Nonvertebral Fractures Due to Postmenopausal Osteoporosis: Evaluation of Effective Preventive Interventions
Osteoporosis is a systemic skeletal disease characterized by compromised bone strength that predisposes affected individuals to an increased risk for fracture.1 In the United States, 20% of postmenopausal white women have osteoporosis. An additional 52% have low bone mass at the hip, placing them at an increased risk for osteoporotic fractures.2 However, osteoporosis is often asymptomatic until fracture occurs. Even after fracture, patients often are not treated. One year after a first hip or wrist fracture, only 4-5% of women 50 years or older were taking medications to reduce the risk of a second fracture.3 The scope and lack of recognition of postmenopausal osteoporosis (PMO) underscores the importance of proactive measures to identify women at risk and provide appropriate treatments to prevent fractures, especially fractures of the hip. This article provides an overview of the epidemiology, risk evaluation, and therapeutic options available for the prevention of nonvertebral fractures in postmenopausal women at risk for osteoporosis.
OSTEOPOROSIS-RELATED NONVERTEBRAL FRACTURES
Epidemiology In the United States, an estimated 300,000 hip fractures, 250,000 wrist fractures, 700,000 vertebral fractures, and 250,000 fractures at other sites related to osteoporosis occur each year.4 For white individuals 50 years and older, the lifetime risk of a hip fracture is 17.5% for women and 6% for men.5 The lifetime risk of a wrist fracture is 16% and 2.5% for the same populations, respectively. The incidence of hip fracture increases exponentially with age; about half of all hip fractures occur after 80 years of age, with most (80%) occurring in women.6 Wrist fractures follow a different pattern, with the incidence in white women increasing linearly from 40-65 years of age and then stabilizing.7
Consequences of nonvertebral fractures
Of the osteoporosis-related fractures, hip fractures are associated with the greatest morbidity. In the United States, hip fractures account for 71% of total hospital days, 77% of total nursing home stays, and the majority (63%) of health care expenditures attributable to osteoporotic fractures.8 Patients sustaining hip fractures regain only 50% of their prefracture function postoperatively; one year after hip fracture, 40% are unable to walk independently, 60% require assistance with daily activities (eg, dressing, bathing, preparing meals), and 80% are unable to perform at least one other activity of daily living (eg, driving, grocery shopping, housecleaning).9 Osteoporotic fractures have a significant negative impact on patients’ health-related quality of life and have substantial psychological and social consequences.10 Anxiety and depression associated with feelings of helplessness and hopelessness often occur when women sustain an initial symptomatic fracture that produces pain and limited mobility. Patients sustaining a hip fracture face an increased risk of mortality; the survival rate five years after hip fracture is reduced by approximately 20% compared with that expected for the age-matched, fracture-free population.11 Furthermore, the risk of mortality is greatest during the first six months after hip fracture.
Postmenopausal women should be evaluated for the presence of risk factors for osteoporotic fracture (Table I), including bone mineral density (BMD) testing according to the guidelines of the National Osteoporosis Foundation (NOF) (Table II).2 These guidelines are consistent with those from the International Society for Clinical Densitometry (ISCD)12 and the U.S. Preventive Services Task Force (USPSTF).13 Prevalent fracture and low BMD are the strongest predictors of nonvertebral fracture risk.14 In addition, a thorough history with regard to falls is an important part of patient evaluation. Prior fracture Osteoporosis can progress rapidly once a fracture occurs. Prior fractures at any site may indicate compromised bone microarchitecture, independent of BMD, or the presence of nonskeletal risk factors.15 Postmenopausal women with osteoporosis who suffer a vertebral fracture have a 20% chance of suffering another vertebral fracture within the year.16 In women 65 years of age and older with existing vertebral deformities, the risk of hip fracture is increased two- to threefold compared with women of similar age without vertebral deformities.17 The risk of hip fracture is also increased twofold by the presence of a wrist fracture in perimenopausal or postmenopausal women.15
Low bone mineral density
Low BMD is a strong independent predictor of fracture and is complementary to a history of prior fractures for predicting fracture risk.14,15 Among women 70 years of age and older, a T-score of less than -2.5 at the femoral trochanter is associated with a sixfold increase in hip fracture risk versus age-matched controls with a T-score of greater than -2.5.14 Although low BMD is an important component of bone strength and fracture risk, multiple factors contribute to bone strength, including geometry, cortical thickness, degree of mineralization, rate of bone turnover, and microarchitecture.18
More than 90% of fractures occur after a fall.19 Impaired mobility is associated with a threefold increase in risk of falls and a fivefold increase in risk of recurrent falls.20 Other risk factors for falls, and subsequently nonvertebral fractures, include dizziness secondary to postural hypotension, poor visual acuity, neuromuscular weakness, impaired cognition, and presence of environmental hazards (eg, throw rugs). Once it is determined that a patient is at risk for osteoporotic fracture, appropriate interventions should be instituted with the intent of preventing the occurrence of a fracture. Early efforts to identify patients at risk and provide rapid protection against all fractures should be considered in selecting an appropriate treatment program.
