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Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update

Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update. Prepared for: Agency for Healthcare Research and Quality (AHRQ ). Accreditation Statement. Physician Credit Designation Statement

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Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update

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  1. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update Prepared for: Agency for Healthcare Research and Quality (AHRQ)

  2. Accreditation Statement Physician Credit Designation Statement PRIME Education, Inc. (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. PRIME® designates this live activity for a maximum of .50 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity. Physician Assistant Accreditation Statement AAPA accepts AMA Category 1 CME Credit™ for the PRA from organizations accredited by ACCME. Nurse Practitioner Accreditation Statement PRIME Education, Inc (PRIME®) is approved as a provider of Nurse Practitioner Continuing Education by the American Academy of Nurse Practitioners. Provider number: 060815. This program is accredited for 0.50 contact hour. Program ID# CER45. This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standards. Nurse Accreditation Statement PRIME Education, Inc. (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. PRIME® designates this activity for .50 contact hour. California Nurse Accreditation Statement PRIME® designates this educational activity for .50 contact hour for California nurses. PRIME® is accredited as an approver of continuing education in nursing by the California Board of Registered Nursing.

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  5. Learning Objectives Upon completion of this activity, the participant is expected to be able to: Compare the effectiveness and efficacy of pharmacologic agents in treating osteoporosis Assess the benefits and harms of osteoporosis medications among certain adult patient subgroups Apply the findings of the systematic review to improve outcomes for adult patients through patient-centered care

  6. Outline of material Introduction to low bone density (LBD) Systematic review methods The clinical questions addressed by the CER Results of studies and evidence-based conclusions on the comparative effectiveness and safety of treatments to prevent fractures in postmenopausal women with osteoporosis Gaps in knowledge and future research needs What to discuss with patients Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  7. Introduction to osteoporosis • Approximately 52 million people in the U.S. are affected by osteoporosis or LBD • Osteoporosis is a severe form of LBD especially common in postmenopausal women • It is a systemic skeletal disease characterized by decreasing bone mass and deterioration of the microarchitecture of bone tissue • It leads to increases in susceptibility to fracture • Clinical diagnosis of osteoporosis may be based on the results of bone mineral density (BMD) measurement with dual energy x-ray absorptiometry (DXA) • Osteoporosis can be diagnosed by the occurrence of fragility fracture. In patients without fragility fracture, osteoporosis is often diagnosed by low bone density Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA 2001;285(6):785-95. PMID: 11176917. Sasser AC, Rousculp MD, Birnbaum HG, et al. Womens Health Issues 2005;15(3):97-108. PMID: 15894195.

  8. Classifications of osteoporosis and low bone density • BMD is classified according to the T-score, which is the number of standard deviations above or below the mean BMD for healthy adults, as determined by DXA • A T-score of -2.5 or less is classified as osteoporosis • A T-score between -2.5 and -1.0 is considered LBD (also known as osteopenia) • A T-score of -1 or greater is considered normal Kanis JA, Melton LJ 3rd, Christiansen C, et al. J Bone Miner Res 1994;9(8):1137-41. PMID: 7976495. National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at www.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Nelson HD, Haney EM, Dana T, et al. Ann Intern Med 2010;153(2):1-11. PMID: 20621892. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  9. Risk factors for osteoporosis (1 of 2) Risk factors include (but are not limited to): • Increasing age • Female sex • Postmenopause for women • Hypogonadism or premature ovarian failure • Ethnic background (risk is greater for whites) • Low body weight • Previous fracture due to minimal trauma • Parental history of hip fracture • Rheumatoid arthritis • Low BMD • Current smoking • Alcohol intake (3 or more drinks per day) • Vitamin D deficiency • Low calcium intake • Hyperkyphosis • Falling • Immobilization National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at www.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  10. Risk factors for osteoporosis (2 of 2) Risk is also increased with the chronic use of some medications, including, but not limited to: • Glucocorticoids • Anticoagulants • Anticonvulsants • Aromatase inhibitors • Cancer chemotherapeutic drugs • Gonadotropin-releasing hormone agonists National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at www.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  11. Predicting fracture risk • Risk scoring methods combine clinical risk factors with BMD testing results • One such tool is the Fracture Risk Assessment Tool (FRAX®) • FRAX was developed by the World Health Organization • It uses race and nation-specific risk factors, combined with patient-specific BMD data (at the femoral neck), to estimate the absolute 10-year risk of major osteoporotic fractures • Only the US FRAX model is race-specific. All other countries are not race-specific Kanis JA, Johansson H, Oden A, et al. Eur J Radiol 2009;71(3):392-7. PMID: 19716672. Kanis JA, Johnell O, Oden A, et al. OsteoporosInt 2008;19(4):385-97. PMID: 18292978. Kanis JA, Oden A, Johnell O, et al. OsteoporosInt 2007;18(8):1033-46. PMID :17323110. Lewiecki EM, Binkley N. EndocrPract 2009;15(6):573-9. PMID: 19491062. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf World Health Organization Collaborating Centre for Metabolic Bone Diseases. WHO Fracture Risk Assessment Tool. Available at www.shef.ac.uk/FRAX.

