Osteoporosis treatment strategy using BMD and Clical Risk Factors (FRAX)

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This presentation give you the rationale as to how do we treat patients with Osteoporosis and prone to have a nontraumatic fracture

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  • Though less common in Af-Ams, the fx rate is the same in those who have osteoporosis.
  • N.b. – This is a recommendation to treat BEFORE the development of osteoporosis
  • So, Who to treat ? As per the NOF guidelines …. For T score b/w -1 to – 2.5, we go by the FRAX risk score.
  • This slide gives an overview of different therapeutic strategies for osteoporosis. Bisphosphonates act by inhibiting bone resorption. Many other modalities including estrogen, serms, calcitonin, denosumab act by inhibiting bone resorption.Few of the treatment are aimed at stimulation of bone formation . PTH analog Teriparatide is the only FDA approoved agent which is an anabolic agent.
  • The mainstay of treatment is bisphosphonates. Alendronate was the first bisphosphonates approved in US f/b rise.., f/b iband…and the most recent one is zoledronate.
  • From medical department approved MCO Slide set. 38 United States Centers, randomized, open label, preference study that evaluated Fosamax 10mg once-daily versus Fosamax 70mg once-weekly. Women with postmenopausal osteoporosis were enrolled to receive 9 weeks of treatment in crossover fashion. Each woman received 4 weeks with each study regimen separated by a 1 week washout period             Page 1873  Simon JA, et al. Clin Ther. 2002;24:1871-1886
  • From medical department approved MCO Slide set. Standard deviations weekly (  4.8%) monthly (  4.8%) Patients who preferred monthly more likely to be younger 50-64 p = 0.05; employed full time p =0.017; initiated therapy <3 yrs ago p = 0.009 Page 33 Simon JA et al. The Female Patient 2005;30:31-6.
  • Source: Boniva ® (ibandronic acid) Clinical Study Report BALTO I (Protocol MA 17843 Research Report 1018546). Pages 42 -43. Ibandronate CI 65.7, 76.6 The primary analysis of the primary endpoint was analyzed using Gart’s test which excluded patients who did not express an opinion for one treatment over the other (see Section 2.9.6.1). Two hundred seventy six patients were included in this analysis and 22 patients were excluded because they did not express a preference for either treatment regimen. Of those patients who expressed a preference for one treatment over the other (92.6% of the patients declared a preference), significantly more patients preferred the 150 mg once-monthly oral ibandronate tablet (71.4%, n= 197, 95% CI 65.7, 76.6) than the 70 mg once-weekly oral alendronate tablet (28.6%, n = 79) ( P <0.0001). The order of intake of the two medications did not have an impact on patient preference for once-monthly ibandronate over once-weekly alendronate (Gart-order-effect P =0.1855).
  • Significantly more women found it more convenient to take once-monthly ibandronate than once-weekly alendronate (74.6% versus 25.4%, P<0.0001). Two hundred sixty-four patients were included in the primary analysis of convenience. Thirty-two patients (10.8%) were excluded from this analysis as they considered the two treatments to be equally convenient (Table 16). The order of the intake of the two medications did not have an impact on this opinion (Gart-Order-Effect P =0.1570).
  • Clinical expertise IS important! Why? Experience with patients: improves efficiency of diagnosis and treatment Improves ability to determine applicability of research data to your patients Allows consideration of patient preferences EBM is the process of systematically finding the most recent applicable research, appraising its validity, and using it as the basis for clinical decisions. Clinical Expertise improves efficiency of Dx and Rx considers patient preferences Overestimates usefulness of therapy -
  • 16/07/13 01:01 Slide 30: Zoledronic Acid 5 mg Clinical Program The robust clinical development program for zoledronic acid 5 mg includes studies for the treatment of Paget’s disease (core study completed, 1 extension study results forthcoming), postmenopausal osteoporosis, osteogenesis imperfecta, corticosteroid-induced osteoporosis, prevention of recurrent hip fractures, and male osteoporosis. Other additional trials under way are not shown here. Zoledronic acid 5 mg is not approved for postmenopausal osteoporosis, male osteoporosis, corticosteroid-induced osteoporosis, prevention of recurrent hip fracture, or osteogenesis imperfecta, as of 1 March 2006. Reference 1. Reid I, Miller P, Fraser W, et al. Comparison of a single infusion of zoledronic acid with risedronate in Paget’s disease. N Engl J Med. 2005;353:898-908.
