Cochrane for Clinicians
Putting Evidence into Practice
Alendronate for Fracture Prevention in Postmenopause
Am Fam Physician. 2008 Sep 1;78(5):579-581.
A 55-year-old postmenopausal woman was recently diagnosed with osteoporosis on dual energy x-ray absorptiometry. She has no history of fracture, and is currently taking a calcium and vitamin D supplement.
Should alendronate (Fosamax) be prescribed for primary and secondary prevention of osteoporotic fractures?
In postmenopausal women, a 10-mg daily dose of alendronate is effective for secondary (number needed to treat [NNT] = 16) and primary (NNT = 50) prevention of vertebral fractures.1 It is also effective for secondary prevention of nonvertebral fractures, including hip or wrist fractures (NNT = 100), but it is not effective for primary prevention of nonvertebral fractures.1 Adverse effects reported in 11 randomized controlled trials (RCTs) were similar for alendronate and placebo.1
Mortality after a hip fracture may reach 20 percent in the first year; 50 percent of patients never return to their previous functional capacity, and 33 percent require longterm care.2 Alendronate has been shown to increase bone mineral density and reduce fractures in a number of clinical trials and is therefore considered a firstline therapy for the prevention and treatment of osteoporosis.3,4
This Cochrane review found 11 studies comparing alendronate with placebo and using a primary outcome of fracture incidence in postmenopausal women.1 The studies followed participants for at least one and up to four years. The mean age of participants was 53 to 78 years. The trials were classified as secondary prevention if they enrolled women with a bone density of at least two standard-deviation values below the peak bone mass, or those who had experienced previous vertebral compression fractures. Studies were also classified as secondary prevention if the average age of study participants was older than 62 years. In studies where this inclusion information was not available, the trials were classified as primary prevention if the average T-score was within two standard deviations of the mean, or if the prevalence of fracture in the study population was less than 20 percent.
For primary prevention, patients who were given alendronate had two fewer out of 100 sustained vertebral fractures (NNT = 50) compared with control results. However, alendronate did not demonstrate any significant benefit in preventing hip, wrist, or other nonvertebral fractures. In women receiving alendronate for secondary prevention, the NNT to prevent one fracture was 16 for vertebral fracture, 100 for wrist or hip fractures, and 50 for other nonvertebral fractures. Alendronate was more effective with increasing age of participants: the NNT to prevent a first vertebral fracture in five years ranged from 1,111 for women in their early 50s to 47 for women in their 90s. To prevent a second fracture, the NNT similarly decreased with age from 444 to 8. To prevent a first nonvertebral fracture, the NNT decreased with age from 272 to 12, and from 167 to 12 for prevention of a second nonvertebral fracture.
The authors' findings are consistent with the clinical practice guidelines published by the American College of Obstetricians and Gynecologists (ACOG) in 2004, which recommend using bisphosphonates, raloxifene (Evista), or estrogen for osteoporosis prevention, and bisphosphonates, raloxifene, calcitonin (Miacalcin), or parathyroid hormone for osteoporosis treatment.3
Background: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate (Fosamax) belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts.
Objectives: To assess the effectiveness of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
Search Strategy: The authors searched Central, Medline, and EMBASE for relevant randomized controlled trials published from 1966 to 2007.
Data Collection and Analysis: The authors undertook study selection and data abstraction in duplicate. The authors performed meta-analysis of fracture outcomes using relative risks, and a relative change greater than 15 percent was considered clinically important. The authors assessed study quality through reporting of allocation concealment, blinding, and withdrawals.
