL MEDICINE. I WANT TO THANK DRS. CHEN AND JOSEPH FOR THE INVITATION TO SPEAK THIS MORNING, AND I’VE BEEN ASKED TO DISCUSS CLINICAL PRACTICE GUIDELINES. AND THESE WERE INTRODUCED YESTERDAY MORNING BY DR. GILL, WHO TALKED ABOUT THE U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS FOR SCREENING AND THE ACP RECOMMENDATIONS FOR TREATMENT. THESE ARE MY DISCLOSURES. MY CONSULTING IS SOLELY IN THE AREA OF OSTEOARTHRITIS. NOT IN THE AREA OF OSTEOPOROSIS. OSTEOARTHRITIS IS MY MAJOR RESEARCH FOCUS THESE DAYS. AND I’M ALSO HERE BECAUSE I’M PRESIDENT OF THE UNITED STATES BONE AND JOINT INITIATIVE, WHICH IS THE U.S. NATIONAL ACTION NETWORK IN THE W.H.O. SPONSORED GLOBAL MUSCULOSKELETAL DISEASE INITIATIVE WHICH GREW OUT OF THE BONE AND JOINT DECADE. SO THIS IS MY SUMMARY. SO THERE’S BROAD AGREEMENT FOR MEASURING BONE MINERAL DENSITY FOR OSTEOPOROSIS IN POSTMEN PAW SAL WOMEN. YOU’VE HEARD THIS BEFORE. IT’S A RIGHT IN THE UNITED STATES. R, I, DW., H, T, THAT ALL WOMEN AGE 65 AND ABOVE SHOULD HAVE A DXA PAID FOR BY MEDICARE. IT DOESN’T HAPPEN. AND THERE’ CLEARLY A LACK OF CONSENSUS FOR BMD TESTING IN MEN WHO HAVE BEEN DISCUSSED A LITTLE BIT THE DURING THIS CONFERENCE. RELATIVE AGREEMENT ON MANY ASPECTS OF THE MANAGEMENT OF OSTEOPOROSIS IN POST-MENOPAUSAL WOMEN. FOR THOSE AREAS WHERE THE GUIDELINES DIFFER, THE PRACTITIONER IS URGED TO FOLLOW HER BEST CLINICAL JUDGMENT AND I FOLLOW THE PRINCIPLE OF SHARED DECISION-MAKING. THIS IS NOT BEEN ELUCIDATED REALLY DURING THE COURSE OF THIS MEETING YET. ENCOMPASSES SITTING PRESENTING TO THE PATIENT HAVING A DISCUSSION WITH OFTEN PRIMARY CARE PROVIDERS DO NOT HAVE THE TIME TO DO DURING A 20 MINUTE VISIT. YOU GENERALLY HAVE TIME TO DO THIS IN AN ACADEMIC PRACTICE. SO TALK ABOUT DIAGNOSIS, YOU’VE HEARD THIS ALREADY BEFORE, I’LL GO OVER THIS VERY BRIEFLY. THIS IS REALLY THE COMPOSITE NATIONAL BONE HEALTH ALLIANCE FROM THE N.O.F. NATIONAL OSTEOPOROSIS FOUNDATION, AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH. A T SCORE OF LESS THAN MINUS 2.5, SOMEONE WHO’S EXPERIENCED A HIP FRACTURE OR HAVING LOW BONE MINERAL DENSITY WITH A HISTORY OF A VERTEBRAL FRACTURE, A HUMERAL FRACTURE, A PELVIC FRACTURE, OR A DISTAL FOREAR OR WRIST FRACTURE. AND THEN HAVING AN ELEVATED FRACTURE RISK-BASED ON FRAX. SO THIS IS WHERE YOU WOULD CONSIDER A DIAGNOSIS TO LEAD TO TREATMENT. NOW WHAT ABOUT THE MANAGEMENT IN 2018 AS WE GO TO GUIDELINES? SO THERE’S NO CURE FOR OSTEOPOROSIS. WE CAN APPROACH THIS AS A TREAT TO TARGET STRATEGY, WHICH AS A RHEUMATOLOGIST, WE’RE USED TO DOING IN PATIENT WITH RHEUMATOID ARTHRITIS, HYPERURICEMIA SECONDARY TO GOUT, JOINT PAIN SECONDARY TO OSTEOARTHRITIS. AND OUR GOALS ARE LISTED HERE. NOW THERE WAS DISCUSSION YESTERDAY ABOUT WHAT THE PRIMARY CARE PROVIDER SHOULD DO, AND SEVERAL OF THE PATIENTS SAID, WELL, THEIR PRIMARY CARE PROVIDERS DIDN’T KNOW WHAT TO DO WHEN THEY WERE FACED WITH A DIAGNOSIS OF OSTEOPOROSIS. WHAT TO DO IS REFER TO AN OSTEOPOROSIS SPECIALIST, TO EVALUATE FOR SECONDARY CAUSES OF OSTEOPOROSIS, AND CONDITIONS WHICH COMPLICATE MANAGEMENT. AND WHO ARE THESE OSTEOPOROSIS SPECIALISTS? THEY’RE LARGELY ENDOCRINOLOGISTS, ROOM RHEUMATOLOGIST, SOME GERIATRICIANS AND SOME PRIMARY CARE PROVIDERS WHO HAVE TAKEN ADVANCED EDUCATION. AND THEN FOR FRACTURE MANAGEMENT MANAGEMENT, INCORPORATE A FRACTURE LIAISON SERVICE IF AVAILABLE IN YOUR COMMUNITY HOSPITAL OR ACADEMIC HOSPITAL IN PATIENTS WHO EXPERIENCE A FRAGILITY FRACTURE. I THINK THAT DR. TOSI IS HERE IN THE AUDIENCE REPRESENTING THE AMERICAN ORTHOPEDIC ASSOCIATION, WHO MIGHT SPEAK TO THIS DURING THE QUESTION AND ANSWER PERIOD LATER ON. SO WE’VE TALKED ABOUT TREATMENT GAPS. MANY PEOPLE ARE NOT BEING TESTED TO DIAGNOSIS OSTEOPOROSIS AND THOSE WITH OSTEOPOROSIS-RELATED FRACTURES ARE NOT BEING DIAGNOSED WITH OSTEOPOROSIS BY THEIR HEALTHCARE PROVIDERS AND CONSEQUENCELY NOT RECEIVING ANY FDA-APPROVED EFFECTIVE PHARMACOLOGIC THERAPIES. YOU’VE SEEN WENT DATA FROM DR. SOME MON’S SOLOMON’S STUDIES
USING MEDICARE, WE I CAN TELL YOU IN THE BALTIMORE HIP STUDIES WHERE WE FOLLOW PATIENTS ADMITTED TO COMMUITY HOSPITALS, THEY’RE COMMUNITY DWELLING ADULTS, THEY HAVE A FRESH HIP FRACTURE, THEY GET SURGICALLY REPAIRED, THERE’S BEEN NO IMPROVEMENT IN THE 20% OF PEOPLE WHO GET STARTED ON THERAPY IN THE YEAR AFTER FRACTURES IN THE PAST 20 YEARS THAT I’VE BEEN WORKING WITH DR. JAY MAGAZINER IN THESE PROJECTS. NOW YOU’VE SEEN THESE SLIDES ALREADY AS WELL MIKE LIEWI
ICKI’S PAPER, SHOWING THE INCIDENCE OF HIP FRACTURE ON THE LEFT WHERE THERE’S A FLATTENING OUT AS OPPOSED TO THE ANTICIPATED DECLINE AND THIS HAS AN ECK LOGIC ASSOCIATION WITH THE REDUCTION IN OSTEOPOROSIS DIAGNOSIS, A REDUCTION IN CAN DXA TESTING, A REDUCTION IN THE NUMBER OF OFFICE DXA PROVIDERS, BUT A MAINTENANCE OR SLIGHT INCREASE IN THE RADIOLOGY PROVIDERS AND HOSPITALS. DR. MILLER HAS ALREADY ADDRESSED THIS. NOW DXAs ARE BEING DONE IN THE HOSPITAL, NOT IN THE OFFICE, AND RADIOLOGISTS ARE NOT REALLY TRAINED. I HATE TO SAY THIS TO MY RADIOLOGY COLLEAGUES, BUT YOU GET A REPORT THAT SAYS, “OSTEOPOROSIS, OSTEOPENIA,” THERE’S NO FRAX SCORE INCLUDED AND THERE’S LITTLE REAL GUIDANCE IN TERMS OF HOW YOU INTERPRET THE DXA. AND THERE ARE MISTAKES IN THE READINGS. SO HOW HAVE I GONE ABOUT PREPARING THIS PRESENTATION? I SEARCHED THE U.S. NATIONAL LIBRARY OF MEDICINE USING PUBMED FROM JANUARY OF 2000 TO SEPTEMBER 30TH BECAUSE I UPDATED THE PRESENTATION. I USED THE SEARCH TERMS LISTED HERE. I IDENTIFIED 79 ARTICLES OF WHICH 68 WERE ENGLISH LANGUAGE, I DON’T READ NON-ENGLISH LANGUAGE ARTICLES. I CHOSE THE MOST RECENT WHEN THERE WERE MULTIPLE PAPERS FROM THE SAME SOCIETY, SUCH AS THE A.C.P. OR THE U.S. PREVENTIVE SERVICES TASK FORCE, AND I INCLUDED ONLY THOSE FROM U.S.-BASED SOCIETIES BECAUSE WE’RE CURRENTLY IN THE UNITED STATES, THIS IS AN NIH-FUNDED CONFERENCE THAT APPLIED TO EITHER POST MEN PAW SHALL WOMEN IN GENERAL OR OLDER MEN. I DID NOT FOCUS ON INDIVIDUAL HIGH RISK DISEASE GROUPS LIKE CELIAC DISEASE, CHRONIC LIVER DISEASE, GLUCOCORTICOID-INDUCED PATIENTS. SO I ENDED UP REVIEWING THESE FIVE RECOMMENDATIONS. I CITE THE NAMES OF THE ORGANIZATIONS AND THE DATE OF PUBLICATION. ONE OF THESE IS NOW NO LONGER ROUTINELY AVAILABLE, THE DEPARTMENT OF VETERANS AFFAIRS INFORMATION LETTER ON OSTEOPOROSIS IN MEN PUBLISHED IN 2017, WHICH UNDERWENT A SUNSETTING BUT I’LL SHOW YOU THE ALGORITHM FROM THAT, AND DR. ADLER WAS THE CHAIR OF THE COMMITTEE THAT PUT TO TOGETHER. I’M GOING TO START WITH THE N.O.N. RECOMMENDATIONS. N.O.F. RECOMMENDATIONS IE. TOLD THEY’RE CURRENTLY UNDER REVISION AND WE SHOULD SEE AN UPDATE IN 2019. THESE ARE THE LIFESTYLE RECOMMENDATIONS. WE HEARD YESTERDAY FROM THE WOMEN THAT THEY FOLLOWED THESE LIFESTYLE RECOMMENDATIONS BUT IT DIDN’T PREVENT THEIR GETTING A FRACTURE. SO MAYBE THEY’RE HELPFUL IN TERMS OF MAINTAINING BONE STRENGTH AND BONE QUALITY, DURING ADULTHOOD AND DURING THE EARLY POST-MENOPAUSAL PERIOD. WE ADVISE ON DIET, WE ADVISE ON VITAMIN D INTAKE. THERE’S CONTROVERSY ABOUT WHETHER WE SHOULD MEASURE 25 HYDROXY-D LEVELS IN PATIENTS AT RISK FOR DEFICIENCY. OR IN THE THE OVERALL GERIATRIC POPULATION. WE RECOMMEND WEIGHT BEARING AND MUSCLE STRENGTHENING EXERCISE, AND I DO REFER PATIENTS FOR TAI CHI AND YOGA AND BALANCE TRAINING AND I DO SINGLE CHAIR STANDS ROUTINELY IN MY CLINICAL PRACTICE. I ASSESS RISK FACTORS FOR FALLS AND WE OBVIOUSLY ADVISE ON CESSATION OF SMOKING AND AVOIDANCE OF EXCESS ALCOHOL INTAKE. WE RECOMMEND DIAGNOSTIC ASSESSMENT. SO WE’VE TALKED ABOUT MEASURING BMD USING DXA IN ALL WOMEN AGED 65 AND ABOVE. BUT WE REALLY HAVEN’T TALKED ABOUT MEN VERY MUCH. AND THE RECOMMENDATIONS THAT WE’LL TALK ABOUT THAT THE N.O.F. SUGGESTS ARE MEN AGED 70 AND ABOVE SHOULD HAVE A ROUTINE DXA MEASUREMENT. AND THEN THERE ARE THE YOUNGER POST-MENOPAUSAL WOMEN AND THE MEN OVER AGE 50 WHO HAVE HAD AN OSTEOPOROTIC-RELATED FRACTURE AT AN ADULT AGE, AND DR. MILLER DISCUSSED THIS. I HAD A RADIAL FRACTURE AT THE AGE OF 55 AND I UNDERWENT A DXA TEST ORDERED BY ONE OF MY COLLEAGUES. AND THEN, WE SHOULD PERFORM VERTEBRAL FRACTURE ASSESSMENT. AND YOU’VE HEARD ABOUT THIS FROM DR. EE TELL EASTELL AND DR.
MILLER IN PEOPLE IN LOW BONE DENSITY, OR IN YOUNGER PEOPLE WITH LOWER BONE DENSITY EVEN IF THEY DON’T HAVE OSTEOPOROSIS BECAUSE INFLUENCES FREETMENT DECISIONS. WE DON’T DO TESTS UNLESS THEY INFLUENCE TREATMENT DECISIONS. I LEARNED THAT AS A FELLOW 40 YEARS AGO. SO WHAT ABOUT THE U.S. PREVENTIVE SERVICES TASK FORCE? THE OLD RECOMMENDATIONS FROM 2011 ARE ON THE LEFT, THE NEW RECOMMENDATIONS FROM 2018 ARE ON THE RIGHT. THE BIG CHANGE IS THE YOUNGER POST-MENOPAUSAL WOMEN WHO WERE AT INCREASED RISK FOR FRACTURE AS DETERMINED BY A FORMAL CLINICAL RISK ASSESSMENT TOOL. DR. GILL REVIEWED FOR YOU YESTERDAY FIVE SUCH TOOLS THAT ARE AVAILABLE. HE RECOMMENDED THE O.S.T. BECAUSE IT’S THE SIMPLEST, WEIGHT IN KILOGRAMS MINUS AGE .2 AND YOU CAN ALSO CALCULATION THE FRAX MEASURE USING WEIGHT INSTEAD OF BONE MINERAL DENSITY. THE U.S. PREVENTIVE SERVICES INSUFFICIENT EVIDENCE TO SUPPORT SCREENING FOR OSTEOPOROSIS IN MEN. INSUFFICIENT EVIDENCE FOR THE TASK FORCE GIVES A CAPITAL I. INSUFFICIENT EVIDENCE IN CLINICAL PRACTICE DOESN’T MEAN YOU SHOULDN’T DO IT. IT MEANS YOU SHOULD RELY ON CONSENSUS RECOMMENDATIONS OF EXPERTS. SO WHAT ABOUT PHARMACOLOGIC TREATMENT? RECOMMENDATIONS FOR INITIATING PHARMACOLOGIC TREATMENT ARE SHOWN HERE FROM THE N.O.F. YOU’VE HEARD ABOUT THESE BEFORE AND I’M NOT GOING TO REPEAT THEM THEM. SO WHERE DO THE OTHER RECOMMENDATIONS DIFFER? SO THE AACE CLINICAL PRACTICE GUIDELINES FOR POST-MENOPAUSAL OSTEOPOROSIS ARE SIMILAR TO THE N.O.F. RECOMMENDATIONS. EXCEPT FOR THESE FOUR BULLET POINTS. USING THE NBHA DEFINITION FOR THE DIAGNOSIS OF OSTEOPOROSIS, RECOMMENDING SPECIFIC ANTIRESORPTIVE AGENTS AS INITIAL THERAPY FOR TREATMENT, RECOMMENDING MORE POTENT AGENTS INCLUDING TARAPARATIDE FOR PATIENTS UNABLE TO USE ORAL THERAPY OR ARE AT ESPECIALLY HIGH RISK FOLLOWING UP ON WHAT WAS SPOKE KEN ABOUT YESTERDAY AND RECOMMENDING AGAINST VERTEBROPLASTY AND KYPHOPLASTY FOR FIRST FINE LION TREATMENT OF VERTEBRAL FRACTURES. WHAT ABOUT THE A.C.P. RECOMMENDATIONS PUBLISHED LAST YEAR? THERE WERE STRONG RECOMMENDATIONS FOR OFFERING PHARMACOLOGIC THERAPY WITH ANTIRESORPTIVE THERAPY AND AGAINST USING MENOPAUSAL ESTROGEN THERAPY OR RALOXIFENE. DR. JACKSON SPOKE TO THIS YESTERDAY. AND THERE ARE WEAK RECOMMENDATIONS USING THE GRADE SYSTEM FOR TREATING OSTEOPOROTIC WOMEN FOR FIVE YEARS. THIS CAN BE A TOPIC OF DISCUSSION. THERE’S A WEAK RECOMMENDATION AGAINST MONITORING BONE DENSITY DURING THE FIVE-YEAR TREATMENT PERIOD. WILL THERE’S A WEAK RECOMMENDATION FOR OFFERING PHARMACOLOGIC THERAPY WITH BISPHOSPHONATES. I WOULD SAY THIS SHOULD BE A STRONG RECOMMENDATION. AND A WEAK RECOMMENDATION FOR USING PRINCIPLES OF SHARED DECISION-MAKING. I THINK THIS SHOULD BE A STRONG RECOMMENDATION PERSONALLY. NOW, THERE ARE SEVERAL AREAS THAT WERE IDENTIFIED AS INCONCLUSIVE. COMPARATIVE EFFECTIVENESS TRIALS ARE LACKING, THIS WAS DISCUSSED YESTERDAY. AND THE OPTIMAL TREATMENT DURATION OF UNKNOWN. AND WE’VE TALKED ABOUT THIS HERE AT THE CONFERENCE WITH REGARD TO, QUOTE, HOLIDAYS, UNQUOTE, WITH BISPHOSPHONATE THERAPY AND BALANCING THE BENEFITS OF FUTURE FRCT FRACTURE RISK REDUCTION VERSUS THE HARMS, AND YOU’VE HEARD ABOUT ALL THIS. NOW, CONCERNS HAVE BEEN RAISED AMONG OSTEOPOROSIS SPECIALISTS ABOUT THE ACP GUIDELINES AND THESE ARE SUMMARIZED IN A PAPER BY LUGARI AND COLLEAGUES IN CLINICAL THERAPEUTICS EARLIER THIS YEAR. THEY DID NOT RECOMMEND ANABOLIC THERAPY AS FRONT LINE AGENTS IN PATIENTS WITH SEVERE OSTEOPOROSIS. DR. KOSPEN SPOKE TO THIS YESTERDAY. THE TREATMENT DURATION IS ARBITRARY AT FIVE YEARS AND IT SHOULD NOT APPLY TO DENOSUMAB. THERE’S NO INDICATION FOR A DRUG HOLIDAY AFTER DENOSUMAB. MONITORING OF BMD MAY AFFECT ADHERENCE TO THERAPY AS DISCUSSED BY DR. SILVERMAN YESTERDAY. AND A DECLINE IN BMD GREATER THAN THE LEAST SIGNIFICANT DIFFERENCE MAY INDICATE A LACK OF RESPONSIVENESS OR EFFICACY. AND RALOXIFENE MAY BE AN APPROPRIATE TREATMENT IN YOUNGER POST-MENOPAUSAL WOMEN AT HIGH RISK FOR VERTEBRAL FRACTURES ESPECIALLY IF THEY’RE AT HIGH RISK FOR BREAST CANCER. THIS IS ONE OF THE DRUGS WHICH HAS SHOWN TO BE EFFECTIVE AT CHEMO PREVENTION FOR BREAST CANCER. NOW WHAT ABOUT OSTEOPOROSIS IN MEN? FINISH UP WITH THE V.A. INFORMATION LETTER. THERE’S A GENDER DISPARITY THAT’S RECOGNIZED IN MORTALITY AND DISABILITY RATES IN HIP FRACTURE. MEN HAVE A GREATER MORTALITY FOLLOWING HIP FRACTURE THAN WOMEN DO WITHIN THE FIRST YEAR AND ARE MORE LIKELY TO HAVE DISABILITY. SO THE V.A. INFORMATION LETTER PROVIDED AN ALGORITHM FOR CASE FINDING IN MEN AGED 50 AND ABOVE, HOW TO PURSUE A CLINICAL EVALUATION OF MEN WITH LOW BMD AND LIFESTYLE COUNSELING AND PHARMACOLOGICAL TREATMENT. THIS IS PROBABLY NOT IN YOUR EVIDENCE REPORT BUT IT’S IN THE SLIDE AND YOU CAN SEE IT HERE. I WON’T GO INTO IT IN DETAIL BECAUSE I’M ALREADY RUNNING OVER. THE ENDOCRINE SOCIETY HAS ALSO SPOKEN ABOUT RECOMMENDATIONS FOR OSTEOPOROSIS IN MEN. SUPPORTS THE N.O.F. IN MEASURING B.M.D. IN MEN AGED 70 AND ABOVE AND THOSE AGED 50 AND ABOVE WITH RISK FACTORS, THEIR UNIVERSAL RECOMMENDATIONS ARE SIMILAR TO N.O.F. AND THEY RECOMMEND PHARMACOLOGICAL TREATMENT FOR MEN AGED 50 AND ABOVE WITH THE SUBSEQUENT INDICATIONS. SO THE KEY RECOMMENDATIONS AT THE CLOSE ARE TO INCREASE AWARENESS THAT LOW TRAUMA FRACTURES IN OLDER ADULTS ARE DUE TO OSTEOPOROSIS. AND FALL PREVENTION STRATEGYIES AS ALREADY MENTIONED ARE PART OF THE MULTIDISCIPLINARY INTERVENTION FOR SECONDARY FRACTURE PREVENTION. I WOULD SUGGEST THAT EVERYBODY GO TO THE ASBMR-SPONSORED WEBSITE, WHICH I DIDN’T LIST THE U.R.L. HERE BUT I’M SURE THAT DR. KIEL AND DR. KOSA WILL PROVIDE IT, I THINK IT’S WWW.SECONDARYFRACTURES.ORG. , TO LOOK AT THE RECOMMENDATIONS FOR SECONDARY FRACTURE PREVENTION. ALL THE GROUPS NOW SHOULD COME TOGETHER SIMILAR TO WHAT THE USB JI SPONSORED WITH THE CHRONIC OSTEOARTHRITIS MANAGEMENT INITIATIVE TO HAVE A CHRONIC OSTEOPOROSIS MANAGEMENT INITIATIVE, AND DEVELOP CONSENSUS RECOMMENDATIONS FOR B.M.D. TESTING AND MANAGEMENT, INCLUDING THE RELEVANT PATIENT AND PROFESSIONAL SOCIETIES SO THAT WE CAN EDUCATE PATIENTS AND PROVIDERS THAT THE BENEFITS OF TREATMENT VASTLY OUTWEIGH THE POTENTIAL HARMS OF ADVERSE EVENTS. I WANT TO THANK YOU VERY MUCH FOR YOUR TIME AND ATTENTION AND I WANT TO APOLOGIZ TO DR. JOSEPH THAT I DIDN’T INCLUDE THE NATIONAL INSTITUTE ON AGING LOGO ON THE BOTTOM OF THIS SLIDE. THANK YOU. [APPLAUSE] GOOD MORNING. I’M KEN SAAG, A RHEUMATOLOGIST AND OUTCOMES RESEARCHER AT UNIVERSITY OF ALABAMA AT BIRMINGHAM AND I ALSO WANT TO THANK THE ORGANIZERS FOR THE IP VI TAITION THE INVITATION TO BE AT THIS GREAT MEETING. I’LL TALK PREDOMINANTLY ABOUT PATIENT AND PROVIDER APPROACHES AND THEN DAN SOLOMON AND I HAVE COORDINATED OUR TALKS A BIT, HE’S GOING TO TALK ABOUT SOME OF THE FINANCIAL IMPLICATIONS, SYSTEMS APPROACH. HERE ARE MY RELEVANT DISCLOSURES WHICH INCLUDE SOURCES OF FUNDING INCLUDING SOME OF THE GRANTS THAT HAVE SUPPORTED SOME OF THE WORK I’LL DESCRIBE AND MY RELATIONSHIPS IN THE PAST AND STILL WITH N.O.F. AND THE A.C.R. AS WELL AS WITH PRIVATE SECTOR ENTITIES. SO HERE IS A SUMMARY THAT PERTAINS BOTH TO THE COMMENTS I’M GOING TO MAKE AND ALSO TO SOME OF THE THINGS THAT I THINK DAN WILL COVER. FIRST THAT WE HAVE AN INCREASING ARM TEARIAN OF IMPLEMENTATION. SOME HAVE BEEN SHOWN TO BE SLIGHTLY SUCCESSFUL, MANY HAVE BEEN SHOWN TO BE MODESTLY SUCCESSFUL IN SELECTED GROUPS, AND A GREAT MANY OF THE THINGS THAT WE’VE LOOKED AT HAVE ACTUALLY NOT WORKED AT ALL. SYSTEM APPROACHES, PRACTICE REDESIGN, HAS LARGELY BEEN SUPERIOR TO APPROACHES THAT TARGET PATIENTS OR PROVIDERS. AND I THINK AS RELEVANT PARTLY THE REASON WE’RE ALL HERE AT THIS MEETING IS NA THAT IMPLEMENTING EVIDENCE AT THE COMMUNITY LEVEL IS NOT EASY. WE’VE SEEN THE GREAT EVIDENCE THAT WE HAVE IN OSTEOPOROSIS BUT HOW DO WE TRANSLATE THAT RESEARCH EFFECTIVELY INTO PRACTICE? TECHNOLOGY OFFERS US PROMISES, CONTEXT AND ENGAGEMENT ARE KEY, THE IDEA OF A TEACHABLE MOMENT, THIS MAY COME RIGHT AFTER A FRACTURE, CAN BE VERY IMPACTFUL IN LEADING TO A CHANGE. WE’VE THOUGHT THAT MULTIMODAL APPROACHES ARE BETTER AND IN SOME CASES THIS IS TRUE, BUT IN GENERAL, ONE SIZE FITS NONE. AND FOR THOSE OF US IN THIS AREA, WE FEEL VERY STRONGLY THAT WE OUGHT TO BE TESTING THESE APPROACHES IN A CONTROL OHED