  • 16/07/13 01:01 以下就是今天五月甫發表於 NEJM 有關於 Zoledronic acid 應用於骨鬆治療 的文獻資料
  • Cumulative Risk of Hip Fracture (Strata I & II) ZOL 5 mg reduced the relative risk of incurring a hip fracture over time by 41% compared with placebo (hazard ratio=0.59; P = .0024). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
  • Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Assessment of number of clinical fractures (painful fractures that led to an office evaluation) occurring over 3 years revealed that a single annual infusion of ZOL 5 mg reduced the risk of clinical vertebral fractures by 77% compared with placebo over 3 years ( P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
  • Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Incidence of clinical non-vertebral fractures was significantly reduced (approximately 25%) over 3 years with ZOL 5 mg treatment compared with placebo ( P = .0002; estimated hazard ratio of 0.75). The most frequent fracture locations were wrist, hip, arm, and rib. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
  • 16/07/13 01:01 看完臨床的資料後,再來看看從骨鬆患者的角度對於這種一年一次靜脈注射的骨鬆治療的看法,這是 2006 於歐洲 ECCEO 所發表的資料 : 以下資料就是 Lindsay 等人分別針對骨鬆患者對一週一次口服 alendronate 70 mg (n = 59) 與一年一針的 Zoledronic acid 5 mg (n = 69) 之喜好度進行為期二十四週的研究,每一位患者會在研究結束後,針對下列方便性、滿意度、長期接受意願及喜好程度等四個問題做回答 1 根據這個多中心、隨機、雙盲的研究結果顯示,整體而言將近有 66.4% 的人 (N = 122) 表示比較喜愛一年一針的治療,另有 19.7% 則是比較喜愛一週一次口服治療,至於其他的 13.9% 則無特別的喜好。 因此,不論是從患者的角度,還是從臨床的角度,都支持 Zoledronic acid 5 mg 這種一年一針的 IV 劑型應用於骨鬆治療的潛力,也請各位醫師們可向患者推薦這種創新、又方便的治療,以有效改善患者醫囑性不佳的老問題,因為惟有持續的治療,才能有效控制骨鬆、達到避免骨鬆惡化、預防骨折的目的 ! Reference 1. Lindsay R, Saag K, Kriegman A, Davis J, Beamer E, Zhou W. A single zoledronic acid 5-mg infusion is preferred over weekly 70 mg oral alendronate in a clinical trial of postmenopausal women with osteoporosis/osteopenia. Poster presented at: 6th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 15-18, 2006; Vienna, Austria.
  • Osteoporosis treatment strategy using BMD and Clical Risk Factors (FRAX)

    1. 1. Rachmat Gunadi WachjudiRachmat Gunadi Wachjudi Divisi ReumatologiDivisi Reumatologi Departemen Ilmu Penyakit DalamDepartemen Ilmu Penyakit Dalam Rumah Sakit Dr Hasan Sadikin BandungRumah Sakit Dr Hasan Sadikin Bandung Critical Challenges in OsteoporosisCritical Challenges in Osteoporosis
    2. 2. What’s osteoporosis?What’s osteoporosis? ► Loss of bone mineral density and destruction of boneLoss of bone mineral density and destruction of bone matrix micro-architecturematrix micro-architecture ► Clinically important disease that increases risk ofClinically important disease that increases risk of fracturefracture ► What about “osteopenia”?What about “osteopenia”? – Old term for “low boneOld term for “low bone mineral density”mineral density” – Not technically a diseaseNot technically a disease
    3. 3. Breaking news:Breaking news: ►We’re getting old!We’re getting old! – 1 in 2 white* women and 1 in 5 men will1 in 2 white* women and 1 in 5 men will have an osteoporotic fracturehave an osteoporotic fracture ►It costs a ton!It costs a ton! – 432,000 hospital admissions432,000 hospital admissions – 180,000 nursing home admissions180,000 nursing home admissions – $17 billion in cost$17 billion in cost ►We can prevent and treat it!We can prevent and treat it!
    4. 4. National OsteoporosisNational Osteoporosis FoundationFoundation Screen with DXA:Screen with DXA: ►Women 65 and older, men 70 and olderWomen 65 and older, men 70 and older ►Anyone 50-69 whose profile increasesAnyone 50-69 whose profile increases riskrisk •Thanks, NOF!Thanks, NOF!
    5. 5. How are results reported?How are results reported?
    6. 6. Who needs treatment?Who needs treatment? ► Anyone with diagnosed osteoporosisAnyone with diagnosed osteoporosis – T-score at hipT-score at hip ≤ -2.5 (ignore Z score)≤ -2.5 (ignore Z score) – Fragility fracture (what’s this?!)Fragility fracture (what’s this?!) ► NOF recommends treating in LBMD if highNOF recommends treating in LBMD if high FRAX risk of fracture:FRAX risk of fracture: – 3% for hip3% for hip OROR – 20% major osteoporosis-related fracture.*20% major osteoporosis-related fracture.* FRAX toolFRAX tool
    7. 7. Clinical Risk FactorsClinical Risk Factors Femoral neck T-scoreFemoral neck T-score ++ ► AgeAge ► Previous low trauma fracturePrevious low trauma fracture ► Current cigarette smokingCurrent cigarette smoking ► Rheumatoid arthritisRheumatoid arthritis ► High alcohol intake (> 2 units/day)High alcohol intake (> 2 units/day) ► Parental history of hip fractureParental history of hip fracture ► Prior or current glucocorticoid usePrior or current glucocorticoid use Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.
