Zoledronate lowers risk of fractures in older women with osteopenia
Treatment with the bisphosphonate zoledronate appears to reduce the incidence of fragility fractures with minimal use of calcium supplements in women with hip bone mineral density characterized as osteopenia, according to the results of a 6-year trial.
“The current trial differs from two phase III trials of zoledronate in that dosing in our trial was at 18-month intervals, and the use of calcium supplementation was very low (approximately 2 percent),” the authors said. [N Engl J Med 2007;356:1809-1822; N Engl J Med 2007;357:1799-1809]
The beneficial effect on fractures observed presently suggests that “annual administration may be unnecessary for maximal efficacy in the prevention of fractures and that even longer intervals between doses should be considered,” they added.
In the current trial, 2,000 women (mean age at baseline 71 years) with a T score of −1.0 to −2.5 at either the total hip or the femoral neck on either side were randomized to receive four infusions of either zoledronate 5 mg (zoledronate group; n=1,000) or normal saline (placebo group; n=1,000) at 18-month intervals for 6 years.
Advised dietary calcium intake was 1 g per day, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol prior to trial initiation (a single dose of 2.5 mg) and during the trial (1.25 mg per month).
Throughout the study, fragility fracture occurred with greater frequency with placebo vs zoledronate (190 vs 122 women). The median 10-year risk of hip fracture was 2.3 percent. [New Engl J Med 2018;doi:10.1056/NEJMoa1808082]
In Cox proportional hazards models, bisphosphonate was associated with about a 30-percent reduction in the risk of total fractures (hazard ratio [HR], 0.63; 95 percent CI, 0.50–0.79; p<0.001). One in 15 women needed to be treated to prevent one instance of fracture.
Compared with those on placebo, women who received zoledronate had a significantly lower risk of nonvertebral fragility fractures (HR, 0.66; p=0.001), symptomatic fractures (HR, 0.73; p=0.003), vertebral fractures (odds ratio [OR], 0.45; p=0.002) and height loss (p<0.001).
A total of 400 participants in the zoledronate arm vs 443 in the placebo group developed serious adverse events (OR with zoledronate, 0.84; 0.70–1.00), which included fractures that led to hospitalization. None of the participants developed atypical femoral fractures or osteonecrosis of the jaw.
There were 68 deaths documented overall: 41 from neoplasms (16 vs 25), eight from strokes (1 vs 7) and seven from cardiac events (4 vs 3). The ORs for death and cancer with the active drug was 0.65 and 0.67, respectively.
Taken together, the present data have important clinical implications, according to Dr Clifford J Rosen, who directs the Center for Clinical & Translational Research at the Maine Medical Center Research Institute, in an accompanying commentary. [New Engl J Med 2018;doi:10.1056/NEJMe1812434]
“Given the effectiveness of infrequent administration of zoledronate in reducing the risk of fragility fracture, this treatment can certainly be added to our armamentarium for treating osteoporosis, and it would represent an approach that would not be hindered by adherence issues,” Rosen continued.
“But just as importantly, this trial reminds us that risk assessment and treatment decisions go well beyond bone mineral density and should focus particularly on age and a history of previous fractures,” he said.