CONTROLLED SETTING TO REALLY FIGURE OUT& WHAT WORKS AND WHAT DOESN’T WORK. SO WHAT’S IMPLEMENTATION RESEARCH? IT’S AT THE INTERSECTION BETWEEN RESEARCH AND QUALITY IMPROVEMENT. IT USES METHODS FROM HEALTH SERVICES RESEARCH AND QUALITATIVE METHODS, IT’S TRANSLATIONAL SCIENCE THAT GOES BEYOND THE BEDSIDE. IF WE LOOK AT THE SPECTRUM FROM THE INSTITUTE OF MEDICINE OF CLINICAL RESEARCH, WE CAN SEE EARLY PHASE TRANSLATIONAL RESEACH AND WE CAN SEE T3 AND T4 RESEARCH AND THAT’S WHERE THIS AREA OF SCIENCE REALLY FITS IN. SO IT’S THE STUDY OF METHODS TO PROMOTE RAPID UPTAKE OF RESEARCH FINDINGS AND TO REDUCE INAPPROPRIATE CARE AND IMPROVE THE HEALTH OF INDIVIDUALS AND POPULATIONS. AND IT DIFFERS FROM TRADITIONAL QUALITY IMPROVEMENT BECAUSE WE’RE TRYING TO GENERATE KNOWLEDGE, WE’RE TRYING TO FIGURE OUT WHAT WORKS AND WHAT DOESN’T WORK. QUALITY IMPROVEMENT WORKS, THERE’S NO DOUBT ABOUT THAT, IT WORKS LOCALLY, BUT OFTEN WE DON’T REALLY KNOW WHAT IT IS WE DID AND WHAT ACTUALLY WORKED IN A PDSA TYPE OF APPROACH. SO WHAT ARE SOME OF THE THINGS THAT HAVE BEEN USED IS HISTORICALLY AND WHAT’S WORK AND AND NOT WORKED IN GENERAL? WE CAN HAND OUT GUIDELINES AND OTHER PRINTED MATERIALS AND THAT DOESN’T WORK. YOU CAN GO TO A TRADITIONAL C.M.E. LECTURE OR GIVE ONE, AND PEOPLE CAN GET SMARTED BUT THEY DON’T CHANGE THE WAY THEY PRACTICE. WE CAN DO INTENSIVE CONFERENCING AROUND THINGS LIKE SMOKING CESSATION, VERY EFFECTIVE BY BU UTILIZES A LOT OF RESOURCES. YOU CAN USE COMPUTERIZED TOOLS, THIS HAS GREAT PROMISE BUT MANY CLINICIANS HAVE LEARNED HOW TO TURN OFF ALL THESE POP-UPS IN THE E.H.R., AND THE IDEA OF ACADEMIC DETAILING HAS BEEN SHOWN TO WORK HE HAVE WELL BUT COSTS A VERY WELL BUT COSTS A LOT OF MONEY. I’LL TALK ABOUT FEEDBACK AND MULTIFACETED APPROACHES. IT’S REALLY IMPORTANT AS WE LOOK AT THE LITERATURE TO KEEP IN MIND THE TREMENDOUS HETEROGENEITY IN THE STUDIES THAT WE’RE GOING TO REVIEW. THERE’S A LOT OF VARIABILITY IN THE QUALITY OF THE STUDY, SOME ARE TRUE R.C.T.s OFTEN ACCOUNTING FOR CLUSTERING, OTHERS ARE OPEN LABEL, UNCONTROLLED. THERE’S OTHER TARGETS, PRIMARY VERSUS SECONDARY PREVENTION IN THE TIMING OF THE FRACTURE EVENT ENDS UP BEING QUITE IMPORTANT IN INFLUENCING SOME OF THE RESULTS. AND ARE WE TALKING ABOUT TRYING TO GET PEOPLE ON THERAPY AND TO TEST INITIALLY, OR AS WE HEARD YESTERDAY FROM DEBBIE GOLD WHEN WE START TO THINK OF ADHERENCE, THIS IS MORE COMPLICATED AS WELL. THEN THERE’S DIFFERENT TYPES OF OSTEOPOROSIS. I’VE HAD AN INTEREST IN STAIRT INDUCED BONE DISEASE, THE FACTORS MAY BE DIFFERENT THAN SAY IN POST-MENOPAUSAL BONE DISEASE. VERY IMPORTANTLY, WHAT WORKS IN EUROPE, WHAT WORKS IN A MANAGED CARE SYSTEM, A GROUP MODEL H.M.O. IN THE U.S. MAY NOT WORK IN OUR DISORGANIZED FEE FOR SERVICE ENVIRONMENT. SO HERE’S AN EXAMPLE OF ONE OF THE PROBLEMS. THIS INVASIVE CARE GAB BETWEEN WHAT GAP BETWEEN WHAT DOCTORS KNOW AND WHAT THEY DO. IT’S LIKE ASKING PATIENTS, ASKING DOCTORS HOW THEY TAKE CARE OF PATIENTS AND WHAT THEY DO IS SIMILAR TO ASKING PATIENTS ABOUT HOW MUCH THEY SMOKE. AS WE HEARD YESTERDAY, I THINK DR. GILL GAVE A GREAT TALK AND REALLY HIGHLIGHTED THAT AT THE PATIENT AND SYSTEM LEVEL, THERE MAY BE PROBLEMS WITH INFORMATION. AT THE PHYSICIAN LEVEL, IT’S REALLY MORE ABOUT LACK OF TIME, INERTIA, POORLY ALIGNED INCENTIVES. THESE ARE REALLY THE MAJOR BARRIERS, NOT SO MUCH LACK OF KNOWLEDGE. SO HERE’S AN EXAMPLE FROM DIABETES OF AUDIT FEEDBACK. THIS WAS DONE BY MY COLLEAGUES USING SOMETHING KNOWN AS THE ACHIEVABLE BENCHMARK OF CARE. IT’S A STANDARD ESTABLISHED BASED ON THE TOP 10% OF PHYSICIANS WITH THE BAYESIAN ADJUSTMENT. YOU CAN SEE PROVIDING THIS FEEDBACK ALONG WITH THE STATEWIDE PROJECT AVERAGE SHOWS HOW THAT PERSON IS DOING. PHYSICIANS AND HEALTHCARE PROVIDERS TEND TO BE VERY COMPETITIVE SO YOU SEE THIS REPORT AND IT MAY INFLUENCE HOW YOU PRACTICE, AND INDEED, THE ABCs LED TO A SIGNIFICANTLY GREATER RATE OF UP TAKE OF THESE QUALITY MEASURES THAN THE TRADITIONAL FEEDBACK, AND CMS ADOPTED THIS STANDARD APPROACH. WE THOUGHT WE WOULD APPLY THIS TO A POPULATION OF PATIENTS WITHIN A MANAGED CARE ORGANIZATION WHO WERE USING GLUCOCORTICOIDS. DID THE
SAME AFTER THE INTERVENTION, THE INTERVENTION USED ADULT LEARNING THEORY, IT WAS TAILORED, IT HAD THIS ACHIEVABLE BENCHMARK OF CARE, YOU COULD GET ONLINE CONTINUING MEDICAL EDUCATION CREDIT AND WE ROLLED IT OUT OVER A SIX-MONTH PERIOD. IN THE INTEBT TO TREAT ANALYSIS, WE DID NOT SEE A BENEFIT OF THIS STRATEGY, EITHER IN TERMS OF TESTING OR TREATMENT. WHEN WE LOOKED AT A SUBSET OF DOCTORS WHO DID WHAT WE ASKED, WHO WENT ONLINE, DOWNLOADED THEIR FEEDBACK, DID THE CASES, WE START TO SEE SOME TRENDS PERHAPS TOWARDS SOME BENEFIT AND IT REALLY SPEAKS TO THIS ISSUE OF ENGAGEMENT. OTHER STUDIES IN STRI-INDUCED OSTEOPOROSIS HAVE REACHED A SIMILAR CONCLUSION. IT’S A VERY DIFFICULT NON-TEACHABLE MOMENT, IF YOU WILL. YOU CAN SEE THE RCTs AND SOME NON-RANDOMIZED TRIALS ALSO WITH NEGATIVE RESULTS. THERE WAS ONE STUDY THAT ACTUALLY LOOKED A LITTLE BIT MORE PROMISING, AND THAT WAS KIND OF AN UNUSUAL SLIGHTLY ODD INTERVENTION IN TASMANIA. THE STUDY WAS NON-RANDOMIZED, PRE/POST, THE INTERVENTION WAS IN NORTHERN TASMANIA, THE CONTROL IN SOUTHERN TASMANIA, THEY MEASURED THE OUTCOME AMONG HOSPITALIZED PATIENTS WHO ARE NOT EXACTLY WHERE WE WOULD EXPECT TO SEE OSTEOPOROSIS CARE BEING DELIVERED BUT YOU SEE SOME SMALL IMPROVEMENT, A SLIGHTLY UNUSUAL APPROACH, IT’S REALLY IMPORTANT AGAIN TO LOOK UNDER THE HOOD AND SEE WHAT THESE STUDIES ARE DOING. IN CONTRAST, THIS IS, I THINK, A REALLY ELEGANTLY DONE, SOMEWHAT SIMPLE APPROACH TO THE PROBLEM, AND I WANT TO HONOR THE LATE SUMIT MUJUNDAR WHO REALLY DID SOME THOUGHTFUL WORK IN THIS FIELD. HE SHOWED IF YOU JUST TAKE X-RAYS DONE IN THE E.D. AND MESSAGE THE PHYSICIANS IN REALTIME, IN THE PINK BARS, YOU CAN SEE THIS RESULTED IN SIGNIFICANT INCREASES IN TREATMENT TESTING OR EITHER COMPARED WITH USUAL CARE. THE ADDITION OF A PATIENT EDUCATIONAL APPROACH WAS MODESTLY ADDITIONALLY BENEFICIAL, BUT IT SUGGESTS THAT SOME STRATEGIES, PARTICULARLY WHEN THERE’S A TEACHABLE MOMENT, MAY BE EFFECTIVE. SO IT’S REALLY CAUSED US TO RECONSIDER THE TARGETS OF THESE APPROACHES AND TO THINK ABOUT MOVING AWAY FROM THE PHYSICIAN AND PROVIDER. THEY’RE JUST TOO BUSY. HOW DO WE BETTER ENGAGE THE HEALTHCARE SYSTEM AND CAN WE GO AND ACTIVATE PATIENTS TO GET THEM MORE ENGAGED IN IMPROVING THEIR CARE. SO HERE’S A PATIENT ACTIVATION INTERVENTION FUNDED BY N.I.A., DONE BY PETER KRA AMM AS THE
P.I. IN IOWA, KAISER OF GEORGIA COLLABORATING. TWO ARMS, USUAL CARE OR A TAILORED LETTER CONTAINING DXA TEST INFORMATION AND AN EDUCATIONAL BROCHURE AIMED AND TRYING TO BETTER EDUCATE PATIENTS ABOUT THEIR RESULTS AND DO THIS IN A STANDARDIZED WAY TO PROMOTE A MORE MEANINGFUL ENGAGEMENT WITH THE PHYSICIAN. YOU CAN SEE THE STUDY REQUIRED A FAIRLY LARGE SAMPLE SIZE WHICH WE ACHIEVEED, AND YOU CAN SEE A LOT OF THE WOMEN, MOSTLY CAUCASIAN, COMPLETED THE STUDY, AND IN THE PRIMARY ANALYSIS, THERE WAS NOT A DIFFERENCE IN IN TERMS OF THE INTERVENTION VERSUS THE CONTROL FOR GUIDELINE CONCORDANT THERAPY. NOW WE DID SEE SOME MOVEMENT ALONG THE CONTINUUM. WE SAW THAT PATIENTS WERE MORE LIKELY TO KNOW THEIR DXA RESULTS AND THEY WERE SIGNIFICANTLY MORE LIKELY TO SPEAK WITH THEIR PHYSICIANS AND THESE ARE NECESSARY PRELIMINARY STEPS TO IMPROVING QUALITY WITH TARGET AT THE PATIENT LESM. ANOTHER APPROACH IS TO THINK OF NARRATIVE STORYTELLING, TESTIMONIAL, YOU TURN ON THE TV, YOU SEE AN AD, BEING ABLE TO RELATE TO THE PEOPLE TELLING THE STORIES, HOMOPHILY. THE POWER OF THE NARRATIVE TO CHANGE BELIEF HAS NEVER BEEN DOUBTED AND ALWAYS BEEN FEARED. SO BRAINWASHING, IF YOU WILL, BUT HOPEFULLY FOR A POSITIVELY OUT COME. HERE WAS A STUDY IN “HYPERTENSION” DONE AT U.A.B., A VERY NICE SIMPLE STUDY AS WELL USING A VERY GRAINY HOME MOVIE STYLE DVD, SITTING PATIENTS DOWN AT THE WAITING ROOM AT THE SAFETY NET HOSPITAL, SHOWING THEM PICTURES OF OLDER MEN SIMILAR TO THEM, SIMILAR RACE, ETHNICITY, TALKING ABOUT WHAT HAPPENS WHEN YOU DON’T TAKE YOUR BLOOD PRESSURE MEDICINE. AND YOU CAN SEE THE IMPACT THIS HAD IN IMPROVING BLOOD PRESSURE CONTROL, BETTER THAN WHAT WE MIGHT SEE IN SOME CLINICAL TRIALS, AND PARTICULARLY GOOD AMONG THE MEN THAT HAD PARTICULARLY BAD BLOOD PRESSURE INITIALLY. SO WE DID THIS WITHIN THE GLO COHORT. WE CONDUCTED AN R.C.T. LOOKING AT USUAL CARE, WE DELIVERED OUR MATERIALS EITHER ONLINE OR FOR PEOPLE THAT DIDN’T HAVE MAIL ACCESS, THE SAMPLE SIZE ACCOUNTED FOR THE CLUSTERING, THE DESIGN EFFECT SHOULD BE USED TO ADDRESS THIS ANALYTICALLY, AND YOU CAN SEE HOW DIFFICULT IT IS TO GET TO THE PATIENTS. HAVING EMAIL, HAVING CELL PHONE ACCESS RESULTED IN STILL A RELATIVELY MODEST 45% ENGAGEMENT WITH THE WEBSITE. YOU CAN LOOK AT ALL THE DIFFERENT THINGS WE HAD TO DO TO TRY TO ACHIEVE THIS. AND THIS SCRUS SHOWS YOU THE LEVEL OF TAILORING THAT WE USE BASED EITHER ON KNOWN BARRIERS TO THERAPY OR ON THE LEVELS OF READINESS FOR CHANGE, AND WE GAVE LITTLE VIDEO SNPPETS THAT WERE RACE, AGE AND SEX-APPROPRIATE IN AN ERT TO TRY TO TAILOR THIS TO EITHER BARRIERS OR CONCERNS THAT THESE INDIVIDUALS MIGHT HAVE. I WANTED TO JUST SHOW YOU ONE OF THESE SNPPETS, AND THE WAY WE DEVELOP THE STORIES IS WE DID QUALITATIVE WORK WITH PATIENTS AND THEN WE DID SOME EDITING AND TOOK THOSE STORIES AND HAD THEM PORTRAYED BY ACTRESSES OR ACTORS WHO WERE OF THE SAME RACE, ETHNICITY AND AGE RANGE OF THE PATIENTS WHO WE WERE TARGETING.>>WHEN I LOOK AT THE ODDS AS FAR AS HOW OFTEN ONJ MAY HAPPEN COMPARED TO MY FAMILY HISTORY OF OSTEOPOROSIS, DOWN TO EVEN MY FATHER AND MY GRANDFATHER HAVING OSTEOPOROSIS, I WOULD SAY THAT I WOULD HAVE A BETTER CHANCE OF A BETTER OUTCOME TAKING THE MEDICINE VERSUS DOING NOTHING.>>WELL, AGAIN, IT’S DIFFICULT TO IMPROVE QUALITY. NO DIFFERENCES IN TREATMENT RATES BETWEEN THE INTERVENTION AND CONTROL ARMS. THERE WERE MORE INDIVIDUALS IN THE INTERVENTION ARM THAT SHIFTED FROM A PRECONTEMPLATIVE TO A CONTEMPLATIVE STATE. THIS IS AN INTERESTING FINDING. BE CAREFUL WHAT YOU WISH FOR BECAUSE WHEN WE GAVE INFORMATION TO THESE PATIENTS ABOUT THEIR BARRIERS, THEY ACTUALLY BECAME MORE CONCERNED ABOUT SOME OF THESE THINGS, SO IT REALLY DEPENDS WHO’S DELIVERING SOME OF THE MESSAGES. SOME OF THE SUBGROUP ANALYSES LOOKED PROMISING, AND YOU CAN SEE A LOT OF STUDIES HAVE BEEN DONE. THIS IS JUST A SAMPLE OF SOME OF THE ONES THAT HAVE BEEN DONE. DAN DID ONE OF THE LARGEST LOOKING AT A MOTIVATIONAL INTERVIEWING APPROACH, YOU CAN SEE THAT IT WAS BORDERING ON STATISTICAL SIGNIFICANCE BUT MPRs, MEDICATION RATIOS WERE RELATIVELY LOW. THE ONE STUDY IN THIS LIST THAT LOOKS SUCCESSFUL WAS AFTER PEOPLE ALREADY HAD A PRESCRIPTION AND THEY WERE GIVEN AN OPPORTUNITY TO GET SOME INTERACTIVE VOICE RESPONSE CALLS IN AN EFFORT TO GET THEM TO ACTUALLY START THEIR MEDICINE. THAT ACTUALLY WORKED. SO THERE’S MANY STEPS IN THIS IDEA OF ACTIVATING PATIENTS. WE HAVE TO MAKE SURE THE PATIENT IS AWARE, WE’VE GOT TO GET THE PATIENT AND PHYSICIAN TO DISCUSS THIS, THE PHYSICIAN NEEDS TO TAKE ACTION IN EITHER ORDERING A TEST OR PRESCRIBING A THERAPY, THE PATIENT NEEDS TO FILL THEIR PRESCRIPTION AND TAKE THE MEDICINE, LEADING TO THIS CHANGE IN PROCESS OF CARE, WHICH BASED ON THE R.C.T.s THAT WE’VE BEEN HEARING ABOUT OUGHT TO LEAD TO A BENEFIT AND AN OUT COME, NAMELY, REDUCTION IN FRACTURES. SO IT’S A MULTISTAGE COMPLEX PATHWAY, INVOLVES PATIENTS AND CLINICIANS AND SUCCESS AS WE SAW IN THE LAST EXAMPLE MAY DEPEND ON WHERE YOU ARE IN THIS PATHWAY, BEING FARTHER ALONG MEA MAY MAKE IT EASIER TO GET TO A BENEFICIAL PLACE. SO LET ME SPEND JUST A MINUTE AND THEN TURN THIS OVER TO DAN ON SYSTEM INTERVENTIONS AND SHOW YOU ONE EXAMPLE OF A SYSTEMS APPROACH, KAISER IN GEORGIA, KAISER NORTHWEST, THIS WAS A MULTIMODAL INTERVENTION THAT INVOLVED A VERY SIMPLE LOW TECH SYSTEM REDESIGN APPROACH OF ALLOWING WOMEN TO SCHEDULE THEIR OWN DXA. YOU CAN GET YOUR OWN FLU SHOT, YOUR OWN MAMMOGRAM, WHY NOT GIVE THEM A 1-800 NUMBER AND LET THEM SCHEDULE THEIR OWN DXA. WE ALSO DID SOME PATIENT EDUCATION AND WITH PROVIDER INTERVENTIONS THEY ACTUALLY SERVED AS A CONTROL GROUP TO BRING THE PHYSICIANS ON BOARD AND AGREE TO PARTICIPATE AND LET THEIR PATIENTS PARTICIPATE WITHIN THE KAISER. AND WHAT WE SAW IS THAT THE SYSTEM APPROACH, THE PRACTICE REDESIGN OF ALLOWING PEOPLE TO SCHEDULE THEIR OWN DXAs WITHIN BOTH KAISERS RESULTED IN A SIGNIFICANT INCREASE IN APPROPRIATE DXA UTILIZATION. WE DIDN’T SEE AN ADDED VALUE OF THE PATIENT INTERVENTION AND YOU CAN SEE HOW USUAL CARE REMAINED RELATIVELY LOW. SO THERE’S BEEN A HOST OF APPROACHES AT A SYSTEMS LEVEL. DAN IS GOING TO TALK MORE EXTENSIVELY ABOUT THIS. HERE’S A COUPLE EXAMPLES PHARMACY DELIVERED INTERVENTIONS AND DIFFERENT FORMS OF FRACTURE LIAISON SERVICES. THE ONE STUDY HERE THAT DOESN’T LOOK LIKE IT WORKED ALL THAT WELL HAD A CEILING EFFECT. THE MEDICATION POSSESSION RATIO IS ALREADY UP AROUND 80% SO YOU WOULDN’T EXPECT NECESSARILY TO DO A WHOLE LOT BETTER THAN THAT. AND I WANT TO JUST CONCLUDE REALLY WITH THIS SLIDE BECAUSE I THINK WHILE I’VE SWITCHED