The Case for a Fosamax Holiday

Washington, DCThe US Food and Drug Administration (FDA) may resemble a slow-moving juggernaut when it comes to addressing concerns over existing medications. However, once the agency gets around to identifying a concern and calls in a review panel for a second opinion, the FDA shows its nerdy side and produces a plethora of data for their expert panelists to chew on. Case in point is the 45 pages of data tagging the suspicions and concerns surrounding oral bisphosphonates such as alendronate (Fosamax), and the Fosamax side effects that often ensue.

Fosamax was the first oral bisphosphonate to see regulatory approval on September 29, 1995. And with good reason: given the size of the post-war Baby Boom demographic and the looming arrival of the first wave of Boomers to reach retirement age, the promise of bisphosphonates toward the easing of osteoporosis symptoms such as brittle bones and fractures was both welcome and necessary. But a funny thing happened: a drug that was supposed to ward against fractures now appears to play a role in causing them. To wit, Fosamax and femur fractures is one of the reasons why the expert panel has been called to order in the first place.

On the surface, the concerns warrant increased scrutiny. Fosamax fractures, which involve the femur and have been reported to occur with minimal causal trauma (such as a fall or a weighted strike to the bone), have resulted in many a Fosamax femur lawsuit. Other bisphosphonate side effects involving alendronate include Fosamax osteonecrosis, a rare degradation of the jawbone more commonly affecting, but not exclusive to, cancer patients. There have been lawsuits over that affliction, often referred to as Fosamax dead jaw, as well.

And yet, Fosamax and other drugs in the bisphosphonate family appear to have proven effective for the osteoporosis indication, according to statistical data contained in the FDA pre-panel briefing released September 9. To that end, the FDA admits "bisphosphonate medications are highly effective at decreasing the fracture risk associated with osteoporosis, as demonstrated by the required fracture registration trials where morphometric vertebral fracture is the primary endpoint.

"In addition, recent studies have analyzed the epidemiology of hip fractures from 1996–2006. Using the National Hospital Discharge Survey from 1996 to 2006, the annual hip fracture incidence in patients over the age of 50 years fell from 600/100,000 in 1996 to 400/100,000 in 2006. This occurred at a time when the age of the population is increasing and it has been well documented that age is a major risk facture for osteoporotic fracture."

And yet there have been problems—and not only with Fosamax fractures, but also Fosamax osteonecrosis of the jaw, often referred to as ONJ. "In the osteoporosis population, ONJ has been reported with oral bisphosphonate use," states the FDA in its report, with many of those cases associated specifically with Fosamax. Adverse reports databases mined since March of 2005 have uncovered a total of 47 unduplicated cases of Fosamax ONJ associated specifically to alendronate.

And there are other concerns. Cancer of the esophagus related to bisphosphonate use has been studied, although the FDA is quick to point out that such adverse reactions, akin to the others, warrant further study in order to arrive at any kind of definitive conclusion.

Still, there are examples that suggest a potential link. The FDA pre-panel communiqué references participants in Fosamax clinical trials who developed esophageal cancer in association with Fosamax use. One patient with a history of prostate cancer had used Fosamax for four years. Three months after enrolling in a trial of lipid-lowering drugs, the patient was diagnosed with cancer of the esophagus.

Another patient, aged 52, with no prior association to alendronate, began experiencing pain, difficulty swallowing and persistent vomiting just 10 days after starting Fosamax in a study for Paget's disease. It wasn't long before tests revealed adenocarcinoma of the esophagus with metastases.

All these issues formed the basis of an FDA expert panel debate September 9. Would the outcome comprise votes of confidence? Or a challenge to the tenet that the benefits of Fosamax outweigh the risks? Among the expected considerations was the potential for an official position on the value of a so-called "drug holiday" for Fosamax and other bisphosphonates, given the suspicion that the effectiveness of alendronate and other drugs in its class diminish with long-term use, while the risks increase.

In the end, the panel decided not to establish a time limit on Fosamax or its bisphosphonate cousins. Instead, in a majority vote of 17–6, the advisory panel recommended additional labeling with regard to the risks associated with long-term use. Those risks, among others, are for Fosamax ONJ and sudden fractures to the femur.

In other words, an educated consumer is ultimately preferable to the mandating of restrictions to the drug. That's good news for Fosamax manufacturer Merck & Co, as well as other bisphosphonate manufacturers. At present, Fosamax is the most widely prescribed drug in the oral bisphosphonate class.

And that class is substantial. For the period encompassing 2005–2009 in the United States, more than 150 million prescriptions were dispensed in the outpatient setting for oral bisphosphonates, says the FDA. "When evaluated by age, 5.1 million patients over the age of 55 years received a prescription for a bisphosphonate in year 2008. We estimate that for every 100 U.S. population, seven patients received a prescription for a bisphosphonate in the outpatient setting."

Even with the aging Boomer population, those numbers could drop if a drug holiday were mandated. While the agency is not bound by the recommendations of its expert panels, in most instances those recommendations are adopted. The FDA could, in its wisdom, mandate a drug holiday anyway. But given the expert panel's position on the matter, such an outcome is highly unlikely.