Melissa M. Blair, PharmD, BCPS Deborah Stier Carson, PharmD, BCPS Rebecca Barrington, PharmD Charleston, South Carolina, and Winston Salem, North Carolina From the Medical University of South Carolina, Charleston (M.M.B., D.S.C.) and Wake Forest University Baptist Medical Center, Winston Salem (R.B.). Reprint requests should be addressed to Melissa M. Blair, PharmD, BCPS, Family Medicine Center, 295 Calhoun Street, PO Box 250192, Charleston, SC 29425. E-mail: blairmm@musc.edu.
References
The methodologic quality of the trials was agreed on by the 2 reviewers. Scores ranged from 1 to 4 with 1 trial scoring 1,41 2 trials scoring 2,48,53 2 trials scoring 3,45,47 and 8 trials scoring 4.42-44,46,49-52 All studies were reported as randomized; only 1 trial, however, described the randomization process.44 Three of the 13 (23%) did not report using double-blind methodology.41,48,53
The primary outcome assessed in all selected clinical trials is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. This complies with the ACR guidelines that recommend measurement at the lumbar spine and femoral neck. In regard to the studied primary outcomes, changes in BMD at the lumbar spine in treatment groups ranged from means of -0.137% to 4.9%; the control group values ranged from 3.7% to 0.98%. Three of 13 studies (23%) did not show a significant benefit at the lumbar spine when compared with the control group41,47,48; however, 2 of these studies41,48 used unusual doses of bisphosphonate. BMD changes at the femoral neck on treatment ranged from 1.28% to 3.6%; control group changes from baseline ranged from 3.6% to 3.64%. Nine of the 13 studies (69%) were not able to show statistical significance between the treatment and control groups at the femoral neck.41-43,48-53 Changes in the treatment groups at the femoral trochanter ranged from -1.35% to 2.7%; placebo changes ranged from 3.06% to 1.5%. More than one half of studies reporting data at the femoral trochanter (6/10) showed that the treatment group was not significantly better than control group.41,42,45,46 Specific BMD results from each trial are available in [Table 2]. Results varied based on the population, the bisphosphonate being investigated, the dosing regimen, and other distinctions in the study design.
Six studies42,43,45,46,49,52 addressed the possible differences in treatment effect based on sex and menopausal status. The effect of bisphosphonate treatment on BMD in postmenopausal women was significant in 4 of the trials.42,45,46,52 One study included postmenopausal women taking HRT and found alendronate 10 mg led to a higher increase in BMD in women not receiving estrogen.45 Only one study, however, found a significant effect on BMD in premenopausal women receiving etidronate.42 Also, an increase in the BMD of men was found to be significantly increased in one study.46
The percentage change from baseline of the BMD of the distal and midshaft radius was measured in 1 study of etidronate and 2 studies of risedronate42,46,47; statistical significance was not obtained in any of the results. Other secondary outcomes measured in selected citations were: biochemical markers of bone resorption and formation including pyridinium crosslinks, osteocalcin, parathyroid hormone, ionized calcium, serum alkaline phosphatase, serum alanine aminotransferase, and bone-specific alkaline phosphatase. However, these are not discussed in detail because of the uncertainty of their relationship to fracture risk.
Fracture Risk
Although not a specified primary end point, the risk of fracture development was addressed in 9 of the studies.42,43,45-49,51-52 Since the rate of fractures was low in most studies and no studies were powered on the basis of fracture risk, some data were reported without statistical analysis. Six studies42,43,45-47,51 analyzed the difference between treatment and control groups with respect to fracture risk. Three of these studies reported at least a trend in reduced fracture rates42,45,46; however, only 1 (in abstract) found a statistical difference in the overall population.47 A 10.1% reduction in vertebral fractures was found in patients receiving risedronate (either 2.5 mg or 5 mg) at 12 months (P=.021).47 According to an abstract, when these results were pooled with another trial46 it was found that risedronate 5.0 mg statistically decreased the incidence of vertebral fractures at 1 year (16.2% vs 5.4%, P=.01).54 Therefore, it would be necessary to treat 10 CIO patients for 1 year with risedronate 5 mg per day to prevent one vertebral fracture.
Although the fracture rate was not significant in most trials, the subpopulation of postmenopausal women experienced the greatest number of fractures and seemed to benefit the most from treatment. Two studies found borderline significance in the fracture rate when postmenopausal women were analyzed separately.42,45 Etidronate and alendronate use led to an absolute risk reduction of 18.7% (P=.05) and 8.6% (P=.05), respectively. Men were the only other group to experience fractures in any of the studies. No fractures were reported in the premenopausal population.
When interpreting the results of these studies it is important to remember that trial results can vary according to a number of factors, including: definition of fracture, initial number of fractures, baseline BMD, and population differences. Therefore, the reported data should not be extrapolated to all populations. It should also be mentioned that all of the fracture data presented consisted of radiologically reported fractures, which does not necessarily correlate with clinical fractures.
