Overview Page 2

In order to demonstrate a consistent treatment effect of alendronate in women with or without existing vertebral fractures, a combined analysis was performed; the results are summarized in Table 2. This showed a risk reduction of 48%, 87%, and 53% for vertebral, multiple vertebral, and hip fractures, respectively.

The results of FIT also showed that the benefits of treatment with alendronate are apparent fairly soon after initiating treatment, with reductions in fracture risk becoming statistically significant as early as 12-18 months after initiation of treatment (Figure 2). Furthermore, only a modest number of women with osteoporosis need to be treated to prevent fracture (Table 3). Alendronate can be given in a once-weekly dose of 70 mg, since the study demonstrated its equivalency to the 10-mg daily dose in increasing BMD and suppressing bone markers.



Risedronate is another nitrogen-containing bisphosphonate approved for the prevention and treatment of osteoporosis in postmenopausal women. A meta-analysis was conducted of eight randomized, placebo-controlled trials of postmenopausal women receiving either risedronate or placebo who were followed for at least one year.²¹ The trials provided data on bone density and/or fracture rate. In patients receiving 2.5 mg/day or more of risedronate, the reduction in risk of vertebral fractures was 35% compared with placebo; for nonvertebral fractures, the risk reduction was 27%. Risedronate also had positive effects on the percentage change in BMD of the lumbar spine, combined forearm, and femoral neck. The pooled estimate for the difference in percentage change in BMD between 5 mg risedronate and placebo after the final year of treatment (range 1.5 to 3 years) was 4.54% for the lumbar spine and 2.75% for the femoral neck.

Two large-scale studies included in the above meta-analysis were the basis for the FDA approval of risedronate. Both trials studied postmenopausal women with severe osteoporosis (two or more vertebral fractures at baseline or one vertebral fracture and a BMD score < -2.0). The treatment groups and control arms in both trials received calcium 1 g/day and vitamin D 500 IU/day if patients' vitamin D levels were below 40 nmol/L. The Vertebral Efficacy with Risedronate Therapy (VERT) trial studied the effects of risedronate in 2458 postmenopausal women less than 85 years of age in a three-year, randomized, placebo-controlled, doubleblind trial.²² Subjects were randomly assigned to 2.5 or 5 mg/day of risedronate or placebo. The 2.5-mg/day treatment arm was discontinued after one year; the placebo and 5-mg/day treatment arms completed all three years of the trial. Treatment with 5 mg/day of risedronate decreased the incidence of new vertebral fractures over three years by 41% compared with placebo (p = 0.003). The cumulative incidence of nonvertebral fractures over three years was reduced by 39% in the risedronate group (p = 0.02). Bone mineral density increased significantly at the lumbar spine (5.4% vs. 1.1%), femoral neck (1.6% vs. 1.2%), femoral trochanter (3.3% vs. - 0.7%), and midshaft of the radius (0.2% vs. - 1.4%). The overall safety profile of risedronate was similar to placebo.

In the other large-scale risedronate trial, Reginster et al studied the efficacy and safety of risedronate in the prevention of vertebral fractures in 1226 women with osteoporosis.²³ The 2.5-mg/day group was discontinued by protocol amendment after two years. In this study, treatment with risedronate 5 mg/day reduced the risk of new vertebral fractures over three years by 49% compared with placebo (p < 0.001). The risk of nonvertebral fractures was reduced by 33% (p = 0.06). Risedronate significantly increased BMD at the spine and hip within six months. In this trial, as well as the VERT trial described above, results are compromised by the high dropout rates of 33 to 50%. High dropout rates threaten the validity of these trials because the distribution of prognostic factors (and thus the rate of events) may be very different between the group that completed the trial and the group that dropped out. Thus, the high dropout rate may lose the balance of prognostic factors achieved by randomization.²³

The effect of risedronate on the risk of hip fracture was studied in 5445 women aged 70 to 79 with osteoporosis (indicated by a T-score < -4 or < -3 plus a nonskeletal risk factor).²⁴ The trial also included 3886 women at least 80 years of age who had at least one nonskeletal risk factor for hip fracture or low BMD at the femoral neck (T-score < -4 or < -3 plus a hip-axis length of 11.1 cm or greater). Patients were randomly assigned to receive risedronate 2.5 mg/day, 5 mg/day, or placebo. (The 2.5-mg dose was not discontinued in this threeyear trial.) The overall incidence of hip fracture among women assigned to risedronate was 2.8%, compared with 3.9% among those assigned to placebo; this represents a 30% risk reduction (p = 0.02). In the group aged 70 to 79 with osteoporosis, the reduction in risk of hip fracture was 40% (p = 0.009). In the group of women over age 80 selected primarily on the basis of nonskeletal risk factors, the reduction in hip fracture risk was not significant compared to placebo. The low number of fractures in the placebo group may not have allowed the treatment to show a significant result. The overall results of this trial are also compromised by a lack of follow-up in 36% of enrolled patients. After the results of this study were published, risedronate has been approved as a once-weekly, 35-mg dose.