  12. Interventions to prevent osteoporotic fracture • Interventions to prevent osteoporotic fracture include: • Pharmacologic agents • Dietary and supplemental vitamin D and calcium • Weight-bearing exercise • These interventions have also been studied and used (with less frequency) in patients with osteopenia (T-score between -2.5 and -1.0) Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  13. Pharmacologic agents to prevent osteoporotic fracture • Pharmacologic agents investigated in this systematic review include: • Antiresorptive Agents: • Bisphosphonates: alendronate, risedronate, zoledronic acid, and ibandronate • Estrogen: in the form of menopausal hormone therapy (MHT) • Selective estrogen receptor modulators: raloxifene • Biologic agents: denosumab • Anabolic Agents: • Peptide hormones: teriparatide • Not all drugs currently approved by the U.S. Food and Drug Administration (FDA) for treating patients with LBD were required to demonstrate reduction in fracture risk (e.g., the peptide hormone calcitonin) • Furthermore, approval of a different dose, frequency, or route of administration does not require demonstration of reduced fracture risk • There are no new findings about calcitonin in the report described here Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  14. AHRQ comparative effectiveness review (CER) development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decision-making and in discussions with patients. The Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/lbd.cfm Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  15. Clinical questions addressed by the CER (1 of 5) Key Question (KQ) 1: What are the comparative benefits in fracture reduction among the following therapeutic modalities for LBD: • Bisphosphonate medications, specifically: • Alendronate (Fosamax®, oral) • Risedronate (Actonel®; oral once-a-week) • Ibandronate (Boniva®) • Zoledronic acid (Reclast®, Zometa®, oral and intravenous) • Denosumab (Prolia®) • Menopausal estrogen therapy for women (numerous brands and routes of administration) • Parathyroid hormone (PTH) • 1-34 (teriparatide; Forteo®) • Selective estrogen receptor modulators (SERMs), specifically: • Raloxifene (Evista®) • Calcium • Vitamin D • Combinations or sequential use of above • Exercise in comparison to the agents above Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  16. Clinical questions addressed by the CER (2 of 5) KQ 2: How does fracture risk reduction resulting from treatments vary between individuals with different risks for fracture as determined by the following factors: • BMD • FRAX or other risk-assessment score • Prior fractures (prevention vs. treatment) • Age • Sex • Race/ethnicity • Glucocorticoid use • Other factors (e.g., community dwelling vs. institutionalized, vitamin D deficient vs. not) Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  17. Clinical questions addressed by the CER (3 of 5) Adherence = Compliance, which is “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen” (Cramer et al., 2008). †Persistence = “The duration of time from initiation to discontinuation of therapy” (Cramer et al., 2008). KQ 3: Regarding treatment adherence* and persistence†: What are the levels of adherence and persistence to medications for the treatment and prevention of osteoporosis? What factors affect adherence and persistence? What are the effects of adherence and persistence on the risk of fractures? Cramer JA, Roy A, Burrell A. Value Health 2008;11(1):44-7. PMID: 18237359. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  18. Clinical questions addressed by the CER (4 of 5) KQ 4: What are the short- and long-term harms (adverse effects) of the above therapies (when used specifically to treat or prevent LBD/osteoporotic fracture), and do these vary by any specific subpopulations (e.g., the subpopulations identified in KQ 2)? Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  19. Clinical questions addressed by the CER (5 of 5) KQ 5: With regard to treatment for preventing osteoporotic fracture: How often should patients be monitored (via measurement of BMD) during therapy, how does bone density monitoring predict antifracture benefits during pharmacotherapy, and does the ability of monitoring to predict antifracture effects of a particular pharmacologic agent vary among the pharmacotherapies? How does the antifracture benefit vary with long-term continued use of pharmacotherapy, and what are the comparative antifracture effects of continued long-term therapy with the various pharmacotherapies? Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  20. Summary of study characteristics evaluated in the effectiveness review: “PICOTS” framework • Population: Adults over 18, including healthy adults, those with LBD, those with osteoporosis, and adults at risk of LBD and osteoporosis due to chronic use of glucocorticoids or as a result of a condition associated with LBD (e.g., rheumatoid arthritis, cystic fibrosis, Parkinson’s disease) • Interventions: Pharmacological interventions for prevention or treatment of osteoporosis approved or soon to be approved by the (FDA), calcium, vitamin D, or physical activity • Comparators: Placebo, other doses, other agents in the same or another class • Outcomes: Vertebral, hip, and total fractures • Fractures reported as outcomes, not as adverse events • Timing: Minimum of 6 months • Setting: All settings Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  21. Modes of results and statistical analysis in the CER (1 of 2) 95% Confidence Interval (95% CI): The range of statistically valid results that will include the true population mean in 95 of 100 repeated experiments Mean difference (MD): The difference between treatment and comparison group means Standardized mean difference (SMD) is the mean difference expressed in units of standard deviations. It is a method for normalizing results to a uniform scale for pooled analysis, when different scales are used in trials For MD and SMD, the result is statistically significant (p < 0.05) when the 95% CI does not include 0.0, which is the point of no difference between groups Odds Ratio (OR): The ratio of the odds of an event in the treatment group to the odds of the event in the comparison group Odds are the number of individuals in the group having an event divided by the number of individuals not having the event (Odds = # with/# without; with + without = total # in the group) For OR, the result is statistically significant at p < 0.05 when the 95% CI does not include 1.0, which is the point of equal odds for both groups Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Available at www.cochrane-handbook.org. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  22. Modes of results and statistical analysis in the CER (2 of 2) • Absolute Risk Difference: The absolute value of the mathematical difference between the rates (risk) of an event in the treatment and comparison groups • ARD = | ARC–ART | • Number Needed To Treat or Harm (NNT, NNH): The number of patients to be treated to observe benefit or harm in one patient more than seen in the comparison group. The number of patients to be treated in order to find a benefit or harm attributable to the intervention • NNT or NNH = |ARC–ART|-1 for a benefit or adverse event, respectively • Number of attributable events per 1,000 = 1,000 x |ARC–ART| Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Available at www.cochrane-handbook.org. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  23. Rating the strength of evidence (SOE) from the CER The SOE was classified into four broad categories: Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  24. Benefits of medications (1 of 2) The table below indicates whether the medications specified reduce fracture risk for postmenopausal women with osteoporosis and the strength of evidence (high, moderate, or low) in support of each conclusion. Biphosphonates *Risedronate-mediated wrist fracture did not reach the conventional level of statistical significance ☑ =reduced fracture; ☒=did not reduce fracture risk; NSD = no statistically significant difference; Not specified = drug effect on fracture type is not specified Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  25. Benefits of medications (2 of 2) Regarding the use of calcium in combination with the bisphosphonates, one head-to-head trial found that adding calcium to alendronate treatment reduced the risk of any type of clinical fracture when compared with alendronate alone • Strength of Evidence = Low • no RCTs tested combinations of osteoporosis therapies or sequential therapies in relation to fracture outcomes Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  26. Benefits of medications in subpopulations Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  27. Summary of benefits of medications • Alendronate, risedronate, zoledronic acid, and denosumab reduce the risk of hip and nonvertebral fractures in postmenopausal women with osteoporosis • Strength of Evidence: High • Bisphosphonates as a class, denosumab, teriparatide, and raloxifene reduce the risk of vertebral fractures in postmenopausal women with osteoporosis. • Strength of Evidence: High • The combination of alendronate and calcium decreased the risk for any type of clinical fracture to about one-third that of alendronate alone • Strength of Evidence: Low • Teriparatide reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis • Strength of Evidence: Moderate • Reduced risk of other fracture types and risk reduction in subpopulations is achieved by fewer medications, and the strength of evidence in support of the findings is variable Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  28. Benefits: Exercise and dietary supplementation (1 of 2) • The evidence is insufficient to estimate benefits from exercise or to identify the duration, intensity, or type of exercise program that will decrease fracture risk • Strength of Evidence: Insufficient • Vitamin D (>800 units taken orally), taken in combination with calcium, may reduce fracture risk in people who are institutionalized • Strength of Evidence: Moderate • However, evidence is lacking for clear benefit of vitamin D when taken alone for the general population Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  29. Benefits: Exercise and dietary supplementation (2 of 2) • Studies show no difference between calcium alone and placebo in reducing the risk for vertebral and nonvertebral fractures • Strength of Evidence: Moderate • However, calcium significantly