OVER TO SYSTEM INTERVENTIONS AND THIS INVOLVED BOTH SORT OF PRACTICE REDESIGN AS WELL AS PROVIDER APPROACHES, IT EMPHASIZES THAT THIS IDEA OF A TEACHABLE MOMENT AND GETTING PEOPLE RIGHT AFTER A TRACT AND THINKING ABOUT SECONDARY FRACTURE PREVENTION LOOKS TO BE THE AREA WHERE WE HAVE THE GREATEST LIKELIHOOD OF HAVING AN IMPACT, ABOUT A 20% IMPROVEMENT OVERALL ACROSS THESE NINE RCTs WHICH WERE EXAMINED. LASTLY, JUST TO HIGHLIGHT THIS WORK FROM SAX AND CHALMER, SOME OF THE PIONEERS IN EVIDENCE-BASED MEDICINE, THAT WE NEED TO BE VERY CAREFUL ABOUT STUDIES THAT AREN’T CONTROLLED. YOU MAY SEE THINGS THAT LOOK JUST TREMENDOUS, BUT WHEN YOU ACTUALLY STUDY THEM, AS SEVERAL OF THE EXAMPLES ILLUSTRATED TODAY, SOMETIMES THINGS DON’T WORK THE WAY WE THINK. SO I WANT TO CONCLUDE WITH A FEW RECOMMENDATIONS. RANDOMIZED CONTROLLED IMPLEMENTATION TRIALS IMPROVING OSTEOPOROSIS PROCESS OF CARE ARE NEEDED. SYSTEM AND MULTIMODAL APPROACHES ARE RECOMMENDED OVER PATIENT AND PROVIDER ALONE TARGETS. WELL-DEFINED INTERVENTIONS MAY CLUL ACTIVE COMPARATORS. THIS MAY BE NECESSARY IN THE REAL WORLD IN ORDER TO GET HEALTH SYSTEMS, PATIENTS AND PROVIDERS ENGAGED. AND WE NEED TO RIGOROUSLY DEFINE WHAT WORKS, WHEN IT WORKS, IN WHOM IT WORKS, AND WE NEED TO DO THIS AT A POPULATION LEVEL. OF I DIDN’T HAVE TIME TO TALK ABOUT QUASI EXPERIMENTAL DESIGNS, STEP WEDGES, THESE ARE APPROACHES THAT MAY BE USEFUL WHEN WE REALLY DON’T HAVE EQUIPOISE TO DO RANDOMIZATION. AND IT MAY BE VERY COST-EFFECTIVE AT A FEDERAL LEVEL TO THINK ABOUT LEVERAGING LARGE OBSERVATIONAL STUDIES LIKE GLOW, ALTHOUGH MAYBE IN A DIFFERENT WAY IN THE FUTURE, THAT MAY PROVIDE EFFICIENCIES OF SCALE. SO I WANT TO ACKNOWLEDGE SOME OF THIGH COLLABORATORS AND THANK [APPLAUSE]>>THANKS, KEN. THAT WAS A GREAT WARMUP. TO MY ACT. I WANT TO THANK THE ORGANIZERS AND I WANT TO THANK EVERYBODY FOR HANGING IN THERE. IT’S DAY 2 OF A LONG CONFERENCE WITH A LOT OF DETAILED TALKS, AND I WOULD SAY THAT THE IMPLEMENTATION SCIENCE IS REALLY THE CRITICAL PIECE IN TRYING TO IMPROVE CARE. WE HAVE A LOT OF EVIDENCE ABOUT THE BENEFITS AND A LOT OF EVIDENCE ABOUT THE SCIENCE BUT WE DON’T HAVE A LOT OF SUCCESS STORIES ABOUT HOW TO IMPROVE CARE, AND IMPLEMENTATION SCIENCE IS PROBABLY ONE OF THE SOFTER SCIENCES, BUT IT IS A SCIENCE THAT WE CAN LEARN A LOT FROM AND I THINK WE NEED TO BUILD ON WHAT WE UNDERSTAND ALREADY. SO MY DISCLOSURES, I HAVE A NUMBER RESEARCH GRANTS. THESE ARE REALLY INVOLVED WITH RHEUMATOID ARTHRITIS AND NOT SPECIFICALLY OSTEOPOROSIS. PRIMARY PREVENTION OF OSTEOPOROSIS IS HINDERED BY CONFUSION REGARDING TREATMENT SAFETY AND LACK OF WIDESPREAD USE OF SCREENING TOOLS BY MOST CLINICIANS. SECONDARY PREVENTION IS LIMITED BY FRAGMENTED POST FRACTURE CARE SYSTEM, AND I’LL DESCRIBE THAT IN A LITTLE MORE DETAIL. ALL THE RIGOROUSLY CONDUCT THE PRIMARY PREVENTION STUDIES IN THE U.S. HAVE BEEN NEGATIVE. KEN PUT A POSITIVE SPIN ON SOME STUDIES THAT I THINK IF WE LOOK CAREFULLY, WE’D DESCRIBE THEM AS NEGATIVE STUDIES, BUT SOME OF THE OTHER STUDIES FROM OTHER LOCATIONS HAVE BEEN POSITIVE. SYSTEM LEVEL CHANGES FOR SECONDARY PREVENTION USING THINGS LIKE A FRACTURE LIAISON SERVICE AND FLS DO SEEM TO BE EFFECTIVE AND SEEM TO PROVIDE GOOD VALUE AND I’LL TALK A LITTLE BIT MORE ABOUT THE ECONOMICS, AND WHILE IMPLEMENTATION SCIENCE PROVIDES A ROAD MAP FOR INTERVENTIONS, THERE ARE FEW RIGOROUS INTERVENTIONS THAT INTRN CONDUCTED THAT CHANGE THE FINANCING OF CARE AND I WOULD POSIT THAT THE FINANCING OF CARE IS LIKELY THE MOST POTENT LEVER FOR SOME OF THESE SYSTEM CHANGES CHANGES. SO THE PROBLEM IS, WE’VE BEEN HEARING ABOUT IT FOR THE LAST DAY AND A HALF, IT’S WEAK BONES, IT’S FALLS, IT’S A LOT OF NUANCED ISSUES BUT AT THE END OF THE DAY, IT’S A FRACTURE, AND THE FRACTURE IN THE HEALTHCARE SYSTEM IS OFTEN PICKED UP BY AN AMBULANCE, BROUGHT TO THE EMERGENCY DEPARTMENT AS A PATIENT WITH AN ACUTE INJURY, AND ANOTHER WAY THIS HITS HEALTHCARE SYSTEM IS THROUGH RADIOLOGY, WHEN THERE’S AN INCIDENTAL FINDING OR PERHAPS NOT AN INCIDENTAL FINDING OF SOMEONE WHO HAS A SPINE FRACTURE, CLEARLY ORTHOPEDIC SURGEONS ARE OFTEN ON THE FRONT LINE OF DEALING WITH THESE FRACTURES WHEN THEY CAN BE REPAIRED, AND THE ISSUE BECOMES, AT THE OTHER END, WHERE THERE ARE PRESCRIPTIONS THAT NEED TO BE MADE BY PRIMARY CARE PHYSICIANS, FAMILY PHYSICIANS, RHEUMATOLOGISTS, ENDOCRINOLOGISTS — NOTICE I PUT RHEUMATOLOGISTS BEFORE ENDOCRINOLOGISTS, BUT THAT’S KIND OF THE FRIENDLY INTERNAL COMPETITION THAT WE HAVE HERE. BUT THE PROBLEM IS, IS THAT TOO OFTEN, THIS INFORMATION REALLY GETS SILOED AND DOESN’T GET FROM RADIOLOGY TO THE PRESCRIBER, IT DOESN’T GET FROM THE PATIENT, IT DOESN’T GET FROM THE EMERGENCY DEPARTMENT, AND IT DOESN’T GET FROM THE ORTHOPEDIC SURGEON, AND SO OFTEN AS A CLINICIAN, I’LL HEAR ABOUT A PATIENT WHO, AFTER THEY HAD A FRACTURE, THE FRACTURE WAS REPAIRED, THEY SPENT A WEEK IN REHAB, THEY COME BACK TO SEE ME FOR SOME OTHER RHEUMATIC DISEASE ISSUE, AND WHEN I QUESTION THEM ABOUT WHAT’S HAPPENED TO YOU IN THE LAST COUPLE OF MONTHS, I HEAR ABOUT THESE ACUTE ISSUES, AND THEN WE HAVE TO START FIGURING THEM OUT. SO WHY DON’T MOST DOCTORS RECOGNIZE PATIENTS AT RISK FOR OSTEOPOROSIS AND PROVIDE THE MANAGEMENT? CLEARLY THERE’S TWO MAJOR CLINICAL SCENARIOS. THERE’S LOTS OF NUANCED SCENARIOS BUT THE TWO MAJOR PRIMARY PREVENTION, PATIENT WITH NO PRIOR FRACTURE, HASN’T BEEN DIAGNOSED WITH OSTEOPOROSIS, AND CLEARLY WE’VE HEARD ALL ABOUT THE SCARCITY AND CONFUSION AROUND B.M.D. TESTING, THE FRAX TOOL IS USED RARELY IN TYPICAL PRACTICE, THERE’S OTHER TOOLS BUT THOSE ARE USED UNFORTUNATELY AS WELL INFREQUENTLY, AND THERE’S UNCERTAINTY REGARDING TREATMENTS. RISK VERSUS BENEFITS. I PRACTICE AT BRIGHAM AND WOMEN’S HOSPITAL, A LOT OF SMART PRIMARY CARE DOCTORS. TOO OFTEN I’M CALLING THE PRIMARY CARE PHYSICIAN ASKING THEM, WHY EXACTLY HAVEN’T YOU BEEN PRESCRIBING SOMETHING FOR THIS PATIENT? THERE’S SOMETHING I’M THE NOT UNDERSTANDING AND THEN THEY GET INTO A CONCERN ABOUT BISPHOSPHONATES AND AS WE’VE HEARD, YES, THERE ARE SOME SIDE EFFECTS BUT THESE ARE INCREDIBLY RARE, THESE ARE INCREDIBLY WELL TOLERATED MEDICINES AND IF THEY DON’T WANT BISPHOSPHONATE, THERE’S OTHER MEDICINES. SO THERE’S A LOT OF UNCERTAINTY. THE MAJOR LOW HANGING FRUIT IN MANY OF OUR MIND IS THE SECONDARY PREVENTION, THE PRIOR FRACTURE PATIENT, AND HE’S ARE PATIENTS THAT END UP WITH ORTHOPEDIC SURGEONS WHO ARE OFTEN RELUCTANT TO TREAT IT, THE OSTEOPOROSIS PRESCRIBERS ARE OFTEN NOT ALERTED TO THE FRACTURE OCCURRENCE AS I’VE DESCRIBED, AND THERE’S SOME UNCERTAINTY REGARDING TREATMENT AS WE’VE BEEN DISCUSSING OVER THE LAST DAY AND A HALF. SO WE CAN THINK ABOUT THE THREE LEVELS OF STRATEGIES FOR OVERCOMING THE BARRIERS. THERE’S THE INDIVIDUAL CLINICIAN AND/OR PATIENT LEVEL, WHAT ARE THE STRATEGIES THAT FOCUS ON DOCTORS AND PATIENTS, AND WE CAN DISCUSS THOSE. KEN HAS ALREADY DISCUSSED SOME OF THEM. THERE’S THE HEALTHCARE SYSTEM AND WE CAN THINK ABOUT THE FRACTURE LIAISON SERVICE AS A SYSTEM APPROACH, SO WHAT SHOULD THE FLS CONSIST OF AND HOW TO ACTUALLY DEPLOY IT EFFECTIVELY IN A TYPICAL HEALTHCARE SYSTEM, HEALTHCARE SYSTEMS ARE INCREDIBLY COMPLEX AND DIVERSE, AND THEN THERE’S THE HEALTHCARE FINANCING OR INSURANCE STRATEGIES. AND WHO CAN EFFECT SUCH CHANGE AN WHAT MIGHT IT LOOK LIKE, AND I’VE BEEN TO C.M.S. AND I’VE TALKED TO THE BEAN COUNTERS IEFNED BEEN REMARKABLY UNSUCCESSFUL AT TRYING TO EXPLAIN THAT WE CAN ACTUALLY IMPROVE CARE, LOWER COSTS BY MAKING SOME STRUCTURAL CHANGES
TO OUR FINA NCING SYSTEM. SO GERNTION IMPLEMENTATION SCIENCES IS WHAT WE’RE TALKING ABOUT, AND THE CARTOON IF YOU CAN’T READ IT, “I’M NOT PROCRASTINATING, I’M PROACTIVELY DELAYING THE IMPLEMENTATION OF THE ENERGY- INTENSIVE PHASE OF THE PROJECT UNTIL THE ENTHUSIASM FACTOR IS AT ITS MAXIMUM EFFECTIVENESS.” AND AS ANYBODY WHO’S WORKED IN COMPLEX SYSTEMS, HEALTHCARE OR OTHERWISE, IT IS SO EASY TO NOT TRY TO IMPLEMENT COMPLEX CHANGES BECAUSE THESE SYSTEM CHANGES ARE DIFFICULT, YOU HAVE TO GET MANY PEOPLE ON THE TEAM TO ALL SPEAK THE SAME LANGUAGE AND REALIZE THEY HAVE THE SAME GOAL, AND THESE ARE PEOPLE THAT ALREADY HAVE VERY BUSY LIVES. AND SO IMPLEMENTING CHANGE REALLY TAKES A TREMENDOUS AMOUNT OF ENERGY AND WORK, AND TOO OFTEN, IT DOESN’T OCCUR. BUT WE KNOW THAT THERE’S THIS HUGE DELAY FROM THE BASIC RESEARCH ALL THE WAY THROUGH THE PUBLICATION, THE SYNTHESIS, EVIDENCE-BASED GUIDELINES THAT WE’VE DISCUSSED HERE TODAY, AND MAYBE YEARS LATER, WE SEE A CHANGE IN PRACTICE. AND THIS WAS KIND OF THE 17-YEAR ODYSSEY THAT PEOPLE HAVE DESCRIBED. AND OFTENTIMES PEOPLE — KEN SHOWED YOU ONE IMPLEMENTATION, TREMENDOUSLY IMPORTANT, WE HAVE TO THEN THINK ABOUT TRANSLATING THE BASIC SCIENCE TO HUMAN SCIENCE, WE THINK ABOUT CLINICAL SCIENCE, NON-IDEAL CONDITIONS, AND SOMETIMES WE SEE THAT THERE’S DIFFUSION, PERHAPS, OF HIGHER END EVIDENCE, AS HOWARD HAS DESCRIBED, SYNTHESIS IS TREMENDOUSLY IMPORTANT BUT SOMETIMES THE LEVEL OF EVIDENCE IS WEAK OR INSUFFICIENT, AND OTHER TIMES THERE’S NO DIFFUSION AT ALL AND WE HAVE TO KIND OF WORK ON FIGURING OUT HOW TO GET THE SCIENCE INTO THE HANDS OF CLINICIANS. SO THINKING ABOUT THESE THREE LEVELS OF TARGETS, WE CAN THINK AT THE INDIVIDUAL CLINICIAN AND PATIENT LEVEL WHICH KEN HAS DESCRIBED, THE HEALTHCARE SYSTEM LEVEL AND THE HEALTHCARE FINANCING, AND I JUST WANT TO TALK THROUGH SOME OF THE PROS AND CONS. AT THE INDIVIDUAL CLINICIAN AND PATIENT LEVEL, KEN HAS ALREADY SHOWN YOU SOME RATHER UNSUCCESSFUL STUDIES, SOME OF THEM THAT I’VE MAINLY DRIVEN. ON THE PRO SIDE, DOCTORS HAVE RESPONSIBILITY FOR APPROPRIATE CARE. THEY TYPICALLY NEED TO ORDER THE TESTING AND THE MEDICATIONS WHEN APPROPRIATE. PATIENTS WANT TO BE ENGAGED AND TAKE RESPONSIBILITY, AND I THINK KEN’S RECENT STUDY REALLY PUSHED ON THAT ISSUE AND UNFORTUNATELY DID NOT CHANGE BEHAVIOR. AFFECTING POSITIVE IMPROVEMENT, ONE CLINICIAN AT A TIME, IS UNBELIEVABLY LABOR INTENSIVE AND TIME INTENSIVE, AND MANY OF THE SOLUTIONS MAY NOT BE TRANSFERABLE ACROSS SETTINGS. THERE’S SO MUCH DIVERSITY, AS KEN SAID, ONE SIZE FITS NONE. WE HAVE TO TAILOR THESE INTERVENTIONS SO IN SUCH A NUANCED WAY THAT IT’S REALLY QUITE DIFFICULT. AT THE HEALTHCARE SYSTEM LEVEL, THESE ARE SYSTEMS ISSUES. SYSTEM PROBLEMS REQUIRE SYSTEM SOLUTIONS. INTERDEAN VEENING
ONINTERCONVENIENTING ON THE CYST TEMG IS MUCH MORE EFFICIENT THAN INTERVENING ONE PATIENT AT A TIME. IF WE THINK ABOUT A FRACTURE LIAISON SERVICE, IF WE CREATE THAT SERVICE IN A TRUST — YOU KNOW, IN THE U.K. OR ACROSS A LARGE HEALTHCARE SYSTEM KAISER PARTNERS, U.A.B., ET CETERA, PERHAPS WE CAN REALLY AFFECT CHANGE AT A BROAD LEVEL. HOWEVER, THE CONS, HEALTHCARE SYSTEMS DIFFER SO SOLUTIONS MAY NOT BE EASILY TRANSFERABLE AND SYSTEMS IS INCREDIBLY HARD.CARE- IT’S REALLY A TEAM SPORT, AS JIM GILL DESCRIBED. YOU HAVE TO GET EVERYBODY FOCUSED AND AGAIN, EVERYBODY IS SO INVOLVED IN THEIR OWN SILO, THEIR OWN ACTIVITIES THAT GETTING EVERYBODY ON THE SAME PAGE TAKES A LOT OF WORK. HEALTHCARE FINANCING CHANGES, MONEY SPEAKS. CLINICIANS AND HEALTHCARE SYSTEMS FIGURE OUT HOW TO IMPROVE THEMSELVES WHEN THERE’S DOLLARS ON THE LINE. IF YOU SAY YOU’RE NOT GOING TO GET PAID FOR THAT — TAKING CARE OF A HIP FRACTURE UNLESS THE PATIENT GETS SCREENED AND TREATED APPROPRIATELY, THINGS WILL CHANGE OVERNIGHT. AND CHANGING HEALTHCARE FINANCING SOMETIMES TAKES AN ACT OF GOD OR AT AN ACT OF CONGRESS AND I’M NOT SURE HOW TO EFFECT THAT CHANGE MYSELF. SO WHAT WORKS TO IMPROVE TREATMENT RATES, AND I SAY IN NORTH AMERICA BECAUSE I’VE FOCUSED ON U.S. AND CANADA BECAUSE I THINK THE TAZ TAS
MAINIAN EXAMPLE THAT KEN IMAIF, I’M NOT SURE HOW APPLICABLE IT WOULD BE IN OUR SETTING HERE. KEN HAS ALREADY TALKED ABOUT PETER KRAMM’S STUDY, THIS IS KEN’S STUDY, THE FIRST THOWR
AUTHOR. THE FIRST STUDY BY KRA MANAGEMENT M WAS INDIVIDUAL LEVEL RANDOMIZATION A AT DXA CENTERS, GUIDELINE CONCORDANT OSTEOPOROSIS CARE AT 52 WEEKS WAS REALLY NO DIFFERENT IN THIS INDIVIDUAL LEVEL RANDOMIZED TRIAL. THE DANILLA U.S. DI THAT KEN WAS THE P.I. ON, THESE WERE WOMEN IN GLOW, I THINK ABOUT 2500 WOMEN, TAYLOR EDUCATION DIRECT TO PATIENT VIDEOS. AGAIN, THE OSTEOPOROSIS TREATMENT OF 24 WEEKS REALLY DID NOT DIFFER. KEN, I THINK, SHOWED SOME OF THE INTERMEDIATE END POINTS WHERE THERE MAY HAVE BEEN SOME DIFFERENCE. WHEN YOU HEAR WHAT I’M SHOWING YOU ON THE TOP, THE M.D. PATIENT INTERVENTIONS, PRIMARY PREVENTION, THE KRAMM, SECOND, THE DANILLA IF WE THINK ABOUT SYSTEM LEVEL CHANGES LIKE A FRACTURE LIAISON SERVICE OR F.L.S., THERE ARE NO PRIMARY PREVENTION BECAUSE FRACTURE LIAISON SERVICE ARE PEOPLE WHO HAVE FRACTURED. SO WE THINK ABOUT SECONDARY PREVENTION, THIS IS THE GILAL STUDY FROM CANADA, I THINK IT WAS ABOUT 35 COMMUNITY HOSPITALS, WOMEN OVER THE AGE OF 49, UNDER 40, SORRY ABOUT THAT TYPO, AND IT WAS A CENTRALIZED COORDINATOR WITH PATIENT AND PCP FOLLOW-UP BY TELEPHONE AND MAIL. SO IT REALLY LOOKED LIKE A FRACTURE LIAISON SERVICE OR EARLY VERSION OF THAT. IT WAS A CLUSTER RANDOMIZED TRIAL TAKING INTO ACCOUNT DESIGN EFFECT, AND THEY DID SEE A SIGNIFICANT IMPROVEMENT IN GUIDELINE-CONCORDANT OSTEOPOROSIS CARE AT 24 WEEKS, 32% IN THE INTERVENTION ARM, AND 20% IN USUAL CARE. SO THERE ARE SOME POSITIVE EVIDENCE IN CONTROLLED TRIALS AROUND F.L.S., AND IF WE THINK ABOUT FINANCING, THERE’S NOTHING NOTHING. THIS IS NOT TO SAY THAT THERE AREN’T CHANGES IN FINANCING THAT HAVE OCCURRED. THERE’S PLENTY OF — I WAS TALKING TO DR. COMSTON ABOUT THE CHANGES IN THE U.K. AND PLENTY OF TRUSTS HAVE CHANGED, PUT MORE MONEY ON THE LINE FOR FRACTURELY LIAISON SERVICES. THERE REALLY AREN’T CONTROLLED TRIALS OF THIS, I LOOKED PRETTY HARD, COULDN’T FIND THEM IN NORTH AMERICA OR THE U.S., AGAIN, WE HAVEN’T TRIED THAT HERE. THERE HAVE BEEN SOME OTHER ATTEMPTS AND THERE’S SEVERAL THAT ARE UNDERWAY BUT I COULDN’T FIND ANY OF THE PUBLISHED EVIDENCE TO PRESENT HERE. SO THERE IS THIS ONE TRIAL THAT I THINK IS A VERY IMPORTANT ONE THAT JUST CAME OUT IN “LANCET,” KEN POINTED IT OUT TO ME, THE SCOOP TRIAL, SCREENING IN THE COMMUNITY TO REDUCE FRACTURES IN OLDER WOMEN. IT WAS A PRAGMATIC UNBLINDED TWO-ARM RANDOMIZED TRIAL IN 100 G.P. PRACTICES IN THE U.K., INVOLVED ABOUT 12,000 WOMEN, 6,000 IN EACH ARM. THE WOMEN WERE AGED 70 TO 85, NOT 84, AND THEY WERE NOT ON OSTEOPOROSIS DRUGS ALREADY. THREE QUARTERS HAD NO FRACTURES, SO A QUARTER HAD A PRIOR FRACTURE. AFTER GIVING INFORMED CONSENT, THEY ALL UNDERWENT THIS FRAX, WHICH IS A WAY OF SCREENING PATIENTS AND ASSIGNING A RISK OF FUTURE FRACTURES, AND THIS WAS DONE PRIOR TO ANY BMD TESTING. AFTER THE FRAX WAS COMPLETED, THEY WERE RANDOMIZED, THEN THEY WERE ASSIGNED, BASED ON THEIR AGE, INTO THESE RISK THRESHOLDS BASED ON THE TABLE ON THE BOTTOM LEFT, SO WOMEN WHO WERE 70 TO 74, IF THEIR