Oral Bisphosphonates Triple Aseptic Osteonecrosis Rate

By John Gever
VANCOUVER, British Columbia, Jan. 18 -- Patients with severe bone necrosis are almost three times more likely to have been treated with oral bisphosphonates for osteoporosis than those without aseptic osteonecrosis, researchers here found. In a study of 196 aseptic osteonecrosis patients requiring hospitalization, the adjusted risk ratio for having a history of oral bisphosphonate drug therapy was 2.87 (95% CI: 1.71 to 5.05), compared with 1,960 age-matched controls, reported Mahyar Etminan, Pharm.D., M.Sc., of Vancouver General Hospital, and colleagues online in the Journal of Rheumatology. Case reports and small case series have been published of osteonecrosis, particularly osteonecrosis of the jaw, in patients with a history of bisphosphonate use, including alendronate (Fosamax), risedronate (Actonel), and etidronate (Didronel). This association was reported primarily in patients receiving intravenous bisphosphonates.
Dr. Etminan and colleagues' findings came from analysis of 87,837 case records from Quebec, involving cardiovascular patients ages 65 or older. The records database includes information on prior prescriptions as well as hospitalizations, diagnoses, and procedures.
For each of the 196 cases of osteonecrosis requiring hospitalization who were identified, the investigators obtained records for 10 control patients matched by age, date of treatment, and length of follow-up.
Raw data showed that 14.8% of cases had taken bisphosphonates at some point, compared with 3.8% of controls, suggesting a crude risk ratio of 4.61.
But adjusting for factors including age, comorbidity, coronary artery surgery, history of fractures, malignancies, all medication use, corticosteroid use, diabetic medications, and dental procedures reduced the risk ratio to 2.87.
A history of statin or ACE inhibitor drug use did not show a similar pattern of increased osteonecrosis, Dr. Etminan and colleagues reported.
When patients currently taking bisphosphonate were separated from those with a previous bisphosphonate history, both groups still showed a significant association with osteonecrosis.
Among those with current use, the adjusted risk ratio was 3.14 (95% CI: 1.68 to 5.88). The adjusted risk ratio for those with only previous use was 2.52 (95% CI: 1.01 to 6.26).
"Additional studies are needed not only to confirm these preliminary observations but also to investigate further the role of specific bisphosphonates, their dose-response relationship, duration of therapy, and the exact sites of bone necrosis," Dr. Etminan and colleagues wrote.
They pointed out that their data did not include information on necrosis site. Because corticosteroid use was more than three times as common among cases versus controls, the researchers said it was likely that most cases involved sites other than the jaw, particularly the hip.
Because the study was observational, it did not prove causality, the investigators noted.
Nevertheless, Dr. Etminan said in an interview that the study bolsters the cautions expressed by the FDA and others about musculoskeletal side effects of bisphosphonates.
"Obviously a lot of people are taking these medications … and are benefiting from them," he said. Nevertheless, he added, they involve a tradeoff of risks and benefits. He said patients and physicians need to be aware of the side effects, which may often go unreported.
The FDA issued an alert this month on unexplained sudden and severe musculoskeletal pain associated with these drugs, although this effect's relationship to the reports of osteonecrosis was not detailed.
The FDA has said it plans to evaluate the reports of severe musculoskeletal pain with bisphosphonates by July. Labeling information for all drugs in this class currently include cautions about this side effect.
One co-author reported receiving financial support from le Fonds de la Recherche en Santé du Québec.
Primary source: Journal of RheumatologySource reference:Etminan M, et al "Use of oral bisphosphonates and the risk of aseptic osteonecrosis: a nested case-control study" J Rheumatology 2008.