Atypical Fractures and Bisphosphonate Therapy

Pharmacology Watch

In this issue: Fractures and bisphosphonate therapy, warfarin anticoagulation and influenza vaccine and cotrimoxazole, antiplatelet therapy with clopidogrel and aspirin, FDA Actions.

Bisphosphonates and atypical fractures

Atypical fractures of the femur have been linked with bisphosphonate therapy in several recent news stories. A recent industry-sponsored study looks to quell these concerns. Secondary analysis from three large randomized bisphosphonate trials with more than 14,000 women showed that among 284 hip or femur fractures recorded, a total of 12 fractures in 10 patients were classified as occurring in the subtrochanteric or diaphyseal femur, a combined rate of 2.3 per 10,000 patient years. As compared with placebo, the relative hazard ratio for the three trials did not meet statistical significance, although confidence intervals were wide. The authors conclude that the occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare even among women who had been treated with bisphosphonates for as long as 10 years (N Engl J Med; published on-line March 24, 2010). An accompanying editorial published on-line at the same time by Elizabeth Shane, MD, Columbia University, acknowledges that despite excellent safety profiles, bisphosphonates have been associated with "atypical" fractures of the femur that occur with minimal or no trauma, generally affecting the proximal third of the femoral shaft. Most of these fractures have occurred in women on long-term alendronate therapy, occasionally taken together with other antiresorptive drugs, corticosteroids, or proton pump inhibitors. Shane points out that while these fractures represent concern, they are uncommon and actually occur more frequently in patients who are not on bisphosphonates. The results of this study "provide assurance that subtrochanteric fractures are extremely rare" and many more hip fractures are "prevented by bisphosphonates than are potentially caused by the drugs." Treatment with bisphosphonates up to 10 years is more effective than shorter-term treatment in preventing new vertebral fractures and nonvertebral fractures, but she also suggests that patients should be considered for "drug holidays with careful observation" if they have been on long-term therapy.

Warfarin, flu vaccine, and cotrimoxazole

Anticoagulation with warfarin requires careful monitoring. Concomitant use of medications may result in changes in the international normalized ratio (INR), which may increase the risk of bleeding or decrease the effectiveness of therapy. Two studies in the April 12 issue of Archives of Internal Medicine clarify the risk of two commonly used medications, influenza vaccine and the antibiotic trimethoprim-sulfamethoxazole. Patients on warfarin have been told that they need careful monitoring after the influenza vaccine, although the effect is not clear. Some guidelines have suggested that flu shots prolonged INRs, while others suggest the vaccine reverses the anticoagulation effect.

In this study, 104 patients on a stable warfarin regimen were randomized to receive influenza vaccine and subsequent placebo administration or vice versa. All patients were tested for coagulation variables and followed for clinical events. The influenza vaccine had no effect on anticoagulation compared to placebo. There were no fatal or major bleeding events. The authors conclude that the influenza vaccine has no significant effect on INR values or warfarin weekly doses in patients on chronic warfarin therapy and that close monitoring of INR values after influenza vaccine is not required (Arch Intern Med 2010;170:609-616).

Conversely trimethoprim-sulfamethoxazole (cotrimoxazole) may significantly prolong INRs with adverse clinical outcomes. In the population-based, nested case-controlled study using health care databases in Canada, residents 66 years or older who were treated with long-term warfarin were evaluated for upper gastrointestinal (GI) tract hemorrhage. Of the more than 134,000 patients on warfarin, 2151 patients were hospitalized for upper GI hemorrhage. Recent use of cotrimoxazole was almost four times more common in those hospitalized (adjusted odds ratio, 3.84; 95% CI, 2.33-6.33). The odds ratio for treatment with ciprofloxacin also was higher (1.94), but no significant association was observed with amoxicillin, ampicillin, nitrofurantoin, or norfloxacin. The authors conclude that among older patients receiving warfarin, cotrimoxazole is associated with a significantly higher risk of upper GI tract hemorrhage. Ciprofloxacin was also associated with risk and whenever possible clinicians should prescribe alternate antibiotics in patients receiving warfarin (Arch Intern Med 2010;170:617-621).

Clopidogrel and aspirin

What is the optimal duration of dual antiplatelet therapy with clopidogrel and aspirin in patients with drug-eluting stents? In previous studies, early discontinuation of dual antiplatelet therapy has been identified as a risk factor for late stent thrombosis. A new study seeks to determine whether dual antiplatelet therapy for more than 1 year is of value. In a study that merged data from two concurrent randomized, clinical trials, 2701 patients who had received drug-eluding stents and had been free of major adverse cardiac events, cerebrovascular events, or major bleeding for a period of at least 12 months were randomized to receive clopidogrel plus aspirin or aspirin alone. The primary endpoint was a composite of myocardial infarction (MI) or death from cardiac causes. The cumulative risk of the primary outcome at 2 years was 1.8% with dual antiplatelet therapy as compared with 1.2% with aspirin monotherapy (hazard ratio, 1.65; 95% confidence interval, 0.80-3.36; P = 0.17). The individual risks of MI, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death did not differ significantly between the two groups. However, there was a trend toward higher risk for these outcomes in the dual therapy group (P = 0.051 for MI, stroke, or death from any cause; P = 0.06 for MI, stroke, or death from cardiac cause). The authors conclude that use of dual antiplatelet therapy for longer than 12 months is not more effective than aspirin alone in patients who have received drug-eluding stents (N Engl J Med 2010;362:1374-1382).

FDA Actions

Rifaximin, Salix Pharmaceutical's minimally absorbed (nonsystemic) oral antibiotic has been approved to reduce the risk of recurrent hepatic encephalopathy in patients with advanced liver disease. Rifaximin was previously approved to treat traveler's diarrhea. The drug, which is taken orally twice a day, appears to reduce ammonia levels by reducing gut flora. It is marketed as Xifaxan®.

The FDA has approved Pancreaze, a new pancreatic enzyme product for patients who do not produce enough pancreatic enzymes (due to cystic fibrosis, chronic pancreatitis, pancreatic surgery, etc.). Pancreaze is the third approved pancreatic enzyme product on the market after Abbott's Creon® and Eurand's Zenpep®. The approval coincides with the FDA's deadline to cease marketing unapproved pancreatic enzyme products that have been available for many years. In October 2007, the FDA announced a deadline of April 28, 2010, after which time unapproved products would no longer be available.

The FDA has approved the first generic version of the popular antihypertensive losartan (Cozaar®) as well as the combination of losartan and hydrochlorothiazide (Hyzaar®). This represents the first generic angiotensin receptor blocker on the market, a development that has been anxiously awaited by consumers. Losartan carries a boxed warning against using the drug during pregnancy. Generic losartan is available in 25 mg, 50 mg, and 100 mg strengths, while losartan/hydrochlorothiazide is available in 50 mg/12.5 mg, 100 mg/12.5 mg, and 100 mg/25 mg strengths.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468; E-mail: