Bisphosphonate drugs, which are used to reduce bone fractures in patients with osteoporosis, may cause severe and even “incapacitating” musculoskeletal pain, says the US Food and Drug Administration in an alert issued on 7 January.
The pain can occur within days or years after starting treatment, says the agency. Severe musculoskeletal pain is mentioned in the prescribing information for all bisphosphonates, but the agency issued the alert because of “a sizable number of additional reports of severe bone, joint, and/or muscle pain in patients taking a variety of bisphosphonates” since a 2005 report on the problem.
The agency cautions that “the association between bisphosphonates and severe musculoskeletal pain may be overlooked, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics.”
In the 2005 report of 112 patients who developed pain described as “extreme” and “disabling,” the connection to bisphosphonates was not made as doctors attributed the symptoms to underlying osteoporosis (Archives of Internal Medicine 2005;165:346).
In most patients, pain resolved when treatment was stopped, but others obtained only partial or delayed relief. The risk factors for developing pain are unknown.
The agency distinguished severe musculoskeletal pain from a spontaneously resolving acute phase reaction “characterized by fever, chills, bone pain, myalgias, and arthralgias,” which can occur initially with intravenous bisphosphonates or with once weekly or once monthly doses of oral formulations.
The agency recommends that healthcare professionals consider “temporary or permanent discontinuation of the drug” in patients who develop pain, adding that it will issue further recommendations in six months.
In a statement to the BMJ, the agency said that the reports number in the “hundreds” while “hundreds of thousands” of patients take bisphosphonates. But it continued: “The absence of a significant increase in . . . pain in subjects treated with bisphosphonates vs placebo in controlled trials does not exclude the possibility that bisphosphonates are associated with these symptoms [since] clinical trials included highly screened, relatively healthy patients who are treated for limited durations.”
Ethel Siris, professor of medicine at Columbia University and president of the National Osteoporosis Foundation, says that in her experience, patients rarely develop significant pain. Postmenopausal women at increased risk of fracture, she said, “are excellent candidates for bisphosphonates” because alendronate, risedronate, and zoledronate lead to a “substantial and highly clinically meaningful” reduction in the risk of spine and other fractures.
Intravenous zoledronate also reduces all cause mortality among postmenopausal women and older men with a recent hip fracture, she said (New England Journal of Medicine 2007;357:1799).
Sidney Wolfe, director of Public Citizen’s Health Research Group, a non-profit, public interest group in Washington, DC, agrees that the drugs are useful for patients at substantial risk of bone fractures. But, he says, the drugs are being “grossly overprescribed” to women at minimal risk with minor degrees of bone mineral density loss and no previous history of fracture.