Cochrane for Clinicians

Putting Evidence into Practice

Alendronate for Fracture Prevention in Postmenopause

kathryn k. holder, COL, USAF, MC, and sara shelton kerley, CAPT, USAF, MC,
David Grant Medical Center, Family Medicine Residency Program, Travis AFB, California

Clinical Scenario

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.

Clinical Question

Should alendronate (Fosamax) be prescribed for primary and secondary prevention of osteoporotic fractures?

Evidence-Based Answer

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

Practice Pointers

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 long-term 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 first-line 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 treatment, and bisphosphonates, raloxifene, calcitonin (Miacalcin), or parathyroid hormone for osteoporosis prevention.3

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 bacteria-rich 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 half-life of alendronate and its potentially prolonged use in postmenopausal women, the paucity of long-term 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.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Air Force Medical Department or the U.S. Air Force Service at large.

Address correspondence to Kathryn K. Holder, COL, USAF, MC, at kathryn.holder-02@travis.af.mil. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

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. Woo SB, 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.

Cochrane Briefs

Induction of Labor at or Beyond Term

Clinical Question

In low-risk pregnancies, does inducing labor at or beyond term improve maternal or neonatal outcomes?

Evidence-Based Answer

Fetal or neonatal deaths in women who delivered after their due date and before 42 weeks occur at a rate of less than 0.5 percent, regardless of whether labor is induced or spontaneous. Compared with awaiting spontaneous labor, inducing labor between 41 and 42 weeks is associated with fewer perinatal deaths and fewer cases of meconium aspiration. However, there were no differences in admissions to the neonatal intensive care unit (NICU). Induction beyond term does not increase rates of cesarean delivery.

Practice Pointers

Postterm delivery beyond 42 weeks' gestation poses risks to mothers and babies, including increased perinatal death, increased cesarean deliveries, perineal injuries from macrosomia, and labor dystocias. Physicians have turned to induction of labor or antenatal surveillance as a means of preventing complications.1

This Cochrane review included randomized controlled trials (RCTs) comparing induction of low-risk pregnant women at a predetermined gestational age versus expectant management until an indication for delivery arose. A variety of neonatal, maternal, and health service use outcomes were reported. Nineteen RCTs that included a total of 7,984 women were included and analyzed in three groups of trials, in which labor was induced at 37 to 40 completed weeks, 41 completed weeks, and 42 completed weeks.

For the outcome of perinatal death, no significant difference was noted between induction and expectant groups in any of the individual gestational age categories. However, if the results from groups induced at 41 and 42 completed weeks were combined, there was a significant reduction in fetal and neonatal deaths, and fewer cases of meconium aspiration syndrome occurred in studies when labor was induced at either 41 or 42 weeks. However, there was no significant difference in NICU admissions. In no category of studies was there a significant difference in the rate of cesarean delivery between induction and expectant management.

Data reviewed here can guide patient counseling on the magnitude of risks involved with induction or awaiting labor. The evidence favors induction between 41 and 42 weeks to reduce perinatal mortality and meconium aspiration, but the absolute risk of these outcomes is small. In the combined category of induction at 41 or 42 weeks, one out of 2,986 newborns in the induction group and nine out of 2,953 in the spontaneous labor group died. Because there is no increased risk of cesarean delivery rates, instrumented deliveries, use of analgesia, or abnormalities in fetal heart rate tracings, the disadvantages of induction are small. In light of these findings, the American College of Obstetricians and Gynecologists (ACOG) recommends that women with postterm gestations who have unfavorable cervices can undergo labor induction or be managed expectantly, but they acknowledge that many physicians routinely induce labor by 42 weeks. There is no evidence regarding the effectiveness of antenatal testing in women who are postterm. However, based on expert consensus, ACOG recommends a nonstress test and amniotic fluid index twice weekly, starting at 41 weeks.1

There is not strong evidence to determine the exact optimal timing of induction between 41 and 42 weeks' gestation. In clinical practice, the decision between induction and expectant management should include favorability of the cervix, maternal parity, and patient preferences, and often includes patient or physician convenience.

Kathleen Kearns, MD

Author disclosure: Nothing to disclose.

Source: Gülmezoglu AM, Crowther CA, Middleton P. Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev. 2006;(4):CD004945.

REFERENCE

1. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical management guidelines for obstetricians-gynecologists. Number 55, September 2004 (replaces practice pattern number 6, October 1997). Management of Postterm Pregnancy. Obstet Gynecol. 2004;104(3):639-646.

The Cochrane Abstract on the next page 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.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). See CME Quiz on page 559.

The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.

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