PREVENTION OF NONVERTEBRAL FRACTURES
Falls, cigarette smoking, excessive alcohol consumption, inadequate intake of calcium and vitamin D, and decreased mobility are risk factors for fracture that can be reduced or eliminated with environment and lifestyle modifications.2 Implementing changes that eliminate or reduce these modifiable risk factors may reduce the risk of osteoporotic fracture. These interventions are important for maintaining bone health in all patients and should be implemented as part of the osteoporosis treatment regimen for those at risk for fracture.
Fall risk reduction
Measures that reduce the risk of falls also reduce the risk of consequent fractures (Table III).2,21-23 Patients at an increased risk for falls should be encouraged to use appropriate walking aids, including grab bars and handrails, and use adaptive footwear when necessary. Hip protectors have been shown to reduce the risk of hip fracture by 60% (P = 0.008) in elderly patients at high risk for hip fracture.24 Physical exercise improves bone mass, muscle strength, and coordination, and may prevent bone loss.2 Health permitting, weight-bearing and muscle-strengthening exercise should be strongly encouraged.2
Calcium and vitamin D supplementation
All patients should be advised to maintain an adequate intake of elemental calcium. Current guidelines recommend all postmenopausal women receive calcium 1200 mg per day and vitamin D 400-800 IU per day including supplements, if necessary.2 Clinical trials evaluating the combination of calcium and vitamin D supplementation were found to be effective at reducing hip25 and nonvertebral25,26 fracture risk in older persons. Calcium and vitamin D supplementation alone, however, may not be sufficient to prevent fracture in patients with PMO. Those at risk for osteoporosis, as determined by risk assessment and BMD testing, also require pharmacologic intervention.2
Table II summarizes the NOF recommendations for initiating pharmacologic therapy in postmenopausal women. The medications currently approved by the Food and Drug Administration (FDA) for the prevention and treatment of PMO include the bisphosphonates (risedronate, alendronate, and ibandronate) and raloxifene. Salmon calcitonin and teriparatide are approved for treatment of osteoporosis, and hormone replacement therapy (HRT) is approved for prevention of osteoporosis. Table IV includes a summary of the dosages, interactions, and contraindications of available therapies, as well as information on some new treatments in development. Fracture prevention is the primary goal of treatment. Although BMD is important for diagnostic purposes, treatment-induced increases in BMD alone cannot explain the observed reductions in fracture risk.27,28 Osteoporosis treatments have been shown to have a positive effect on other factors of bone strength, such as bone turnover and bone microarchitecture.18,29 Fracture efficacy, with an emphasis on nonvertebral fracture, of FDA-approved therapies for PMO as well as some new agents in clinical development are discussed herein. Table V summarizes osteoporosis therapies with evidence of nonvertebral fracture efficacy.30-38
Risedronate. In a large placebo-controlled trial lasting three years, daily treatment with risedronate 5 mg per day significantly reduced the risk of nonvertebral fractures by 39% among postmenopausal osteoporotic women with at least one vertebral fracture.33 In an extension of this study, fracture reduction was sustained for five years.35 Nonvertebral fractures were defined as radiographically confirmed fractures of the clavicle, humerus, wrist, pelvis, hip, or leg, regardless of relationship to trauma. Risedronate also significantly reduced the risk of vertebral fracture compared with placebo.33,39 In a pooled analysis, risedronate demonstrated a significant reduction in nonvertebral fracture risk as early as six months.32 In the Hip Intervention Program,34 risedronate reduced three-year hip fracture risk by 40% in women 70-79 years of age with established osteoporosis (T-score < -3.0) and by 60% in women with osteoporosis and a vertebral fracture at study entry.
