Abstract & Commentary
Synopsis: Use of risedronate in women 80 years and older reduced the incidence of vertebral fractures and was well tolerated.
Source: Boonen S, et al. J Am Geriatr Soc. 2004;52:1832-1839.
Risedronate (Actonel®) is a pyridinyl bisphosphonate, prescribed to treat low bone density. Its mechanism of action is inhibition of bone resorption, which it accomplishes by binding to the mineral surface of bone and reducing osteoclast activity. It decreases the incidence of vertebral and hip fractures in postmenopausal women. Boonen et al sought to answer the question, "Is risedronate safe and effective in women aged 80 years and older?"
By combining data from 3 studies of risedronate (the Vertebral Efficacy with Risedronate Therapy North America, the Vertebral Efficacy with Risedronate Therapy Multinational, and the Hip Intervention Program), Boonen and colleagues were able to amass 1392 women (688 in the placebo group, 702 in the risedronate group) who were 80 years or older (average age 83.0 years). The 2 groups were comparable at baseline. The 3 studies were randomized, double-blind, placebo-controlled conducted between 1993 and 1998. In all of the studies, patients were randomized to risedronate 5 mg daily or placebo. They also received calcium 1000 mg daily. Sixteen percent of patients received vitamin D 500 IU daily because their serum 25-hydroxy-vitamin D levels were low. They weren’t allowed to continue any other medication they were receiving, except for other osteoporosis medications. After baseline assessment, the end points were any new vertebral fracture, any new non-vertebral fracture, bone turnover markers, bone mineral density (BMD), and adverse events.
After 1 year, the incidence of new vertebral fractures was 2.5% in the risedronate group and 10.9% in the placebo group, a statistically significant difference (number needed to treat [NNT] 12). At 3 years the rates were 18.2% and 24.6%, respectively, (NNT 16), again statistically significant. Similarly, the changes from baseline of bone turnover markers and BMD favored the risedronate group. The adverse event rate did not differ significantly between the 2 groups, including incidences of esophagitis and gastric and duodenal ulcer, even in patients who had preexisting gastrointestinal comorbidities or who were taking GI-active medications. At 3 years, there was no significant difference in the rate of new non-vertebral fractures (14% vs 16.2%).
Comment by Allan J. Wilke, MD
This is very good news for our oldest old female patients, who comprise the most rapidly growing portion of the population. Women 80 years and older have a greatly increased prevalence of vertebral fractures, when compared to women in their 50s. Vertebral fractures carry with them pain, deformity, decreased lung function, and decreased mobility. It should be a no-brainer then, to treat them with risedronate (or probably, other bisphosphonates) because it is safe and effective. However, in the immortal words of Pogo, "We have met the enemy and he is us!" As previously reported by Andrade and reviewed in Internal Medicine Alert,3 we do a particularly lousy job of treating women with osteoporosis, even after they suffer fractures. I am afraid that the therapeutic nihilism that we extend to the elderly will only make matters worse and result in many women going without treatment.
There are 2 findings from this paper that merit more attention. The first is that risedronate had an effect on fracture rate reduction during the first year. The second is that there was no improvement in non-vertebral fractures. Boonen and colleagues speculate that this may be because non-vertebral fractures in this group have less to do with BMD and more with increased rates of falls.
There are a few questions that this study does not answer. Is this a class effect? Do the results apply to alendronate (Fosamax®) and other bisphosphonates? Boonen and colleagues say, "We're not sure, but maybe not", but their caution may be related to the support the study received from the manufacturer of Actonel. What happens after 3 years? After all, a woman who is 80 today has a life expectancy of almost 10 years. Are there any long-term benefits or risks? Assuming for the moment that bisphosphonates share characteristics, we can look to a report about alendronate. Bone (how apropos is that?) and colleagues presented data on women whom they had followed for 10 years. They found that alendronate remains safe and effective even if taken for the entire follow-up period and that its bone-protective effects attenuate after discontinuation.
Dr. Wilke, Associate Professor of Family Medicine, Medical College of Ohio, Toledo, OH, is Associate Editor of Internal Medicine Alert.
1. Harris ST, et al. JAMA. 1999;282:1344-1352.
2. Melton LJ 3rd, et al. Osteoporos Int. 1993;3:113-119.
3. Andrade SE, et al. Arch Intern Med. 2003;163:2052-2057.
4. Wilke AJ. Internal Medicine Alert. 2003;25(21):163-164.
5. Bone HG, et al. N Engl J Med. 2004;350:1189-1199.