    8. 8. OSC Guideline, 2002 Major and Minor Risk FactorsMajor and Minor Risk Factors MajorMajor MinorMinor Age > 65Age > 65 Rheumatoid arthritisRheumatoid arthritis Vertebral compression fractureVertebral compression fracture History of hyperthyroidismHistory of hyperthyroidism Fragility fracture after age 40Fragility fracture after age 40 Anticonvulsant therapyAnticonvulsant therapy Family history of osteoporsis/ #Family history of osteoporsis/ # Low dietary calcium intakeLow dietary calcium intake Steroids > 3 monthsSteroids > 3 months SmokingSmoking MalabsorptionMalabsorption Excess caffeine intakeExcess caffeine intake Primary hyperparathyroidismPrimary hyperparathyroidism Weight < 57 kgWeight < 57 kg Propensity to fallPropensity to fall Weight loss > 10%Weight loss > 10% Osteopenia on x-rayOsteopenia on x-ray Chronic heparin therapyChronic heparin therapy HypogonadismHypogonadism Early menopause (< age 45)Early menopause (< age 45)
    9. 9. Intervention ThresholdIntervention Threshold ►A fracture probability above whichA fracture probability above which it isit is cost-effectivecost-effective to treat withto treat with pharmacological agentspharmacological agents ►Based on statistical modeling usingBased on statistical modeling using many medical, social, andmany medical, social, and economic assumptionseconomic assumptions
    10. 10. •Canadian Guidelines RecommendCanadian Guidelines Recommend
    11. 11. Who to treat ?Who to treat ? •Prior h/o hip/vertebral #Prior h/o hip/vertebral #•Prior h/o hip/vertebral #Prior h/o hip/vertebral # •oror•oror •T Score < -2.5T Score < -2.5•T Score < -2.5T Score < -2.5 •oror•oror •T Score -1 to -2.5 &T Score -1 to -2.5 & •10 yr risk (FRAX) :10 yr risk (FRAX) : •HIP # > 3 % orHIP # > 3 % or •major osteoporotic # > 20 %major osteoporotic # > 20 % •T Score -1 to -2.5 &T Score -1 to -2.5 & •10 yr risk (FRAX) :10 yr risk (FRAX) : •HIP # > 3 % orHIP # > 3 % or •major osteoporotic # > 20 %major osteoporotic # > 20 % •Postmenopausal women /men > 50 yrsPostmenopausal women /men > 50 yrs •witwit hh
    12. 12. • •Anti-resorptive Anti-resorptive •Anabolic Anabolic •‘‘Dual action’ Dual action’
    13. 13. •Bone marrow precursorsBone marrow precursors •OsteoblastsOsteoblasts •OsteoclastOsteoclast •Lining cellsLining cells Stimulators ofStimulators of Bone FormationBone Formation • FluorideFluoride • PTH analogsPTH analogs • Sr Ranelate (?)Sr Ranelate (?) •Inhibitors ofInhibitors of •Bone ResorptionBone Resorption • Estrogen, SERMsEstrogen, SERMs • BisphosphonatesBisphosphonates • CalcitoninCalcitonin •Inhibitors ofInhibitors of •RANKLRANKL •Cathepsin KCathepsin K Therapeutic strategiesTherapeutic strategies
    14. 14. •Treatments & EfficacyTreatments & Efficacy Vertebral Fx Non-vertebral Fx Other Fx Hip Fx Oral HRT Yes Yes Yes Etidronate* Yes Alendronate* Yes Yes Yes Risedronate* Yes Yes Yes Ibandronate* Yes [Yes] Raloxifene* Yes Calcitriol* Yes Strontium Ranelate* Yes Yes [Yes]
    15. 15. Vertebral Fx Non-vertebral Fx Other Fx Hip Fx Subcutaneous Teriparatide* Yes Yes 1-84 PTH* Yes Denosumab* Yes Yes Yes Intravenous Pamidronate Ibandronate* Zoledronate* Yes Yes Yes Intranasal or Subcutaneous Calcitonin* Yes
    16. 16. Vertebral Fx Nonvertebral Fx Other Fx Hip Fx Alendronate* Yes Yes Yes Risedronate* Yes Yes Yes Zoledronic acid* Yes Yes Yes PTH* Yes Yes ??? Strontium ranelate* Yes Yes ??? Denosumab* Yes Yes Yes Appropriate use of appropriate treatmentsAppropriate use of appropriate treatments cancan halvehalve the incidence ofthe incidence of fracturesfractures * plus calcium + vitaminD* plus calcium + vitaminD
    17. 17. Mainstay of treatmentMainstay of treatment :: BisphosphonatesBisphosphonates Approval in US for osteoporosisApproval in US for osteoporosis ►Alendronate : 1995Alendronate : 1995 ►Risedronate : 2000Risedronate : 2000 ►Ibandronate : 2005Ibandronate : 2005 ►Zoledronate : 2007Zoledronate : 2007
    18. 18. DefinitionsDefinitions ► Initiation-Initiation- Getting the prescription filled.Getting the prescription filled. About 10% of prescriptions are neverAbout 10% of prescriptions are never filled.filled. ► Adherence-Adherence- Taking the medicine.Taking the medicine. Often defined as taking more than 80% ofOften defined as taking more than 80% of pills over a specified period of time.pills over a specified period of time. ► Compliance-Compliance- Taking the pills correctly.Taking the pills correctly. Important issue with bisphosphonates.Important issue with bisphosphonates. ► Persistence-Persistence- Still taking the pills.Still taking the pills. Often measured at the one year time point.Often measured at the one year time point.