FRAX PUT THEM BELOW 5.2% FOR THEIR FUTURE RISK OF FRACTURE, THEY DID NOT UNDERGO BMD TESTING IF IT WAS ABOVE 5.2%, THEY THEND THEN UNDERWENT BMD TESTING AND THEN THE HIGH RISK WOMEN AS I SHOW UNDERGO TESTING, BASED ON THE TESTING, A LETTER WAS SENT TO THE G.P. AND TO THE PATIENT, SO IT WAS AN EDUCATIONAL INTERVENTION PRIMARILY, BASED ON THIS RISK ASSESSMENT TO TRY TO FIND THE RIGHT PATIENTS AND THEN THERE WAS A VERY SIMPLE EDUCATION, AGAIN, A LETTER TO THE G.P. OR THE PATIENT ABOUT THEIR FUTURE RISK OF FRACTURE THE NEED FOR TREATMENT IF THEY WERE AT HIGH RISK, AND IF WE LOOK HERE, THIS IS THE INTERMEDIATE END POINT, THE PERCENT OF PATIENTS WITH PRESCRIPTION ANTIOSTEOPOROSIS MEDICATIONS, SO IN THE CREAM-COLORED BAR IS THE INTERVENTION OR THE SCREENING ARM, AND AT ONE YEAR FOLLOW-UP, IT WAS AT 15% OF THE WOMEN ENDED UP ON OSTEOPOROSIS TREATMENT IN THE SCREENING ARM, 4% ON CONTROL. SO A VERY SIGNIFICANT DIFFERENCE OVER THE FIVE YEARS OF FOLLOW-UP, THE 15% STAYED PRETTY STABLE IN THE PREVENTION ARM AND THE CONTROL ARM WENT FROM 4% UP TO 10%. THE PRIMARY OUTCOME WAS ANY OSTEOPOROSIS-RELATED FRACTURE AND OVER THE FIVE YEARS OF THE TRIAL, ABOUT 800 FRACTURES IN EACH ARM, AND THERE WAS NO DIFFERENCE. SO IF SIMPLE EDUCATIONAL TARGETED SIMPLE EDUCATIONAL INTERVENTION WITH A LETTER TO G.P.s AND PATIENTS PRODUCED NO CHANGE IN THE PRIMARY OUTCOME, HOWEVER, THE SECONDARY OUTCOME WHICH WAS HIP FRACTURES, ABOUT 180 VERSUS 210, 180 IN THE INTERVENTION ARM, 210 IN THE THE CONTROL, SO THERE WAS A SUGGESTION IN THE SECONDARY OUTCOME THAT THIS SIMPLE SCREENING BASED EDUCATIONAL INTERVENTION WAS EFFECTIVE. SO THIS IS AN INTERESTING STUDY, UNBLINDED, OBVIOUSLY TOOK PLACE IN THE U.K., THERE WERE SOME INTERESTING DIFFERENCES THAT THE AUTHORS NOTED BETWEEN THE PATIENTS WHO AGREED TO BE RANDOMIZED AND THOSE THAT DIDN’T. THE ONES THAT AGREED TO BE RANDOMIZED HAD A HIGHER S.E.S. SO THERE WAS A SUGGESTION THAT CERTAIN PATIENTS WOULD BE MORE INTERESTED IN THIS, AND AGAIN IT WAS A VERY SIMPLE EDUCATIONAL PROGRAM. I WANTED TO TURN MY ATTENTION THE LAST COUPLE MINUTES TALKING ABOUT ECONOMICS OF FRACTURE LIAISON SERVICES. THIS IS A COST-EFFECTIVENESS ANALYSIS WE PUBLISHED IN JBMR WITH SEVERAL OF MY COLLEAGUES MORE EXPERT AT COST-EFFECTIVENESS. WE LOOKED AT WHETHER FRACTURE LIAISON SERVICES WOULD BE COST-EFFECTIVE AND WE COMPARED NO FRACTURE LIAISON SERVICE TO UNIVERSAL FRACTURE LIAISON SERVICE TO A MORE TARGETED FLS BASED ON DXA WE EXAMINED THE SENSITIVITY OF THE FINDINGS TO WHAT WAS THE TARGET POPULATION, DID THEY HAVE A PRIOR HIP FRACTURE OR OTHER FRACTURES, HOW WE COSTED OUT THE FLS, THE EFFICACY IN INCREASING BISPHOSPHONATE USE OF AN FLS AND THEN THE COST OF MEDICATIONS, AND I THINK MANY IN THE AUDIENCE ARE FAMILIAR WITH THIS METHODOLOGY. WE ADAPTED AN EXISTING COMPUTER — THAT JOHN WAS ABLE TO HELP US WITH, WE PROJECTED COSTS OF THE F.L.S. PROGRAM, OF THE D.X.A.s, OF THE MEDICATIONS, ACUTE COSTS, LONG-TERM CARE COSTS AND THEN WE LOOKED AT THE HEALTH BENEFITS, MEASURED AS QUALITY ADJUSTED LIFE YEARS, LOOKING AT THE CHANGES IN LIFE EXPECTANCY TIMES UTILITIES, AND WE FOLLOWED KIND OF STANDARD METHODOLOGY. WE USED THE MARKOV STATE TRANSITION MODEL AND THIS OUTLINES IT, HEALTH STATES WERE WELL-DEFINED, AND THEN WE LOOK AT CLINICAL EVENTS AFTER EACH CYCLE, THERE WAS A ONE-YEAR SITE MARKUP CYCLE, AND WE USED A NUMBER OF ESTIMATES FROM THE LITERATURE THAT WERE WELL RESEARCHED AND I’M NOT GOING TO GO THROUGH EACH OF THEM, BUT THESE COSTS AND FRACTURE PROBABILITIES HAVE BEEN WELL ESTIMATED IN THE LITERATURE. MANY OF THESE STUDIES OUTSIDE OF THE U.S. AND SO OUR RESULTS IN THE BASE CASE, WE ACTUALLY FOUND THAT AN F.L.S. WAS COST SAVING. IT LOWERS COSTS, IT IMPROVES QUALITY ADJUSTED LIFE YEARS SO IT’S COST SAVINGS. IT WAS VERY BENEFICIAL, IT HAD VERY BENEFICIAL INCREMENTAL COST-EFFECTIVENESS RATIOS ACROSS ALL OF OUR SENSITIVITY ANALYSES. WE KIND OF WENT THROUGH MANY WORST-CASE SCENARIOS AND WE WERE ABLE IT TO GET IT TO COST $112,000, WHICH IS CONSIDERED COST-EFFECTIVE IN 2018. WE ALSO — WE FOUND IN MULTIPLE DIFFERENT COSTS, ZOLEDRONIC ACID, THE F.L.S. WAS STILL COST-EFFECTIVE. THERE’S BEEN OTHER COST-EFFECTIVENESS ANALYSES THAT HAVE SHOWN ABOUT THE SAME COST SAVINGS OR VERY FAVORABLE ISRs FROM U.S. AND CANADIAN-BASED STUDIES. SO KEY RECOMMENDATIONS, WE HAVE TO FOCUS ON IMPLEMENTATION SCIENCE IF WE’RE REALLY GOING TO MOVE THE BAR ON OSTEOPOROSIS CARE, MORE INTERVENTIONS AT THE HEALTHCARE SYSTEM AND HEALTHCARE FINANCING LEVEL, MOTIVATING CLINICIANS WITH INCENTIVES FOR FINDING AND MANAGING UNDIAGNOSED OSTEOPOROSIS AND FRACTURES IS KEY. I WOULD SAY BUNDLING INSURANCE PATIENTS FOR FRACTURED CARE IS ALSO — WOULD CHANGE CARE AND THE PATTERNS OF CARE VERY QUICKLY. WE NEED TO TEST THE IMPLEMENTATION OF SUCCESSFUL LOCAL INTERVENTIONS ACROSS HEALTH SYSTEMS, AND WE NEED TO INCLUDE CLINICAL OUTCOMES IN THE TRIALS BECAUSE SOMETIMES CLINICAL OUT KS COMES DON’T FOLLOW SOME OF OUR INTERMEDIATE END POINTS. SO I WILL STOP THERE AND PUT THIS QUOTE FROM WALTER CRONKITE, AMERICA’S HEALTHCARE SYSTEM IS NEITHER HEALTHY, CARING NOR A SYSTEM. [APPLAUSE]>>GOOD MORNING. I’M DOUG BAUER. I’M A GENERAL INTERNIST AT UCSF WHERE I SEE PATIENTS AND TEACH EVERY WEEK AND I REALLY APPRECIATE THE OPPORTUNITY TO COME TALK, THANK THE ORGANIZERS. I ALSO WANT TO THANK THE PANEL FOR TAKING TIME OUT OF YOUR BUSY LIVES TO HELP US WITH THESE DIFFICULT ISSUES. MY TALK AND I THINK JANE’S, THE NEXT ONE, IS GOING TO BE A LITTLE MORE FORWARD-FACING, TALK A LITTLE ABOUT THE FUTURE BECAUSE I’M HERE TO TALK A LITTLE BIT ABOUT REALLY
EXCITEING OPPORTUNITY TO USE A VERY, VERY LARGE DATABASE TO ANSWER SOME IMPORTANT QUESTIONS RELATED TO SOME OF THE ISSUES THAT WE’VE BEEN TALKING ABOUT. I’VE ENT TITLED MY TALK PREDICTING FRACTURES WITH SURROGATE MARKERS. I HAVE NO DISCLOSURES. SUMMARY OF THE FINDING, I’D JUST LIKE YOU TO FOCUS IN ON THE THIRD AND FOURTH BULLET. SHORT TERM TREATMENT IN BONE DENSITY — ARE STRONGLY RELATED TO THE CLINICAL OUTCOMES WE’RE ALL INTERESTED IN. MOST IMPORTANTLY, CHANGE IN BONE MARROW DENSITY POTENTIALLY MEETS SEVERAL SUROGACY IN HOPES OF FDA VALIDATION. THE PROBLEM. I WON’T SPEND MUCH TIME HERE BECAUSE WE’VE HEARD OF SO MANY DIFFERENT ASPECTS OF THIS ISSUE WE’RE HERE DISCUSSING TODAY BUT I THINK ONE ISSUE THAT PERHAPS HAS NOT BEEN APPROPRIATELY HIGHLIGHTED IS THE PIPELINE FOR NEW TREATMENTS, NEW TREATMENTS THAT ARE BOTH MORE EFFECTIVE AND POTENTIALLY HAVE FEWER SIDE EFFECTS. OF COURSE WE ALL KNOW THAT IN THIS DAY AND AGE, IT’S EXTREMELY DIFFICULT FOR MEDICATION, NEW MEDICATIONS TO MAKE IT THROUGH THE PIPELINE AND TO BE REGISTERED, THIS IS AT LEAST IN PART BECAUSE OF VERY LARGE SAMPLE SIZES, PROLONGED END POINT, PROLONGED FOLLOW-UP, NOT TO MENTION THE ISSUES ABOUT EQUIPOISE AND RANDOMIZING INDIVIDUALS TO PLACEBO IN THIS DAY AND AGE. OF COURSE THIS HAS LED TO A LIMITED PIPELINE, AND UNFORTUNATELY THIS APPEARS TO BE VALIDATED BY QUICKLY REVIEWED CLINICALTRIALS.GOV EARLIER THIS MONTH, AND THERE WERE NO NEW DRUG LISTINGS FOR PHASE 3 OR PHASE 4 FRACTURE END POINT TRIALS. SO I THINK THE PIPELINE IS REALLY SURPRISINGLY LIMITED AT THIS POINT FOR NEW MEDICATIONS THAT MIGHT BE MORE EFFICACIOUS OR HAVE FEWER SIDE EFFECTS. SO THIS BRINGS US TO THE ISSUE ABOUT SUR GHAZI AND SURROGATE ENT POINTS, WHICH WE END POINTS WHICH WE THINK MAY BE A WAY FORWARD TO SPEED THE DEVELOPMENT OF NEW MEDICATIONS. THIS IS NOT NEW. THERE ARE ACCEPTED OR VALIDATED SURROGATE END POINTS FOR A VARIETY OF CLINICAL DISEASES AND OUTCOMES, INCLUDING HIV, SO VIRAL LOAD IS AN ACCEPTED SURROGATE. BLOOD PRESSURE IS AN ACCEPTED SURROGATE FOR STROKE OUTCOMES AND OF COURSE LIPIDS, SPECIFICALLY L.D.L., IS AN ACCEPTED SURROGATE FOR C.H.D. OUTCOMES. POINT HERE IS THAT VALIDATED SURROGATE END POINTS FOR FRACTURE COULD GREATLY REDUCE THE NEED FOR LARGE TRIALS, REDUCE THE DURATION OF THESE STUDIES AS WELL AS THE COST. THE FDA DOES HAVE AN OPINION ABOUT THIS AND THEY HAVE A NUMBER OF REQUIREMENTS THAT THEY EXPECT FOR THE PROCESS OF SURROGATE VALIDATION, AND TWO OF THOSE REQUIREMENTS ARE SHOWN HERE. THE FIRST IS THE COMPILATION OF STEADY LEVEL META REGRESSIONS OF MULTIPLE TRIALS RELATING THE POTENTIAL SURROGATE WITH THE CLINICAL OUT COME OF INTEREST, AND THE SECOND IS INDIVIDUAL LEVEL ANALYSES ESTIMATING THE PERCENT OF TREATMENT EFFECT OR P.T.E. EXPLAINED BY THE SURROGATE ON THE OUTCOME OF INTEREST. NOW I’M GOING TO SPEND A BIT OF TIME TALKING ABOUT THOSE TWO FDA REQUIREMENTS, BY THE WAY, THERE ARE CERTAINLY OTHER FDA REQUIREMENTS RELATED TO THE CONTEXT ABUSE, ET CETERA, BUT THESE ARE THE TWO REALLY HIGH BAR REQUIREMENTS FOR SURROGACY VALIDATION. SO IN TERMS OF OUR FIELD, PREVENTING FRACTURES, THERE ARE REALLY TWO, I THINK, AT LEAST ON THE CURRENT HORIZON POTENTIAL SURROGATE OUTCOMES WHICH MAY BE OF INTEREST AND ARE OF PARTICULAR INTEREST TO OUR GROUP. THE FIRST IS SKELETAL EMAGING, YOU’VE HEARD A LOT DURING THE LAST TWO DAYS ABOUT THE USE OF IMAGING IN PARTICULAR DXA AS PREVIOUSLY POINTED OUT, THERE ARE SMALL BUT QUITE PRECISE CHANGES WITH TREATMENT IN THESE IMAGING MODALITIES OVER TIME, AND WHAT’S QUITE INTERESTING ABOUT THIS IS THAT THE HOPE, IT’S CERTAINLY NOT PROVEN, IS THAT THE TREATMENT-RELATED CHANGES IN THESE IMAGING MODALITIES MAY BE INDEPENDENT OF WHAT THE MECHANISM IS. SO OUR EXAMPLE, AN INCREASE OR BENEFICIAL EFFECT ON THE
IMAGEING MAY BE SIMILAR FOR ANABOLIC OR ANTI-RESORPTIVE AGENT. THERE HAVE BEEN SEVERAL WHICH HAVE BEEN PROPOSED, FINITE ELEMENT ANALYSIS — THIS IS A COMPUTER INTENSIVE ANALYSIS OF IMAGING HIGHLY COORDINATED WITH STRENGTH. THE PROBLEM IS IT’S RARELY OBTAINED IN ROUTINE FRACTURE TRIALS AND, THEREFORE, IT HASN’T BEEN POSSIBLE TO TO THE TYPES OF ANALYSES I’M GOING TO SHOW YOU. BONE MARROW DENSITY ROUTINELY OBTAINED, OH USED IN BOTH TRIALS AS WELL AS CLINICAL PRACTICE. WE ALSO KNOW IT’S MODERATELY CORRELATED WITH SKELETAL STRENTH IN VIVO — IN VITRO, AND AS I MENTIONED, ROUTINELY OBTAINED IN TRIALS. BIOCHEMICAL MARKERS, I’LL SHORTEN TO B.T.M.ss, THE ADVANTAGES HERE, THEY’RE VERY LARGE AND RAPID TREATMENT-RELATED CHANGES. THE PROBLEM IS THEY ARE VERY DRUG-MECHANISM-SPECIFIC AND THE BONE TURN YEAROVER MARKERS ARE
QUITE DIFFERENT FOR ANABOLIC AND ANTIRESORPTIVE AGENTS. SO THAT GIVES ME AN UPDATE — THE BONE QUALITY STUDY WHICH HAS BEEN DONE BY DENNIS BLACK, AS WELL AS A NUMBER OF PEOPLE IN THE AUDIENCE INCLUDING RICHARD EASTELL, AND THE GOAL OF THE STUDY IS TO STUDY POTENTIAL SURROGATES FOR FRACTURE. THE STUDY BEGAN OVER FIVE YEARS AGO, WHEN WE REQUESTED RAW DATA, THAT IS, INDIVIDUAL-LEVEL DATA FROM ALL PLACEBO CONTROLLED OSTEOPOROSIS TRIALS, WITH FRACTURE END POINTS THE. THERE WERE A FEW EXCLUSIONS, MOSTLY SMALL OR SHORT TERM STUDIES AND WE WE SPECIFICALLY DID NOT SEEK TO OBTAIN DATA FOR TRIALS THAT WERE PERFORMED IN DISEASE POPULATION, FOR EXAMPLE, AND THOSE IS BREAST CANCER OR CORTICOSTEROID INDUCED OSTEOPOROSIS. TO DATE, WE’VE BEEN QUITE SUCCESSFUL, IT’S ALL BEEN RECEIVED AS UCSF, AND WE HAVE NOW BEGUN TO ANALYZE ITMENT WE HAVE DATA FROM ABOUT 40 TRIALS THAT INCLUDED OVER 150,000 RANDOMIZED PARTICIPANTS. THIS IS JUST A SUMMARY OF THE TRIALS THAT WE’VE RECEIVED TO DATE AND SOME OF YOU, IF YOU CAN READ IN THE BACK, WILL NOTICE THAT THIS INCLUDES A WIDE VARIETY OF ANTIRESORPTIVE AGENTS INCLUDING ORAL BISPHOSPHONATES, INTRAVENOUS BISPHOSPHONATES, A SUBSTANTIAL NUMBER OF INDIVIDUALS. WE ALSO HAVE OTHER ANTIRESORPTIVE TRIALS INCLUDING DENOSUMAB AS WELL AS SERM DATA. MOST OF THESE STUDIES WERE CONDUCTED BY INDUSTRY AND THEY’VE BEEN EXTREMELY HELPFUL TO HAVE THEIR COLLABORATIVE PARGS PAITION PARTICIPATION TO OBTAIN THIS INDIVIDUAL LEVEL DATA. WE’LL REALLY BE FOCUSING IN ON BONE MINERAL DENSITY PRIMARILY. AGAIN I MENTIONED FINITE ELEMENT ANALYSIS WHICH REQUIRES CT SCANS AND THERE JUST IS TOO FEW OF THOSE MEASUREMENTS MADE IN RANDOMIZED CONTROL TRIALS TO DO THE TYPES OF ANALYSS I’M GOING TO TALK ABOUT. AS MENTIONED, THE FIRST REQUEST BY THE FDA IS DO TO DO A META REGRESSION OF STUDY LEVEL DATA AMONG PUBLISHED TRIALS. THIS IS NOW BEEN DONE USING THIS DATASET WITH SEVERAL DIFFERENT ANALYSES, PRESENTATIONS AND MANUSCRIPTS, AND THIS IS JUST A REPRESENTATIVE EXAMPLE LOOKING AT CHANGE IN BONE MINERAL DENSITY, RELATING THAT TO THE AVERAGE REDUCTION IN FRACTURE. EACH ONE OF THESE LITTLE BUBBLES AS YOU KNOW IS A RANDOMIZED CONTROL TRIAL. THEY ARE PLOTTED ON THE — THE DIFFERENCE BETWEEN THE TREATMENT AND THE PLACEBO GROUPS ON THE X AXIS AND THE RELATIVE HAZARD FOR NON-VERTEBRAL FRACTURE REDUCTION ON THIS AXIS, AND THEN A LINE IS PLOTTED. AS YOU CAN SEE, THIS INCLUDES BOTH ANTIRESORPTIVE AS WELL AS ANABOLIC AGENTS WITH A REASONABLY HIGH CORRELATION, HIGHLY STATISTICALLY SIGNIFICANT. THE CONCLUSION HERE IS THAT THERE’S A STRONG AND SIGNIFICANT ASSOCIATION BETWEEN BONE MINERAL DENSITY CHANGE AND FRACTURE RISK REDUCTION IN THIS META-REGRESSION OF PUBLISHED — OF STUDY-LEVEL DATA. INTERESTINGLY, WE DID SIMILAR ANALYSES USING BONE TURNOVER MARKERS, GEAND, THIS WAS ONE OF THE FIGURES THAT WAS SHOWN BY DR. STELL IN HIS PAPER. THE RESULTS ARE VERY, VERY SIMILAR. THAT IS, GREATER REDUCTIONS IN BONE TURNOVER AT THE STEADY LEVEL ARE ASSOCIATED WITHER RAO HE DUCKS IN FRACTURE WITH REDUCTIONS OF FRACTURE USING THIS TECHNIQUE
OF META-REGRESSION. — EXPLAINED BY THE POTENTIAL SURROGATE AS OPPOSED TO THE META-REGRESSIONS, THIS REQUIRES INDIVIDUAL LEVEL DATA, FROM EACH RANDOMIZED PARTICIPANT, FROM PLACEBO CONTROLLED TRIALS, AND THE OVERALL APPROACH TO P.T.E. FOR THOSE OF YOU NOT FAMILIAR WITH IT, WE USE THE FRIEDMAN METHOD, WHICH IS TO ESTIMATE THE P.T.E. FROM BOTH THE OBSERVED TREATMENT EFFECT, BOTH BEFORE AND AFTER ADJUSTMENT FOR THE SURROGATE OF INTEREST. I’LL JUST GIVE YOU THREE EXAMPLES HERE OF A HYPE
HYPOTHETICAL OSTEOPOROSIS TREATMENT. THE RELATIVE RISK IS .5. EXAMPLE 1, AFTER ADJUSTING FOR THE SURROGATE OF INTEREST, THE RELATIVE RISK STAYS AT .5, MEANING THAT THE P.T.E. IS ZERO, IN OTHER WORDS, THE SURROGATE DID NOT ACCOUNT FOR ANY OF THE OBSERVED EFFECT, ANY OF THE OBSERVED BENEFICIAL EFFECT OF THE TREATMENT. IN EXAMPLE 2, SAME RELATIVE RISK TO BEGIN WITH, AFTER ADJUSTING FOR THE SURROGATE OF INTEREST, THE RELATIVE RISK GOES TO 1. P.T.E. IS NOW 100%, MEANING THAT THE SUR SURROGATE ACCOUNTS FOR