reduced hip fracture risk in one pooled analysis and overall fracture risk in another pooled analysis. • There is no difference between calcium alone and vitamin D alone in reducing vertebral, nonvertebral, or hip fracture risk. • Strength of Evidence: High Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  30. Benefits: Menopausal hormone therapy • In studies of postmenopausal women in general, MHT * reduces the risk of vertebral, nonvertebral, and hip fractures • Strength of Evidence: High • In postmenopausal women with established osteoporosis, MHT does not reduce fracture risk significantly • Strength of Evidence: Moderate • No differences in comparative effectiveness for fracture prevention have been shown between bisphosphonates and MHT (estrogen) • Strength of Evidence: Moderate • No differences in fracture incidence have been shown in comparisions of patients treated with MHT and either raloxifene or vitamin D • Strength of Evidence: Low *The Women’s Health Initiative reported serious adverse events associated with MHT, such that routine use of hormone replacement therapy in postmenopausal women is now discouraged. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  31. Additional information • Fracture risk reduction is greatest in women with established osteoporosis and/or prevalent fractures, and reduction of fracture risk from treatment is not dependent on patient age • Older individuals (65 years and older) are as likely to benefit from treatment as younger individuals • Strength of Evidence: High • Women with established osteoporosis benefit more from treatment than women with osteopenia and without prevalent fractures • Most authorities no longer consider calcitonin to be appropriate treatment for osteoporosis, yet it is still widely prescribed. Evidence supports the conclusion that it is not effective in postmenopausal women with osteoporosis Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  32. Adverse effects of medications for low bone density or osteoporosis (1 of 3) *Mild upper GI events are conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn 95% CI = 95 percent confidence interval; GI = gastrointestinal; IV = intravenous; OR = odds ratio (the odds of the condition developing in those taking the listed medications when compared with the odds in patients receiving placebo treatment) Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  33. Adverse effects of medications for low bone density or osteoporosis (2 of 3) *Mild GI events = conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95% CI = 95 percent confidence interval; GI = gastrointestinal; OR = odds ratio (the odds of the condition developing in those taking the listed medications compared with the odds in patients receiving placebo treatment) Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  34. Adverse effects of medications for low bone density or osteoporosis (3 of 3) *Anderson GL, Chlebowski RT, Aragaki AK, et al. Lancet Oncol 2012 Mar 6 [Epub ahead of print]. PMID: 22401913. † Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. JAMA 2010 ;304(15):1684-92. PMID: 20959578. 95% CI = 95 percent confidence interval; HR = hazard ratio; OR = odds ratio; WHI = Women’s Health Initiative Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  35. Additional possible adverse effects These adverse effects are listed by the FDA but are not findings of the CER. Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  36. Treatment monitoring, adherence, and persistence (1 of 3) • The evidence to date has not clarified the value of BMD monitoring to assess treatment effectiveness. According to indirect evidence, even patients who continue to lose BMD during therapy experience statistically and clinically significant reductions in fracture risk • Strength of Evidence: High • One large randomized controlled trial (RCT) showed that after 5 years of initial alendronate therapy, an additional 5 years of therapy continued to reduce vertebral fracture risk.Continued reduction in nonvertebral fracture risk was found at 10 years (in post-hoc analysis) in: • Women who had osteoporosis (T-scores were less than -2.5) after 5 years of treatment (Strength of Evidence: Moderate) • Women with prevalent vertebral fractures after 5 years of treatment (Strength of Evidence: Moderate) Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  37. Treatment monitoring, adherence, and persistence (2 of 3) • Decreased adherence to bisphosphonates is associated with an increased risk of fracture (vertebral, nonvertebral, or both) • Strength of Evidence: Moderate • In general, RCTs examining bisphosphonates report high levels of adherence (majority over 90%), and trials with raloxifene had adherence rates of 65 to 70 percent • Strength of Evidence: Moderate • However, observational studies of patients taking bisphosphonates in combination with calcium and vitamin D show that adherence and persistence with the treatment regimen are poor • Strength of Evidence: High Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  38. Treatment monitoring, adherence, and persistence (3 of 3) • Observational studies show that adherence to therapy with bisphosphonates is improved with weekly regimens when compared with daily regimens. • Strength of Evidence: High • Evidence is lacking to evaluate comparative adherence to monthly versus weekly regimens. • Observational studies show that other factors affecting adherence and persistence include, but are not limited to: • Dosing frequency • Side effects of medications • Comorbid conditions • Knowledge about osteoporosis • Medication cost • Age, previous history of fracture, and concomitant medication use do not appear to affect adherence or persistence • Strength of Evidence: Moderate Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  39. Conclusions (1 of 2) The ability of medications to decrease fracture risk is most strongly established for postmenopausal women with osteoporosis (i.e., bone density scores in the osteoporosis range and/or pre-existing fractures) Bisphosphonates, denosumab, raloxifene, and teriparatide reduce vertebral fracture risk, but only alendronate, risedronate, zoledronic acid, and denosumab reduce hip fracture risk Raloxifene does not reduce the risk of hip or nonvertebral fractures Limited evidence supports a potential benefit for vitamin D and calcium (alone or in combination) in lowering fracture risk Studies to date are inadequate to provide estimates of the benefits or harms of exercise in relation to fracture risk. (Exercise has been show to be beneficial for other disease conditions) Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  40. Conclusions (2 of 2) Most osteoporosis interventions have notable adverse effects that should be taken into account in decisionmaking Dosing frequency appears to affect adherence and persistence, with weekly doses having improved adherence over daily regimens Limited evidence suggests that treatment extended beyond 5 years can provide additional reductions in vertebral fracture risk (measured at 10 years). For nonvertebral fractures, post-hoc analysis found reduction in risk only for women who had osteoporosis or prevalent vertebral fractures at five years Monitoring BMD during therapy does not fully reflect treatment benefits, as patients with BMD losses during antiresorptive therapy may still experience reduced fracture risk Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  41. Gaps in knowledge (1 of 3) Evidence is insufficient to evaluate potential associations between bisphosphonate use and either esophageal cancer or atrial fibrillation. However, an FDA safety review notes that a relationship between zoledronic acid and atrial fibrillation is still an area of active surveillance, though an association is unproven Evidence for the antifracture effects of currently available osteoporosis therapies is greatest among patients with established osteoporosis Studies comparing exercise with medications are lacking. Additionally, there are no RCTs examining the specific duration, intensity, and type of exercise program required to decrease fracture risk Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  42. Gaps in knowledge (2 of 3) • Evidence is sparse regarding the effectiveness of therapies to prevent or treat osteoporosis in men • Studies have not directly compared the antifracture effectiveness of longer durations of therapy among the various medications • Thus, it is unclear how long patients should remain on therapy • The benefits and harms of drug holidays are also unclear • Data are insufficient to determine the comparative effectiveness among individual bisphosphonates or between bisphosphonates and calcium, raloxifene, or teriparatide Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf .

  43. Gaps in knowledge (3 of 3) No RCTs tested combinations of osteoporosis therapies or sequential use of osteoporosis therapies in relation to fracture outcomes No studies examined explicitly the benefits and adverse effects associated with the popular practice of BMD monitoring during the course of therapy This review did not address quality-of-life issues Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  44. What to discuss with your patients The serious health consequences associated with LBD and fracture Potential benefits & adverse effects associated w/ LBD treatment options The specific instructions for how to take certain medicines such as bisphosphonates and the impact this might have on the patient's lifestyle The importance of adherence and how that affects reduction of fracture risk Risk factors for LBD and fracture including conditions and medications in the elderly that might predispose them to falls Approaches to avoiding falls such as addressing hazards in the home, wearing appropriate footwear, and installing night lights The specific side effects the patient might encounter and when the patient should inform you should these occur Patient values and preferences regarding treatment options Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_20120823.pdf

  45. Thank you for your time • For CE/CME: • www.ce.effectivehealthcare.ahrq.gov/credit • Use code: CER45 • Visit AHRQ’s continuing education website regularly to participate in future programs • For electronic copies of the clinician guide, the consumer guide, and the full systematic review • http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=1007 • Free print copies • AHRQ Publications Clearinghouse: (800) 358-9295

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