Section 1: Introduction

This guide summarizes the effectiveness and safety of various treatments for preventing fractures among postmenopausal women with osteoporosis. It focuses on postmenopausal women because most of the clinical trials of treatment were conducted in this population.

This guide does not examine the effect of treatments on intermediate outcomes, such as bone mineral density or markers of bone turnover.

Treatments reviewed include bisphosphonates, selective estrogen receptor modulators (SERMs), hormonal medications, calcium, and vitamin D. The dose and price of drugs reviewed are listed in section 9.

Clinical Issue

Osteoporosis increases bone fragility and susceptibility to fracture. It occurs in aging individuals of both sexes but is more common in postmenopausal women. It also can result from secondary causes, such as treatment with glucocorticoids. Each year in the United States, about 1.5 million people experience a fracture related to osteoporosis. Of those with hip fractures, one in five die, and the same number end up in a nursing home within a year of the fracture.

The goal of treating osteoporosis is to prevent fractures and their associated disability. Candidates for treatment include individuals at high risk for fracture as defined by low bone density, history of prior fracture, significant secondary causes for developing osteoporosis, and risk factors for falls, such as difficulty with walking or balance. Selecting treatment requires careful consideration of the benefits, risks, and costs as well as the likelihood of adherence.

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Section 2. Clinical Bottom Line

Confidence Scale

The confidence ratings in this guide are derived from a systematic review of the literature. The level of confidence is based on the overall quantity and quality of clinical evidence.

High

There are consistent results from good quality studies. Further research is very unlikely to change the conclusions.

Medium

Findings are supported, but further research could change the conclusions.

Low

There are very few studies, or existing studies are flawed.

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Section 3: Treatment Approaches

Bone Mineral Density

The clinical definition of osteoporosis is based either on evidence of fracture or on the densitometric measurement of bone, bone mineral density (BMD).The most common BMD test is a DXA (dual-energy x-ray absorptiometry). BMD measurements are interpreted according to the number of standard deviations from the mean of a reference population of young adults. This is referred to as the T-score.

A negative value indicates a BMD measurement below the mean. A T-score lower than -2.5 is diagnostic of osteoporosis. If a postmenopausal woman has had a nontraumatic fracture (fragility fracture), she is considered to have osteoporosis regardless of her T-score.

Bone Health

Many individuals, especially those at highest risk for osteoporotic fractures, do not obtain adequate calcium and vitamin D. While evidence is limited about the benefits of calcium and vitamin D supplements for fracture prevention, adequate calcium and vitamin D is essential to bone health.

The U.S. Surgeon General's report Bone Health and Osteoporosis (2004) recommends routine use of calcium and vitamin D supplements for postmenopausal women with inadequate dietary intake (see chart below). Daily calcium should not exceed 2,500 mg, and vitamin D should not exceed 2,000 IU daily for people without a documented vitamin D deficiency.

The report also encourages regular physical activity as a way to reduce falls by improving balance, strength, and endurance. Smoking and heavy alcohol use both increase the risk of fractures and should be discouraged.

Fracture Prevention Medications

Nonvertebral fragility fractures and vertebral compression fractures are commonly due to osteoporosis. Women who experience one fracture are more likely to have subsequent fractures.

The medications used for fracture prevention fall into three classes: bisphosphonates, selective estrogen receptor modulators (SERMs), and hormonal medications. With the exception of teriparatide (recombinant parathyroid hormone), all these drugs work as antiresorptive agents, which inhibit osteoclastic activity. Teriparatide is an anabolic agent that stimulates new bone formation by activating osteoblasts.

Research shows that most of the drugs in each of the three classes reduce the risk of fracture among women who have osteoporosis. Most of the research looks at prevention of vertebral fractures. There is less research on nonvertebral sites. The evidence is summarized below.

1 These drugs were evaluated in the systematic review. 2 Trials focus primarily on transplant and cancer patients; few focus on postmenopausal women. 3 Based on a single study of women at increased risk of breast cancer with unknown bone mineral density. 4 The largest study of estrogen was the Women’s Health Initiative, which included postmenopausal women with unknown bone mineral density. 5 Insufficient evidence for hip fracture prevention; effective for prevention of other nonvertebral fractures. =Effective for prevention of fractures with Level of Confidence: or . INSF=Insufficient evidence. SERMs=Selective estrogen receptor modulators.
Efficacy of Drugs1 for Prevention of Osteoporotic Fractures
Drug (Brand)	Vertebral Fractures	Hip and Other Nonvertebral Fractures
Bisphosphonates
Alendronate (Fosamax®)
Etidronate (Didronel®)		INSF
Ibandronate (Boniva®)		INSF
Pamidronate2 (Aredia®)	INSF	INSF
Risedronate (Actonel®)
Zoledronic acid (Reclast®)
SERMs
Raloxifene (Evista®)		INSF
Tamoxifen3 (Nolvadex®)	INSF	INSF
Hormonal Medications
Calcitonin (Miacalcin®, Fortical®)		INSF
Estrogen4 (Premarin®, Prempro®, Premphase®)
Teriparatide (Forteo®)		INSF5/

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Section 4: Possible Harms of Treatment

Bisphosphonates

Gastrointestinal Problems

Gastrointestinal (GI) problems have been reported with all oral bisphosphonates. Mild upper GI symptoms include acid reflux, esophageal irritation, nausea, vomiting, and heartburn. Serious GI symptoms include esophageal and nonesophageal upper GI perforations, ulcers, and bleeds.

