ARCH INTERN MED/VOL 165, FEB 14, 2005. P346-7 EDITOR”S CORRESPONDENCE
The oral bisphosphonate alendronate sodium (Fosamax; Merck & Co Inc, Whitehouse Station, NJ) was first approved for osteoporosis by the Food and Drug Administration (FDA) in September 1995. From its initial marketing date and up to November 2002, the FDA received Serious Adverse Event (SAE) (defined as death, life threatening, hospitalization [initial or prolonged], disability, congenital anomaly, required intervention to prevent permanent impairment or damage, or important medical event) reports of severe bone, joint, and/or muscle pain, that developed in 112 women, 4 men, 1 adult of unknown sex, and l child after starting therapy with the drug. The age range was 7 to 84 years; (n= 109; median=67 years). The child was a 7 year old boy who mistakenly received alendronate instead of methylphenidate and developed extreme bone pain in his hips, knees, and ankles after l dose. Bones, joints, and muscles throughout the body were affected. In some individuals, pain began at 1 site and then migrated and became diffuse. lt was often described as "severe," "extreme," "disabling," or "incapacitating." Many patients were unable to walk, climb stairs, or perform usual activities. Some became bedridden, and others required walkers, crutches, or wheelchairs. Many underwent numerous diagnostic tests with mostly normal findings. For the 96 patients with information, the alendronate doses were 5 mg/d (n = 4; 4%); 10 mg/d (n = 7 1; 74%); 20 to 35 mg/d (n = 4; 4%); and 70 mg/wk (n = 17; 18%). The median time to onset of pain after starting alendronate therapy was 14 days (n= 107; range, same day to 52 months [mean=91 days]). Pain was treated with a variety of analgesics including opioids and ketorolac. Of 83 patients with information, 55 (66%) experienced relief after alendronate therapy was discontinued. Nine U 1%) of the 83 patients redeveloped pain following re-administration of the drug therapy. After discontinuation of the drug treatment, some patients experienced immediate improvement while the majority had more gradual improvement. The FDA received 6 US SAE reports of severe bone, joint, or muscle pain for risedronate sodium (Actonel; Procter & Gamble Pharmaceuticals, Cincinnati, Ohio), and less widely used bisphosphonate, between initial marketing in September 1998 and June 2003. The data suggest a possible class effect. The clinical trials leading to FDA approval of alendronate and risedronate were reviewed and did not show meaningful differences between drug and placebo for SAE ports of severe bone, joint, and/or muscle pain. However, differences in reported adverse events are sometimes seen for market place experience compared with pre-approved clinical trails. Underreporting of pain is probably considerable because of its subjective nature and because physicians may attribute pain to osteoporosis. Serious or severe bone, joint, and/or muscle pain that begins shortly after bisphosphonate use should be reported to physicians for consideration of discontinuing drug therapy. Diane K. Wysowski, PhD Correspondence: Dr Wysowski, Division of Drug Risk Evaluation, HFD 430, Food and Drug Administration, Parklawn Building, Room 15B 08, Rockville, MD 20857 (diane.wysowski@fda.hhs.gov).
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