100% OF THE PREFERRED INTERVENTION — WHERE THE P.T.E. IS 26% AFTER ADJUSTMENT FOR P.T.E. SO P.T.E.s HAVE BEEN RECORDED, FOR BONE MINERAL DENSITY AS WELL AS B.T.M.S RELATED TO A VARIETY OF DIFFERENT OUTCOMES. IN GENERAL, THESE HAVE BEEN QUITE VARIABLE. THIS IS UNDERSTANDABLE BECAUSE BOTH THE METHODS TO CALCULATE THE P.T.E. AS WELL AS THE SPECIFIC APPROACHES DIFFERENTED, AND THE CONFIDENCE INTERVLS HAVE BEEN QUITE WIDE. AND FORTUNATELY, THERE’S BEEN NO PTEs REPORTED FOR HIP FRACTURE. SO A HYPOTHESIS FROM OUR STUDY WAS THAT WE COULD IMPROVE THIS ANALYSIS OF P.T.E.s BY USING THE POOL DATA FROM FINH, ACROSS ALL THE STUDIES. SO THIS IS SOME OF THE METHODS TO ACTUALLY CALCULATE, WE EXAMINED CHANGE BETWEEN BONE MINERAL DENSITY MEASURED AT THREE SITES, AS WELL AS LOOKING AT THREE FRACTURE OUTCOMES THAT YOU’VE HEARD ABOUT OVER THE LAST TWO DAYS, VERTEBRAL FRACTURES, HIP FRACTURES AND NON-VERTEBRAL FRACTURES, AND FOR THE BONE MINERAL DENSITY ANALYSIS, WE POLLED 22 RANDOMIZED CONTROLLED TRIALS WHICH INCLUDED NOT ONLY ANTIRESORPTIVES FOR BP TRIALS, BUT ALSO ANABOLICS, THREE STUDIES AS WELL AS TSH YOU —
YOU CAN SEE THIS IS SUBSTANTIAL, COLLATING THIS AMOUNT OF RAW DATA FROM THIS NUMBER OF INDIVIDUALS. FOR EACH OF THE FRACTURE OUTCOMES, THERE WERE A SUBSTANTIAL NUMBER OF EVENTS OVER 4,000 FOR VERTEBRAL AND ALMOST 900 FOR HIP FRACTURE. THESE ANALYSES HAVE NOT YET BEEN PUBLISHED BUT PRESENTED BY DENNIS BLACK AT ASBMR JUST ABOUT A MONTH AGO. THESE ARE OVERALL RESULTS IN FOR P.T.E.s RELATING A 24-MONTH CHANGE IN BONE MINERAL DENSITY AT THREE SITES. TO THE THREE FRACTURE OUTCOMES. EACH OF THE FRACTURE OUTCOMES IS A ROW. THE BONE MINERAL DENSITY SITES ARE COLUMNS. AS YOU CAN SEE FOR VERTEBRAL FRACTURES, THE P.T.E.s RANGED FROM A LOW OF 30% AT THE SPINE TO A HIGH OF AROUND 60% AT THE HIP. NOTICE THAT THE CONFIDENCE INTERVALS EXCLUDE A YEAR OWE AND THEREFORE THESE WERE ALL SIGNIFICANTLY SIGNIFICANT. IT’S IMPORTANT TO POINT OUT THAT THE LOWER BOUND OF THE CONFIDENCE LEVEL IS IMPORTANT BECAUSE THIS GIVES US AN ESTIMATE OF THE MINIMAL AMOUNT OF P.T.E. THAT IS THE LEAST PLAUSIBLE AMOUNT THAT THE SURROGATE ACCOUNTS FOR. SO YOU WOULD INTERPRET THIS AS SAYING FOR TOTAL HIPBONE MINERAL DENSITY AND VERTEBRAL FRACTURE OUTCOMES, TOTAL HIP ACCOUNTS FOR AT LEAST 50% OF THE EFFECT OF THESE DRUGS. FOR HIP FRACTURES, THE RESULTS WERE SIMILAR, P.T.E.s RANGING FROM 40% TO 50%, AND FOR NON-SPINAL FRACTURE, SOMEWHAT SURPRISINGLY, THE P.T.E.s TENDED TO BE EVEN HIGHER WITH A LOW OF 50 TO A HIGH OF 70%. SO WE DID SIMILAR ANALYSES FOR THE BONE TURNOVER MARKERS AS I MENTIONED. THESE WERE ALSO PRESENTED EARLIER THIS YEAR. AND I’LL JUST SUMMARIZE TO SAY THAT THE RESULTS WERE QUALITATIVELY SIMILAR BUT THE CONFIDENCE INTERVALS WERE QUITE A BIT WIDER FOR THE THREE B.T.M.s THAT WE ANALYZED. SUGGESTING THAT IT’S PERHAPS A LESS USEFUL PARAMETER FOR THIS TYPE OF A ANALYSIS OF P.T.E. ALSO WANT TO POINT OUT THESE RESULTS WERE CONSISTENT BETWEEN THE DIFFERENT TYPES OF ANALYSES WHICH I THINK SHOULD BE REASSURING TO THE FDA. WE DID A SIMPLE SPHIMENT SAYING THAT AN OSTEOPOROSIS TREATMENT THAT INCREASED SPINE BONE MINERAL DENSITY BY 3% WOULD BE EXPECTED TO REDUCE VERTEBRAL FRACTURE BY ABOUT 63% IN THE ANALYSES OF STEADY LEVEL META-REGRESSION AND WOULD BE EXPECTED TO REDUCE VERTEBRAL FRACTURES BY ABOUT 56% IN THE INDIVIDUAL LEVEL META ANALYSES THAT I’VE JUST SHOWN. SIMILARLY FOR THE B.T.M.s, APT RESORPTIVE THERAPY THAT REDUCED BY 30% WOULD BE EXPECTED TO REDUCE VERTEBRAL FACT BY ABOUT 42% AND 31% IN THE INDIVIDUAL LEVEL P.T.E. ANALYSES. SO QUITE A BIT OF CONSISTENCY BETWEEN THOSE TWO APPROACHES. JUST TO CONCLUDE, AFTER POOLING MULTIPLE OSTEOPOROSIS TREATMENT TRIALS, SHORT TERM CHANGES IN BOTH BONE MINERAL DENSITIES AND BONE TURNOVER MARKERS ARE ASSOCIATED WITH FRACTURE RISK REDUCTION IN META REGRESSIONS OF THESE ASSOCIATIONS WERE STRONG AND STATISTICALLY SIGNIFICANT AND IMPORTANTLY, BOTH DMAINGS B.M.D. AND B.T.M.ss ACCOUNT FOR A SUBSTANTIAL PROPORTION OF THE TREATMENT EFFECT AS CALCULATED BY B.T.E. AND IT’S INTERESTING TO NOTE THAT HIPBONE MINERAL DENSITY HAD A HIGHER P.T.E. THAN SPINAL EVEN FOR SPINE FRACTURES. ANOTHER IMPORTANT CONCLUSION OF THESE ANALYSES IS THAT B.T.M.s, ALTHOUGH CERTAINLY WERE QUALITATIVELY IN THE SAME DIRECTION, HAD CONSIDERABLY MORE IMPRESESSION OF THE ESTIMATES AND MAY NOT BE AS USEFUL FOR THIS TYPE OF ANALYSIS. WE FEEL THESE MAY FULFILL SOME OF THE REQUIREMENTS FOR FDA QUALIFICATION. JUST A COUPLE OF IMPLICATIONS AND NEXT STEPS BEFORE I TURN THE MIC OVER TO JANE TO SUMMARIZE THE TWO DAYS. IF VALIDATED, US THE USE OF THESE PRO TENSIO SURROGATES MIGHT REDUCE THE NEED FOR LARGE FRACTURE TRIALS BUT IT’S IMPORTANT TO POINT OUT THEY WOULD NOT ADDRESS SAFETY CONCERNS. AGAIN, THESE ARE EFFICACY SURROGATES, AND THE ISSUES RELATED TO SAFETY CONCERNS WOULD STILL NEED TO BE ADDRESSED BY OTHER STUDY DESIGNS AND OTHER POTENTIAL SURROGATES. WE ARE CURRENTLY PURSUING FDA QUALIFICATION FOR CHANGE IN BONE MINERAL DENSITY AS A SURROGATE FOR FRACTURE OUTCOMES, AND I’M HAPPY TO REPORT SINCE DENNIS PRESENTED THIS DATA AT ASBR IN MONTREAL, WE RECEIVED AN ENCOURAGING LETTER OF RESPONSE FROM THE FDA SAYING THEY SUPPORT THIS ENDEAVOR AND ENCOURAGE YOU TO CONTINUE SO AT LEAST FROM THE FDA STANDPOINT, THEY ARE ENCOURAGING US TO MOVE FORWARD, AND WE ARE HOPEFUL BECAUSE THESE RESULTS, WE BELIEVE, COMPARE FAVORABLY TO THE OTHER SURROGATES WHICH HAVE BEEN PREVIOUSLY VALIDATED. RECOMMENDATIONS. ONE THING THROUGH THIS PROCESS HAS BEEN QUITE UNCLEAR EXACTLY WHAT THE FDA IS THINKING, SO OUR ONE RECOMMENDATION IS JUST TO WORK WITH THE FDA TO CLARIFY CLEARLY WHAT THEIR PREFERENCES ARE FOR STUDY DESIGN AS WELL AS THE RIGOR OF BOTH THE CONTEXT OF USE AS WELL AS THE SPECIFIC ANALYSES FOR THE STUDIES AND TO HELP EXPLORE WHAT ARE THE SPECIFIC CRITERIA THAT WOULD BE — MUST BE REACHED FOR VALIDATION, AND FINALLY, TO PROMOTE FURTHER TYPES OF ADDITIONAL WORK IN THIS AREA WOULD BE TO PROMOTE THE MEASUREMENT OF POTENTIAL SURROGATE OUTCOMES BY EMBEDDING THEM IN FUTURE TRIALS AND FACILITATING TRIALS ACROSS TRIALS AS WELL AS ENCOURAGING INDUSTRY TO SHARE DATA FOR POOLING EFFORTS SUCH AS WAS DONE HERE. THIS HAS BEEN A HUGE TEAM EFFORT. GAYLE LESTER IN THE AUDIENCE IS THE CHAIR OF THE NIAMS PROJECT, KE NIS BLACK DENNIS BLACK IS THE P.I., A HOST OF COMPANIES, FUNDERS, AS WELL AS HARD WORK BY OUR COLLEAGUES AT UCSF, AND I REALLY APPRECIATE YOUR TIME, AND THANK YOU VERY MUCH. [APPLAUSE]>>HELLO. IT’S A PLEASURE TO BE HERE. THANK YOU VERY MUCH FOR DRS. CHEN AND JOSEPH FOR INVITING ME TO SPEAK, AND THANK YOU ALSO FOR ALL OF YOU FOR SITTING DOWN AND LISTENING TO ALL THESE TALKS AND I’M THE LAST TALK, SO THANK YOU FOR YOUR PATIENCE. SO I FELT A NEED BECAUSE OF THE HORRIBLE, HORRIFIC THINGS THAT HAPPENED IN PITTSBURGH THAT I WANTED TO ACKNOWLEDGE THAT PITTSBURGH IS VERY MUCH A FOOTBALL TOWN. WE HAVE A BASEBALL TEAM BUT WE’RE NOT REALLY — YOU KNOW, AS REALLY THE PIRATES HAVEN’T BEEN VERY GOOD FOR A LONG TIME, BUT ONE TIME GQ MAGAZINE CALLED THE MEN IN PITTSBURGH THE WORST DRESSED MEN IN THE UNITED STATES. AND THEY SAID THIS WAS BECAUSE IT’S GAME DAY EVERY DAY. SO YOU WEAR YOUR STEELERS SHIRTS ALL THE TIME. SO I JUST WANTED TO SHOW THAT THE STEELER COMMUNITY AND THE PITTSBURGH COMMUNITY IS VERY MUCH BEHIND OUR JEWISH COMMUNITY AND OUR FRIENDS, AND WE’RE ALL SUPPORTIVE OF TRYING TO BE STRONGER THAN THE HATE THAT HAS HAPPENED IN OUR COUNTRY AS OF LATE. OKAY. [APPLAUSE] THANK YOU. SO I HAVE NOTHING TO DISCLOSE. SO THE SUMMARY OF OUR FINDS, DR.
CHEN AND JOSEPH ASKED ME TO SUMMARIZE ALL THE TALKS THAT �HAVE BEEN GOING ON FOR THE LAST DAY AND A HALF, AND I HAD TO BASE THAT ON THE EARLY SETS OF SLIDES THAT WERE DISTRIBUTED, AND SO SOME OF IT, I MAY HAVE NOT GOT EXACTLY RIGHT BECAUSE YOU CHANGED YOUR SLIDE OVER THAT COURSE, BUT BASICALLY WE KNOW FROM DR. SHANE THAT OSTEOPOROSIS IS A SIGNIFICANT HEALTH PROBLEM AND THERE’S ALSO A CRISISIN THE TREATMENT OF OSTEOPOROSIS. SHORT TERM TREATMENT DECREASES FRACTURE RISK BY ABOUT 20 TO 60%. LONG TERM TREATMENT DECREASED VERTEBRAL FRACTURES BUT HAD NO EFFECT ON NON-VERTEBRAL FRACTURES FROM THE TWO EXTENSION STUDIES. INITIATION OF DRUG THERAPY AND ADHERENCE TO DRUG THERAPY IS POOR. THE RISK ESPECIALLY WITH LONG TERM USE OF AFF AND ONJ HAVE BEEN SUMMARIZED. THERE’S LITTLE DATA ON LONG TERM TREATMENT AND DRUG HOLIDAY, AND THE FUTURE, WE HAVE ONGOING INITIATIVES WHICH I’M GOING TO DESCRIBE BY ASBMR, IOF AND THE FRACTURE FRAGILITY NETWORK, IMPLEMENTATION SCIENCE, AFF AND ONJ PERHAPS THE DEVELOPMENT OF A RISK FACTOR ALGORITHM WOULD BE BETTER TO TARGET OUR THERAPIES TO PATIENTS WHO ARE NOT AT HIGH RISK FOR AFF. A DEVELOPMENT DOUG WENT OVER BEAUTIFULLY, THE DEVELOPMENT OF B.M.D. AS A SURROGATE MARKER, NEED MORE DATA ON LONG TERM TREATMENT AND AS WELL AS DRUG HOLIDAYS. SO IN TERMS OF THE SCOPE OF THE PROBLEM, IT’S A HEALTH THREAT FOR 44 AMERICANS, ABOUT 10 MILLION IN THE U.S. HAVE OSTEOPOROSIS AND ANOTHER 34 MILLION HAVE LOW BONE MASS. 68% OF THOSE THAT ARE AFFECTED ARE WOMEN. ONE OUT OF EVERY TWO WOMEN AND ONE OUT OF EVERY FIVE MEN WON’T EXPERIENCE WILL EXPERIENCE AN OSTEOPOROTIC FRACTURE IN THEIR LIFETIME. FRACTURES ARE ASSOCIATED WITH SIGNIFICANT MORBIDITY. FRACTURES BEE GET MO ARE FRACTURES, THE COST IS $17 BILLION ANNUALLY IN THE U.S. OSTEOPOROSIS TREATMENT AFTER HIP FRACTURE, BAD NEWS AND IT’S GETTING WORSE. SO THE KEY QUESTIONS, WHAT ARE THE BENEFITS AND RISKS
AND WHAT FACTORS INFLUENCE THE OUTCOME? WE KNOW THAT THERE ARE HIGHLY EFFICACIOUS TREATMENTS, 20 TO 60% DECREASES IN FRACTURE RISK, BAW THERE’S NOT A CURE, IT’S NOT 100% DECREASED RISK. WE WANT IT TO TREAT WOMEN AT THE HIGHER RISK WHICH IS THOSE WOMEN WHO HAVE PREVIOUS FRACTURE, LOW B.M.D., AGE 65 AND OLDER WITH RISK FACTORS, BUT THERE ARE RESEARCH GAPS. WHETHER, WHEN AND FOR WHOM DO WE CONTINUE TREATMENT AFTER THREE YEARS AND DO WE NEED TO ENGAGE OUR PRIMARY CARE PHYSICIANS AND WE NEED TO LISTEN TO OUR PATIENTS BETTER. OF COURSE WE NEED NEW DRUGS, ESPECIALLY ANTIBIOTICS, BECAUSE WE NEED A CURE RIGHT NOW. AS I MENTIONED, THEY DON’T DECREASE FRACTURES 100%. THIS IS A SLIDE FROM DR. ROSEN WHO RECOMMENDED THAT TREATMENT, I PRETTY MUCH WENT OVER THIS, HE SUMMARIZED WHO WE DON’T WANT TO NECESSARILY TREAT AT THE TIME. THE P2P, KEY QUESTION 2, WHAT ARE THE BENEFITS AND RISKS OF OSTEOPOROSIS DRUGS OVER THE LONGER TERM, GREATER THAN THREE YEARS, AND WHAT FACTORS INFLUENCE THOSE OUTCOMES? WE DON’T HAVE A LOT OF DATA HERE, MOST COMES FROM THE FLEX TRIAL WHICH WAS AN EXTENSION OF THE FIT TRIAL OF ALLEN DROA NAID AND THE EXTENSION OF THE HORIZON TRIAL WHICH IS AN EXTENSION OF — WE HAVE EVIDENCE THAT CONTINUING DRUG THERAPY FOR THREE TO FIVE YEARS MAY REDUCE VERTEBRAL FACTORS BUT HAD NO EVENT ON NON-SPINE FRACTURE RISK, ALTHOUGH DR. BLACK SHOWED THAT THERE WAS NO — WHEN COMPARED TO THE VIRTUAL CONTROL GROUP, THERE WOULD BE SOME EFFECT OF —
PERHAPS DEVELOPMENT OF A FRAX-LIKE SCORE FOR AFF, BETTER UNDERSTANDING OF THE PATHOGENESIS OF AFF, THE GENETICS OF AFF AND PERHAPS USING RARE BONE DISEASE MODELS AND EFFORTS TO MINIMIZE THE RISK RISK. THE O.N.J. INCREASED WITH BISPHOSPHONATE USE, THE META-ANALYSIS SAID THERE WAS ABOUT A TWO TO THREE TIMES INCREASED RISK, AND DR. COMSTON WENT OVER THE RISK OF ATRIAL FIBRILLATION AND MORTALITY AND G.I. CANCERS AND WE REALLY NEED MORE DATA THERE. HORMONE THERAPY BY DR. JACKSON WAS NOT RECOMMENDED FOR THE PRIMARY MANAGEMENT OF OSTEOPOROSIS, BUT PERHAP THERE’S SOME AREA OF USING LOW DOSE ESTROGEN AND TRANSDERMAL ESTROGEN THAT MAY BE PROMISING IN WOMEN WHO ARE HAVING HOT FLASHES WHO ALSO HAVE OSTEOPOROSIS. WE NEED FROM DR. COSMAN, WE LEARNED THAT PROACTIVE ANABOLIC THERAPY AND SEQUENTIAL MONO THERAPY FOR HIGHEST RISK PATIENTS MAY MINIMIZE DURATION OF USE AND MAXIMIZE BENEFITS, AND FINALLY, MORE EVIDENCE IS NEEDED ON THE LONG TERM TREATMENT REGARDING RISK BENEFITS AND WHO, WHEN AND HOW WE SHOULD TARGET OUR LONG TERM THERAPY. THIS WAS ALSO SHOWN BY DR. ROW
ROSEN THAT SECONDARY FRACTURE PREVENTION WORKS. THIS WAS THE KEN LYLE STUDY SHOWING THAT GIVEING ZOLE AFTER
A HIP FRACTURE REDUCES CLINICAL FRACTURES AS WELL AS MORTALITY. SO THE P2P QUESTION THREE WAS, DO DRUG HOLIDAYS IMPROVE OUTCOMES? THIS WAS REVIEWED BY DR. SHOBACK AND EASTELL ALTHOUGH MANY OF THE OTHER SPEAKERS DID SPEAK TO DRUG HOLIDAYS. SO B.M.D. AT THE HIP, T SCORE OF 2.5 AT THE END OF FIRST LINE TREATMENT COULD BE A MARKER FOR WOMEN WHO SHOULD REMAIN ON THERAPY. OLDER AGE, HIGH RISKS OF FALLING, CAUTION REGARDING DRUG HOLIDAY. THERE’S NO GUIDELINES, EVIDENCE LACKING, AND FUTURE RESEARCH SHOULD USE B.M.T. AND BONE TURNOVER MARKER DURING A DRUG HOLIDAY AND CHANGES IN B.M.D. AND FRACTURE RISK TO HELP PERHAPS TARGET WHO SHOULD BE ON A DRUG THERAPY, AND BONE TURNOVER MARKER DATA WAS ALSO ELEGANTLY DESCRIBED BY DR. EASTELL AS WELL AS THE B.M.D. DATA, AND NOTED THAT PERHAPS VERTEBRAL FRACTURE ASSESSMENT MAY ALSO BE UTILIZED FOR DECIDING WHO, IN FACT, WOULD BENEFIT FROM CONTINUED LONG TERM USE. SO THE P2 QUESTION 4, BOTH PARTS 1 AND 2, WAS DRUG THERAPY FOR OSTEOPOROSIS PREVENTION, PATIENT AND CLINICIAN FACTORS AFFECTING INITIATION AND ADHERENCE. THIS WAS COVERED BY A NUMBER OF SPEAKERS. WE KNOW INITIATION AND ADHERENCE TO OUR DRUGS ARE POOR. THERE ARE BARRIERS TO TREATMENT IN PRIMARY CARE THAT WERE REVIEWED. THE BEST MO KEL MODEL TO
IMPLEMENT SCREEN SCREENING AND TREATMENT IN PRIMARY CARE IS NOT KNOWN. THE OPTIONS IN DOSING INTERVALS DIDN’T SEEM TO HAVE ANY EFFECTS AS DR. GOLD REVIEWED. AND BOTH THE PATIENTS, THE DOCTORS AND SYSTEM CONTRIBUTE TO THESE BARRIERS, THESE LACK OF INITIATION AND THE POOR ADHERENCE. THE CHALLENGES ARE BOTH MEDIA COVERAGE OF OUR MEDICINES AND DEMOGRAPHIC FACTORS. WE NEED TO IMPROVE COMMUNICATION, AND WE NEED TO CONSIDER THE PATIENT PERSPECTIVE, AND PERHAPS CONSIDER THE RISK OF NO TREATMENTS ON THEIR PERSONAL LIFE, THEIR ROLES AS A WIFE, A MOTHER, A DAUGHTER, ET CETERA. AND IMPROVE THE PERCEPTION OF THE RISK AND BENEFITS. DRUGS WORK VERY WELL, THESE RISKS ARE REAL BUT THEY ARE RARE, THANKFULLY, BUT WE NEED TO IMPROVE THE PERCEPTION OF THESE RISK AND BENEFITS. IN THE FUTURE, DR. SOLOMON AND SAAG TALKED ABOUTPLEM TAITION SCIENCE, THREE LEVELS OF TARGET. WE TARGET INDIVIDUAL — THE HEALTHCARE SYSTEM AS WELL AS HEALTHCARE FINANCING, AND PERHAPS INCORPORATING FRACTURE LIAISON SERVICES WOULD BE ONE WAY TO IMPROVE OUR TREATMENT, IMPROVE THE TREATMENT GAP. AND WE NEED TO DEFINE WHAT IS HIGH QUALITY CARE AND WE NEED RCTs THAT ACTUALLY IMPROVE OSTEOPOROSIS PROCESS OF CARE. DR. SAAG SHOWED YOU THAT WITHOUT A CONTROL GROUP, IT LOOKS LIKE WE ARE SEEING A BENEFIT BUT THE CONTROLLED STUDIES DID NOT HAVE THE SAME EFFECT. SO WE REALLY NEED OUR RANDOMIZED TRIALS FUNDED TO TRY INTERVENTIONS TO IMPROFIT PROCESS OF CARE. SO THE FUTURE, DR. BAUER TALKED ABOUT THE FNIH BONE QUALITY PROJECT, ABOUT B.M.D. AS A SURROGATE MARKER, SHORT TERM CHANGES IN B.M.D. AND BONE TURNOVER MARKER ARE SOASHTDED WITH FRACTURE RISK REDUCTION, AND ACCOUNT — AT LEAST B.M.D. DOES, ACCOUNT FOR A SUBSTANTIAL PROAR PORTION OF THE OBSERVED TREATMENT EFFECT. AND NOW THIS APPLICATION FROM THE FDA IS MOVING ON. ASBMR SECONDARY FRACTURE PREVENTION INITIATIVE LED BY DR.