    19. 19. Non-AdherenceNon-Adherence How Large is The Problem?How Large is The Problem? Studies of patient behavior show thatStudies of patient behavior show that LESS THAN 50%LESS THAN 50% of the people who leave a doctor'sof the people who leave a doctor's office with a prescriptionoffice with a prescription adhere and comply with drug therapyadhere and comply with drug therapy
    20. 20. Simons, et al MJA 1996; 164:208. n = 610 Persistence with Lipid-LoweringPersistence with Lipid-Lowering TherapyTherapy 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 Months on lipid lowering therapy %persisting
    21. 21. The Effects of Non-AdherenceThe Effects of Non-Adherence 1) Poor patient outcomes due to1) Poor patient outcomes due to sub-optimal therapeutic responsesub-optimal therapeutic response 2) Increased cost burden to society2) Increased cost burden to society Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97
    22. 22. Poor Patient OutcomesPoor Patient Outcomes ► Increased Morbidity due to diseaseIncreased Morbidity due to disease “exacerbations”“exacerbations” ► More treatment “Failures” with potential forMore treatment “Failures” with potential for addition or switching of medications due toaddition or switching of medications due to perceived inefficacyperceived inefficacy ► More frequent Physician VisitsMore frequent Physician Visits ► Increased HospitalizationsIncreased Hospitalizations ► Excess MortalityExcess Mortality Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97
    23. 23. What Are the Possible Causes ofWhat Are the Possible Causes of Poor Adherence?Poor Adherence? Disruption to daily routine? (need for frequent dosing) Concern about side effects? “Target disease" eclipsed by other chronic conditions? Lack of positive reinforcement? Complex dosing guidelines? Poor patient education (Health Illiteracy) POOR ADHERENCE
    24. 24. Health Literacy *(Selden et al. 2000; Healthy People 2010, HHS 2000; Ratzan & Parker 2000) **(Institute of Medicine report- 2004) The degree to which individuals have the capacity toThe degree to which individuals have the capacity to obtain, process, and understand basic information andobtain, process, and understand basic information and make appropriate decisions about their health*make appropriate decisions about their health* 90 million people in the United States, nearly half of all90 million people in the United States, nearly half of all adults, have difficulty understanding and using healthadults, have difficulty understanding and using health information**information**
    25. 25. Patient Beliefs Affect CompliancePatient Beliefs Affect Compliance ► Don’t believe diagnosis or the seriousnessDon’t believe diagnosis or the seriousness of the diagnosisof the diagnosis ► Believe other diseases are more importantBelieve other diseases are more important ► Believe side effects outweigh benefitsBelieve side effects outweigh benefits ► Concerned about their ability to carry outConcerned about their ability to carry out recommended actionrecommended action AARP Survey, 1985 National Prescription Buyers’ Survey, USA 1985
    26. 26. Lack of CommunicationLack of Communication ► Study of 300 medical encounters:Study of 300 medical encounters: doctorsdoctors spent average 1.3 minutes givingspent average 1.3 minutes giving informationinformation11 ► Study of 264 visits to family physicians.-Study of 264 visits to family physicians.- during patient initial statement of theduring patient initial statement of the problem,problem, physician interrupted afterphysician interrupted after average of 23 seconds.average of 23 seconds.22 ► 50% of50% of patientspatients leave office visitleave office visit notnot understandingunderstanding what the doctor saidwhat the doctor said33 Clement, Diab Care 1995;18:1204. Waitzkin. JAMA 1984;252:24411 Kravitz et al. Arch Intern Med 1993;153:1869. 2 Roter and Hall. Ann Rev Public Health 1989;10:163. Marvel JAMA 1999;281:283. 3
    27. 27. Nonadherence toNonadherence to Osteoporosis Medications:Osteoporosis Medications: How Common Is It?How Common Is It?
    28. 28. Adherence With OsteoporosisAdherence With Osteoporosis Medications Is Sub-optimalMedications Is Sub-optimal Tosteson ANA, et al. Am J Med. 2003;115:209-216. 20% to 25% of Patients Abandon Therapy Within 7 Months20% to 25% of Patients Abandon Therapy Within 7 Months PatientsAbandoning Treatment(%) 30 25 20 15 10 5 0 Hormone Replacement Therapy (n=334) Bisphosphonate (n=366) Selective Estrogen Receptor Modulator (n=256) Telephone survey of 956 randomly selected women with postmenopausal osteopenia or osteoporosis who initiated therapy in 2000-2001. Mean follow-up was 7 months. 26% 19% 19%
    29. 29. Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325. A HIPAA-compliant, longitudinal patient database of prescriptions dispensed from ~25% of US retail pharmacies was used to assess discontinuation of bisphosphonates over a 12-month period in women aged ≥50 years.* * Primary usage in osteoporosis; however, data may include use in other indications. Adherence With Oral Bisphosphonates IsAdherence With Oral Bisphosphonates Is Suboptimal, Regardless of DosingSuboptimal, Regardless of Dosing Percentage of Patients on Therapy (defined as having at least 1 day of medication supply in the month) P<0.001 vs daily therapy 10 20 30 40 50 60 70 80 90 100 Oct 2002 Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct 2003 PatientsonTherapy(%) Daily Bisphosphonates (n=33,767) Weekly Bisphosphonates (n=177,552) 54.6% 36.9%
    30. 30. Surgeon General’s Report Cites Need toSurgeon General’s Report Cites Need to Improve Adherence With Osteoporosis TherapiesImprove Adherence With Osteoporosis Therapies ► Long-term adherence rates withLong-term adherence rates with any medication are poor (~50%)any medication are poor (~50%) ► Follow-up strategies thatFollow-up strategies that improve adherence to should beimprove adherence to should be applied to osteoporosisapplied to osteoporosis – Simplifying the treatmentSimplifying the treatment regimenregimen – CounselingCounseling – Addressing patient concernsAddressing patient concerns about side effectsabout side effects – Maintaining an encouragingMaintaining an encouraging provider-patient relationshipprovider-patient relationship US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; 2004.
