Prepared for: Agency for Healthcare Research and Quality (AHRQ)

Prepared for: Agency for Healthcare Research and Quality (AHRQ)
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)

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Disclosure Information
Program Disclosure Information Advisory Board Consultant Grants/ Research Salary/ Contractual Supported Promotional Education Stock/Shareholder Other Financial Support Silvina Levis, MD Planner None Carolyn LePage, PhD, ARNP Barry University Heidi Wynn Maloni, PhD, ANP-BC Consensus Management Carolyn J Crandall, MD, MS Reviewer Joyce M Knestrick, PhD, CRNP, FAANP Kathleen A Jarvis, MS, RN, CCM Chris R Prostko, PhD Scientific Program Director PRIME® Lynn Goldenberg, RN, BSN Director of Accreditation & Compliance Disclosures AHRQ contracted faculty of PRIME and TTM, Inc.

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 Learning objectives: To compare the benefits and harms of osteoporosis agents for treating osteoporosis or LBD in adults and use the findings in this comparative effectiveness report to guide decisions about appropriate treatments for managing osteoporosis in adults.

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 Outline of Material The material begins with an introduction to low bone density (LBD), its prevalence, and interventions to treat the disorder. Systematic review methods used to create the CER are described. The clinical questions addressed by the CER are presented. The results of studies and the evidence-based conclusions on the comparative effectiveness and safety of treatments to prevent fractures in postmenopausal women with osteoporosis are described. Gaps in knowledge and future research needs revealed by the systematic review process are presented. Some suggestions are made about what to discuss with patients and their caregivers, based on the review findings. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Introduction to Osteoporosis Approximately 52 million people in the United States are affected by osteoporosis or LBD. Osteoporosis is a severe form of LBD especially common in postmenopausal women. It is a systematic skeletal disease characterized by decreasing bone mass and deterioration of bone tissue that leads to consequential increases in susceptibility to fracture. Osteopenia is a less severe form of LBD. References: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence- based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285(6): PMID: Sasser AC, Rousculp MD, Birnbaum HG, et al. Economic burden of osteoporosis, breast cancer, and cardiovascular disease among postmenopausal women in an employed population. Womens Health Issues 2005;15(3): PMID: Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA 2001;285(6): PMID: Sasser AC, Rousculp MD, Birnbaum HG, et al. Womens Health Issues 2005;15(3): PMID:

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 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. A T-score of 1 or greater is considered normal. References: Kanis JA, Melton LJ 3rd, Christiansen C, et al. The diagnosis of osteoporosis. J Bone Miner Res 1994;9(8): PMID: National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; Available at Nelson HD, Haney EM, Dana T, et al. Screening for osteoporosis: an update for the U.S. Preventive Services Task Force. Ann Intern Med 2010;153(2):1-11. PMID: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Kanis JA, Melton LJ 3rd, Christiansen C, et al. J Bone Miner Res 1994;9(8): PMID: National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at Nelson HD, Haney EM, Dana T, et al. Ann Intern Med 2010;153(2):1-11. PMID: Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Risk Factors for Osteoporosis (1 of 2) Risk factors for osteoporosis include, but are not limited to, increasing age, female sex, being a postmenopausal woman, having hypogonadism or premature ovarian failure, ethnic background, low body weight, previous fracture due to minimal trauma, parental history of hip fracture, rheumatoid arthritis, low BMD, current smoking, alcohol intake of three or more drinks per day, vitamin D deficiency, low calcium intake, hyperkyphosis, falling, and immobilization. References: National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; Available at Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Risk Factors for Osteoporosis (2 of 2) The risk of developing osteoporosis is also increased with the chronic use of some medications, including but not limited to: glucocorticoids, anticoagulants, anticonvulsants, aromatase inhibitors, cancer chemotherapeutic drugs, and gonadotropin-releasing hormone agonists. References: National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; Available at Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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. References: Kanis JA, Johansson H, Oden A, et al. Assessment of fracture risk. Eur J Radiol 2009;71(3): PMID: Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19(4): PMID: Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007;18(8): PMID: Lewiecki EM, Binkley N. Evidence-based medicine, clinical practice guidelines, and common sense in the management of osteoporosis. Endocr Pract 2009;15(6): PMID: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at World Health Organization Collaborating Centre for Metabolic Bone Diseases. WHO Fracture Risk Assessment Tool. Available at Kanis JA, Johansson H, Oden A, et al. Eur J Radiol 2009;71(3): PMID: Kanis JA, Johnell O, Oden A, et al. Osteoporos Int 2008;19(4): PMID: Kanis JA, Oden A, Johnell O, et al. Osteoporos Int 2007;18(8): PMID : Lewiecki EM, Binkley N. Endocr Pract 2009;15(6): PMID: Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: World Health Organization Collaborating Centre for Metabolic Bone Diseases. WHO Fracture Risk Assessment Tool. Available at

