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INTRODUCTION

Clinicians who treat women in their perimenopausal and postmenopausal years increasingly find that prevention and management strategies for osteoporosis are a topic of uncertainty and controversy. Although the long-anticipated Women’s Health Initiative study showed a clear benefit for osteoporosis prevention from long-term hormone therapy (HT) [Rossouw 2002], disturbing data about increased cardiovascular, cerebrovascular [Kuller 2003], and cancer risks [Antoine 2004] associated with HT continue to appear. These developments have increased the reluctance of many physicians and patients to continue or initiate HT and decreased preventive therapy options for many patients at risk of osteoporosis.

The aging of the United States population has increased the number of women who reach perimenopause or menopause each year and also intensified the urgency for effective prevention and treatment of osteoporosis. However, recent studies have shown that underdiagnosis of low BMD and osteoporosis is common and the optimum use of screening methods, non-pharmacological strategies, and pharmacological therapies is complex and not fully resolved.

Recent developments in the field of osteoporosis also include new results from clinical trials that show risks and benefits of long-term drug therapy for women with osteoporosis. This monograph will review current events in the field of osteoporosis and discuss current treatment strategies in light of these events.

RECENT DEVELOPMENTS AFFECTING TREATMENT OF OSTEOPOROSIS

The Women's Health Initiative Study Results
As expected, initial and continuing results from the WHI showed that HT significantly increased bone mineral density (BMD) and reduced the risk of fracture compared to placebo.[ Cauley 2003] However, data that began to appear from the estrogen/progestin arm of the WHI in 2002 also showed an increased risk of breast cancer and stroke, with little or no cardiovascular benefit from long-term HT.[Chlebowski 2003; Wassertheil-Smoller 2003; Manson 2003] With the exception of increased breast cancer risk, these results were recently confirmed in the estrogen-alone arm of the study [Anderson 2004], which also suggested increased risk of dementia and cognitive impairment associated with HT in a subgroup of women over age 65.[Shumaker 2004; Espeland 2004]

Because of these developments, many postmenopausal women in the United States discontinued HT or continued with much lower doses of HT for shorter periods of time.[Ettinger 2003] Both accelerated and normal rates of bone loss were documented in cohorts of patients after discontinuation.[Gallagher 2002] After 5 years, the risk of hip fracture in women who had discontinued HT was the same as in women who had never received HT. In another study, the risk of hip fracture during the first 5 years after discontinuation was as high or higher in women who had discontinued HT as in women who had never received HT.[Yates 2004]

Although many physicians and patients are reluctant to rule out HT altogether, these results have provoked discussion about alternative prevention measures for women who have discontinued HT or will use it for limited periods.

The Dilemma of Diagnosis
Another current issue in osteoporosis is low rates of BMD screening and diagnosis of osteoporosis in postmenopausal women. A recent alarming study of patients who had already suffered vertebral compression fractures showed that only 38%, including 46% of women and 19% of men, had received a diagnosis of osteoporosis before the fracture, and only 69% of the women who had been diagnosed were receiving osteoporosis prescription medications.[Neuner 2003]

New Questions for Treatment
In view of increased awareness of the need for close monitoring of BMD in postmenopausal women who may have discontinued HT or changed to low doses of HT, the National Osteoporosis Foundation recently revised its guidelines for determining who should be treated. Hip and spine dual-energy x-ray absorptiometry should be used to measure BMD. The number of standard deviations from the average BMD of young adults is the T-score. In addition, the contribution of risk factors, such as history of fractures, a family history of osteoporotic fractures, smoking, a thin build, and frequent falls, is evaluated for each patient. Patients with BMD T-scores less than -2.0 and no other risk factors, patients with BMD T-scores below -1.5 and one or more other risk factors, and patients who have had a prior vertebral or hip fracture should receive osteoporosis therapy.[NOF 2004]

The role of high bone turnover as a risk factor for fractures is another issue that has not been resolved. Testing of serum and urine markers of bone turnover is not routine in primary care, but may be considered when women are discontinuing estrogen therapy or rapid bone loss is suspected. Some evidence suggests that changes in markers of bone turnover may predict fracture risk as well as, or better than, changes in BMD.[Sarkar 2004]

New Clinical Trial Results for Alendronate (Fosomax^®)
Alendronate has been available in the United States since 1995 and is associated with the most extensive clinical experience of any non-hormonal therapy for prevention of osteoporosis. A recent publication in the New England Journal of Medicine [Bone 2004] reports results for 247 postmenopausal women with osteoporosis who received alendronate for up to 10 years in a randomized, double-blind, placebo-controlled study.

In patients who received 5 mg/d or 10 mg/d alendronate for up to 10 years, BMD at the lumbar spine continued to increase during years 6 through 10 and years 8 through 10 (Figure 1). The alendronate groups had no decreases in BMD at any skeletal site during years 6 through 10. Markers of bone remodeling were reduced to low levels that were stable throughout the study. In patients who discontinued active treatment and began to receive placebo after 5 years, decreases in BMD occurred at several sites but remained above baseline at the 10-year follow-up measurement. Also, bone markers increased in patients who discontinued active treatment but remained below baseline measurements.[Bone 2004]


After 5 years, the risk of hip fracture in women who had discontinued HT was the same as in women who had never received HT.

Patients who received alendronate during the study had lower rates of loss of height and lower rates of vertebral fracture compared with patients who discontinued treatment. Safety profiles were similar in treatment and placebo groups.[Bone 2004]

Preliminary results are also available from a year-long study (the Efficacy of Fosamax^® vs Evista^® Comparison Trial, or EFFECT) that compared increases in BMD in 456 women with osteoporosis. The patients were randomized to receive alendronate 70 mg once weekly or raloxifene 60 mg per day and BMD was measured at baseline, after 6 months of treatment, and after 12 months of treatment. The primary end point was percent change in BMD at the lumbar spine at the one-year time point.[Luckey 2004]

After one year, increases in lumbar-spine BMD in patients who received alendronate were more than 2-fold higher than increases in patients who received raloxifene (4.4% vs 1.9%; p<0.001). Total hip BMD increased 2.0% for patients who received alendronate and 1.0% for patients who received raloxifene at the one-year time point (p<0.001). The response rate, defined as the percentage of patients who increased or maintained BMD, was 94% for the alendronate group and 75% for the raloxifene group.[Kagan 2003] There were no clinically apparent vertebral or hip fractures in either treatment arm. These data were presented at the 51st Annual Meeting of the American College of Obstetricians and Gynecologists.[Kagan 2003]