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)

 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 Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 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). Introduction to Osteoporosis Newberry SJ, Crandall CC, 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:

 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 or less is classified as osteoporosis.  A T-score between and is considered LBD (also known as osteopenia).  A T-score of - 1 or greater is considered normal. Classifications of Osteoporosis and Low Bone Density 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: Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at ww.effectivehealthcare.ahrq.gov/lbd.cfm.

Risk Factors for Osteoporosis (1 of 2)  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 include (but are not limited to): National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) National Osteoporosis Foundation. Clinician’s Guide To Prevention and Treatment of Osteoporosis. Available at Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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. Predicting Fracture Risk 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: Newberry SJ, Crandall CC, 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 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 Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 Osteoporotic Fracture Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 KQ 2: How does fracture 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 KQ 3: 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). Clinical Questions Addressed by the CER (3 of 5) Cramer JA, Roy A, Burrell A. Value Health 2008;11(1):44-7. PMID: Newberry SJ, Crandall CC, 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 KQ 5: 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? Clinical Questions Addressed by the CER (5 of 5) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 Framework Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version Available at Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version Available at Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the CER Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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. Benefits of Medications (1 of 2 ) Medication VertebralNonvertebralHipWrist Bisphosphonate s Alendronate  High  Low Risedronate  High  Low* Zoledronic acid  High Not specified Ibandronate  HighNot specified Denosumab  High Not specified Teriparatide  High  ModerateNot specified Raloxifene  High  High  Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance.  = reduced fracture risk;  = did not reduce fracture risk; NSD = no statistically significant difference Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 Benefits of Medications (2 of 2)

Patient PopulationPharmacotherapies 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 glucocorticoidsAlendronate Teriparatide Risedronate 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 Risedronate Moderate Transplant recipients and patients treated chronically with corticosteroids Inconclusive support for any agentInsufficient Medications that reduce the risk of fragility fracture in the given patient populations: Postmenopausal women with osteopenia who do not have prevalent vertebral fractures RisedronateLow to Moderate Benefits of Medications in Subpopulations Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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. Summary of Benefits: Medications Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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. Benefits: Menopausal Hormone Therapy Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

MedicationAdverse EffectMagnitude 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, 1.15High Hypocalcemia9/301 treatment vs. 0/207 placeboModerate Zoledronic acidHypocalcemiaOR = 7.22; 95% CI 1.81, 42.7Moderate 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.) High *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) Adverse Effects of Medications for Low Bone Density or Osteoporosis (1 of 3) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

MedicationAdverse EffectMagnitude of Association Strength of Evidence Raloxifene Pulmonary embolismOR = 5.27; 95% CI 1.29, 46.4High Thromboembolic eventsOR = 1.63; 95% CI 1.36, 1.98High Myalgias, cramps, and limb pain OR = 1.53; 95% CI 1.29, 1.81High Hot flashesOR = 1.58; 95% CI 1.35, 1.84High Teriparatide HypercalcemiaOR = 12.9; 95% CI 10.49, 16.0 Moderate HeadachesOR = 1.44; 95% CI 1.24, 1.67Moderate Denosumab Mild GI events*OR = 2.13; 95% CI 1.11, 4.4Moderate RashOR = 2.01; 95% CI 1.5, 2.73High InfectionOR = 1.28; 95% CI 1.02, 1.60High *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) Adverse Effects of Medications for Low Bone Density or Osteoporosis (2 of 3) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

MedicationAdverse Effect Magnitude of Association (From Pooled Analysis of Clinical Data) 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 1.57 High Thromboembolic events Estrogen: OR = 1.36; 95% CI: 1.01 to 1.86 Combination: OR = 2.27; 95% CI: 1.72 to 3.02 High Breast cancer Estrogen: In the WHI,* 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, † 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). *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: % CI = 95 percent confidence interval; HR = hazard ratio; OR = odds ratio; WHI = Women’s Health Initiative Adverse Effects of Medications for Low Bone Density or Osteoporosis (3 of 3) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

MedicationAdverse Effect(s) Alendronate, Risedronate, and Ibandronate Musculoskeletal pain Hypocalcemia Osteonecrosis of the jaw Severe irritation of upper gastrointestinal mucosa Zoledronic acid Musculoskeletal pain Renal toxicity and acute renal failure Denosumab Hypocalcemia Osteonecrosis of the jaw 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 adverse effects are listed by the FDA but are not findings of the CER. Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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.  Women with prevalent vertebral fractures after 5 years of treatment.  Strength of Evidence: Moderate Treatment Monitoring, Adherence, and Persistence (1 of 3) Newberry SJ, Crandall CC, 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.  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 Treatment Monitoring, Adherence, and Persistence (2 of 3) Newberry SJ, Crandall CC, 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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. Conclusions (1 of 2) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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) Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at

 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 What To Discuss With Your Patients Newberry SJ, Crandall CC, Gellad WG, et al. Comparative Effectiveness Review No. 53. Available at