Abstract
Postmenopausal osteoporosis is associated with significant morbidity, mortality, reduction in quality of life, and increasing health care costs. It is estimated that 1.5 million women in the United States have one or more osteoporosis-related fractures annually. Fractures may occur at any site, but vertebral fractures are the most common. Longitudinal studies have demonstrated a decreased life expectancy associated with both vertebral and nonvertebral fractures. Once an initial fracture occurs, there is a fivefold increased risk of a second fracture within 1 year. The management of osteoporosis today incorporates multiple modalities of therapy. In addition to early detection, patient education, exercise, and nutritional supplementation, multiple therapeutic agents should be implemented early in an attempt to prevent initial and subsequent fractures. This article reviews currently approved modalities of therapy for the prevention and treatment of postmenopausal osteoporosis.
Osteoporosis is a systemic metabolic bone disease with protean clinical, physical, and socioeconomic implications.
1 Reports of osteoporosis date back to before the Early Bronze Age and indicate that despite an active agrarian lifestyle, the early development of low bone mineral density (BMD) placed women at greater risk for fracture.
2
According to the World Health Organization (WHO), osteoporosis is now widely recognized as a progressive systemic disease characterized by low BMD and microarchitectural deterioration in bone that predisposes patients to increased bone fragility and fracture.
3 Results from the National Osteoporosis Risk Assessment (NORA) study of more than 200,000 healthy postmenopausal women revealed an unexpectedly high prevalence of osteopenia and osteoporosis, resulting in increased risk for fracture.
4
The importance of screening patients at risk, early detection of bone loss in accordance with WHO standards,
4 and the implementation of therapy in accordance with National Osteoporosis Foundation (NOF) guidelines
5 is necessary to prevent further bone loss and increased bone fragility and fracture.
3,6 Multiple modes of therapy should be incorporated into the management of patients with postmenopausal osteoporosis. Before initiation of therapy, however, the risk factors associated with postmenopausal osteoporosis must be identified and assessed (
Figure 1).
Postmenopausal women with established risk factors should undergo an evaluation for osteoporosis that includes a comprehensive medical and family history and physical examination, including vital signs and height assessment. Routine laboratory testing should be done and should include:
All postmenopausal women should be considered for BMD testing, particularly all women older than 65 years, regardless of risk factors, and all postmenopausal women 65 years old or younger who have one or more risk factors for osteoporosis other than menopause (
Figure 2).
1,3 Bone mineral density should be measured by dual-energy x-ray absorptiometry (DXA) to evaluate the lumbar spine, femoral neck, and total femur. The diagnosis of osteopenia or osteoporosis based on a T-score should be established before initiation of therapy.
The T-score represents the number of SDs above or below the mean BMD for the young, healthy female population. It is most frequently used for diagnosis of osteoporosis, determination of fracture risk, and assessment of efficacy in clinical trials.
3 Advancing age and low BMD are strongly associated with increased risk of fracture.
7 According to the WHO Task Force, osteoporosis is defined by a T-score of less than - 2.5 SD in women without fragility fractures.
3 For each 1 SD decrease in BMD, there is an approximate doubling of fracture risk.
1,3,7 After the baseline establishment of metabolic bone disease, subsequent annual clinical evaluations and repeated assessment of BMD should assist in the ongoing management of osteoporosis in postmenopausal women.
1,3
Bisphosphonates are considered the mainstay of current medical management of postmenopausal osteoporosis. This class of therapeutic agents contains the chemical structures of two phosphate groups attached to a single carbon atom, thereby facilitating a high affinity for bone through binding to the hydroxyapatite in bone. These agents inhibit bone resorption by cellular effects on osteoclasts. Bisphosphonates remain in bone for long periods after absorption and are eliminated primarily through the urine. Although a number of parenteral bisphosphonates are available, current clinical practice guidelines include the use of enteral bisphosphonates, including alendronate sodium and risedronate sodium, both of which are approved by the FDA for the prevention and treatment of osteoporosis.
Alendronate significantly increases BMD and helps to prevent vertebral and nonvertebral fractures in postmenopausal women. The Fracture Intervention Trial, a double-blind study, involved 6459 postmenopausal women. This study was subdivided into two arms, the vertebral fracture arm (VFA)
14 and the clinical fracture arm (CFA).
15 In both arms, women were randomly assigned to groups that received either placebo or alendronate sodium, 5 mg/d for the first 2 years and 10 mg/d for the remainder of the trial.
In the VFA,
14 2027 women with preexisting vertebral fractures were studied for 3 years. In the VFA, the risk of radiographically documented vertebral fracture was 47% lower in the alendronate-treated group compared with that in the group receiving placebo. In the CFA,
15 4432 women without preexisting vertebral fracture and femoral neck BMD T-score of less than or equal to 1.6 at baseline were studied for 4 years. In this study, 5.8% of patients in the placebo arm had at least one vertebral fracture, compared with 2.9% of patients in the alendronate arm. Overall, alendronate demonstrated a reduction in the incidence of vertebral fractures. Alendronate reduced the incidence of osteoporotic hip fractures in patients with and without a history of vertebral fracture.