Adherence to dose instructions for oral medications can minimize the effects. These instructions include:

• Taking the pill on an empty stomach.
• Taking it with a large glass of water.
• Not eating or lying down for 30-60 minutes.

Atrial Fibrillation

There is concern that bisphosphonates, particularly zoledronic acid, may increase the risk of atrial fibrillation, but the current evidence is conflicting.

Musculoskeletal Pain

Severe musculoskeletal pain in people taking bisphosphonates is highlighted in a January 2008 Food and Drug Administration (FDA) alert. It may occur within days, months, or years after drug initiation and require discontinuation. These symptoms are in contrast to an acute response that may accompany initial exposure to bisphosphonates and resolve with continued use.

Osteonecrosis of the Jaw

This condition has been reported among patients taking bisphosphonates. The vast majority of cases occurred among people with cancer using intravenous bisphosphonates. A few cases occurred in women taking oral bisphosphonates for postmenopausal osteoporosis.

SERMs and Hormonal Medications

Stroke

• Estrogen increases the risk of stroke.
  
  Level of Confidence:

Thromboembolic Events

• Raloxifene and tamoxifen increase the risk of pulmonary embolism.
  
  Level of Confidence:
• Raloxifene and estrogen increase the risk of venous thromboembolic events.
  
  Level of Confidence:

Breast Cancer

• Estrogen combined with progestin increases the risk of breast cancer.
  
  Level of Confidence:

Gynecologic and Breast Problems

• Estrogen and tamoxifen increase the risk of gynecologic problems, such as endometrial bleeding.
  
  Level of Confidence:
• Estrogen increases the odds of breast abnormalities other than cancer, including pain, tenderness, and fibrocystic changes.
  
  Level of Confidence:

Osteosarcoma

Based on the results of animal studies with large doses of teriparatide, the FDA warns against prescribing it to those at increased risk for osteosarcoma, such as people with Paget’s disease. The FDA also recommends against using teriparatide for longer than 2 years.

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Section 5: Adherence

Treatment to prevent fractures is usually long term. Consider how well the woman will be able to take the medication as prescribed (adherence) and the possible barriers to continuing treatment (persistence).

• Rates of adherence and persistence with alendronate, etidronate, risedronate, raloxifene, estrogen, calcitonin, calcium, and vitamin D are low in women with osteoporosis.
  
  Level of Confidence:

• Factors that affect adherence and persistence include side effects, absence of disease-related symptoms, comorbid conditions, ethnicity, socioeconomic status, and dosing regimens.
  
  Level of Confidence:

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Section 6: Selecting a Treatment Approach

Most of these drugs prevent fractures among postmenopausal women with osteoporosis. When selecting a treatment, consider these other factors.

Consider barriers to adherence and persistence, including mode of administration, dosing regimens, and cost.

• Weekly users of bisphosphonates have higher rates of adherence and persistence compared with daily users.
• Cost may be a barrier. Generics are not widely available. Intravenous drugs incur additional expense. Drugs, doses, and prices are listed in section 9. The Partnership for Prescription Assistance can also provide information on public and private assistance programs. Web site: www.pparx.org. Phone: (800) 477-2669.

Consider the risk of adverse events.

• GI problems can occur with oral bisphosphonates. Women who experience symptoms such as reflux or nausea may need to switch medications.
• Women with a history of serious GI disease, such as GI bleeds, should avoid bisphosphonates, except zoledronic acid.
• Avoid zoledronic acid for women at high risk for atrial fibrillation.

Consider supplementation.

• Adequate calcium and vitamin D intake is needed for normal bone homeostasis. Encourage women to take calcium supplements in divided doses and get adequate vitamin D.

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Section 7: Resource for Patients

Osteoporosis Treatments That Help Prevent Broken Bones: A Guide for Women After Menopause is a companion to this Clinician’s Guide. It can help women talk with their health care professional about treatment options. It provides information about the effectiveness of osteoporosis treatments for preventing fractures, side effects, and costs.

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Section 8: Still Unknown

• There is no research comparing exercise with other treatments for fracture prevention.
• We do not have enough data to determine if one class of drugs is superior to another for fracture prevention.
• We do not have enough data to determine if any of the bisphosphonates are more effective than the others for fracture prevention.

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Section 9. Price

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Section 10: Source

The source material for this guide is a systematic review of 101 research publications about efficacy and 490 research publications about adverse events. The review, Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis (2007), was prepared by the Southern California Evidence-based Practice Center at RAND. The Agency for Healthcare Research and Quality (AHRQ) funded the systematic review and this guide. The guide was developed using feedback from clinicians who reviewed preliminary drafts.

AHRQ created the John M. Eisenberg Center at Oregon Health & Science University to make research useful for decisionmakers. This guide was prepared by David Hickam, M.D., Bruin Rugge, M.D., Theresa Bianco, Pharm.D., Sandra Robinson, M.S.P.H., Erin Davis, B.A., Martha Schechtel, R.N., and Valerie King, M.D., of the Eisenberg Center.

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Section 11: For More Information

For current osteoporosis screening recommendations, visit the U.S. Preventive Services Task Force Web site: http://www.ahrq.gov/clinic/uspstf/uspsoste.htm

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