KIEL AND DR. KHOSLA WHO ARE BOTH IN THE AUDIENCE. THIS IS A PAPER THAT WAS A TASK FORCE FROM ASBMR THAT WAS PUBLISHED IN 2012, MAKING THE FIRST FRACTURE THE LAST FRACTURE, AND IT WAS A REPORT ON SECONDARY FRACTURE PREVENTION. SO ASBMR HAS BEEN REALLY CONCERNED ABOUT SECONDARY FRACTURE PREVENTION FOR QUITE A LONG TIME. IN 2016, THERE WAS AN ASB CALL TO ACTION. YOU CAN SEE THE PRESS CONFERENCE THAT WAS HELD BY MANY OF THE SPEAKERS THAT ARE HERE TODAY, ORGANIZATIONS THAT HAVE PLEDGED TO INTENSIFY EFFORTS TO INCREASE SCREENING, SCREENING, DIAGNOSIS AND TREATMENT OF HIGH RISK INDIVIDUALS, AND THEN IN 2017, WE DEVELOPED A STRATEGIC ROAD MAP, AN ACTION PLAN TO PREVENT SECONDARY FRACTURES. THIS IS A NEUTRAL PLATFORM FOR MANY MULTI-STAKEHOLDERS DIALOGUE IN ACTION AND WE HAVE A 40 ORGANIZATION COALITION. THE TARGET PLAN, THIS IS REALLY IMPORTANT. SO THE ASBMR SECONDARY FRACTURE PREVENTION IS FOCUSING ON MEN AND WOMEN AGED 65 YEARS AND OLDER WHO HAVE SUFFERED A HIP OR VERTEBRAL FRACTURE THAT COMES TO CLINICAL ATTENTION. AND WE ARE SAYING THESE INDIVIDUALS SHOULD BE EVALUATED FOR TREATMENT. THIS SUBPOPULATION, WE KNOW, IS AT VERY HIGH RISK FOR A SECOND FRACTURE AND EVIDENCE IS ROBUST IN SUPPORTING TREATMENT OF THIS POPULATION. IT’S NOT INTENDED TO IMPLY THAT OTHER POPULATIONS SHOULD NOT BE TREATED. ALL NEED TO BE EVALUATED AS INDIVIDUAL BUT WE WANT TO TARGET THIS POPULATION BECAUSE IT’S WELL-DEFINED AND WE THINK THAT THERE’S GENERAL CONSENSUS THAT A PUBLIC HEALTH INITIATIVE IS INDEED ACHIEVABLE. THESE ARE SOME OF THE STEPS THAT WE HAVE CARRIED OUT IN DEVELOPING THE ACTION PLAN AND THE CLINICAL RECOMMENDATIONS. THERE IS A STEERING COMMITTEE AND A COALITION I MENTIONED OF ABOUT 40 ORGANIZATIONS. THEY WENT THROUGH STEPS TO IDENTIFY LESSONS LEARNED FROM OTHER PROGRAMS SUCH AS CHOLESTEROL REDUCTION, WHAT DID WE LEARN ABOUT THAT, DEVELOP INFORMATION FOR EDUCATIONAL AND SUPPORTIVE MATERIALS, AND WE WANT TO REALLY IDENTIFY A QUANTITATIVE GOAL, LIKE HOW MUCH — HOW CAN WE IMPROVE A GOAL OF REDUCING SECONDARY FRACTURES. THEY HAVE INITIATED, AS DR. SOLOMON MENTIONED, MONEY TALKS, SO WE HAVE INITIATED A DISCUSSION WITH A C.M.S. TO IMPROVE REIMBURSEMENT OPTIONS, IMPROVE REIMBURSEMENT OPTION FOR EXAMPLE FOR FRACTURE LIAISON SERVICE, AND WE THINK PART OF THE CONFUSION AMONGST PRIMARY CARE PERHAPS IS ALL THE DIFFERENT RECOMMENDATIONS. THESE WERE SUMMARIZED BY DR. HOCHBERG AND HE NOTED HOW THEY DIFFER AND WHERE THEY’RE SIMILAR, BUT PERHAPS WE CAN DEVELOP CONSENSUS RECOMMENDATIONS AND THAT WILL HELP. PRIMARY CARE CLINICIANS IN TERMS OF SECOND FRACTURE PREVENTION. WE’RE DESIM NATEING THE ACTION PLAN, I BELIEVE IT’S ON THE ASBMR WEBSITE, AND WE ARE COORDINATING OUR MESSAGES AND EXPLORING PILOT STUDIES WITH INTEGRATED HEALTH SYSTEMS. SO THIS IS THE BOTTOM LINE I MENTIONED THAT WHO SHOULD BE TREATED AND WE THINK THAT MULTIDISCIPLINARY SYSTEM THAT INCLUDES CASE MANAGEMENT SUCH AS THE F.L.S. AND THE BOTTOM LINE IS THAT THESE PEOPLE, AGE 65 YEARS AND OVER WHO EXPERIENCE A HIP OR VERTEBRAL FRACTURE, SHOULD BE TREATED FOR OSTEOPOROSIS. AND AGAIN, JUST LIST SOME OF THE ELEMENTS OF OUR ACTION PLAN. PROMOTE CLINICAL RECOMMENDATIONS RECOMMENDATIONS, WE WANTED TO ESTABLISH A NATIONAL FRACTURE REGISTRY, BUT THAT SEEMS TO BE RUNNING INTO SOME DIFFICULTIES GIVEN THE MANY DIFFERENT HEALTH SYSTEMS THAT WE HAVE IN THE UNITED STATES. IT’S NOT AS EASY IN A COUNTRY LIKE THE U.K. OR SOME OF OUR SCANDINAVIAN COLLEAGUES. WE WANT TO INCREASE THE NUMBER OF CAPABILITIES OF CASE MANAGEMENT AND FRACTURE LIAISON SERVICES, IMPROVE THE DIAGNOSIS AND COMMUNICATION ABOUT PATIENTS WITH VERTEBRAL FRACTURES, AND EXPLORE POTENTIAL USES OF REIMBURSEMENT AND FINANCIAL INCENTIVES. AND AGAIN, THESE ARE SOME OF THE OTHER ACTION PLAN ELEMENTS WHICH YOU CAN READ ABOUT ON THE WEBSITE. AND MARK HOCHBERG DID, IN FACT, GET THE WEBSITE CORRECT AND IT’S SHOWN HERE ON THE SLIDE, WWW.SECONDARYFRACTURES.ORG TO GET MORE INFORMATION ABOUT THE ASBMR’S SECONDARY FRACTURE PREVENTION INITIATIVE. SO WHAT ABOUT — WHAT ELSE IS HAPPENING AROUND THE WORLD? I GOT THESE NEXT COUPLE SLIDE FROM DR. CYRUS COOPER, WHO IS THE PRESIDENT OF I.O.F., AND THEY’RE REALLY FOCUSING ON THEIR PROGRAM CALLED “CAPTURE THE FRACTURE,” AND IT’S A GLOBAL CAMPAIGN FACILITATING THE INFLAMMATION OF COORDINATOR-BASED POST FRACTURE MODELS OF CARE FOR SECONDARY FRACTURE PREVENTION. SO THEY AWARD THESE VARIOUS LEVELS OF ACHIEVEMENT TO VARIOUS PROGRAMS, AND THE GROWTH OF THE F.L.S. NETWORK HAS BEEN REMARKABLE FROM A NUMBER OF 57 IN 2013 UP TO 246, AND YOU CAN SEE FROM THIS SLIDE THAT IT’S REALLY ALL OVER THE WORLD. AND 40 COUNTRIES. AND OVER 300,000 FRA SILT FRACTURES HAVE BEEN SEEN BY THE F.L.S. NETWORK. AND THERE’S ALSO THE FRACTURE, FRAGILITY FRACTURE NETWORK HAS A PROGRAM, AND YOU CAN SEE THAT THEIR GLOBAL CALL TO ACTION WAS PUBLISHED IN THE MANUSCRIPT THE JOURNAL OF INJURY, AUGUST OF 2018. THESE NEXT SLIDES COME FROM PAUL MITCHELL, AND THEY’RE ALSO FOCUSING ON MULTIDISCIPLINARY CARE FOR ANY PERSON WHO SUFFERS A HIP, CLINICAL VERT OR OTHER MAJOR FRAGILITY FRACTURES. THEY’RE FOCUSING AGAIN ALSO ON RAPID SECONDARY PREVENTION AFTER THE FIRST OCCURRENCE OF THESE FRACTURES, AND ITS ON GOING POST ACUTE CARE PEOPLE WHOSE AIN’T TO FUNCTION IS IMPAIRED BY HIP AND MAJOR FRAGILITY FRACTURES SO REALLY FOCUSING ON THE DISABILITY THAT’S ASSOCIATED WITH THESE FRACTURES. AND SO JUST TO SUMMARIZE EACH ONE OF THE TALKS HAD A KEY RECOMMENDATION SO I’M JUST BRIEFLY SUMMARIZING IT BUT I THINK THE PANEL WILL HE REALLY IMPORTANT FOR YOU TO LOOK AT THE KEY RECOMMENDATIONS OF EACH OF THE SPEAKERS. SO WE NEED TO GENERATE MORE EVIDENCE FOR LONG TERM TREATMENT FOR DECISION-MAKING, THIS IS A MAJOR RESEARCH GAP AND OPPORTUNITY, AND IN FACT, WE NEED TO KNOW WHEN, WHO, HOW, PERHAPS WHAT DRUG, WHAT SEQUENTIAL THERAPIES OF DRUG SHOULD BE USED FOR A DRUG HOLIDAY. I THINK IT’S REALLY IMPORTANT FOR THE THREE MAJOR ORGANIZATIONS THAT ARE FOCUSED ON SECONDARY FRACTURE PREVENTION THAT THEY COLLABORATE, AND I KNOW AT OUR LAST ASBMR MEETING, WE HAD A SESSION AND WE HAD REPRESENTATIVES FROM ALL THREE ORGANIZATIONS TALK ABOUT THEIR INDIVIDUAL PROGRAMS. I THINK THE IDEA OF MOVING FORWARD WITH IMPLEMENTATION SCIENCE IS VERY EXCITING AND I THINK THAT DR. SOLOMON AND DR. SAAG BROUGHT UP SOME IMPORTANT WAYS THAT PERHAPS WE CAN IMPROVE CARE BY FOCUSING ON THE SYSTEM. FOCUSING ON THE HEALTHCARE SYSTEM AND FINANCING INCLUDING CASE MANAGEMENT MOTTLES SUCH AS FRACTURE LIAISON SERVICES. WE NEED TO INCREASE AWARENESS BY THE PATIENT, FAMILIES AND PROVIDERS INCLUDING PRIMARY CARE AND REALLY INCREASE THE UNDER STANDING OF THE MEDIA OF OUR PROBLEM AND OF THE IMPORTANCE OF THE DRUGS AND THE SAFETY OF THE DRUGS AND THE RARITY OF THESE SIDE EFFECTS. SIMPLIFY CLINICAL GUIDELINES FOLLOWING THE ASBMR EFFORT, AND OF COURSE TO PREVENT FRACTURES, WE NEED TO — DR. MILLER TALKED ABOUT FALL PREVENTION STRATEGIES AND MAKING SURE THAT THESE ARE INCORPORATED IN TO OUR PRIMARY CARE. THANK YOU VERY MUCH. IT’S BEEN A PLEASURE. [APPLAUSE] SO FIRST LET ME THANK DR. CAULEY FOR GIVING US THE FIRST WORKING DRAFT, AT LEAST, OF THE REPORT. [LAUGHTER] LET ME TURN TO THE PANELISTS FOR THE FIRST ROUND OF QUESTIONS.>>THANK YOU, EVERYONE. ARE WE MISSING A PANELIST? SO THANK YOU FOR ALL YOUR PRESENTATIONS AND YOUR WORK. I THINK ONE OF THE THINGS WE LEARNED IS THE MANY DISCIPLINES THAT MAY BE RELATED TO THE SECONDARY PREVENTION OR THE PRIMARY SCREENING OF THOSE AT RISK FOR OSTEOPOROSIS AND POTENTIAL TREATMENTS. I WAS WONDERING, WE HEARD ON A COUPLE DIFFERENT SPEAKERS MENTION SARCOPENIA. OFTEN MANY OF THE N.I.A.-SUPPORTED PRESENTATIONS I’VE ATTENDED FOCUS A LOT ON SARCOPENIA. I CAN’T HELP BUT THINK BONES AND MUSCLES MUST HAVE SOME TANGENTIAL RELATIONSHIP, AS WELL AS A LOT OF WORK ON FALLING REALLY WORKS ON BALANCE AND STRENGTH EXERCISES. SO COULD YOU MAYBE TALK ABOUT IT IN A CONTEXT ALSO OF SARCOPENIA?>>OKAY, I’LL START. SO WHEN I’M IN CLINIC, I ROUTINELY DO A SINGLE CHAIR STAND ON PATIENTS. I TELL THE POSTDOCTORAL FELLOWS, INTERNAL MEDICINE RESIDENTS, MEDICAL STUDENTS, THAT THE INABILITY TO PERFORM A SINGLE CHAIR STAND PREDICTS FALLS, PREDICTS HIP FRACTURE, PREDICTS GOING INTO A NURSING HOME AND PREDICTS MORTALITY WITHIN THE FIRST YEAR. AND THIS IS LARGELY DUE TO LOWER EXTREMITY PROXIMAL MUSCLE WEAKNESS. NOW, SARCOPENIA IS A CONSTRUCT. AND IT’S A CONSTRUCT WHICH INCLUDES EITHER MUSCLE WEAKNESS, WHICH IS EASILY MEASURED BY GRIP STRENGTH, FOR WHICH THERE ARE STANDARDIZED POPULATION NORMATIVE DATA, AS WELL AS LOW APPENDICU LA. R MUSCLE MASS MEASURED BY FULL BODY DXA AND SLOW WALKING SPEED. VAIRVARIABLY DEFINED, LESS THAN 8 METERS PER SECOND. IT’S DIFFICULT IN ROUTINE CLINICAL PRACTICE, EVEN IN A CLINICAL RESEARCH SETTING, TO MEASURE WALKING SPEED. WE’VE LAID OUT IN OUR V.A. IN THE HALLWAY THREE-METER PATH WITH BLUE TAPE ON THE FLOOR, BUT IT’S TOUGH TO INCLUDE MEASURING REGULAR AND FAST WALKING SPEED DURING ROUTINE CLINICAL VISITS. THE V.A. HAS 20 FUNDED GERIATRIC RESEARCH EDUCATION AND CLINICAL CENTERS, THE MAJORITY OF THESE INVOLVED IN REHABILITATION RESEARCH, OURS CERTAINLY IS IN BALTIMORE, AND WE HAVE EXPERTS IN MEASURING SARCOPENIA, DR. ALICE RYAN WHO USES FULL BODY DXA TO LOOK AT AP DECK LAR LEAN MASS, DR. BROCK BEMER, WHOSEs SPECIAL AREA OF INTEREST IS IN FALLS AND BALANCE RESEARCH, EXERCISE FACILITIES, ET CETERA. SO SARCOPENIA CONTRIBUTES BECAUSE IT’S A RISK FACTOR FOR FALL, AND FALL IS THE RISK FACTOR FOR NON-VERTEBRAL FRACTURES. TWO OF THE WOMEN YESTERDAY MENTIONED FALLING WHILE THEY WERE WALKING THEIR DOGS. I MENTIONED THIS TO ANNE THIS MORNING, MAYBE THAT’S SOMETHING THAT NEEDS TO BE CONSIDERED. THERE ARE BENEFICIAL EFFECTS OF HAVING PETS BUT MAYBE THERE ARE HARMFUL EFFECTS OF HAVING PETS. SO THERE’S A MUSCLE-BONE INTERACTION. DR. KIEL, I THINK, CHAIRED A SYMPOSIUM ABOUT THIS IN THE PAST. THERE’S GOING TO BE ONE NEXT YEAR IN MUSCLE-BONE INTERACTION THE DAY BEFORE THE ANNUAL MEETING. AND THIS IS CLEARLY A RESEARCH INTEREST.>>I JUST WANT TO POINT OUT, PEGGY — AND SHELLEY AND HARVARD HAVE A RESEARCH GRANT BECAUSE ONE OF THE DIFFICULTIES WITH SARCOPENIA HAS BEEN THE SO I THINK THAT’S HINDERED SOME OF THE RESEARCH IN THAT AREA. SO THEY HAVE A CONSENSUS PANEL TO DEVELOP AND RECOMMEND DEFINITIONS OF SARCOPENIA. SO I THINK THAT WILL BE COMING OUT. I KNOW WE HAVE A MEETING RIGHT BEFORE THE GERONTOLOGY MEETING IN NOVEMBER.>>I WOULD JUST ADD, THERE’S ALSO A LARGE P CORY FUNDED STUDY LOOKING AT WAYS TO REDUCE FALLS. I THINK IT’S A CRITICAL QUESTION, PERHAPS THE ONE THING WE DIDN’T EMPHASIZE ENOUGH IN THIS SERIES OF TALKS AT THIS MEETING BECAUSE AS YOU HEARD, HIP FRACTURES ARE THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN OSTEOPOROSIS AND IF YOU DON’T FALL, YOU DON’T GENERALLY BREAK YOUR HIP. SO WE’VE GOT TO FIGURE OUT A WAY TO UNDERSTAND THE BASIC BIOLOGY OF FALLS, SARCOPENIA CONTRIBUTES ALONG WITH MEDICATIONS, PERHAPS DOGS, NEUROLOGIC ISSUES, ARTHRITIS, MANY THINGS CONTRIBUTE, WE’VE GOT TO ADDRESS THAT, AND WE’VE GOT TO THINK ABOUT WHAT ARE THE INTERVENTIONS THAT WE CAN DEFINE THAT HAVE GOOD VERACITY AND GOOD GENERALIZE ABILITYD THAT WILL REDUCE THE RISK OF FALLING.&>>ALONG THOSE LINES, OFTEN OUR OLDEST OLD HAVE THE GREATEST RISK OF FALLS, AND I WAS WONDERING IF SOME OF THESE SYSTEM LEVEL INTERVENTIONS, HOW THOSE WOULD ACTUALLY APPLY TO OUR AMERICANS IN SKILLED NURSING FACILITIES, IN ASSISTED LIVING SITUATIONS, IN THOSE WHO MAY BE LESS SAVVY WITH TECHNOLOGY AND YET WHEN WE TALK ABOUT WHO WAS AT THE HIGHEST RISK, I HAVEN’T HEARD ANYBODY TALK ABOUT ALZHEIMER’S OR RELATED DEMENTIAS, AND POSSIBLY THE DIFFICULTIES IN THE TREATMENT OF THIS GROWING POPULATION.>>I’LL JUST ADD AGAIN, I THINK YOU’VE HIGHLIGHTED A KEY RESEARCH AGENDA EAMPLET I KNOW SEVERAL OF US WORK WITH INVESTIGATORS IN THE U.S. WHO JUST RECEIVED FUNDING FOR A LARGE STUDY IN PARKINSON’S DISEASE THAT I BELIEVE N.I.A. IS GOING TO SUPPORT, AND THAT’S GOING TO REALLY BE CRITICAL IN ADDRESSING SOME OF THE ISSUES YOU’RE RAISING, THAT GO BEYOND TRADITIONAL OSTEOPOROSIS RISK GROUPS BUT DEAL WITH PEOPLE WITH SERIOUS NEUROLOGIC ILLNESS THAT ARE AT A HIGH RISK FOR FALSE.>>I THINK I WOULD I WOULD COMMENT, WE’VE REPORTED FROM THE WOMEN’S HEALTH AND AGING STUDY THAT OLDER WOMEN WITH PARKINSON’S DISEASE WERE AT INCREASED RISK OF HIP FRACTURE, AND IT’S WELL RECOGNIZED THAT VARIOUS CONDITIONS THAT ARE ASSOCIATED WITH AN INCREASED RISK OF FALLS ARE RISK FACTORS FOR HIP FRACTURE. I THINK IN THESE POPULATIONS THAT YOU DESCRIBE, MORE ATTENTION NEEDS TO BE DIRECTED TOWARDS THE PROVISION OF REHABILITATION SERVICES AND ASSISTIVE DEVICES, PARTICULARLY QUAD CANES, WALKERS AND OTHER ASSISTIVE DEVICES NOrd TO TRY TO REDUCE THE RISK OF FALLS IN THIS POPULATION AS WELL AS GETTING RID OF THROW RUGS, GETTING — TRYING TO GET PEOPLE TO LIVE ON ONE LEVEL, ET CETERA, SLIPPERS AND VARIOUS AND SUNDRY SHOES AS WELL.>>I JUST WANTED TO POINT OUT, DR. SUSAN GREENSPAN, WHO HAPPENS TO BE AT THE UNIVERSITY PITTSBURGH, SHE DID A STUDY OF ZOL IN A NURSING HOME, AND IT WAS EMPOWERED TO LOOK AT FRACTURES BUT SHE DID SHOW THE DRUG WAS WELL TOLERATED IN THESE VERY OLD PATIENTS AND IT DID IMPROVE BONE DENSITY. SO THAT’S THE ONE STUDY THAT I CAN THINK OF THAT WAS DONE IN A NURSING HOME.>>I HAVE A QUESTION.>>I JUST WANTED TO ADD ONE QUICK THING, ACTUALLY THERE’S A FOLLOW-UP STUDY FOR THAT STUDY WHICH IS ACTUALLY A FRACTURE END POINT, CALLED ZES2, AND THE PARKINSON’S STUDY WHICH WAS ALLUDED TO IS REALLY A NOVEL STUDY BECAUSE IT’S GOING TO BE ALL DONE IN HOME, BOTH THE EVALUATION AND THE ADMINISTRATION OF YEARLY ZOL, AND WE ESTIMATE 20 TO 30% OF THOSE PARTICIPANTS WILL HAVE COGNITIVE DYSFUNCTION.>>QUESTION ON THE FRAX METHODOLOGY. TWO MESSAGES CAME UP THIS MORNING. ONE, THAT IT DOESN’T RECONCILE THE FALL ISSUE, AND THEN THE OTHER MESSAGE LIKE IT’S THE ONLY THING OUT THERE, SO WHAT’S THE SENSE IN TERMS OF FRAX?>>WHEN FRAX CAME OUT, I THINK WE WERE ALL VERY EXCITED BECAUSE IT HAD VALIDATED NINE RISK FACTORS AND HOW THEY INTERACTED TO PREDICT RISK. THOSE ARE VALUABLE. BECAUSE THE RISK FACTOR THEMSELVES, AND THEY’RE PRINTED OUT ON THE DXA MANS AND
