The Journal of Informed Pharmacotherapy 2000;3:206-208.
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Reviewer: Alan Low,
Reviewer's email address: firstname.lastname@example.org
Reviewer's profession/specialty: Ambulatory Care, Neurology
ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women
with postmenopausal osteoporosis. JAMA 1999;282:1344-52. PubMed Cit
This randomized, double-blind, placebo-controlled, parallel-group study was conducted at 110 study centres across North America. It was designed to test the efficacy of risedronate 2.5mg and 5mg compared to placebo given daily over 3 years in reducing the incidence of vertebral and other fractures in women who were at least 5 years post menopause, no older than 85 years of age, and had either 2 or more radiographically identified vertebral fractures or had one vertebral fracture with bone mineral density measurements that were at least 2 standard deviations below the mean for young adults. The main outcome measure was the incidence of patients with new vertebral fractures. Secondary outcome measures included the cumulative incidence of non-vertebral fractures, change in bone mineral density (BMD) and markers of bone turnover, and overall incidence of adverse events. All subjects received calcium 1000mg/day taken with the evening meal. For subjects with baseline levels of 25-hydroxyvitamin D less than 40nmol/L, supplementation with Vitamin D (cholecalciferol) up to 500IU/day was provided.
1. Was assignment of patients randomized?
Yes. All patients were randomly and equally assigned into one of three groups and received either risedronate 2.5mg, risedronate 5mg or placebo. Patients across all three groups had similar demographics reported.
Yes. All baseline demographics were similar between the three treatment arms at the start of the trial.
Yes. All subjects received calcium 1000mg/day taken with the evening meal. Subjects with baseline levels of 25-hydroxyvitamin D less than 40nmol/L received supplementation with Vitamin D (cholecalciferol) up to 500IU/day. The specific dose of Vitamin D administered was not specified.
1. How large was the treatment effect?
The proportion of subjects with at least 1 incident vertebral fracture over the 3 year study period (primary endpoint) was 11.3% for the risedronate 5mg group and 16.3% for the placebo group (relative risk 0.59 [95%CI 0.43-82]), p=0.003). This represents an absolute risk reduction of 5% or a number needed to treat of 20 over three years. The cumulative incidence of non-vertebral fractures (secondary outcome) over 3 years of treatment was 5.2% for risedronate 5mg and 8.4% for placebo (relative risk 0.6 [95%CI 0.39-0.94, p=0.02] which corresponds to an absolute risk reduction of 3.2% or a NNT of 32 over three years.
Over 3 years, the subjects in the 5mg risedronate group had significant increases in BMD compared to placebo for the following areas measured: lumbar spine (5.4%), femoral neck (1.6%), and femoral trochanter (3.3%). Markers of bone turnover (i.e. bone-specific alkaline phosphatase and the deoxypyridinoline-creatinine ratio) were available for only 32% of study subjects and, in comparison with placebo, declined with risedronate treatment. The overall incidence of adverse effects was similar between the risedronate 5mg (34%) and placebo (29%) groups. Serious adverse events were observed in 29% and 27% of the groups, respectively. Since bisphosphonates are known to commonly cause upper gastrointestinal tract adverse effects, the investigators also reported the incidence of any upper gastrointestinal adverse events (30% vs. 27% for risedronate 5mg and placebo groups). The groups also appeared to have a similar incidence of specific gastrointestinal symptoms.
2. How precise was the estimate of the treatment effect?The relative risk 95% CI for the cumulative incidence of vertebral fractures over the 3 years revealed a statistically significant effect. In my opinion, the effect is clinically relevant and the reduction of incident vertebral fractures is clinically important.
2. Were all clinically important outcomes considered?
This study involved a sufficient sample size to detect a difference in fracture rate associated with risedronate therapy for non-vertebral fractures that are clearly clinically relevant. Unfortunately, this type of fracture was only a secondary endpoint in this trial. Since this study was placebo-controlled and thus did not involve other alternatives currently used to reduce fractures in this population, it is difficult to determine the current role of this drug. This study does, however, demonstrate that risedronate appears to be an effective agent for the reduction of vertebral fractures in this population and that this drug may also reduce the incidence of non-vertebral fractures. Another advantage of this study is that subjects with previous or active gastrointestinal illnesses or concomitant use of ASA or an NSAID were included. These patient groups have been excluded in some of the earlier trials involving bisphosphonates. Finally, this study shows that risedronate is certainly another option available to help reduce vertebral fractures in this study population that can be generalized to our practice population.
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