Main Results: Eleven trials representing 12,068 women were included in the review. Relative and absolute risk reductions for the 10-mg dose were as follows. For vertebral fractures, a 45 percent relative risk reduction was found (relative risk [RR] = 0.55; 95% confidence interval [CI], 0.45 to 0.67). This was significant for primary prevention, with a 45 percent relative risk reduction (RR = 0.55; 95% CI, 0.38 to 0.80) and 2 percent absolute risk reduction; and for secondary prevention, with 45 percent relative risk reduction (RR = 0.55; 95% CI, 0.43 to 0.69) and 6 percent absolute risk reduction. For nonvertebral fractures, a 16 percent relative risk reduction was found (RR = 0.84; 95% CI, 0.74 to 0.94). This was significant for secondary prevention, with a 23 percent relative risk reduction (RR = 0.77; 95% CI, 0.64 to 0.92) and a 2 percent absolute risk reduction, but not for primary prevention (RR = 0.89; 95% CI, 0.76 to 1.04). There was a 40 percent relative risk reduction in hip fractures (RR = 0.60; 95% CI, 0.40 to 0.92), but only secondary prevention was significant, with a 53 percent relative risk reduction (RR = 0.47; 95% CI, 0.26 to 0.85) and a 1 percent absolute risk reduction. The only significance found for wrist fractures was in secondary prevention, with a 50 percent relative risk reduction (RR = 0.50; 95% CI, 0.34 to 0.73) and a 2 percent absolute risk reduction. For adverse events, the authors found no statistically significant difference in any included study. However, observational data raise concerns about potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw.
Authors' Conclusions: At 10 mg of alendronate per day, clinically important and statistically significant reductions in vertebral, nonvertebral, hip, and wrist fractures were observed for secondary prevention. The authors found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
Although the studies included in this review revealed no difference between alendronate and placebo with regard to adverse events, osteonecrosis of the jaw is a serious adverse effect that has been reported with prolonged alendronate use. Bones are dependent on osteoclastic and osteoblastic activity to repair microtrauma. With the inhibition of osteoclastic activity by bisphosphonates, bone turnover is suppressed to the extent that trauma cannot be repaired. The jaw is thought to be more susceptible than other sites. In the mouth, there is only a thin layer of mucous membrane separating the bone from trauma, and it is a bacteriarich environment. A 2006 review found that most patients who developed osteonecrosis of the jaw associated with bisphosphonates were receiving intravenous therapy and were being treated for multiple myeloma or bone metastases.5 Additionally, most of those patients had recently undergone a dental procedure before the development of osteonecrosis. However, osteonecrosis of the jaw has been reported in patients taking oral alendronate at a dose of 10 mg per day for osteoporosis.5 Given the long halflife of alendronate and its potentially prolonged use in postmenopausal women, the paucity of longterm safety data is an important consideration when prescribing bisphosphonates.5
In nine of the 11 studies cited in this Cochrane review, calcium supplementation was used in addition to alendronate. However, since the review's publication, some concern has been raised about the use of calcium supplementation in older women. An RCT published in January 2008 (in which 1,471 postmenopausal women were randomized to receive calcium supplementation or placebo) noted an increase in cardiovascular events among the calcium supplementation group.6 These data—when taken in context with several other studies showing a similar trend of increased cardiovascular risk with calcium supplementation—should be considered when advising postmenopausal patients.6
The data in this Cochrane review are consistent with the current standard of care in treating women with osteoporosis. Although alendronate was found to provide greater protection in secondary prevention of osteoporotic fractures, there is still some benefit in its use as primary prevention.
1. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.
2. Brown JP, Josse RG, for the Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada [published corrections appear in CMAJ. 2003;168(4):400, CMAJ. 2003;168(6):676, and CMAJ. 2003;168(5):544] CMAJ. 2002;167(10 Suppl):S1–S34.
3. American College of Obstetricians and Gynecologists, Women's Health Care Physicians. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 50, January 2003 Obstet Gynecol. 2004;103(1):203–216.
4. National Osteoporosis Foundation, American Academy of Orthopaedic Surgeons. Physician's Guide to Prevention and Treatment of Osteoporosis. 2nd ed. Washington, DC: National Osteoporosis Foundation, 2003.
5. SB Woo, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws [published correction appears in Ann Intern Med. 2006;145(3):235] Ann Intern Med. 2006;144(10):753–761.
6. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008;336(7638):262–266.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Drs. Holder and Kerley present a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab001155.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
Copyright © 2008 by the American Academy of Family Physicians.
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