14 Alendronate sodium is currently available in a daily (5 mg, 10 mg) and a once-weekly (35 mg) dose.
Risedronate is another FDA-approved bisphosphonate for the prevention and treatment of postmenopausal osteoporosis; it is available in a daily (5 mg) and a once-weekly dose (35 mg).
The Vertebral Efficacy with Risedronate Therapy (VERT) trial was a randomized, double-blind 3-year study conducted at multiple centers in North America, Europe, and Australia.
16
The North American arm of the VERT trial enrolled 2458 women who were at least 5 years postmenopausal with two or more radiographically identified vertebral fractures or one vertebral fracture and low lumbar BMD, defined as a T-score of less than or equal to 22.0. The multinational arm of the VERT trial
17 enrolled 1226 women who were at least 5 years postmenopausal with at least two radiographically confirmed vertebral fractures.
In both studies, women were randomly assigned to receive risedronate sodium, 2.5 mg/d; risedronate sodium, 5 mg/d; or placebo. The primary endpoint was vertebral fracture incidence over 3 years. Other efficacy measures included radiographically confirmed nonvertebral osteoporosis-related fractures.
16,17
In the North American arm of the VERT trial,
16 risedronate reduced the incidence of vertebral fracture by 41%. In the multinational arm of the VERT trial,
17 risedronate reduced the incidence of vertebral fracture by 49%. These findings demonstrate that risedronate reduces the incidence of vertebral fracture in postmenopausal women.
The Risedronate Hip Intervention Program (HIP) study
18 enrolled two groups of women to assess the effect of risedronate on hip fractures in women with osteoporosis. One group consisted of women with osteoporosis (defined as femoral neck BMD T-score ≤ -4.0 or BMD T-score ≤ -3.0, with at least one risk factor for hip fracture) between the ages of 70 and 79 years. The other group consisted of women 80 years of age and older who had at least one nonskeletal risk factor for fracture. Bone mineral density was not a required criterion in this group. Baseline vertebral fractures were present in 39% of the 5445 patients in the younger age group and 45% of the 3886 patients in the older age group. The primary endpoint was the occurrence of hip fracture.
Findings from the HIP study
18 indicate that treatment with risedronate for 3 years decreased the incidence of hip fracture by 40% in the younger group of patients, compared with the older patient population. In women aged 80 years and older, there was no significant reduction in the incidence of hip fracture. Risedronate is indicated to reduce the incidence of a composite endpoint of vertebral and nonvertebral osteoporosis-related fractures.
Pamidronate disodium and ibandronate sodium, parenteral bisphosphonates administered every 3 months, offer yet another option; however, parenteral bisphophonate therapy should be reserved for special clinical circumstances until its efficacy in the prevention of fractures and its long-term safety have been established.
19
Bisphosphonates are generally considered the drugs of choice for most patients with osteoporosis, This preference prevails especially for older patients at high risk for hip fracture, as both alendronate and risedronate have been found to be protective against hip fracture. Although parenteral forms of bisphosphonates are available, the once-weekly administration of the enteral form is preferred and facilitates patient compliance. Among younger women, in whom hip fracture is less common, the SERM raloxifene may be a good option.
New anabolic modes of therapy (ie, PTH) appear promising for the management of severe osteoporosis. Available data suggest that PTH can dramatically increase BMD; however, only short-term data are currently available. Over time, greater risk reduction with PTH may be demonstrated. At this time, however, no data are available suggesting that protection against fractures is better with PTH than with bisphosphonates.
In the future, other therapeutic classes will be introduced that may dramatically change the manner in which patients with postmenopausal osteoporosis are evaluated and treated.
Dr Murphy is presently a consultant and a member of the speakers bureaus for Merck & Co, Inc; Procter & Gamble Pharmaceuticals, Inc; Pfizer Inc; Wyeth; Amgen Inc; and Abbott Laboratories. Dr Kivitz has received research grants from Merck & Co, Inc; Procter & Gamble Pharmaceuticals, Inc; Aventis Pharmaceuticals; Pfizer Inc; Wyeth; Amgen Inc; Neurogen; Novartis Pharmaceuticals Corporation; and Abbott Laboratories. Dr Sands, formerly a regional senor medical adviser for Procter & Gamble Pharmaceuticals, is currently director of clinical operations for women's health at Solvay Pharmaceuticals, Inc.
This manuscript was developed from a presentation at the 40th Annual Convention of the American College of Osteopathic Family Physicians on March 22, 2003, in Nashville, Tenn.
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