Alendronate. In the Fracture Intervention Trials, alendronate did not significantly reduce the risk of overall nonvertebral fractures in postmenopausal women with low BMD and no vertebral fractures,40 or with prevalent vertebral fractures.31 Alendronate significantly reduced the risk of vertebral fractures compared with placebo in these populations. In one trial,31 alendronate reduced hip fracture risk by 51% relative to placebo in women with a prevalent vertebral fracture at baseline. In a retrospective analysis of a one-year study, alendronate reduced the risk of nonvertebral fractures (reported as adverse events) relative to placebo in postmenopausal women with low BMD.30
Ibandronate. Ibandronate 150 mg per month was recently approved by the FDA for PMO. After three years of treatment, daily and intermittent therapies reduced vertebral fracture risk, but not nonvertebral fracture risk in postmenopausal women with at least one vertebral fracture at baseline.41
Hormone replacement therapy. The Women’s Health Initiative evaluated the consequences of long-term HRT in healthy postmenopausal women. Both unopposed estrogen and estrogen plus progestin significantly reduced the risk of hip and clinical vertebral fractures by about one-third compared with placebo.36,37 However, both arms of the trial were discontinued because of an increased risk of stroke,36,42 and the estrogen-plus-progestin arm also showed an increased risk of coronary heart disease, invasive breast cancer, dementia, and venous thromboembolism.42 Currently, the FDA recommends using the lowest dose of HRT for the shortest duration, and consideration of nonestrogen options for osteoporosis.
Raloxifene. In postmenopausal women with osteoporosis (femoral neck or lumbar spine BMD T-score < -2.5 or prevalent vertebral fracture), raloxifene (60 mg daily) did not show a benefit on nonvertebral fracture risk after three years compared with placebo.43 In the same study, vertebral fracture risk was reduced. Salmon calcitonin. In postmenopausal women with established osteoporosis and one to five prevalent vertebral fractures at baseline, salmon calcitonin nasal spray (200 IU daily) did not reduce nonvertebral fracture risk, but decreased vertebral fracture risk after five years.44
Teriparatide. Teriparatide is an anabolic agent approved by the FDA for the treatment of osteoporosis in postmenopausal women and in men who are at high risk for fracture. In postmenopausal women with at least one vertebral fracture, daily teriparatide injections of 20 µg reduced the risk of nonvertebral fractures by 35% after 21 months of treatment.38 It also demonstrated a reduction in new vertebral fractures. Because osteosarcomas were observed in teriparatide-treated rats, the teriparatide pivotal study was ended early (median 21-month follow-up), and the prescribing information carries a warning for osteosarcoma. Because long-term data are not available, teriparatide use for more than two years is not recommended.
Injectable bisphosphonates. Zoledronic acid and pamidronate are injectable bisphosphonates; however, neither are approved by the FDA for osteoporosis. In a clinical trial with zoledronic acid, injections of 0.25-1.0 mg every three months resulted in BMD increases comparable to a 4.0-mg once-yearly dose.45 In a group of patients with low bone mass or fractures who had undergone a liver or heart transplant, intravenous pamidronate 30 mg every three months for one year increased BMD compared with controls.46 These agents may be an alternative for patients who cannot tolerate oral agents or have difficulty adhering to their treatment regimens; however, fracture data are needed to better assess their efficacy in the treatment of osteoporosis.
Fractures are the most devastating consequence of osteoporosis, and nonvertebral fractures carry the highest morbidity and mortality. Yet many patients at high risk for osteoporotic fracture are not receiving treatment to prevent further bone loss or fracture. Low BMD and prior fracture are strong risk factors for osteoporosis-related fracture, and falling is a significant risk factor for hip fracture. Once a patient is deemed to be at risk for osteoporosis-related fractures, preventive intervention is indicated. Environmental hazards should be minimized, physical conditioning encouraged, and calcium and vitamin D intake optimized or supplemented. Current guidelines can assist physicians in determining when to initiate therapy with FDA-approved agents. The goal of osteoporosis treatment is fracture prevention, and several agents available for the prevention and/or treatment of osteoporosis have shown reductions in nonvertebral fracture risk in clinical studies.
Risedronate and alendronate have demonstrated reductions in both hip and nonvertebral fracture risk. Teriparatide has also shown reductions in nonvertebral fractures, and HRT has demonstrated a reduction in the risk of hip fractures. Long-term therapy with teriparatide or HRT, however, is not recommended because of insufficient long-term data and safety concerns, respectively. Intranasal salmon calcitonin, raloxifene, and ibandronate have not demonstrated a benefit regarding risk of nonvertebral fractures in prospective studies. All of these FDA-approved agents, however, are effective in reducing vertebral fracture risk. These data should be taken into consideration along with potential drug interactions and contraindications when tailoring a treatment program for the individual patient.
The author gratefully acknowledges Ruth Pereira and Kelly Reith for their editorial assistance with the preparation of this review article.