Once-yearly zoledronic acid to treat osteoporosis
The following study discusses zoledronic acid (zoledronate, marketed by Novartis as Reclast and Zometa) that is given as once-yearly IV injections to treat osteoporosis. This medication isn't approved by the FDA for use in osteoporosis, but has been approved for treatment of some cancers metastatic to the bones. Here is a Wikipedia article with more basic information about zoledronate for those interested.
N Engl J Med. 2007 May 3;356(18):1809-22. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis, Black DM and others. PMID: 17476007. This is a very large multicenter study with 3889 patients receiving once-yearly 5-mg doses of zoledronic acid and with 3876 assigned to the placebo group. All participants were postmenopausal women. The primary end point was vertebral and hip fracture reduction. All patients received 1000-1500 mg daily calcium and 400-1200 IU of vitamin D as supplements. The 3-year incidence of vertebral fractures was 10.9% (310 women) in the placebo group vs. 3.3% (92) women in the zoledronic acid group, a 70% fracture reduction. Hip fracture incidence was 2.5% (88 women) in the placebo group and 1.4% (52) women in the zoledronic acid group for a 41% fracture reduction. Those in the zoledronic-acid group also had significantly less height loss that patients in the placebo group. Bone mineral density (BMD) increased significantly after three years at the total hip, lumbar spine and femoral neck 6.02%, 6.71% and 5.06% respectively when compared to the placebo group. Primarily due to post-dose symptoms, the number of patients with adverse events was significantly higher in the zoledronic acid group than the placebo group. Additionally the noteworthy problem in the zoledronic acid group was a significantly higher incidence of arrhythmia, 266 patients or 6.9% vs. 203 patients or 5.3% compared to the placebo group. Also a total of 50 patients in the zoledronic acid group had serious atrial fibrillation (1.3%) compared to 20 patients (0.5%) in the placebo group (P<0.001). The authors reported, ". . .two cases of potential osteonecrosis of the jaw were identified (one in the placebo group and one in the zoledronic-acid group)." Both cases subsequently resolved with antibiotics and debridement. Editor's comments: The fracture reduction reported in this study is quite noteworthy and the reason we all take medications for our osteoporosis. Also the convenience of a once-yearly IV is hard to overlook. This could be especially important for those who suffer a osteoporosis-related fracture that requires hospitalization. During that hospital stay for fracture reduction the patient could also receive the first annual dose of zoledronic acid, a particularly convenient service. Of equal importance would be the convenience to those with problems taking oral medications, inability to stand or sit for one-half hour after taking an oral bisphosphonate, etc. The high incidence of serious atrial fibrillation is worthy of further study and an item to take into consideration when evaluating which medication to take for osteoporosis. The authors note, "The events [serious atrial fibrillation events] were uniformly distributed over time, with the vast majority of events occurring more than 30 days after infusion, by which time zoledronic acid is undetectable in the circulation." Another question is whether this serious side effect, if not a coincidence, only results from IV zoledronic acid or if other bisphosphonates might also cause it. In this same NEMJ issue on pgs. 1895-6 there is a letter to the editor regarding alendronate and atrial fibrillation by Cummings SR and others. They mention the Fracture Intervention Trial (FIT), a randomized study of alendronate sponsored by Merck, which involved 6459 postmenopausal women. They note, "The final 1997 analysis that was reported to the Food and Drug Administration showed 47 serious atrial-fibrillation adverse events (1.5%) among patients receiving alendronate versus 31 (1.0%) among those receiving placebo during an average of 4 years (relative hazard, 1.51; 95% confidence interval [CI], 0.97 to 2.40; P=0.07 (fig. 1). There was no increased risk of all atrial-fibrillation adverse events: 81 events (2.5%) versus 71 events (2.2%) (relative hazard, 1.14; 95% CI, 0.83 to 1.57; P=0.42)." They also note, "The trend toward an increased risk of serious but not atrial-fibrillation adverse events in the FIT trial resembles the pattern observed in the study of zoledronic acid by Black et al." One caveat is that both these studies involved only women. Although the effects of bisphosphonates on BMD are not gender-specific whatsoever, atrial fibrillation events could be. But to be on the safe side, until proven otherwise, my suggestion is to assume that bisphosphonates also increase the risk of serious atrial fibrillation events for men and women. This should be particularly important for anyone already having, or prone to have, cardiac arrhythmias and an item you should discuss with your care provider when first deciding to take one of the approved osteoporosis medications. I also want to comment on the two cases of osteonecrosis of the jaw (ONJ). This is the first time I've ever seen a mention of ONJ occurring in a member of the placebo group. For that reason, and because both cases resolved readily, I would lean toward some other diagnosis than ONJ for both cases. If they are indeed ONJ, the risk for ONJ would remain extremely small based upon one case in 3889 patients in the treatment group during three years of therapy.