    31. 31. Non-Adherence to OsteoporosisNon-Adherence to Osteoporosis Medication Affects BMDMedication Affects BMD 0 0.5 1 1.5 2 2.5 3 3.5 4 Compliant Non-compliant Yood R, et al Osteoporosis int 14:2003. 965-68 LumbarLumbar BMDBMD
    32. 32. Non-Adherence to OsteoporosisNon-Adherence to Osteoporosis Medication Increases Fracture RiskMedication Increases Fracture Risk 3.4 3.6 3.8 4 4.2 4.4 4.6 Non-compliant Compliant 11,249 women suffering from osteoporosis with a mean age of 68.4 years and average follow-up of 2 years 16% decrease Caro JJ et al. Osteoporosis Int 14, 2003, Suppl 7 Fracture Rate %
    33. 33. * P<0.0001. † Compliant is defined as taking medication ≥80% of the time over a 24-month period. Retrospective cohort study that used longitudinal medical and pharmacy claims data from Medstat MarketScan® Research Databases to assess adherence and fracture risk over 24 months (1999-2003). Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC. Better Long-term Compliance ReducesBetter Long-term Compliance Reduces the Risk of Fracturethe Risk of Fracture Compliance With Bisphosphonates and Fracture Risk Over 2 Years in Women ≥45 Years With Postmenopausal Osteoporosis (n=6825) %PatientsWithFracture 0 2 4 6 8 10 12 14 Compliant Noncompliant (n=3400) (n=3425) * † 9.4% 12.6%
    34. 34. How Can AdherenceHow Can Adherence Be Improved?Be Improved?
    35. 35. Improving Adherence byImproving Adherence by Reinforcing Treatment EfficacyReinforcing Treatment Efficacy ►Patient monitoring may be helpfulPatient monitoring may be helpful inin demonstrating effects ofdemonstrating effects of treatmenttreatment1-31-3 – BMDBMD – Biochemical markers of boneBiochemical markers of bone turnoverturnover ►Frequent visits or calls from staffFrequent visits or calls from staff 1. Clowes et al. JCEM. 2004;89:1117-1123). 2. Deal CL. Curr Rheumatol Rep. 2001;3:233-239. 3. Chapurlat RD, Cummings SR. Osteoporos Int. 2002;13:738-744.
    36. 36. Improving Adherence Through Modifying DosingImproving Adherence Through Modifying Dosing Interval: Focus on BisphosphonatesInterval: Focus on Bisphosphonates ►Survey data suggests that patientsSurvey data suggests that patients prefer more widely-spaced dosingprefer more widely-spaced dosing intervalsintervals ►Retrospective data suggest improvedRetrospective data suggest improved adherence with once-weekly versusadherence with once-weekly versus daily bisphosphonatesdaily bisphosphonates ►To date, there are no prospective dataTo date, there are no prospective data demonstrating that extended dosingdemonstrating that extended dosing regimens improve patient adherenceregimens improve patient adherence and clinical outcomesand clinical outcomes
    37. 37. Women Preferred Weekly over DailyWomen Preferred Weekly over Daily ►288 postmenopausal women with osteoporosis288 postmenopausal women with osteoporosis – 4 weeks of alendronate Weekly followed by 4 weeks alendronate Daily4 weeks of alendronate Weekly followed by 4 weeks alendronate Daily – 4 weeks of alendronate Daily followed by 4 weeks alendronate Weekly4 weeks of alendronate Daily followed by 4 weeks alendronate Weekly ►At the final visit, patients completed a preference studyAt the final visit, patients completed a preference study questionnaire: Which Treatment Routine…questionnaire: Which Treatment Routine… AlendronateAlendronate Simon JA et al Clin Ther 2002;24:1871-1886 86.4% 89.0% 87.5% 9.2% 7.7% 8.5% 4.4% 3.3% 4.0% 0 20 40 60 80 100 Once weekly Once daily No preference Do You Prefer?Do You Prefer? Patients(%)Patients(%) Is More Convenient?Is More Convenient? Would Be Easier toWould Be Easier to Comply With For aComply With For a Long Period of Time?Long Period of Time?
