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For free print copies of this summary, call 800-358-9295. Ask the Publications Clearinghouse for AHRQ Publication 12-EHC023-3

Treatment To Prevent Osteoporotic Fractures: An Update

Clinician Summary – May 16, 2012

Treatment To Prevent Osteoporotic Fractures: An Update


Table of Contents

Focus of Research for Clinicians

As an update to the 2007 report, a systematic review of 567 clinical studies published between January 2005 and March 2011 examined the comparative effectiveness and safety of treatments to prevent fractures in people with low bone density (including osteoporosis). The full report, listing all studies, is available at This summary, based on the full report of research evidence, is provided to inform discussions of options with patients and to assist in decisionmaking along with consideration of a patient’s values and preferences. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.


Approximately 52 million people in the United States are affected by osteoporosis or low bone density. Osteoporosis, a severe form of low bone density especially common in postmenopausal women, is a systemic skeletal disease characterized by decreasing bone mass and microarchitectural deterioration of bone tissue and consequential 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).1

Risk factors for osteoporotic fracture include (but are not limited to): increasing age, female sex, postmenopause for women, hypogonadism or premature ovarian failure, ethnic background (higher for whites), low body weight, previous fracture, previous vertebral fracture due to minimal trauma, parental history of hip fracture, rheumatoid arthritis, low BMD, current smoking, higher alcohol intake (three or more drinks per day), vitamin D deficiency, low calcium intake, hyperkyphosis, falling, and immobilization. Risk is also increased with the chronic use of certain medications, including glucocorticoids, anticoagulants, anticonvulsants, aromatase inhibitors, cancer chemotherapeutic drugs, and gonadotropin-releasing hormone agonists.

Risk scores that combine clinical risk factors with BMD testing results have been developed to better predict a patient’s risk of osteoporotic fracture. One such tool is the Fracture Risk Assessment Tool (FRAX®) developed by the World Health Organization. FRAX is a set of race- and nation-specific algorithms that take into account a patient’s individual risk factors to estimate the absolute 10-year risk of major osteoporotic fractures.

Interventions to prevent osteoporotic fracture include pharmacologic agents, dietary and supplemental vitamin D and calcium, and weight-bearing exercise. These interventions have been studied and used (with less frequency) in patients with osteopenia (T-score between -2.5 and -1.0). Pharmacologic agents investigated in the systematic review include bisphosphonates, teriparatide (a peptide hormone), estrogen in the form of menopausal hormone therapy (MHT), the selective estrogen receptor modulator raloxifene, and the biological agent denosumab.

These pharmacologic agents are antiresorptive, with the exception of teriparatide, which is anabolic. There were no new findings about calcitonin in this updated report.

1 BMD is classified according to T-score, the number of standard deviations above or below the mean BMD for healthy adults, determined by DXA. A T-score of -2.5 or less is classified as osteoporosis; between -2.5 and -1.0 is considered low bone density (osteopenia); and -1 or greater is considered normal.


The ability of medications to decrease fracture risk is most strongly established for postmenopausal women with osteoporosis (BMD 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 other nonvertebral fractures. Limited evidence supports a potential benefit of 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 from exercise. Most osteoporosis interventions have possible adverse effects, which 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 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 5 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.

Clinical Bottom Line


Pharmacologic Agents

  • Alendronate, risedronate, zoledronic acid, and denosumab reduce the risk of hip and other nonvertebral fractures in postmenopausal women with osteoporosis. evidence high
  • Bisphosphonates (alendronate, risedronate, zoledronic acid, and ibandronate), denosumab, teriparatide, and raloxifene reduce the risk of vertebral fractures in postmenopausal women with osteoporosis. evidence high
  • Teriparatide reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis. evidence medium
  • Regarding the need for calcium with bisphosphonates, the combination of alendronate and calcium significantly decreased the risk for any type of clinical fracture when compared with alendronate alone. evidence low
  • Reduced risk of other fracture types and risk reduction in subpopulations is achieved by fewer medications and supported by varied strengths of evidence. (See Tables 1 and 2 for details.)

