Osteoporosis results in 1.5 million fractures per year in the United States, with the vast majority occurring in postmenopausal women. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of −2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk.
Management of postmenopausal osteoporosis includes nonpharmacologic treatment (e.g., weightbearing exercise and fall-prevention strategies) and pharmacologic treatment. Bisphosphonates are considered first-line treatment in most women. In a new Clinical Practice article, benefits and rare potential risks are discussed.
• What is the Fracture Risk Assessment Tool (FRAX)?
The overriding goal in managing postmenopausal osteoporosis is the prevention of future fractures. Therefore, identifying women at the highest risk is a clinical priority. Low bone mineral density (BMD), particularly at the hip, is a strong risk factor for fracture: for each 1-SD decrement in BMD, the risk of fracture increases by a factor of 2 or 3. However, a more comprehensive assessment of clinical risk factors is helpful to define absolute risk for an individual and to select patients for treatment. The Fracture Risk Assessment Tool (FRAX), which was developed by the World Health Organization on the basis of data from several international cohorts, incorporates established risk factors and BMD at the femoral neck to predict individual 10-year risk of hip or major osteoporotic fracture; its use is endorsed by several professional organizations.
• What are some of the nonpharmacologic therapies for patients with postmenopausal osteoporosis?
Resistance and weight-bearing exercise can increase muscle mass and can transiently increase BMD. Exercise and balance programs (e.g., yoga and tai chi) may result in improved balance and an increase in muscle tone and may secondarily reduce the risk of falls among some elderly persons. Besides exercise, assessment of the home for hazards, withdrawal of psychotropic medications (when possible), and the use of a multidisciplinary program to assess risk factors are prudent strategies for potentially reducing the risk of falls. Other measures should include counseling about cigarette smoking (which is linked to reduced BMD) and about excess alcohol intake (which can increase the risk of falls).
Morning Report Questions
Q: What class of drug is prescribed most often for the treatment of postmenopausal osteoporosis?
A: The bisphosphonates as a class represent the vast majority of prescriptions for osteoporosis treatment, and all are now available in generic form. Bisphosphonates inhibit bone remodeling. Several oral and intravenous bisphosphonates have been shown in randomized trials to reduce the risk of fractures. FDA-approved oral bisphosphonates include alendronate (the first one approved), risedronate, and ibandronate. Although data from randomized trials and clinical experience indicate that they are generally safe, mild hypocalcemia and muscle pain occur infrequently. Two rare but more serious adverse effects have also been observed. These are atypical femoral fractures (i.e., fractures in the subtrochanteric region that have a transverse orientation and noncomminuted morphologic features, show focal lateral cortical thickening, occur with minimal trauma, and may be bilateral) and osteonecrosis of the jaw, which is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks. Use of bisphosphonates should be limited to persons who have an estimated creatinine clearance greater than 35 ml per minute and normal serum vitamin D levels; symptomatic hypocalcemia can develop in patients with low levels of 25-hydroxyvitamin D who receive concomitant treatment with bisphosphonates. Oral bisphosphonates should not be prescribed for patients with clinically significant esophageal disease (e.g., achalasia). Adherence to oral bisphosphonates is low, and it is estimated that less than 40% of persons who are prescribed oral medications are still taking them after 1 year. Intravenous bisphosphonates (ibandronate and zoledronic acid) are alternatives that do not require frequent patient use.
Q: What is the risk-benefit ratio associated with bisphosphonate treatment for postmenopausal osteoporosis?
A: The relative importance of the two rare adverse effects (atypical fractures and osteonecrosis of the jaw) versus the benefits of antiresorptive therapy is uncertain and remains controversial. The concerns of many women regarding these potential adverse effects have increasingly become a substantial barrier to initiation of antiosteoporosis therapy and to treatment adherence. Case–control and cohort studies and a few randomized trials have assessed the risk of atypical femoral fractures; in all the studies, the incidence of these fractures is low, ranging from approximately 1 in 100,000 to 5 in 10,000 among bisphosphonate users. Calculations based on recent reviews and meta-analyses suggest a highly favorable benefit-to-risk ratio associated with treatment for up to 5 years in women with osteoporosis, with fewer than 1 event caused per 100 fractures prevented. The incidence of osteonecrosis of the jaw is similarly very low (estimated at <1 case per 10,000 bisphosphonate users). Given concerns about an increased risk of atypical femur fractures with long-term treatment, the possibility of a drug holiday (temporary discontinuation for up to 5 years) has been suggested, although the preferred timing and duration of drug holidays with bisphosphonate therapy are uncertain. Randomized trials have indicated that with discontinuation of alendronate after 5 years of use or of zoledronic acid after 3 years of use, benefits (as determined primarily by assessment of BMD loss and changes in biochemical markers of bone turnover as compared with those with placebo) are generally retained for up to 5 years. The value of monitoring therapy after discontinuation with the use of biochemical markers of bone turnover or BMD to aid in clinical decision making about restarting bisphosphonates is controversial. These recommendations regarding drug holidays do not apply to risedronate or ibandronate, because these agents have not been systematically evaluated, or to other osteoporosis therapies, whose benefits are quickly lost after cessation.