An accurate assessment of the relative efficacy of alendronate vs. risedronate must await head-to-head comparisons in controlled trials. Nevertheless, the confidence intervals around the alendronate pooled estimates for risk reduction for vertebral fractures suggest that the risk reduction is unlikely to be less than one-third while, for risedronate, the risk reduction is unlikely to be less than one-quarter.²⁵ While the evidence for antifracture efficacy is strong, it is not yet known how long patients should be treated with these and other antiresorptive therapies.

Recombinant Parathyroid Hormone
Human recombinant 1,34 N-terminal parathyroid hormone (PTH) is a potent stimulator of bone formation and resorption and, depending on its administration route (continuous IV or daily subcutaneous injections), it can increase or decrease bone mass.²⁶ Neer et al conducted a randomized controlled study of PTH to determine its effects on fracture risk in postmenopausal women with prior vertebral fractures.²⁶ They randomly assigned 1637 women to receive subcutaneous PTH 20 µg/day (n=541), 40 µg/day (n=552), or placebo (n=544). The study employed PTH 1,34, which includes the hormone's first 34 amino acids; these are primarily responsible for its biologic effects. Vertebral radiographs were obtained at baseline and at the end of the study (median duration: 21 months). At baseline, BMD was similar among the three groups. The period from enrollment to final visit did not differ significantly among the three groups.

Of the 1326 women for whom radiographs were available, 105 had one or more new vertebral fractures. Compared with placebo, PTH 20 µg and 40 µg reduced the risk of one or more new vertebral fractures by 65% and 69%, respectively, while the risk of two or more new vertebral fractures was reduced by 77% and 86%, respectively (Figure 3). New or worsening back pain was reported by 23% of women in the placebo group and 17% and 16% of those in the 20-µg and 40-µg groups, respectively (p=0.007). Nonvertebral fragility fractures were reduced by 53% and 54%, respectively. Treatment with PTH also produced significant, dose-dependent increases in the BMD of the spine and hip, as well as total-body bone mineral.


A total of 32 women in the placebo group (6%), 35 in the 20-µg group (6%), and 59 in the 40-µg group (11%) withdrew from the study because of adverse events. Nausea and headache occurred significantly more frequently in the group taking 40 µg of PTH than with placebo. Although preclinical studies showed a higher incidence of osteosarcoma in Fisher rats receiving PTH, there were no cases of osteosarcoma in this study.

This study demonstrated that recombinant PTH has a potent effect on bone mass and strength and appears to be effective in preventing fractures in postmenopausal women, although it wasn't powered to detect reductions in hip fractures. PTH recently received FDA approval for the treatment for osteoporosis. However, questions remain about its therapeutic niche. Given its route of administration as a daily subcutaneous injection and its considerable cost, PTH at this time is seen as a second-line therapy for patients with severe osteoporosis who fail on or cannot tolerate bisphosphonates. Preliminary studies indicate greatest efficacy when used without other antiresorptives. However, further studies are needed to address this isue, as well as the optimal duration of treatment.

Conclusions
Table 4 is an estimate of the relative efficacy of available agents in reducing vertebral and nonvertebral fractures based on the meta-analysis of controlled studies by Cranney et al.²⁵ The authors caution that, for a variety of reasons, direct comparisons between trials are unreliable. They also note that confidence intervals around the magnitude of treatment effect sometimes overlap, so that apparent differences in the point estimates may not reliably reflect actual differences in treatment effect. The quality of the available data appears strongest for alendronate, risedronate and, to a lesser degree, for vitamin D. Results for these agents tend to be consistent from one study to the next.²⁵

Thus, while there are a number of factors besides efficacy that affect the choice of an agent to prevent or treat osteoporosis, the weight of the evidence clearly justifies the current role of bisphosphonates as first-line therapy.

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