    38. 38. 33% Once a monthOnce a month Once a weekOnce a week Women Preferred Monthly over WeeklyWomen Preferred Monthly over Weekly Dosing Schedule PreferenceDosing Schedule Preference (n = 367)*(n = 367)* p <0.001p <0.001 ** Among women expressing a preference, 67% prefer once-a-month dosing,Among women expressing a preference, 67% prefer once-a-month dosing, a statistically significantly higher proportion than the 33% who prefer once-a-week dosinga statistically significantly higher proportion than the 33% who prefer once-a-week dosing Patients Say They Prefer a Once-a-monthPatients Say They Prefer a Once-a-month Over a Once-a-week Dosing ScheduleOver a Once-a-week Dosing Schedule 67% Simon JA et al Female Patient 2005;30:31-6
    39. 39. * p < 0.0001 vs alendronate* p < 0.0001 vs alendronate Excludes those patients who did not express a preference for one treatment / m ITT populationExcludes those patients who did not express a preference for one treatment / m ITT population Twenty-two patients did not express preferenceTwenty-two patients did not express preference Patient Preference: Ibandronate MonthlyPatient Preference: Ibandronate Monthly vs Alendronate Weeklyvs Alendronate Weekly 28.6% 71.4%* 0 10 20 30 40 50 60 70 80 Ibandronate Alendronate Preferred TreatmentPreferred Treatment Patients(%)Patients(%) n = 197 n = 79 Emkey R et al Curr Med Res Opin. 2005 Dec;21(12):1895-903 (Patients Expressing Preference)(Patients Expressing Preference)
    40. 40. * p < 0.0001 vs alendronate* p < 0.0001 vs alendronate Excludes those patients who did not express a preference for treatmentExcludes those patients who did not express a preference for treatment Thirty-two patients found both treatments equally convenientThirty-two patients found both treatments equally convenient 25.4% 74.6%* 0 10 20 30 40 50 60 70 80 Ibandronate Alendronate More Convenient TherapyMore Convenient Therapy Patients(%)Patients(%) n = 197 n = 67 Patient Preference: Ibandronate MonthlyPatient Preference: Ibandronate Monthly vs Alendronate Weeklyvs Alendronate Weekly (Those Expressing Convenience)(Those Expressing Convenience) Emkey R et al Curr Med Res Opin. 2005 Dec;21(12):1895-903
    41. 41. Principles of Evidence-Based MedicinePrinciples of Evidence-Based Medicine ►AcquireAcquire the Evidencethe Evidence ►CriticallyCritically AppraiseAppraise the Evidencethe Evidence ►ApplyApply the Evidence to the Individualthe Evidence to the Individual PatientPatient
    42. 42. Evidence-Based Medicine: Integrate FindingsEvidence-Based Medicine: Integrate Findings With Clinical Expertise and Patient NeedsWith Clinical Expertise and Patient Needs Clinical Expertise Research Evidence Patient Preferences Rx Adapted from: Sackett DL et al. Evidence-Based Medicine: How to Practice and Teach EBM. 2nd ed. Churchill Livingstone; 2000
    43. 43. Bisphosphonate algorithmBisphosphonate algorithm
    44. 44. A cure for every ailmentsA cure for every ailments
    45. 45. Zoledronic acid 5 mgZoledronic acid 5 mg IV once a yearIV once a year
    46. 46. Once Yearly Zoledronic Acid ReducesOnce Yearly Zoledronic Acid Reduces FracturesFractures HORIZON Pivotal Fracture TrialHORIZON Pivotal Fracture Trial Multi-national, multi-center, RCTMulti-national, multi-center, RCT 7,736 women age 65-89 with T-score < -2.57,736 women age 65-89 with T-score < -2.5 or fracture plus T-score < -1.5or fracture plus T-score < -1.5 Calcium 1000-1500 mg/day vit D (400-1200Calcium 1000-1500 mg/day vit D (400-1200 IU/day)IU/day) Zoledronic acid IV infusion 5 mgZoledronic acid IV infusion 5 mg Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007
    47. 47. ZOLZOL reducesreduces hiphip fracturefracture •*Relative risk reduction (95% confidence interval) vs placebo*Relative risk reduction (95% confidence interval) vs placebo •Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007 •PP = .0024= .0024 •11 •22 •33 •00 •Placebo (n = 3861)Placebo (n = 3861) ZOL 5 mg (n = 3875)ZOL 5 mg (n = 3875) •CumulativeIncidence(%)CumulativeIncidence(%) •Time to First Hip Fracture (months)Time to First Hip Fracture (months) •00 •33 •66 •99 •1212•1515•1818•2121•2424•2727•3030•3333•3636 •41%*41%* (17%, 58%)(17%, 58%)
    48. 48. •PP < .0001< .0001 •CumulativeIncidence(%)CumulativeIncidence(%) •Time to First Clinical Vertebral Fracture (months)Time to First Clinical Vertebral Fracture (months) •00 •33 •66 •99 •1212•1515•1818•2121•2424•2727•3030•3333•3636 •77%77% (63%, 86%)(63%, 86%) •Placebo (n = 3861)Placebo (n = 3861) ZOL 5 mg (n = 3875)ZOL 5 mg (n = 3875) •11 •22 •33 •00 ZOLZOL reducesreduces vertebralvertebral fxfx •*Relative risk reduction (95% confidence interval) vs placebo*Relative risk reduction (95% confidence interval) vs placebo •Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007
