Clinical Review


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A roundup of medical and other interventions that make a difference (or don’t, in some cases)



The past year has seen continuing variety in pharmaceutical and nonpharmaceutical approaches to osteoporosis, which remains—and will remain—a significant source of morbidity and mortality as the Baby Boom generation ages. As more people who are less healthy live longer, the sequelae of fragility fractures, mainly of the hip and spine, will increase as well, unless we continue to make strides in the identification of risk and in the prevention, detection, and treatment of osteoporosis.

In this article, I highlight:

  • two trials of the newly FDA-approved denosumab (Prolia) that demonstrate its benefits and risks
  • a recent report on osteonecrosis of the jaw in bisphosphonate users, including low-risk women taking an oral formulation
  • guidance from Canada on how to derive maximum benefit from vitamin D
  • disappointing findings on the benefits of resistance training for women
  • two studies detailing the benefits of another SERM, lasofoxifene.

Denosumab outperforms alendronate as well as placebo

Cummings SR, San Martin J, McClung MR, et al; for FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.

Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial [published online ahead of print December 14, 2009]. J Bone Miner Res. doi:10.1359/jbmr.080910.

In their report from the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), Cummings and colleagues describe this prospective, placebo-controlled study of 7,868 postmenopausal women, all with a T-score worse than –2.5. Participants were randomized to 60 mg of subcutaneous denosumab or placebo every 6 months for 3 years. Those taking denosumab experienced a 68% reduction in the rate of new vertebral fracture (P < .001), a 20% reduction in nonvertebral fracture (P =.02), and a 40% reduction in hip fracture (P =.04), compared with placebo.

Denosumab is a fully human monoclonal antibody against the receptor activator of RANKL, which is a cytokine essential for the formation, function, and survival of osteoclasts. By binding to RANKL, denosumab prevents the usual interaction between RANKL and its receptor on osteoclast precursors and osteoclasts. And by preventing this interaction, denosumab reversibly inhibits osteoclast-mediated bone resorption, thereby reducing bone turnover and increasing bone mineral density (BMD).

Denosumab received FDA approval in June 2010 for the treatment of osteoporosis in postmenopausal women who have a high risk of fracture (defined as a history of osteoporotic fracture, the presence of multiple risk factors for fracture, or the failure of or intolerance to another form of osteoporosis therapy).

Details of the FREEDOM trial

The average age of women in the trial was 72.3 years (range, 60 to 90 years). At baseline, 23% of participants had a preexisting vertebral fracture. The primary endpoint was new vertebral fracture, with nonvertebral fracture and hip fracture as secondary endpoints.

No significant differences were found between denosumab and placebo in:

  • total incidence of adverse events
  • serious adverse events
  • discontinuation of treatment because of adverse events
  • overall incidence of cancer
  • overall incidence of cardiovascular events
  • adverse or serious adverse events of infection
  • local reactions at the site of injection.

No neutralizing antibodies developed in either group.

Four cases of opportunistic infection were reported in the denosumab group, and three were reported in the placebo group. Eczema was reported by 3% of women in the denosumab group, versus 1.7% in the placebo group (P < .001). Falls that were not associated with a fracture were reported by 4.5% of subjects taking denosumab, versus 5.7% of those taking placebo (P =.02). Flatulence was more common among women taking denosumab (2.2%) than among those taking placebo (1.4%) (P =.008). Twelve women (0.3%) in the denosumab group reported serious adverse events of cellulitis, compared with one woman taking placebo (<0.1%) (P =.002).

Seventy women (1.8%) died in the denosumab group, compared with 90 (2.3%) in the placebo group (P =.08).


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