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) Interventions To Prevent Osteoporotic Fracture Interventions to prevent osteoporotic fracture include pharmacologic agents, dietary and supplemental vitamin D and calcium, and weight-bearing exercise. These interventions are also used (although with less frequency) in patients with osteopenia, a less severe degree of low bone density. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Pharmacologic Agents To Prevent Low Bone Density Pharmacologic agents investigated in this systematic review include: the bisphosphonates, which include alendronate, risedronate, zoledronic acid, and ibandronate; peptide hormones (teriparatide); estrogen, in the form of menopausal hormone therapy (MHT); selective estrogen receptor modulators (raloxifene); and biologic agents: denosumab. 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. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Agency for Healthcare Research and Quality (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 decisionmaking and in discussions with patients. The Summaries and the full report, with references for included and excluded studies, are available at Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Clinical Questions Addressed by the CER (1 of 5) Key Question (KQ) 1 asked: 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®); and 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 PTH (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 Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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) Clinical Questions Addressed by the CER (2 of 5) KQ 2 asked: How does fracture reduction resulting from treatments vary between individuals with different risks for fracture as determined by the following factors: - Bone mineral density - 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) Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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? Clinical Questions Addressed by the CER (3 of 5) KQ 3 asked: Regarding treatment adherence* and persistence†: a. What are the adherence and persistence to medications for the treatment and prevention of osteoporosis? b. What factors affect adherence and persistence? c. What are the effects of adherence and persistence on the risk of fractures? 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). References: Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008;11(1):44-7. PMID: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at 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). Cramer JA, Roy A, Burrell A. Value Health 2008;11(1):44-7. PMID: Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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)? Clinical Questions Addressed by the CER (4 of 5) KQ 4 asked: 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)? Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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? Clinical Questions Addressed by the CER (5 of 5) KQ 5 asked: With regard to treatment for preventing osteoporotic fracture: a. 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? b. 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? Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS Development of clinical studies of effectiveness of medical interventions is guided by the PICOTS (population, interventions, comparators, outcomes, timing, and setting) framework. These items are critical elements that will help to answer important clinical questions. In the CER, the clinical study literature was reviewed and summarized by using the PICOTS framework. The evidence concerning the outcomes identified here was examined in: 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 Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Modes of Results Reporting and Statistical Analysis in the CER (1 of 2) 95 Percent Confidence Interval: 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. To determine a standardized mean difference (SMD), results from different scales are normalized to a common, standardized scale before calculating the mean difference. For MD and SMD, the result is statistically significant (p < 0.05) when the 95 percent confidence interval does not include 0.0, which is the point of no difference between groups. Relative Risk (RR): The ratio of the rate (absolute risk, probability) of an event in the treatment group, to the rate of the event in the comparison group. For RR, the result is statistically significant at p < 0.05 when the 95 percent confidence interval does not include 1.0, which is the point of equal risk for both groups. References: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version London: The Cochrane Collaboration; March Available at handbook.org. Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence- based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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| Modes of Results Reporting 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 = 1000 x |ARC–ART | References: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version London: The Cochrane Collaboration; March Available at Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