    49. 49. •PP = .0002= .0002 •Time to First Clinical Non-vertebral Fracture (months)Time to First Clinical Non-vertebral Fracture (months) •22 •44 •66 •88 •11 00 •1212 •00 •33 •66 •99 •1212 •1515 •1818 •2121 •2424 •2727 •3030 •3333 •3636 •25%25% (13%, 36%)(13%, 36%)•Placebo (n = 3861)Placebo (n = 3861) ZOL 5 mg (n = 3875)ZOL 5 mg (n = 3875) •00 •CumulativeIncidence(%)CumulativeIncidence(%)ZOLZOL reducesreduces non-vertebralnon-vertebral fxfx •*Relative risk reduction (95% confidence interval) vs placebo*Relative risk reduction (95% confidence interval) vs placebo •Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007
    50. 50. Zoledronic Acid willZoledronic Acid will ImproveImprove PatientPatient ComplianceCompliance asas Once-Yearly IV Therapy is PreferredOnce-Yearly IV Therapy is Preferred •Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria. •16.416.4 •18.918.9 •Both Are EqualBoth Are Equal •Once-Yearly IVOnce-Yearly IV •Once-Weekly PillOnce-Weekly Pill •MoreMore convenientconvenient •More willingMore willing to take longto take long termterm •OverallOverall preferencepreference •N = 122N = 122 •66.466.4 •59.859.8 •00 •2020 •4040 •6060 •8080 •100100 •68.068.0 •66.466.4 •15.615.6 •18.018.0 •20.520.5 •15.615.6 •19.719.7 •13.913.9 •% of Patients% of Patients •MoreMore satisfyingsatisfying
    51. 51. 56 J Bone Miner Res. 2012;27:240–242J Bone Miner Res. 2012;27:240–242 •HORIZON-PFT 3-years data:HORIZON-PFT 3-years data: •Black DM, et al.Black DM, et al. N Engl J MedN Engl J Med. 2007;356:1809-1822. 2007;356:1809-1822 •(HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly)(HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly) •HORIZON-Pivotal Fracture Trial ExtentionHORIZON-Pivotal Fracture Trial Extention
    52. 52. 57 • 3-year, randomized, double-blind, placebo-controlled extension trial3-year, randomized, double-blind, placebo-controlled extension trial • 2456 postmenopausal women2456 postmenopausal women • Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3 • Secondary endpoints: BMD at other sites, BTMs, fracture incidence,Secondary endpoints: BMD at other sites, BTMs, fracture incidence, safetysafety •HORIZON-PFT Extension: StudyHORIZON-PFT Extension: Study OverviewOverview Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242
    53. 53. 58 •Primary Endpoint:Primary Endpoint: •% Change of ZOL 5 mg Treatment% Change of ZOL 5 mg Treatment in Femoral Neck BMDin Femoral Neck BMD •at Years 6 VS Years 3at Years 6 VS Years 3 *P < 0.0001, P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables*P < 0.0001, P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables **P value computed from 2-way ANOVA with treatment and region as explanatory variables.**P value computed from 2-way ANOVA with treatment and region as explanatory variables. MITT = modified intention to treatMITT = modified intention to treat 11 Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822 22 Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242 Z6 n= 589 609 608 600 524 450 Z3P3 n= 599 613 606 602 540 467 Z3 n= 3851Z3 n= 3851 PBO n= 3845PBO n= 3845
    54. 54. 59 ZOL n= 268 262 236 228 PBO n= 265 258 226 212 Z6 n= 101 100 Z3P3 n= 102 84 ZOL n= 268 262 236 228 PBO n= 265 258 226 212 Z6 n= 101 100 Z3P3 n= 102 84 *P = 0.1910 **P < 0.0001*P = 0.1910 **P < 0.0001 11 Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822 22 Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242 •Secondary Endpoint:Secondary Endpoint: •% Change of ZOL 5 mg Treatment in% Change of ZOL 5 mg Treatment in Lumbar SpineLumbar Spine BMDBMD at Years 6 VS Years 3at Years 6 VS Years 3
    55. 55. 60 •Secondary Endpoint:Secondary Endpoint: •6 years of annual ZOL 5 mg infusions provides6 years of annual ZOL 5 mg infusions provides continued fracture protectioncontinued fracture protection •Discontinuation of ZOL 5 mg treatment afterDiscontinuation of ZOL 5 mg treatment after 3 years still giving residual effect on3 years still giving residual effect on prevention nonvertebral fracturesprevention nonvertebral fractures •Continuation of ZOL 5 mg treatment for 6Continuation of ZOL 5 mg treatment for 6 years significantly reduced Newyears significantly reduced New Morphometric Vertebral FracturesMorphometric Vertebral Fractures Core study:†P < 0.001 relative risk reduction vs placebo (PBO); n = the number of patients in the analysis population with X-rays at Year 3 andCore study:†P < 0.001 relative risk reduction vs placebo (PBO); n = the number of patients in the analysis population with X-rays at Year 3 and Year 6; ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. †The event rate is from Kaplan-MeierYear 6; ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. †The event rate is from Kaplan-Meier estimate at Month 36 in the extension studyestimate at Month 36 in the extension study 11 Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822 22 Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242 •*P = 0.0348*P = 0.0348 •**PP < 0.001< 0.001
    56. 56. 61 A single infusion of ZOL 5 mg reduced boneA single infusion of ZOL 5 mg reduced bone resorption marker rapidly than weekly oral ALN 70 mgresorption marker rapidly than weekly oral ALN 70 mg (Urine NTX)(Urine NTX) (Serum(Serum β-β-CTX )CTX ) •* P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide;* P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-β-CTX: SerumCTX: Serum β-β-C-C- telopeptide of type I collagentelopeptide of type I collagen •Saag, et al.Saag, et al. BoneBone 2007;40:1238-12432007;40:1238-1243
