Désirée Lie, MD, MSEd
Ann Intern Med. Published online December 17, 2007.

The agents evaluated were bisphosphonates (alendronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronic acid), calcitonin, estrogen, teriparatide, selective estrogen receptor modulators (raloxifene and tamoxifen), testosterone, and vitamins (vitamin D) and minerals (calcium).
Studies reporting the rate or risk for fractures were selected for the efficacy analysis. For the adverse event analysis, studies were selected that reported the relationship between a particular drug and cardiovascular, thromboembolic, or upper gastrointestinal tract events, malignant conditions, and osteonecrosis.
The review authors used a standardized protocol to abstract data regarding fractures, adverse events, agents and comparators, study design, and variables of methodologic quality for 76 randomized trials and 24 meta-analyses selected. No large trials directly compared 2 or more agents or firmly established superiority of any agent.
Evidence is good suggesting that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (PTH 1-34), and raloxifene prevent vertebral fractures to a greater extent than placebo. For calcitonin, evidence concerning prevention of vertebral fractures was fair.
For prevention of hip fractures, the evidence is good that alendronate, risedronate, and estrogen are more effective than placebo. For zoledronic acid, the corresponding evidence was only fair.
Good evidence suggests that estrogen monotherapy is associated with a decreased incidence of vertebral, nonvertebral, and hip fractures. The effects of vitamin D for prevention of both vertebral and hip fractures varied with dosage, analogue of vitamin D used, and study population.
"Consistent with FDA [Food and Drug Administration] requirements to demonstrate reduced fracture risk to obtain approval of an agent for osteoporosis treatment, many trials performed were powered to detect a difference in fracture risk among postmenopausal osteoporotic women," the review authors write. "These studies provide good evidence that the bisphosphonates alendronate, etidronate, ibandronate, and risedronate, as well as the hormones calcitonin and teriparatide and the selective estrogen receptor modulator raloxifene, prevent vertebral, nonvertebral, or hip fractures in this high-risk group. Each of these agents, with the exception of etidronate, has been approved by the FDA for osteoporosis treatment."
A published meta-analysis and several large randomized trials showed that calcium alone was not statistically significantly different from placebo in preventing vertebral, nonvertebral, and hip fractures in postmenopausal women. Among all participants, the risk for vertebral fracture for calcium vs placebo ranged from 0.70 to 2.77 (confidence interval, 0.39 - 19.65) in a trial with 2643 participants, with similar magnitude of risk reduction for nonvertebral and hip fractures. In 1 trial, the risk for vertebral fractures for calcium vs placebo was 37% lower among participants who consumed 80% of their study tablets vs participants who were not compliant. With adverse events, raloxifene, estrogen, and estrogen-progestin increased the risk for thromboembolic events, whereas etidronate increased the risk for esophageal ulcerations and gastrointestinal tract perforations, ulcerations, and bleeding. Although there have been published cases of osteonecrosis of the jaw in patients with cancer who take large doses of bisphosphonates intravenously, the review authors were unable to calculate this risk.
Limitations of this review include the possibility that trials published in non–English-language publications were missed, publication bias resulting in an overestimation of the efficacy of these treatments, failure of many studies to measure fracture risk, inadequate power in most trials that measured fracture risk to detect even large differences, studies heterogeneous with respect to study design, failure of most studies to consider adherence to the medication regimens, and counts of adverse events limited to those that were explicitly reported in the reviewed studies.
"Few direct comparisons have been conducted between different agents or classes of agents used to treat osteoporosis," the review authors conclude. "Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, data are insufficient to determine the relative efficacy or safety of these agents. It is unlikely that such studies will be performed unless they are required as part of the approval process for these agents."
The Agency for Healthcare Research and Quality funded this review. Dr. MacLean is employed by WellPoint. Another review author has disclosed stock ownership or options in Johnson & Johnson.