Rating the strength of evidence (SOE) from the CER
The SOE was classified into four broad categories: High Further research is very unlikely to change the confidence in the estimate of effect Moderate Further research may change the confidence in the estimate of effect and may change the estimate Low Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate Insufficient Evidence is either unavailable or does not permit estimation of an effect Rating the Strength of Evidence From the CER The Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit estimation of an effect). The authors may also independently evaluate the applicability to real-world practice of the total body of evidence within a given clinical indication by using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework. References: Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality, March AHRQ Publication No. 10(11)-EHC063-EF. Chapters available at Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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. Medication Vertebral Non-vertebral Hip Wrist Alendronate ☑ High ☑ Low Risedronate ☑ Low* Zoledronic acid Not specified Ibandronate Insufficient Denosumab Teriparatide ☑ Moderate Raloxifene ☒ High Biphosphonates Benefits of Medications (1 of 2) For postmenopausal women with osteoporosis, the following medications reduce the risk of the listed fracture types. The strength of evidence, high, moderate, or low, is listed for each. The bisphosphonates are alendronate, risedronate, zoledronic acid, and ibandronate. Alendronate and risedronate each reduce the risk of vertebral, nonvertebral, hip, and wrist fractures. The strength of evidence is high for evidence about vertebral and hip and other nonvertebral fractures. The strength of evidence is low for wrist fracture prevention by risedronate and alendronate, and in the case of risedronate, the evidence for reduced risk of wrist fractures did not reach the conventional level of statistical significance. Zoledronic acid reduces the risk of vertebral, nonvertebral, and hip fractures. The strength of evidence in support of these findings is high. The effect of zoledronic acid on wrist fracture risk was not specified. Ibandronate reduces the risk of vertebral fractures, and the strength of the evidence in support of the finding is high. The effect of ibandronate on nonvertebral, hip, and wrist fractures was not specified. Denosumab reduces the risk of vertebral, hip, and other nonvertebral fractures. The strength of evidence in support of these findings is high. The effect of denosumab on risk of wrist fractures was not specified. Teriparatide reduces the risk of vertebral and nonvertebral fractures. The strength of evidence for prevention of vertebral fractures is high, and for nonvertebral fractures the strength of evidence for the finding is moderate. The effect of teriparatide on hip and wrist fracture risk was not specified. Raloxefine reduces the risk of vertebral fractures, and this finding is supported by high strength of evidence. Raloxifene does not reduce the risk for nonvertebral, hip, or wrist fractures, and the evidence in support of these conclusions is high. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at *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:

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 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 Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

Benefits of medications in subpopulations
Patient Population Pharmacotherapies Strength of Evidence Medications that reduce overall fracture risk in the given patient populations: Patients with high risk for fracture (including postmenopausal women with osteoporosis) Alendronate Ibandronate Risedronate Zoledronic acid Denosumab Teriparatide Raloxifene High Patients treated with glucocorticoids Alendronate Teriparatide Moderate to High Patients with a higher risk of falling (e.g., patients with hemiplegia, Alzheimer’s disease, or Parkinson’s disease) Alendronate Vitamin D Moderate Transplant recipients and patients treated chronically with corticosteroids Inconclusive support for any agent Insufficient Medications that reduce the risk of fragility fracture in the given patient populations: Postmenopausal women with osteopenia who do not have prevalent vertebral fractures Low to Moderate Benefits of Medications in Subpopulations Patients with high risk for fracture (including postmenopausal women with osteoporosis) are likely to benefit from alendronate, denosumab, ibandronate, risedronate, teriparatide, raloxifene, and zoledronic acid. The strength of evidence for these findings is high. Patients treated with glucocorticoids are likely to benefit from alendronate, risedronate, and teriparatide. The strength of evidence for these findings is low to moderate. Patients with a higher risk of falling (e.g., patients with hemiplegia, Alzheimer’s disease, or Parkinson’s disease) are likely to benefit from alendronate, risedronate, and vitamin D. The strength of evidence for these findings is moderate. For transplant recipients and patients treated chronically with corticosteroids, there is inconclusive support for any agent, and the evidence is insufficient to permit conclusions. The risk of fragility fracture is reduced in postmenopausal women with osteopenia who do not have prevalent vertebral fractures when treated with risendronate. The strength of evidence for this finding is low to moderate. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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. 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 Benefits: Medications (2 of 2) Alendronate, risedronate, zoledronic acid, and denosumab reduce the risk of hip and nonvertebral fractures in postmenopausal women with osteoporosis. The strength of evidence for this conclusion is high. Bisphosphonates as a class (alendronate, risedronate, zoledronic acid, and ibandronate), as well as denosumab, teriparatide, and raloxifene, reduce the risk of vertebral fractures in postmenopausal women with osteoporosis. The strength of evidence for this conclusion is high. The combination of alendronate and calcium significantly decreased the risk for any type of clinical fracture when compared with alendronate alone. The strength of evidence for this conclusion is low. Teriparatide reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis. The strength of evidence for this conclusion is 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. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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. Vitamin D (>800 units taken orally), taken in combination with calcium, may reduce fracture risk in people who are institutionalized. The strength of evidence for this finding is moderate. However, evidence is lacking for clear benefit of vitamin D when taken alone for the general population. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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. The strength of evidence for this finding is 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. The strength of evidence for this finding is high. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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) 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 Benefits: Menopausal Hormone Therapy In studies of postmenopausal women in general, MHT reduces the risk of vertebral, nonvertebral, and hip fractures. The strength of evidence for this finding is high. However, in postmenopausal women with established osteoporosis, MHT does not reduce fracture risk significantly. The strength of evidence for this conclusion is moderate. No differences in comparative effectiveness have been shown between bisphosphonates and MHT in preventing fractures (Strength of Evidence: Moderate). In addition, no differences in fracture incidence have been shown between patients treated with MHT and raloxifene or vitamin D (Strength of Evidence: Low). As a footnote to this evidence, it is important to note that the Women’s Health Initiative (WHI) reported serious adverse events associated with MHT, such that routine use of hormone replacement therapy in postmenopausal women is now discouraged. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence- based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at *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:

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 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 are as likely to benefit from treatment as younger individuals. The strength of evidence in support of this conclusion is 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 an appropriate treatment for osteoporosis, yet it is still widely prescribed. Evidence supports the conclusion that it is not effective in postmenopausal women with osteoporosis. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

Magnitude of Association
Adverse effects of medications for low bone density or osteoporosis (1 of 3) Medication Adverse Effect Magnitude of Association Strength of Evidence Bisphosphonates Bisphosphonates (as a class) Possible association with atypical subtrochanteric fractures of the femur Not available, but the risk for this type of fracture is low. (Data are not consistent, but the FDA has issued a boxed warning about this possible adverse effect.) Low Alendronate Mild upper GI events * OR = 1.08; 95% CI 1.01, 1.15 High Hypocalcemia 9/301 treatment vs. 0/207 placebo Moderate Zoledronic acid OR = 7.22; 95% CI 1.81, 42.7 IV forms of zoledronic acid and ibandronate Osteonecrosis of the jaw Less than one case per 100,000 person-years of exposure. (Nearly all cases of osteonecrosis of the jaw are reported in people being treated for cancer.) Adverse Effects of Medications for Low Bone Density or Osteoporosis (1 of 3) For bisphosphonates (as a class), a possible association with atypical subtrochanteric fractures of the femur has been of concern. The magnitude of the association is not known, but the risk for this type of fracture is low. Data are not consistent, but the FDA has issued a boxed warning about this possible adverse effect. The strength of evidence for this finding is low. Alendronate is more often associated with mild upper gastrointestinal (GI) events. Mild upper GI events are conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. The odds ratio for the risk of upper GI events is 1.08, with a statistically valid range for the likelihood, as defined by the 95 percent confidence interval, falling between 1.01 and The strength of evidence for this finding is high. Hypocalcemia is associated with alendronate, but the risk has not been calculated as there are zero events in the placebo group. Data show 9 out of 301 alendronate-treated patients experienced hypocalcemia versus 0 of 207 in the placebo-treated group. The strength of evidence for this finding is moderate. Zoledronic acid is associated with hypocalcemia, with a 7.22-fold likelihood compared with placebo and a statistically valid range for the association between and 42.7-fold. The strength of evidence for this finding is moderate. Patients treated with intravenous (IV) forms of zoledronic acid and ibandronate have been considered to have greater risk of osteonecrosis of the jaw. The evidence to date indicates less than 1 case per 100,000 person-years of exposure with these agents. Nearly all cases of osteonecrosis of the jaw are reported in people being treated for cancer. The strength of evidence for this finding is moderate. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at *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:

Magnitude of Association
Adverse effects of medications for low bone density or osteoporosis (2 of 3) Medication Adverse Effect Magnitude of Association Strength of Evidence Raloxifene Pulmonary embolism OR = 5.27; 95% CI 1.29, 46.4 High Thromboembolic events OR = 1.63; 95% CI 1.36, 1.98 Myalgias, cramps, and limb pain OR = 1.53; 95% CI 1.29, 1.81 Hot flashes OR = 1.58; 95% CI 1.35, 1.84 Teriparatide Hypercalcemia OR = 12.9; 95% CI 10.49, 16.0 Moderate Headaches OR = 1.44; 95% CI 1.24, 1.67 Denosumab Mild GI events* OR = 2.13; 95% CI 1.11, 4.4 Rash OR = 2.01; 95% CI 1.5, 2.73 Infection OR = 1.28; 95% CI 1.02, 1.60 Adverse Effects of Medications for Low Bone Density or Osteoporosis (2 of 3) Raloxifene is associated with pulmonary embolism. The likelihood is 5.27-fold that of untreated groups, and the statistically valid range for the association is from to 46.4-fold. The strength of evidence for this finding is high. Raloxifene is associated with thromboembolic events. The likelihood is 1.63-fold that of untreated groups, and the statistically valid range for the association is from to 1.98-fold. The strength of evidence for this finding is high. Raloxifene is associated with myalgias, cramps, and limb pain. The likelihood is 1.53-fold that of untreated groups, and the statistically valid range for the association is from to 1.81-fold. The strength of evidence for this finding is high. Raloxifene is associated with hot flashes. The likelihood is 1.58-fold that of untreated groups, and the statistically valid range for the association is from to 1.84-fold. The strength of evidence for this finding is high. Teriparatide is associated with hypercalcemia and headaches. The likelihood of hypercalcemia is 12.9-fold that of untreated groups. The statistically valid range for the association is from to 16-fold. The strength of evidence for this finding is moderate. The likelihood of headaches is 1.44-fold that of untreated groups. The statistically valid range for the association is from to 1.67-fold. The strength of evidence for this finding is moderate. Denosumab is associated with mild GI events, rashes, and infections. The likelihood of GI events is 2.13-fold that of untreated groups. The statistically valid range for the association is from to 4.4-fold. The strength of evidence for this finding is moderate. The likelihood of rashes is 2.01-fold that of untreated groups. The statistically valid range for the association is from 1.5- to 2.73-fold. The strength of evidence for this finding is high. The likelihood of infection is 1.28-fold that of untreated groups. The statistically valid range for the association is from to 1.60-fold. The strength of evidence for this finding is high. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at *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:

Adverse effects of medications for low bone density or osteoporosis (3 of 3)
Magnitude of Association (from pooled analysis of clinical date) Menopausal hormone therapy: estrogen alone and estrogen-progestin combination Cerebrovascular accidents Estrogen: OR = 1.34; 95% CI: 1.07 to 1.68 Combination: OR = 1.28; 95% CI: 1.05 to High Thromboembolic events Estrogen: OR = 1.36; 95% CI: 1.01 to 1.86 Combination: OR = 2.27; 95% CI: 1.72 to High Breast cancer (This evidence comes from the reference WHI (see citation), not this comparative effectiveness report, so there is no strength of evidence) Estrogen: In the WHI*, is associated with reduced incidence of breast cancer in women who have had a hysterectomy when compared with placebo (HR = 0.77; 95% CI: 0.62 to 0.95), but subgroup analysis noted that the risk reduction was concentrated in women without benign breast disease or family history of breast cancer. No risk reduction was seen in women at high risk for breast cancer. Combination: In the WHI†, is associated with more occurrences of invasive breast cancer than with placebo (HR = 1.25; 95% CI: 1.07 to 1.46), tumors more likely to have lymph node metastases (HR = 1.78; 95% CI: 1.23 to 1.58), and more breast cancer-related deaths (HR = 1.96; 95% CI: 1.00 to 4.04). Adverse Effects of Medications for Low Bone Density or Osteoporosis (3 of 3) The adverse effects associated with MHT (consisting of estrogen alone or estrogen in combination with progestin) are well known and extend to postmenopausal women taking the therapy for treatment of osteoporosis. The risk of cerebrovascular accidents is elevated by estrogen, with an odds ratio of 1.34-fold likelihood of a cerebrovascular accident (95 percent confidence interval [95% CI] of to 1.68-fold). Combination therapy increases the risk with a 1.28-fold likelihood (95% CI from to 1.57-fold). The strength of evidence in support of these findings is high. The risk of thromboembolic events is elevated by estrogen, with an odds ratio of fold likelihood (95% CI of to fold). Combination therapy increases the odds again, with a 2.27-fold likelihood (95% CI from to 3.02-fold). The strength of evidence in support of these findings is high. Breast cancer risk was reported as an outcome of the WHI. Estrogen, as reported in Anderson et al. (2012), is associated with reduced incidence of breast cancer in women with hysterectomy when compared with placebo (hazard ratio [HR] = 0.77; 95% CI: 0.62 to 0.95), but subgroup analysis noted that the risk reduction was concentrated in women without benign breast disease or family history of breast cancer. No risk reduction was seen in women at high risk for breast cancer. In the WHI, as reported in Chlebowski et al. (2010), combination therapy is associated with more occurrences of invasive breast cancer than with placebo (HR = 1.25; 95% CI: 1.07 to 1.46), tumors more likely to have lymph node metastases (HR = 1.78; 95% CI: 1.23 to 1.58), and more breast cancer-related deaths (HR = 1.96; 95% CI: 1.00 to 4.04). References: Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo- controlled trial. Lancet Oncol 2012 Mar 6 [Epub ahead of print]. PMID: Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304(15): PMID: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at *Anderson GL, Chlebowski RT, Aragaki AK, et al. Lancet Oncol 2012 Mar 6 [Epub ahead of print]. PMID: † Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. JAMA 2010 ;304(15): PMID: 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:

Additional possible adverse effects
These adverse effects are listed by the FDA but are not findings of the CER. Medication Adverse Effect(s) Alendronate, Risedronate, and Ibandronate Musculoskeletal pain Hypocalcemia Osteonecrosis of the jaw Severe irritation of upper gastrointestinal mucosa Zoledronic acid Renal toxicity and acute renal failure Denosumab Teriparatide Increased risk of bone cancer Vitamin D Signs of toxicity: nausea, vomiting, anorexia, polyuria, constipation, weakness, and weight loss By raising blood levels of calcium, excessive vitamin D can cause dementia, memory loss, and arrhythmias Excess vitamin D can cause irreversible kidney damage and renal failure Additional Possible Adverse Effects These potentially severe adverse effects are listed by the FDA but are not findings of the CER: Alendronate, risedronate, and ibandronate are associated with musculoskeletal pain, hypocalcemia, osteonecrosis of the jaw, and severe irritation of the upper gastrointestinal mucosa. Zoledronic acid is associated with musculoskeletal pain, renal toxicity and failure, and atrial fibrillation. Denosumab is associated with hypocalcemia and osteonecrosis of the jaw. Teriparatide is associated with an increased risk of bone cancer. Symptoms of vitamin D toxicity include nausea, vomiting, anorexia, polyuria, constipation, weakness, and weight loss. Excessive vitamin D causes hypercalcemia, which can cause dementia, memory loss, and arrhythmias, as well as irreversible kidney damage and renal failure. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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) 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. The strength of evidence in support of this conclusion is high. One large randomized controlled trial (RCT) showed that after five years of initial alendronate therapy, an additional five years of therapy continued to reduce vertebral fracture risk. Continued reduction in nonvertebral fracture risk was found at 10 years (in post-hoc analysis) only in women who after five years of treatment had osteoporosis (T-scores less than -2.5) or prevalent vertebral fractures. The strength of evidence in support of this finding is moderate. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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 Treatment Monitoring, Adherence, and Persistence (2 of 3) Decreased adherence to bisphosphonates is associated with an increased risk of fracture (vertebral, nonvertebral, or both). The strength of evidence is 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. The strength of evidence is moderate. Observational studies of patients taking bisphosphonates in combination with calcium and vitamin D, however, show that adherence and persistence is poor in many patients. The strength of evidence is high. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 Treatment Monitoring, Adherence, and Persistence (3 of 3) Observational studies show that adherence to therapy with bisphosphonates is improved with weekly compared with daily regimens. (Evidence is lacking to evaluate comparative adherence to monthly versus weekly regimens.) The strength of evidence for this finding is high. 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, and medication cost. Age, previous history of fracture, and concomitant medication use do not appear to affect adherence or persistence. The strength of evidence for this finding is moderate. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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) 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. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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 of treatment. Monitoring BMD during therapy does not fully reflect treatment benefits, as patients with BMD losses during antiresorptive therapy may still experience reduced fracture risk. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence- based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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, and few head-to-head comparisons of medications exist. Studies comparing exercise with medications are lacking. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 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 effects of longer durations of therapy among the various medications. It is thus unclear how long patients should remain on therapy. Data are insufficient to determine the comparative effectiveness among individual bisphosphonates or between bisphosphonates and calcium, raloxifene, or teriparatide. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence- based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at: .

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 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. Quality-of-life issues were not assessed by this review. Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence- based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

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 What To Discuss With Your Patients - The serious health consequences associated with LBD and fracture - The potential benefits and adverse effects associated with 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 Reference: Newberry SJ, Crandall CC, Gellad WG, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update to the 2007 Report. Comparative Effectiveness Review No. 53 (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 12-EHC023-EF. Available at Crandall CC, Newberry SJ, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at:

Thank you for your time For CE/CME:
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 Free print copies AHRQ Publications Clearinghouse: (800)

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