No Easy Choice for Fracture Prevention Agents

By Crystal Phend
SANTA MONICA, Calif., Dec. 20 -- Choosing among the multitude of agents to prevent osteoporotic fractures is no snap, according to a systematic review.The review showed a disjointed field with few and poor comparisons among therapies, Margaret Maglione, M.P.P., of the Rand Corporation here, and colleagues reported online in the Annals of Internal Medicine.These findings followed on the heels of a report this week in the Journal of the American Medical Association reinforcing the need for preventive therapy for older women with evidence of a vertebral fracture regardless of bone-mineral density. In the systematic review, no studies have shown one treatment for osteoporosis superior to another, and no head-to-head study has been powered to detect even large differences between therapies.
"Data are insufficient to determine the relative efficacy or safety of these agents," reported Maglione and colleagues.
"It is unlikely that such studies will be performed unless they are required as part of the approval process for these agents," they added.
Their systematic review included 76 randomized trials and 24 meta-analyses evaluating bisphosphonates, calcitonin, estrogen, teriparatide (Forteo), selective estrogen receptor modulators, testosterone, and vitamin D and calcium.
For adverse events, the review included 417 randomized trials, 25 other controlled clinical trials, 11 open-label trials, 31 large observational studies, and nine reports of osteonecrosis among bisphosphonate users.
There was good evidence -- a total sample size greater than 1,000 and consistent findings across studies -- that alendronate (Fosamax), etidronate (Didronel, not FDA approved for osteoporosis treatment), ibandronate (Boniva), risedronate (Actonel), calcitonin, parathyroid hormone (PTH 1-34), and raloxifene (Evista) prevented vertebral fractures compared with placebo.
Likewise, good evidence from multiple trials and meta-analyses suggested alendronate and risedronate prevented nonvertebral and hip fractures compared with placebo.
Although zoledronic acid (Zometa) is not FDA approved for treatment or prevention of osteoporosis, the evidence was good for efficacy against vertebral and nonvertebral fractures in high-risk populations and was fair for hip fracture risk reduction.
A large randomized trial reported that PTH 1-34 prevented nonvertebral fractures, but the evidence was inconsistent with no benefit seen in two smaller trials.
Estrogen was supported by good evidence for reduction of vertebral, nonvertebral, and hip fractures compared with placebo. The largest meta-analysis looking at estrogen showed a 55% reduction in fracture compared with placebo (relative risk: 0.45, 95% confidence interval: 0.45 to 0.98). However, a second large meta-analysis found that the reduction was not significant (RR: 0.68, 95% CI: 0.41 to 1.07).
The review turned up no evidence that tamoxifen (Nolvadex) or testosterone reduce fracture risk, and neither is FDA approved for treatment or prevention of osteoporosis.
Calcium by itself was not effective compared with placebo in a meta-analysis or several large randomized trials for vertebral, nonvertebral, and hip fractures in postmenopausal women.
But, a large study showed that adherence might obscure calcium's benefit. One trial showed a significant risk reduction in nonvertebral fractures among participants who consumed at least 80% of their calcium tablets (RR: 0.63, 95% CI: 0.41 to 0.96).
Vitamin D did not reduce risk of vertebral, nonvertebral, and hip fractures compared with placebo in meta-analyses or a large trial with the exception of one meta-analysis that found a significant 23% reduced risk of nonvertebral fractures and 26% reduction in hip fractures for vitamin D2 or D3.
Evidence was better for the vitamin D analogues. Vertebral fracture risk dropped significantly with 1, 25-hydroxyvitamin D and 1-hydroxyvitamin D compared with placebo (RR range: 0.52 to 0.64 across three meta-analyses). Nonvertebral and hip fracture risk was reduced significantly by vitamin D analogues in four of seven reported comparisons (RR range: 0.16, 95% CI: 0.04 to 0.69, to 0.87, 95% CI: 0.29 to 2.59).
While vitamin D may not universally reduce risk, the data did "suggest that vitamin D analogues reduce the risk for vertebral fractures," they said, "and that, in high enough doses, standard vitamin D may prevent fractures in some high-risk populations."
No randomized trials comparing bisphosphonates showed superiority for any agent in fracture prevention. The one head-to-head comparison looking at fracture risk showed no difference between risedronate and etidronate against vertebral fractures (RR: 0.66, 95% CI: 0.32 to 1.36).
The sixteen trials comparing agents across classes were "too small and too short to detect clinically important differences in fracture incidence between groups," the researchers said.
The only other head-to-head comparison of fracture outcomes, between raloxifene and alendronate, was underpowered and revealed no difference in the hip, wrist, or total vertebral fractures, although there were fewer moderate-to-severe vertebral fractures with raloxifene (P=0.04).
Maglione and colleagues concluded that bisphosphonates have not been shown better for prevention of fractures than calcitonin, calcium, or raloxifene, or estrogen.
The agents were associated with adverse events, including thromboembolic events with raloxifene and estrogen and esophageal symptoms with bisphosphonates. Despite several reports of osteonecrosis of the jaw with high-dose, intravenous bisphosphonates, the investigators could not calculate the risk overall.
Furthermore, there was limited evidence for lower risk populations, including men and women with osteopenia.
The review was conducted under contract with the Agency for Healthcare Research and Quality. One of the researchers reported stock ownership or options in Johnson & Johnson and another reported being employed by WellPoint.
Primary source: Annals of Internal MedicineSource reference:MacLean C, et al "Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis" Ann Intern Med 2008; 148.