MANAMACHINES, THEY NOW THINK ABOUT THOSE RISK FACTORS AND THAT’S VERY VALUABLE. I THINK ONE OF THE PROBLEMS THE FACT THAT FOR ME, IN MY PARTICULAR PRACTICE SITUATION WHERE I SEE A LOT OF PEOPLE WHO HAVE ALREADY HAD A FRACTURE, AS SOON AS THEY’VE HAD A FRACTURE, I DON’T NEED A CALCULATED FRAX SCORE, I NEED THEM WORKED UP AND TREATED. SO IT HAS LIMITATIONS AS WELL AS THE FALL ISSUE, AND I THINK THAT I CAN GATHER A LOT OF INFORMATION BY TALKING TO PATIENTS AND LOOKING AT THE BONE DENSITY, LOOKING AT THE LATERAL FILMS TO SEE — THEY HAVE A VERTEBRAL FRACTURE, AND DON’T GET — I DON’T GET A LOT OF ADDITIONAL INFORMATION FROM IT.>>I THINK FRAX HAS BEEN A MAJOR ADVANCE IN THE FIELD. IT MOVED US FROM THE IDEA OF RELATIVE RISK, WHAT A T SCORE IS, TO ABSOLUTE RISK, WHICH IS NOT HOW DO YOU COMPARE WITH THE PERSON SITTING NEXT TO YOU ABOUT WHAT’S YOUR RISK OVER THE NEXT 10 YEARS OF BREAKING SOMETHING. SO THAT’S BEEN THE BIG PUBLIC HEALTH ADVANCE. YES, IT’S IMPERFECT, IT’S IMPERFECT IN LARGE PART BECAUSE OF THE DATABASES USED TO CREATE IT. INCLUDING SOMETHING LIKE FALLS THIS THERE WOULD BE WONDERFUL, BUT IT’S NOT SYSTEMATICALLY CAPTURED IN LARGE INTERNATIONAL DATABASES, SO IT BECOMES CHALLENGING TO PULL IN ALL OF THE FACTORS THAT FORM THE LARGE REGRESSION EQUATION THAT LED TO ITS EQUATION. SO IT’S THE BEST WE HAVE, AND THERE’S OTHER SCREENING TOOLS THAT ARE OUT THERE, BUT I THINK FRAX HAS BEEN A MAJOR ADVANCE IN OUR FIELD.>>I JUST WANTED TO SPEAK TO FRAX. BEFORE FRAX, IT WAS JUST BASED ON — MAYBE TREATMENT DECISION WERE BASED ON BONE MINERAL DEPS IT BUT IT MOVES CLINICIANS TO CONSIDER NOT ONLY BONE DENSITY BUT CLINICAL RISK FACTORS, WAWS MOST OF THE LARGE COHORT STUDIES HAVE SHOWN THAT EVEN IF YOU HAVE A GOOD B.M.D. BUT YOU’VE GOT SIX RISK FACTORS, YOU HAVE A HIGH RISK OF FRACTURE. SO IT’S EXIENING COMBINING THEM,
AND THAT’S IMPORTANT.>>DID WE LOSE DR. SOLOMON? WE DID? OKAY. DR. LOMAN, DR. CHARLES? OKAY. KEN, PERHAPS THIS FALLS TO YOU. WE HAVE A RICH EVIDENCE BASE HERE IN OSTEOPOROSIS TREATMENT, DRUG TREATMENT. BUT WE ALSO HAVE SOME GAPS, AS YOU KNOW, DR. CAULEY SUMMARIZED IN HER COMMENTS. DANAZOL MON TOLD USDAN SOLOMON
TOLD US IMPLEMENTATION SCIENCE OUGHT TO BE THE FOCUS. I WAS JUST WONDERING, TO WHAT EXTENT DO YOU BELIEVE SOME OF THESE GAPS, PARTICULARLY IN TERMS OF WHO WE TREAT, WHEN WE START, WITH WHAT, IN WHAT SEQUENCE, ET CETERA, YOU KNOW, POSE BARRIERS AND ISSUES FOR AN IMPLEMENTATION SCIENCE?>>I THINK YOUR QUESTION RAISES AN IMPORTANT POINT. THAT IS I DON’T THINK WE CAN OVERSTEP THE EVIDENCE. WE’VE GOT REALLY GREAT EVIDENCE AROUND THE EFFICACY OF THE NUMBER OF VERY EFFECTIVE THERAPIES ACROSS A NUMBER OF RISK GROUPS, WHERE MANY GROUPS INCLUDING ASBMR, N.O.F., SEVERAL THAT JANE SUMMARIZED SO NICELY HAVE FOCUSED IS ON WHAT MANY OF US CONSIDER TO BE THE LOW HANGING FRUIT. AND THAT’S PEOPLE AFTER A FRACTURE. IF YOU FALL DOWN FROM STANDING AND YOU BREAK YOUR HIP, THERE’S NOT A LOT OF DEBATE THAT YOU NEED TO BE EVALUATED AND VERY MUCH LIKELY TREATED FOR OSTEOPOROSIS. THAT CONSTITUTES A FRAGILITY FRACTURE, AND THERE I THINK THERE’S NOT MUCH DEBATE ABOUT MOVING FROM EFFICACY TO EFFECTIVENESS TO SCALING THIS UP AT A NATIONAL/INTERNATIONAL LEVEL. OTHER CIRCUMSTANCES, WE MAY BE EARLIER, WE MAY NEED MORE EFFICACY DATA, WE MAY NEED TO FIGURE OUT HOW TO BETTER BALANCE RISKS AND BENEFITS AROUND SELECTED GROUPS BUT FOR PEOPLE POST FRACTURES, THOSE ON HIGH DOSE GLUCOCORTICOIDS, THESE ARE GROUPS THAT WE’VE GOT THE DATA, SO NOW WE JUST HAVE TO FIGURE OUT HOW TO TRANSLATE IT INTO PRACTICE.>>QUESTIONS FROM THE AUDIENCE?>>MY NAME IS LAURA FROM COLUMBUS, OHIO. I WANTED TO ADD ABOUT FRAX IN MY OWN PRACTICE, I FIND IT’S A VERY USEFUL IMPLEMENTATION TOOL. IT’S A VISUAL AID TO HELP PATIENTS GET A BETTER SENSE OF THEIR RISK OF FRACTURE, BUT MY QUESTION FOR THE PANEL WAS, THERE’S BEEN A LOT OF TALK ABOUT DRUG HOLIDAY AND THERE’S NOT THE REALLY BEEN ANY MENTION OF WHAT TO DO AFTER DENOSUMAB, AFTER SIX YEARS, AFTER EIGHT YEARS, THE FRACTURE DATA THAT WE HAVE ONLY GOES TO 10 YEARS KIND. I WAS JUST CURIOUS IF YOU ARE AWARE OF ANY STUDIES THAT WILL BE HELPING TO ANSWER WHAT TO DO WITH DENOSUMAB.>>THE
LONG TERM SAFETY DATA IS VERY REASSURING. I THINK SAFETY IN PRACTICE TRUMPS EFFICACY. BUT THE LONG TERM SAFETY DATA IS VERY REASSURING THAT WE JUST PUBLISHED N.O.I. NOT TOO LONG AGO. I THINK MIKE MCCLONE WAS THE FIRST AUTHOR. THE DRUG IS METABOLIZED IN THE RETICULOENDOTHELIAL SYSTEM. THERE’S NO EFFECT ON G.F.R. AND KIDNEY FUNCTION. WE’VE GOT TO WATCH THE SERUM CALCIUM IN THAT POPULATION. IN PEEMENT THAT HAVE PIEM THAT
HAVE HAD PR IOR FRACTURES, IT’S RISKY BUSINESS TO STOP. MY CONCEPT TO THE PATIENT IS, YOU AND I ARE GOING TO BE INVOLVED IN THIS FOR A LONG TIME. I’LL WORK WHEN I CAN’T WORK ANYMORE AND I TELL THEM IF FOR SOME REASON WE LOSE CONTACT BY WHATEVER REASON, OR YOU MOVE, YOU MAKE SURE YOU COMMUNICATE WITH US SO WE CAN FIND YOU A PROVIDER TO STAY ON IT. BECAUSE TO STOP IT, PARTICULARLY IF WE’VE HAD FRACTURES, IS ASSOCIATED WITH A REBOUNDING INCREASE IN FRACTURE. SO I’M LOOKING AT THIS RIGHT NOW AS LONG TERM, MAYBE LIFELONG THERAPY. I DON’T HAVE THE SAFETY DATA 20 YEARS OUT, AND THAT’S THE — BUT HOPEFULLY WE’LL BE GETTING THAT, IF THESE POPULATIONS FROM FREEDOM CONTINUE TO BE FOLLOWED.>>SO I WANTED TO THANK THE SPEAKERS AND THE PANEL FOR REALLY AN OUTSTANDING TWO DAYS. THERE WAS AN IMPORTANT, I GUESS, NUANCE OR DISCREPANCY FROM YESTERDAY THAT I WANTED TO HIGHLIGHT FROM THE PANEL, AND THAT HAS TO DO WITH WHAT WAS DISCUSSED ABOUT SHORT TERM THERAPY FOR THREE TO FIVE YEARS. SO IN DR. ROSEN’S TALK, WHERE HE SPECIFICALLY FOCUSED ON STUDIES IN PATIENTS WITH OSTEOPOROSIS BY BONE DENSITY, I.E., T. SCORE LESS THAN 2.5 OR PREVIOUS OS PRO TICK FACTORS, HE PRESENTED REALLY ROBUST EVIDENCE THAT IN THOSE PATIENTS, THE DRUGS THAT WE HAVE ARE REALLY VERY EFFECTIVE IN PREVENTING FRACTURES. THAT WAS DIFFERENT FROM WHAT WAS PRESENTED IN HER EVIDENCE REVIEW. I SPOKE WITH HER, I DON’T KNOW IF SHE’S HERE, BUT THAT EVIDENCE REVIEW ACTUALLY EXCLUDED PATIENTS WITH FRACTURES. SO IT WAS A VERY DIFFERENT POPULATION FROM THE POPULATION THAT DR. ROSEN TALKED ABOUT AND THE POPULATION THAT WE’RE ALL CONCERNED ABOUT. WE’RE NOT GOING TO BE TREATING THE PATIENTS FROM THAT EVIDENCE REVIEW. SO AS YOU DELIBERATE OVER KIND OF THE SHORT TERM FINDINGS, I THINK THAT’S AN IMPORTANT POINT KIND OF TO KEEP IN MIND BETWEEN THOSE TWO PRESENTATIONS. THANK YOU.>>QUESTION FOR DR. BAUER. FIRST A COMMENT, WHICH IS WITH REGARD TO LUMBAR SPINE B.M.D., THERE ARE CONFOUNDERS FOR LUMBAR SPINE B.M.D. FROM DEGENERATIVE CHANGES AND AORTIC CALCIFICATION, ET CETERA, THAT MAY EXPLAIN WHY IT’S LESS VALUABLE AS A PREDICTER OR POTENTIAL END POINTS THAN HIP B.M.D. IS. THE QUESTION IS WHETHER YOU’VE HAD A CHANCE TO LOOK YET ACROSS AGES OR OTHER FACTORS THAT MIGHT INDICATE WHETHER OR NOT THERE’S A DIFFERENCE IN THE EFFICACY OF B.M.D. AS A SURROGATE IN DIFFERENT SUBGROUPS.>>GREAT POINT. EVERY CLINICIAN IN THE ROOM KNOWS THAT THE HOLDER YOU GET, THE LESS PREDICTIVE SPINE B.M.D. IS BECAUSE OF THE PROBLEMS WITH ARTIFACT. MOST OF THE TRIALS INCLUDED SOME YOUNGER INDIVIDUALS SO THOSE TYPES OF AGE STRATIFICATION SHOULD BE POSSIBLE BUT WE HAVEN’T DONE THEM YET. IT’S A VERY GOOD POINT, THOUGH.>>THE COMMENT RELATES TO THE MEDIA ACTIVITY WHICH WE’VE HEARD A LOT ABOUT IN USING INAPPROPRIATELY GRAPHIC LANGUAGE ABOUT THE SIDE EFFECTS WHICH MAY �AND DOCTORS AS A RESULT OF
THAT. BUT THE OTHER VERY HARMFUL EFFECT THEY’VE HAD IS I THINK ENCOURAGING THE PERCEPTION THAT DOCTORS OFTEN CAN’T BE TRUSTED, THAT THEY SIT IN THE LABS OF PHARMACEUTICAL COMPANIES AND THEIR MOTIVES ARE NOT ALWAYS THE BEST. I REMEMBER SEEING SOME OF THE EMAILS THAT CAME THAT ELIZABETH AND SANDEEP GOT FROM PATIENTS AND THAT WAS A LARGE PART OF IT, A LACK OF TRUST IN THE PHYSICIANS, AND I’D BE INTERESTED TO HEAR A WHAT KEN AND PAUL HAVE TO SAY ABOUT THAT AND MAYBE ALSO DEBBIE. SO MAYBE I’LL ASK MY QUESTION AFTER THE ANSWER TO THAT.>>IT’S CRITICAL. YOU KNOW, WE’RE PHYSICIANS, WE TAKE CARE OF SICK PEOPLE. THEY COME IN SCARED, THEY’RE NERVOUS, THEY DON’T KNOW WHAT’S GOING TO HAPPEN TO THEM. THEY MAY NOT SHOW THAT HERE BUT THEY’RE FRIGHTENED, NO ONE WANTS TO GO TO A DOCTOR’S OFFICE. AND I THINK THAT WITH ALL THE PRESSURE THAT WE HAVE ON TIME, AND PEOPLE KNOCKING ON OUR DOORS BECAUSE IT’S A LITTLE BIT TOO MUCH TIME, I HAVE TO KEEP REMINDING ALL OF MY COLLEAGUES THAT OUR GREATEST JOB IS HOLDING THEIR HAND, LOOKING THEM IN THE EYES AND GETTING TRUST. I THINK THE OTHER COMMENT THAT I WOULD LIKE TO MAKE IS THAT IF WE EVER LOSE HUMANISM IN MEDICINE, WE LOSE THE PROFESSION.>>SO ONE OF THE THINGS WHICH HAS GOTTEN IN THE WAY OF THE PATIENT/PHYSICIAN RELATIONSHIP IS THE COMPUTER. WHICH SITS IN THE OFFICE OF EVERY HEALTHCARE PROVIDER WHO SEES A PATIENT WHO USE AN ELECTRONIC MEDICAL RECORD. NOW, THE PANEL IS ALL SITTING IN FRONT OF THEIR LAPTOPS, OKAY? WHEN YOU SEE A PATIENT, YOU SIT IN FRONT OF THE COMPUTER AND YOU’RE TYPING, AND YOU’RE NOT REALLY LOOKING AT THE PATIENT UNLESS YOU LEARNED HOW TO TOUCH- TYPE WHEN YOU WERE IN ELEMENTARY SCHOOL. WHICH I FORTUNATELY DID. SO I CAN LOOK AT THE PATIENT AND TYPE MY NOTE AS I INTERVIEW THE PATIENT, BUT MOST YOUNGER PEOPLE ARE ACTUALLY LOOKING AT THE SCREEN. AND THEY’RE NOT LOOKING AT THE PATIENT. SO THAT INTERFERES. THE SECOND, WE HEARD FROM DR. GILL YESTERDAY, THEY SPEND 20 MINUTES AT A PRIMARY CARE APPOINTMENT, SO IF YOU HAVE THE LUXURY IN ACADEMIC SED MEDALLION SIN OR WITHIN THE V.A. SYSTEM TO SPEND TIME WITH A PATIENT, YOU CAN ENGENDER MORE TRUST BECAUSE YOU CAN DISCUSS THINGS WITH THE PATIENT AND YOU CAN ENTER INTO THIS WHOLE PRINCIPLE OF SHARED DECISION-MAKING. BUT IN THE COMMUNITY, THE TRUST OF PHYSICIANS IN THE UNITED STATES HAS PLUMMETED PROBABLY TO WHERE WE’RE AROUND THE LEVEL OF CONGRESS, THE NEWS MEDIA, OR LAWYERS. [LAUGHTER]>>I WAD TO ADD TO MARC’S COMMENT, I THINK ON THE ONE HAND THERE IS SOME TENDENCY TO SORT OF BRUSH THIS OFF AS A SOCIETAL PROBLEM AND SAY WE CAN’T CHANGE THE WAY PEOPLE PERCEIVE THE CETERA, BUT IT SEEMS TO BE PREFERENTIALLY AFFECTING OSTEOPOROSIS, AND WHEN YOU LOOK AT STATINS OR PPIs, OTHER DRUGS THAT HAVE FAIRLY SERIOUS SIDE EFFECTS, THEY’RE GOING UP. PEOPLE ARE USING MORE OF THOSE DRUGS. SO I THINK THERE’S TWO IMPORTANT GROUPS THAT WE REALLY HAVE TO WORK WITH AND THIS CONFERENCE HAS BEN HIT FITTED BENEFITED BY
THAT INPUT , WAWND IS AND ONE IS PATIENTS. AS PARTNERS IN DEVELOPING THE RESEARCH. THE OTHER CRITICAL PIECE THAT MANY OF US IN THIS ROOM REGRETTABLY ARE SOMEWHAT GUILTY OF IS WE HAVEN’T HAD ENOUGH DIALOGUE WITH OUR COLLEAGUES IN PRIMARY CARE. IT’S BEEN A LITTLE BIT OF A SOUND VACUUM AND AN ECHO CHAMBER AROUND THIS DIALOGUE IN BONE HEALTH. SOME OF THE DOCS IN THE COMMUNITY FEEL LIKE THEY’VE BEEN SOLID A BAG OF GOODS WITH REGARD TO BISPHOSPHONATE SIDE EEFNGHTS AND OTHER THINGS WE JUST SIMPLY DIDN’T KNOW ABOUT WHEN WE STARTED USING THESE DRUGS. SO THE N.O.F. AND OTHER GROUPS HAVE REALLY REACHED OUT, AND I WAS DELIGHTED TO SEE DR. GIL
GILL HERE AT THIS MEETING BUT WE’VE GOT TO ENGAGE OUR COLLEAUES IN PRIMARY CARE, THEY’VE GOT TO BE PART OF THE DIALOGUE, WE’VE GOT TO SOMEHOW WORK TOGETHER BETTER TO GET THE MESSAGES OUT.>>THANK YOU. MY QUESTION IF I MAY IS TO DOUG. IF YOU GET FINALLY B.M.D. ACCEPTED AS A SURROGATE FOR DRUG TRIALS, WHAT IMPACT WILL THAT HAVE ON, A., THE NUMBER OF PEOPLE WHO NEED TO BE INVOLVED — PATIENTS WHO NEED TO BE INVOLVED, AND B., THE DURATION OF THE STUDY, AND GOING ON FROM THAT, WHAT IMPACT IS THATS GOING TO HAVE ON COLLECTING SAFETY DAY A TA? PRESUMABLY THE NUMBERS WILL BE REDUCED, THE DURATION WILL BE REDUCED AND WE’LL THEREFORE LOSE OUT ON GETTING GOOD SAFETY DATA.>>YOU’VE HIT THE NAIL ON THE HEAD AND I’LL JUST MAKE TWO QUICK OBSERVATIONS. ONE IS THAT THE FDA REQUIRES SHOCKINGLY LITTLE SAFETY DATA NOW. SO THIS WON’T CHANGE THAT. AND I CAN’T REMEMBER THE EXACT AMOUNTS BUT IT’S TWO OR 300 PEOPLE FOR SIX MONTHS IN A RANDOMIZED CONTROL TRIAL FOR SAFETY DATA. SO IT REALLY IS NOT GOING TO CHANGE THE FUNDAMENTAL ISSUE THAT THERE ARE POTENTIALLY LONG TERM PROBLEMS THAT NEED TO BE FOLLOWED IN LONG TERM FOLLOW-UP STUDIES, EITHER RANDOMIZED CONTROL TRIALS OR OTHER THINGS. SECOND, IT DOES REDUCE THE NUMBER OF INDIVIDUALS AND DURATION OF THE TRIALS DRAMATICALLY. IF WE WERE TO USE A D.M.D. END POINT, WE’RE TALKING ABOUT HUNDREDS OF PARTICIPANTS FOR UP TO TWO YEARS, PERHAPS EVEN AS EARLY AS ONE YEAR IN THE CHANGE, AS OPPOSED TO THREE TO FIVE YEARS DEPENDING ON THE FRACTURE OUTCOME. THIS IS REALLY HEAVILY DEPEND
