FDA Reminds Physicians of Link Between Bisphosphonates and Musculoskeletal Pain

By Peggy Peck
ROCKVILLE, Md., Jan. 7 -- The FDA called attention today to evidence suggesting that bisphosphonates may be associated with the sudden onset of otherwise unexplained severe musculoskeletal pain. In an alert to clinicians, the agency cited several trials that have reported such an association, but stated that physicians often overlook it. The FDA said its evaluation of these reports would take about six months to complete.
The FDA characterized the alert as a wakeup call to physicians who might not consider bisphosphonates as the cause of new onset pain, especially because symptom onset varies from a few days to years after initiating bisphosphonate therapy.
The alert includes bisphosphonates marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa.
Although musculoskeletal pain was reported in clinical trials of bisphosphonates, the FDA said the severity of pain was not always documented.
In 2005, the FDA published findings from a post-marketing case review of bone, joint, and/or muscle pain of a serious nature associated with alendronate (Fosamax) and risedronate (Actonel).
The range of time to onset of pain after starting alendronate was one day to 52 months (mean, 91 days; median, 14 days). Pain was not isolated to a particular anatomical site, and some patients reported initial focal pain that developed into diffuse pain.
In the most severe cases, pain was described as extreme, disabling, or incapacitating, and for some patients the pain was so severe that they were unable to continue their normal activities and required aids for walking. In a search for a cause of the musculoskeletal pain, many patients underwent numerous diagnostic tests with mostly normal findings.
The FDA said pain was treated with a variety of analgesics, including opioids. Many patients had relief after the bisphosphonate was discontinued, but while relief was immediate after drug discontinuation in some patients, others had a slower, partial resolution.
The FDA said that the precautions section of the labeling for all bisphosphonates includes information about severe incapacitating musculoskeletal pain, which was in contrast to typical acute phase response that can include fever, chills, bone pain, myalgias, and arthralgias. Symptoms related to acute phase response usually resolve within days and do not require discontinuation of the drug.
The risk factors for and occurrence rates of severe musculoskeletal pain associated with bisphosphonates are unknown.
In today's alert, the FDA said severe pain was more common among patients older than 65. It suggested that all bisphosphonate patients be closely monitored for pain and other drug-related symptoms. If, however, pain does not resolve within days -- especially within days of withdrawing bisphosphonate therapy -- another diagnosis should be considered.