Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.
One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.17 This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.18,19
Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.20,21 Injection site reactions have been reported in those receiving IV infusions,17 and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.
Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.22 The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).
In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).23
In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,22 there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).
Other issues to keep in mind
Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,24 although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.
In 2010, the FDA announced requirements for a black box warning about a possible link,25 highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.
While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.24
Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.26,27 One way of improving adherence is to reduce the frequency of dosing required.27 With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.
Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.
Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. 28 After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.