DEPENDENT ON THE OPINIONS AN PREFERENCES OF THE FDA AND OART REGULATORY AGENCIES IN THE WORLD, SO WE ARE REALLY ON A NEW TERRITORY AND FRACTURE VALIDATION FOR SURROGATES IS QUITE DIFFERENT ACTUALLY FROM SOME OF THE OTHER ONES THAT HAVE BEEN APPROVED, FOR EXAMPLE, FOR VIRAL LOAD WHERE THERE VEILY A STRONG UNDERSTANDING OF THE UNDERLYING BIOLOGY. SO THIS IS GOING TO BE A BRAVE NEW WORLD FOR US BUT WE’RE ANXIOUS TO SEE IF WE CAN MOVE FORWARD.>>THANKS.>>A COUPLE THINGS, WURNTION I WANTED TO SAY HOW MUCH I APPRECIATED THE FOCUS ON EFFICACY AND TREATMENT FOR WOMEN 65 AND OVER AND THIS COALITION FOR PREVENTING THE SECONDARY FRACTURE, BUT THERE WERE TWO GROUPS THAT I WANT TO MAKE SURE THE PANEL THINKS ABOUT. AND ONE OF THOSE ARE THOSE WOMEN WHO ARE REALLY AT SEVERE RISK FOR VERTEBRAL FRACTURE, THAT HAVEN’T YET FRACTURED AT WHATEVER AGE AND THAT WE HAVE THESE NEWER ANABOLICS THAT THIS TREATMENT MIGHT BE THE FIRST THERAPY INSTEAD OF ALWAYS STARTING WITH THE BISPHOSPHONATE FIRST, SO JUST THE CONCEPT THAT THE REALLY HIGH RISK WOMEN NEED TO BE TREATED A LITTLE BIT DIFFERENTLY. AND SECOND, THIS CONCEPT OF PREVENTION OR TREATMENT WITH HORMONE THERAPY. THE W.H.I. ANSWERED SOME VERY IMPORTANT QUESTIONS ABOUT WHAT STANDARD DOSE DOES AND DOESN’T DO BUT IT DIDN’T REALLY ADDRESS THE LOWER DOSES, THE EFFICACY ON THE BONE, THE FACT THAT WE HAVE TRANSDERMALS THAT WE HAVE NEWER PROGESTINS, WE HAVE WAYS OF TREATING THESE HYPOESTROGENIC WOMEN DURING THAT TIME FROM MENOPAUSE TO BEFORE THEY’RE 65 OR EVEN 65 AND OLDER FOR SOME OF THEM WITH LOW DOSE HORMONE THERAPY THAT MAY BE AN OPTION SO THAT WE DON’T GET TO THE POINT WHERE THEY NEED TO BE ON A BISPHOSPHONATE. THANK YOU.>>THIS COMES FROM ONE OF OUR ONLINE VIEWERS AND IT’S DIRECTED TO DR. BAUER. IT SEEMS MOST IMPORTANT –>>CAN YOU GET A LITTLE CLOSER TO THE MIC?>>SURE. IT SEEMS MOST IMPORTANT FOR CLINICAL APPLICATION TO DETERMINE WHAT PROPORTION OF FRACTURE REDUCTION IS EXPLAINED BY CHANGES IN B.M.D. AND B.T.M.s DURING THERAPY RATHER THAN JUST DETERMINING WHETHER THEY ARE CORRELATED.>>I DON’T TOTALLY UNDERSTAND THE QUESTION BUT I THINK THAT IS ACTUALLY WHAT THE P.T.E. ANALYSES DO, THEY PROVIDE QUANTITATIVE ASSESSMENT OF THE PROPORTION OF THE TREATMENT EFFECT THAT IS EXPLAINED BY THAT MARKER. THAT IS RELATIVELY STRAIGHT FORD BUT THERE ARE NUANCE IN THE METHODOLOGY TO CALCULATE P.T.E. AND THE NUANCE AROUND THAT BUT WHAT I’LL SAY IS THE BIGGEST PROBLEM HERE IS HOW GOOD IS GOOD ENOUGH? SO IF IT’S 70% P.T.E., IS THAT GOOD ENOUGH TO MOVE FORWARD IN SURROGACY OR SOMETHING HIGHER, 80, 90%? SO THAT’S GOING TO REQUIRE AN IT ITTIVE INTERACTION WITH THE FDA. AND I HOPE I ANSWERED THAT PERSON’S QUESTION AND I APPRECIATE THEM LOOKING IN ONLINE ON US.>>SO I WOULD LIKE TO MAKE A COMMENT THAT IS AT VARIANCE WITH SOME OF THE DISCUSSION THAT JUST HAPPENED IN TERMS OF BLAMING THE PRESS, ET CETERA, FOR SOME OF OUR FAILURES. I DO NOT BELIEVE THAT FEAR OF THE SIDE EFFECTS OF OUR EFFECTIVE DRUGS IS A SUFFICIENT EXPLANATION OF WHY PATIENTS ARE FAILING TO TAKE THEM. PATIENTS TAKE THESE VERY SAME DRUGS AT THE SAME OR HIGHER DOSES WHEN PRESCRIBED BY ONCOLOGISTS. WHAT WE ARE DOING OR WHAT WE ARE NOT DOING IS WE ARE FAILING TO CONVINCE PATIENTS OF THE BENEFITS OF THERAPY AS OPPOSED TO WHAT HAPPENS IN THAT ONCOLOGY SETTING. THE PATIENTS KNOW WHY THEY’RE TAKING THE DRUG, THEY KNOW HOW IT’S GOING TO HELP THEM, AND WHAT WE HAVE NOT DONE EFFECTIVELY AS A COMMUNITY IS TO COMMUNICATE TO PATIENTS WHAT THE BENEFIT OF THERAPY IS IN A WAY THAT THEY UNDERSTAND. SO I DON’T THINK THAT IT’S JUST THE FEAR OF SIDE EFFECTS. I THINK IT’S A FAILURE TO IDENTIFY THE BENEFIT. IT’S NOT THE RISK SIDE, IT’S THE BENEFIT SIDE WHERE WE’VE FAILED.>>THANKS. I THINK FIRST OF ALL THE PATIENT HAS FRACTURED, IT’S USUALLY NOT A PROBLEM IN TERMS OF — IT’S THE PEOPLE OF THE SILENT CONDITION THAT HAVE A BONE DENSITY LEVEL AND HASN’T FRACTURED THAT WE’RE TRYING TO CONVINCE THAT THIS IS GOING TO BENEFIT THEM. THAT’S ALWAYS A CHALLENGE. THEY WON’T DENY WANT TO DENY
THEY HAVE A CONDITION THAT’S BEING ASSOCIATED WITH BEING OLD AND FRAIL.>>SO EVEN AFTER THE FRACTURE, THAT’S STILL HARD BECAUSE THEY SAY ANYONE WOULD HAVE FRACTURED IF THEY’D FALLEN THE WAY I’D FALLEN. WE HAVE REALLY NOT COMMUNICATED TO THEM THAT THEY HAVE A BIOLOGICAL SUBSTRATE THAT PREDISPOSES THEM TO INJURY.>>SO IN THE BALTIMORE HIP STUDIES, I MAILED THE RESULTS OF DXA TESTING WITH A COVER LETTER WHICH SUMMARIZED THE N.O.F. RECOMMENDATIONS THAT EVERYBODY OVER 65 WITH A HIP FRACTURE SHOULD BE TREATED FOR OSTEOPOROSIS TO ALL THE PRIMARY CARE PROVIDERS, OF ALL THE SUBJECTS THAT ENROLLED IN OUR STUDY. IT HAD NO EFFECT. SO THIS WAS NOT DIRECTED TO THE PATIENT, WHICH MAYBE IT SHOULD HAVE BEEN WITH IMPLEMENTATION SCIENCE HAD I CONSULTED WITH MY FRIEND KEN BEFORE WE DID THIS, BUT IT WAS TO THE PROVIDER AND IT DID NOT AFFECT THE PROVIDERS AT ALL. I THINK THERE’S A DIFFERENCE BETWEEN HAVING A DIAGNOSIS OF CANCER, WHERE YOU’RE GOING TO RECEIVE CHEMOTHERAPY, RADIATION THERAPY, NOW IMMUNOTHERAPY WITH NO OBSTRUCTION FROM THE INSURANCE COMPANY, BY THE WAY, ON GETTING THIS FUNDED, AND IF YOU DON’T GET ADEQUATELY TREATED, YOU’RE GOING TO DIE, AND YOU RECOGNIZE THAT YOU’RE GOING TO DIE AND YOUR FAMILY RECOGNIZES THAT YOU’RE GOING TO DIE, AND YOU’RE BEING GIVEN A POTENT BISPHOSPHONATE TO PREVENT THE COMPLICATIONS IF YOU HAVE PROSTATE CANCER, MULTIPLE MYELOMA OR METASTATIC DISEASE, AGAIN, I THINK THERE’S NOT AS MUCH RECOGNITION IN THE COMMUNITY AMONG INDIVIDUALS THAT HIP FRACTURES KILL PEOPLE, AND VERTEBRAL FRACTURES ARE SOASHTDED WITH INCREASED MORBIDITY, INCREASED MORTALITY, INCREASED RISK FOR FRACTURES. SO THERE’S BEEN POOR COMMUNICATION, BUT THERE’S ALSO BEEN AN EMPHASIS ON THE RARE ADVERSE EVENTS OF THE DRUGS WHICH SCARE PEOPLE. I WOULD SUGGEST IF YOU HAD THE SAME FOCUS ON NECROTIZING MYOSITIS WITH STATIN THERAPY, THERE WOULD BE A REDUCTION IN THE NUMBER OF PEOPLE WHO ARE TAKING LONG TERM STATINS FOR TREATMENT OF HYPERLIPIDEMIA WHERE THERE’S SOME BUT NOT GREAT EVIDENCE THAT YOU’RE GOING TO BE REDUCING MYOCARDIAL INFARCTION.>>I THINK IT’S FAIR TO SAY THAT THIS IS PROBABLY MULTIPLE FACTORS AT PLAY. LET ME TAKE ONE FINAL QUESTION FROM THE AUDIENCE AND THEN ASK DR. BERNARD TO COME UP.>>– SANTORA, FORMER MERCK EMPLOY EE. WHEN I READ READ SOME
OF THESE EVIDENCE-BASED PRESENTATION, I THINK THEY’RE VERY VALUABLE BUT THERE ARE TIMES WHEN I’M REALLY CONFUSED ABOUT LOW EVIDENCE. I GUESS IT’S A SITUATION WHERE YOU SAY, THERE JUST ISN’T ENOUGH EVIDENCE TO EVALUATE THIS QUESTION. IF THAT COULD BE DISCLOSED, THAT WOULD GO A LONG WAY FOR ME. AND ACTUALLY WOULD APPLY TO, SAY, NON-VERTEBRAL FRACTURE RISK IN A DRUG HOLIDAY. I’M PRETTY FAMILIAR WITH THAT DATA AND I WILL HONESTLY ADMIT, WE DON’T REALLY KNOW, BUT I WOULD SAY WE JUST DON’T KNOW THE ANSWER TO THAT QUESTION. THANKS.>>FAIR ENOUGH. THANK YOU. LET ME TAKE THIS OPPORTUNITY TO THANK THE SPEAKER PANEL, AND ASK MARIE BERNARD TO COME UP.>>GOOD AFTERNOON, EVERYONE. MY NAME IS RIN LINDEN JOSEPH, ONE OF THE COPLANNERS ALONG WITH DR. CHEN FROM NIAMS, I WOULD JUST LIKE TO THANK ALL THE SPEAKERS FOR ALL YOUR DEDICATION AND YOUR EFFORT AND FOR PUTTING UP WITH ALL THE EMAILS ABOUT YOUR ABSTRACT, YOUR SLIDES, YOUR TRAVEL PLANS, REALLY APPRECIATE THE EFFORT YOU GUYS PUT IN. I’D LIKE TO THANK THE PANEL IN ADVANCE FOR THE INCREDIBLE TASKS THAT YOU HAVE AT HAND TO SYNTHESIZE AND PUT IT TOGETHER, THANK YOU FOR YOUR DEDICATION AS WELL. THANK EVERYBODY FOR HANGING IN THERE, AND REALLY APPRECIATE ALL THE EFFORT THAT HAS GONE INTO THIS. I WOULD LIKE TO REMIND PEOPLE WHO ARE HERE AND ON THE WEBCAST TO CHECK THE WEBSITE AND RESPOND TO THE E.P.C. DOCUMENT FOR THE OPEN COMMENT PERIOD. IT’S GOING TO BE OPEN UNTIL NOVEMBER 27TH, SO REMIND YOU GUYS TO PLEASE COMMENT AND ADD YOUR SUGGESTIONS. LIKE TO INTRODUCE DR. MARIE BERNARD. SHE IS THE DEPUTY DIRECTOR OF THE NATIONAL INSTITUTE ON AGING, AND SHE WOULD GIVE THE CLOSING REMARKS. THANK YOU. [APPLAUSE]>>GOOD AFTERNOON, EVERYONE. FIRST I’D LIKE TO THANK YOU FOR THE INTRODUCTION, LINDEN, AND FOR THE AMAZING JOB YOU’VE DONE IN WORKING ON THIS WORKSHOP. I’D ALSO LIKE TO EXTEND THANKS TO DR. FAYE CHEN OF THE NATIONAL INTS TEUT OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, NIAMS AND NIH OFFICE OF DISEASE PREVENTION, O.D.P., FOR ALL OF THE WORK BECAUSE IT TAKES QUITE A BIT OF EFFORT TO BRING TOGETHER SUCH A WONDERFUL CONVENING SCIENTIFICALLY. I’D ALSO LIKE TO EXTEND THANKS TO NIAMS, THE O.D.P. AND OTHER FEDERAL AGENCIES RESPONSIBLE FOR SPONSORING THIS WORKSHOP. THIS IS REALLY, AS WE ALL KNOW, A VERY IMPORTANT TOPIC. IT’S MEANINGFUL TO ME NOT ONLY AS A STAFF MEMBER OF THE NATIONAL INSTITUTE ON AGING BUT AS A GERIATRICIAN WHO OVER THE LAST DECADE HAS BEEN VERY DISTRESSED TO SEAT DECREASED SEE
THE DECRE ASED TREATMENT OF THE — OFFERED TO OLDER ADULTS. AS HAS BEEN WELL SUMMARIZED, WE’VE HAD A REALLY GOOD RECAP OF SHORT AND LONG TERM USE OF DRUGS FOR OSTEOPOROSIS, DRUG THOL HOLLIDAYS, PATIENT AND CLINICIAN FACTORS THAT AFFECT MEDICATION USE AND ADHERENCE. THERE HAVE BEEN A LOT OF RESEARCH GAPS THAT HAVE BEEN IDENTIFIED. I PERSONALLY WAS REALLY STRUCK BY THE FREQUENCY WITH WHICH THE EVIDENCE-BASED PRACTICE CENTER SAID THAT THE QUALITY OF THE DATA WAS LOW OR INSUFFICIENT. SO LOTS OF OPPORTUNITIES FOR US. KUDOS, DR. SIU AND PANEL MEMBERS, FOR TAKING ON THIS REALLY MONUMENTAL TASK. IT’S REALLY GOING TO BE ARDUOUS, BUT I KNOW THAT THE STIPEND THAT WE PROVIDE YOU FROM THE GOVERNMENT WILL MORE THAN COMPENSATE FOR ALL OF THIS TIME. [LAUGHTER] AND WE, THE FEDERAL PARTNERS, WILL BE IN THE NEXT SEVERAL MONTHS DEVELOPING AN ACTION PLAN PLAN. I’D LIKE TO BRING TO YOUR ATTENTION SOME EXAMPLES, SOME ADDITIONAL EXAMPLES OF PERTINENT RESEARCH. WE’VE BEEN TALKING ABOUT FALLS AND SOME ALLUSION WAS MADE TO THE STRIDE STUDY. THE STRIDE STUDY IS A COLLABORATIVE BETWEEN PCORI, THE PATIENT-CENTERED OUTCOMES RESEARCH INSTITUTE, NIH AND N.I.A. IN PARTICULAR TAKING A LEAD THAT’S DOING A PRAGMATIC TRIAL OF FALLS PREVENTION IN 10 DIFFERENT CLINICAL SITES INVOLVING 86 DIFFERENT PRIMARY CARE PRACTICES, FOCUSING ON 5,000 PLUS SUBJECTS 70 YEARS OF AGE AND OLDER, AND THE INTENT IS TO BRING TOGETHER ALL THAT WE’VE LEARNED OVER THE YEARS ABOUT FALLS PREVENTION. THE INTENT IS TO FOLLOW SUBJECTS FOR AN AVERAGE OF AT LEAST TWO YEARS, AND THEY’VE RECRUITED THEIR SUBJECTS, THE INTERVENTION IS UNDERWAY, AND HOPEFULLY WE’LL HAVE SOME RESULTS FROM THAT IN A COUPLE YEARS THAT CAN BE APPLICABLE TO CONSIDERATIONS ABOUT OSTEOPOROTIC FRACTURES. THEN AGAIN I RECOGNIZE I’M PREACHING TO THE CHOIR HERE, YOU’RE VERY FAMILIAR WITH THE STUDY OF OSTEOPOROTIC FRACTURES, STUT DI OF MORE THAN 5,000 WOMEN STARTED IN THE EIGHTIES, FOLLOWED FOR MORE THAN 25 YEARS THAT REALLY HELPED US IDENTIFY RISK FACTORS FORM FRACTURES AND THE STUDY OF OSTEOPOROTIC FRACTURES IN MEN, AGAIN, 5,000 PLUS, STARTED IN 2002 AND STILL ONGOING WITH FOLLOW-UP. THIS REALLY HELPED US TO UNDERSTAND SOME OF THE GAPS IN STANDARD CARE FOR MEN RELATIVE TO OS PRO CYST. THE REASON I HIGHLIGHT THEM IS THAT THEY’RE GREAT EXAMPLES OF COLLABORATIVES ACROSS ENTITIES AT LEAST HERE AT NIH THAT INVOLVE THE NATIONAL INSTITUTE OF AGING, MUSCULOSKELETAL AND SKIN DISORDERS, NATIONAL CENTER FOR ADVANCEMENT OF TRANSLATIONAL SIGNS, THE NATIONAL HEART, LUNG AND BLOOD INSTITUTE AND THE NIH ROAD MAP. SO THERE HAVE BEEN EFFORTS IN THE PAST THAT HAVE BEEN COLLABORATIVE FEDERAL EFFORTS AND HOPEFULLY WE’LL SEE MORE IN THE FUTURE. SO AS LINDEN AND MANY HAVE SAID, WE REALLY THANK THE AHRQ EVIDENCE BASED PRACTICE CENTER FOR REALLY THOROUGH EVALUATION OF THE DATA, WE THANK YOU, THE INDEPENDENT PANEL, THE SPEERKS AND ALL THE PARTICIPANTS, AND WE REALLY LOOK FORWARD TO THE OUTCOMES OF ALL OF THIS AND WHAT WE WILL GET TO DO IN THE FUTURE. SO THANKS TO ALL. [APPLAUSE] EXOWRN>>LET ME MAKE A FEW CLOSING COMMENTS BEFORE WE END TODAY. MANY THANKS HAVE BEEN PROFFERED, LET ME JUST THANK MY PANELISTS IN ADVANCE FOR THE WORK THAT YOU WILL BE WORKING ON OVER THE NEXT COUPLE DAYS, PROBABLY WEEKS IN TERMS OF FINALIZING THIS REPORT. A SPECIAL THANKS TO ALL OF THE SPEAKERS. YOU HAVE MANAGED TO STAY MORE OR LESS, YOU KNOW, WITHIN OUR TIME LIMITS AND THAT ACTUALLY ALLOWED US TO GET TO THE END AND TO HEAR FROM THE SPEAKERS AT THE END OF THIS CONFERENCE IN A MEANINGFUL WAY. SO A SPECIAL THANKS TO ALL OF YOU FOR DOING THAT. I HAVE TO TELL YOU, AS A GERIATRICIAN, IT IS PARTICULARLY GRATIFYING TO ME TO HEAR A NEPHROLOGIST, DR. MILLER, TALK ABOUT — AND BEING THE GREATEST ADVOCATE THAT I’VE HEARD IN TERMS OF LOOKING AND OBSERVING PATIENTS, GETTING UP FROM A CHAIR, YOU KNOW, IN THE CONTEXT OF AN OFFICE VISIT, SO THANK YOU, DR. MILLER, FOR SHARING THAT ANECDOTE AT LEAST WITH ME. FINALLY A SPECIAL THANKS TO THE STAFF WHO’VE REALLY PULLED THIS OFF, YOU KNOW, OVER THE LAST DAY AND A HALF. A SPECIAL THANKS TO KEISHA SHOPSHREYER, WHO HAS BEEN THE MANAGER, YOU KNOW, OF THE PANELISTS AND THE MANY ASPECTS OF THIS DAY AND A HALF. WE PROBABLY COULD NOT HAVE DONE THIS WITHOUT YOU. THANK YOU ALL.

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