Exercise and Dietary Supplementation

Menopausal Hormone Therapy

  • In studies of postmenopausal women in general, MHT* reduces the risk of vertebral, hip, and other nonvertebral fractures evidence high; however, in postmenopausal women with established osteoporosis, MHT does not reduce fracture risk significantly evidence medium.
  • No differences in comparative effectiveness for fracture prevention have been shown between bisphosphonates and MHT (estrogen). evidence medium
  • No differences in fracture incidence have been shown in comparisons of MHT with either raloxifene or vitamin D. evidence low

* The Women’s Health Initiative reported serious adverse events associated with MHT, such that routine use of MHT in postmenopausal women is now discouraged.

Monitoring, Adherence, and Persistence
  • 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. 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 a post-hoc analysis) only in women who had osteoporosis (T-score < -2.5) or prevalent vertebral fractures after the first 5 years of treatment. evidence medium
  • Decreased adherence to bisphosphonates is associated with an increased risk of fracture (vertebral, nonvertebral, or both). evidence medium
  • Although RCTs examining bisphosphonates report high levels of adherence (majority >90%), those with raloxifene reported adherence rates of 65 to 70 percent. evidence medium
    • Observational studies (perhaps more indicative of the experience in practice) of patients taking bisphosphonates in combination with calcium and vitamin D show that in many patients adherence and persistance with the treatment regimen are poor. evidence high
  • Observational studies show that adherence to therapy with bisphosphonates is improved with weekly regimens when compared with daily regimens. 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, and medication cost. Age, previous history of fracture, and concomitant medication use do not appear to affect adherence or persistence. evidence medium

BMD = bone mineral density; MHT = menopausal hormone therapy; RCT = randomized controlled trial

Strength of Evidence Scale

High: evidence high
There are consistent results from good-quality studies. Further research is very unlikely to change the conclusions.

Moderate: evidence medium
Findings are supported, but further research could change the conclusions.

Low: evidence low
There are very few studies, or existing studies are flawed.

Insufficient: evidence insufficient
Research is either unavailable or does not permit estimation of a treatment effect.

Table 1: Effectiveness of Medications To Prevent Fracture Risk

The table below lists whether or not the following medications reduce the risk of the listed fracture types for postmenopausal women with osteoporosis.

Medication Vertebral Nonvertebral Hip Wrist
check mark = reduced fracture risk; x = did NOT reduce fracture risk
* Risedronate-mediated reduction in wrist fracture did not reach the conventional level of statistical significance.
Bisphosphonates Alendronate evidence high evidence high evidence high evidence low
Risedronate evidence high evidence high evidence high evidence low*
Zoledronic acid evidence high evidence high evidence high Not specified
Ibandronate evidence high Not specified Not specified Not specified
Denosumab evidence high evidence high evidence high Not specified
Teriparatide evidence high evidence medium Not specified Not specified
Raloxifene evidence high evidence high evidence high evidence high

Additional Information


Table 2: Effectiveness in Subpopulations

Patient Population Pharmacotherapies
Medications that reduce overall fracture risk in the given patient populations:
Patients with high risk for fracture (including postmenopausal women with osteoporosis) evidence high
Patients treated with glucocorticoids evidence medium to evidence high
Patients with a higher risk of falling (e.g., patients with hemiplegia, Alzheimer’s disease, or Parkinson’s disease) evidence medium
Transplant recipients and patients treated chronically with corticosteroids evidence insufficient
Medications that reduce fragility fracture risk in the given patient populations:
Postmenopausal women with osteopenia who do not have prevalent vertebral fractures evidence low to evidence medium

Table 3: Adverse Effects With Rated Findings

Medication Adverse Effect Magnitude of Association (From Pooled Analysis of Clinical Data)a
a 95% CI = 95 percent confidence interval; HR = hazard ratio (in cancer research, a measure of how often a particular event happens in one group compared with how often it happens in another group over time); OR = odds ratio (the odds of the condition developing in those taking the listed medications compared with the odds in patients receiving placebo treatment); RR = relative risk (the incidence of the conditions in those taking the listed medications compared with the incidence in patients receiving placebo treatment); WHI = Women’s Health Initiative.

b Mild upper GI events = conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn.

c These findings are from the original 2007 report. Note: The WHI reported adverse events associated with menopausal hormone therapy, including venous thromboembolic events, stroke, and a variable effect on breast cancer.

d 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: 22401913.

e Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010 Oct 20;304(15):1684-92. PMID: 20959578.
Bisphosphonates (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 U.S. Food and Drug Administration has issued a boxed warning about this possible adverse effect.) evidence low
Alendronate Mild upper GI eventsb OR = 1.08, 95% CI: 1.01 to 1.15 evidence high
Hypocalcemia 9/301 treatment vs. 0/207 placebo evidence medium
Zoledronic acid Hypocalcemia OR = 7.22, 95% CI: 1.81 to 42.7 evidence medium
Intravenous forms of zoledronic acid and ibandronate Osteonecrosis of the jaw (ONJ) Less than one case per 100,000 person-years of exposure. (Nearly all cases of ONJ are reported in people being treated for cancer.) evidence high
Raloxifene Pulmonary embolism OR = 5.27, 95% CI: 1.29 to 46.4 evidence high
Thromboembolic events OR = 1.63, 95% CI: 1.36 to 1.98 evidence high
Myalgias, cramps, and limb pain OR = 1.53, 95% CI: 1.29 to 1.81 evidence high
Hot flashes OR = 1.58, 95% CI: 1.35 to 1.84 evidence high
Menopausal hormone therapy: estrogen and estrogen-progestin combination Cerebrovascular accidentsc Estrogen: OR = 1.34, 95% CI: 1.07 to 1.68
Combination: OR = 1.28, 95% CI: 1.05 to 1.57 evidence high
Thromboembolic eventsc Estrogen: OR = 1.36, 95% CI: 1.01 to 1.86
Combination: OR = 2.27, 95% CI: 1.72 to 3.02 evidence high
Breast cancer

Estrogen: In the WHI,d this hormone was associated with reduced incidence of breast cancer in women with hysterectomy when compared with placebo (HR = 0.77, 95% CI: 0.62 to 0.95), but subgroup analysis noted that 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,e estrogen-progestin was 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).

Teriparatide Hypercalcemia OR = 12.9, 95% CI: 10.49 to 16.0 evidence medium
Headaches OR = 1.44, 95% CI: 1.24 to 1.67 evidence medium
Denosumab Mild upper GI eventsb OR = 2.13, 95% CI: 1.11 to 4.4 evidence medium
Rash OR = 2.01, 95% CI: 1.5 to 2.73 evidence high
Infection OR = 1.28, 95% CI: 1.02 to 1.60 evidence high

Table 4: Additional Possible Adverse Effects

The following are additional possible adverse effects listed by the U.S. Food and Drug Administration (FDA) that were not findings of the report.

Medications Adverse Effect(s)
Alendronate, risedronate, and ibandronate
  • Musculoskeletal pain
  • Hypocalcemia
  • Osteonecrosis of the jaw
  • Severe irritation of upper gastrointestinal mucosa
Zoledronic acid
  • Severe musculoskeletal pain
  • Renal toxicity and acute renal failure
  • Hypocalcemia
  • Osteonecrosis of the jaw
  • 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 arrythmias
  • Excess vitamin D can cause irreversible kidney damage and renal failure

Gaps in Knowledge

What To Discuss With Your Patients

  • The serious health consequences associated with low bone density and fracture
  • The potential benefits and adverse effects associated with 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 fracture risk reduction
  • Risk factors for low bone density 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

Resource for Patients

Reducing the Risk of Bone Fracture, A Review of the Research for Adults With Low Bone Density is a free companion to this clinician research summary. It provides:

  • Information about treatment options
  • Current evidence regarding effectiveness and side effects
  • Questions for patients to ask their doctor

Healthy Bones: A Decision Aid for Women After Menopause, an online tool for postmenopausal women, is also available at It provides:

  • A tool to help a woman calculate her risk of breaking a bone
  • Detailed information about medicines to prevent fractures
  • Questions for patients to ask their doctor

Ordering Information

For electronic copies of Reducing the Risk of Bone Fracture, A Review of the Research for Adults With Low Bone Density, this clinician research summary, and the full systematic review, visit To order free print copies, call the AHRQ Publications Clearinghouse at 800-358-9295.


The information in this summary is based on Treatments 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, a Rand Health Center, under Contract No. HHSA 290-2007-10062-I for the Agency for Healthcare Research and Quality, March 2012. Available at

This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Emily White, M.S., Amelia Williamson Smith, M.S., Thomas Workman, Ph.D., Morali Sharma, M.D., Robert Volk, Ph.D., and Michael Fordis, M.D.