    57. 57. 62 Safety:Safety: Overall No Increase in Risk of AEs or SAEs With Long-termOverall No Increase in Risk of AEs or SAEs With Long-term (6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment(6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment Category Z6 (N=613) n (%) Z3P3 (N=616) n (%) P-value Total no. of patients with an AE 552 (90) 552 (89) 0.85 Serious AEs 191 (31) 168 (27) 0.15 Deaths 26 (4) 18 (3) 0.22 Cardiovascular AE Atrial fibrillation AEs 21 (3.4%) 13 (2.1%) 0.17 Atrial fibrillation SAEs* 11 (1.8%) 6 (1.0%) 0.23 Stroke related AEs 26 (4.2%) 19 (3.1%) 0.29 Stroke SAEs 19 (3.1%) 9 (1.5%) 0.06 Stroke deaths* 1 (0.2%) 0 (0%) 0.50 New hypertension AEs† 48 (7.8%) 94 (15.2%) <0.001 *P = 0.1910 **P < 0.0001*P = 0.1910 **P < 0.0001 11 Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822 22 Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242
    58. 58. 63 Safety:Safety: Five most common Post-Dose Symptoms (≤ 3 Days After Infusion)Five most common Post-Dose Symptoms (≤ 3 Days After Infusion) and declined markedly with subsequent infusionsand declined markedly with subsequent infusions •00 •22 •44 •66 •88 •1010 •1212 •1414 •1616 •Annual InfusionAnnual Infusion •PyrexiaPyrexia •MyalgiaMyalgia •Flu-like illnessFlu-like illness •HeadacheHeadache •ArthralgiaArthralgia •11 •22 •33 •11 •22 •33 •11 •22 •33 •11 •22 •33 •11 •22 •33 •Incidence(%)Incidence(%) •15%15% •2%2% •1%1% •1%1% •2%2% •1%1% •2%2% •1%1% •2%2% •1%1% •8%8% •7%7% •6%6% •5%5% •Placebo values cross-hatchedPlacebo values cross-hatched •1%1% •Treatment with antipyretic analgesics appeared to mitigate theseTreatment with antipyretic analgesics appeared to mitigate these symptomssymptoms22 •Acetaminophen four times/day for 3 days significantly reduced theAcetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusionincidence and severity of post-dose symptoms following ZOL infusion33 11 Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822
    59. 59. 64 ZOL= 3595 3574 3284 2989 PBO= 3624 3615 3338 3031 Z6= 613 572 517 459 Z3P3= 616 584 537 475 Renal Safety:Renal Safety: 6 Years of ZOL Therapy Has No6 Years of ZOL Therapy Has No Cumulative Impact onCumulative Impact on Creatinine ClearanceCreatinine Clearance 11 Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822 22 Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242
    60. 60. HORIZON-PFT Extension Study:HORIZON-PFT Extension Study: SummarySummary ► Long-term efficacy -Long-term efficacy - 6 years of ZOL therapy6 years of ZOL therapy ledled to:to: – Significantly greater increases from baseline in FN, THSignificantly greater increases from baseline in FN, TH and trochanter BMD than stopping treatment at 3 yearsand trochanter BMD than stopping treatment at 3 years – Significant risk reduction in vertebral morphometricSignificant risk reduction in vertebral morphometric fracture risk vs stopping treatment at 3 yearsfracture risk vs stopping treatment at 3 years – Maintenance of bone turnover markers within referenceMaintenance of bone turnover markers within reference rangerange – Losses in BMD and BTMs in discontinuation groupLosses in BMD and BTMs in discontinuation group were modestwere modest 65 Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242
    61. 61. • No new safety concerns identified in women with PMONo new safety concerns identified in women with PMO • No statistical difference inNo statistical difference in AFAF SAEs vsSAEs vs discontinuationdiscontinuation of ZOLof ZOL • No long-term effect onNo long-term effect on renalrenal function vsfunction vs discontinuation of ZOLdiscontinuation of ZOL • No increase in risk forNo increase in risk for ONJONJ eventsevents vs discontinuationvs discontinuation of ZOLof ZOL • No cases ofNo cases of atypical fracturesatypical fractures Long-term safetyLong-term safety
    62. 62. SummarySummary ► AdherenceAdherence to daily and weekly bisphosphonatesto daily and weekly bisphosphonates isis suboptimalsuboptimal ► Poor adherencePoor adherence may compromise clinical outcomesmay compromise clinical outcomes and may increase healthcare utilizationand may increase healthcare utilization ► Need toNeed to improve communication and educationimprove communication and education ofof patients utilizing all available resourcespatients utilizing all available resources ► Among other factors,Among other factors, dosing frequencydosing frequency may bemay be an important determinant of adherence withan important determinant of adherence with bisphosphonatesbisphosphonates
    63. 63. ““Drugs don’t work in people thatDrugs don’t work in people that don’t take them”don’t take them” C. Everett Koop, M.D.C. Everett Koop, M.D.
    64. 64. Thank youThank you Keep your boneKeep your bone healthyhealthy

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