Bisphosphonates and Risk of Acute Pseudogout: A Case-Control Study in the Clinical Practice Research Datalink (CPRD).

Abstract

Background/Purpose: Acute pseudogout is the most dramatic clinical manifestation of calcium pyrophosphate crystal deposition (CPPD). CPPD is most commonly sporadic and age-related but can rarely occur secondary to metabolic diseases or a familial trait. Published case reports also suggest that acute pseudogout can occur as a consequence of bisphosphonate therapy. This matched case-control study aimed to examine whether acute pseudogout is associated with bisphosphonate prescription with the preceding 60 days.

Methods: The study was nested within the UK Clinical Practice Research Datalink (CPRD) which houses clinical data from over 600 general practices. Cases aged ≥18 years with a first-ever diagnosis of pseudogout between 01/03/1987 and 31/12/2012 were individually matched for age, gender and practice to four controls without pseudogout. The exposure of interest was prescription of an oral bisphosphonate in the 60 days prior to the diagnosis of pseudogout. It was estimated that 2147 eligible cases of pseudogout would be identified conferring 98% power to detect an odds ratio (OR) of 2.0. Unadjusted conditional logistic regression was used to assess the association between oral bisphosphonate prescriptions and pseudogout and then adjusted for hyperparathyroidism, osteoarthritis, rheumatoid arthritis, and prescription of diuretics and corticosteroids. Analyses were then repeated for individual bisphosphonates. In order to address the possibility of misdiagnosis of crystal arthritis, a sensitivity analysis was undertaken excluding cases or controls who had a prior diagnosis of gout. ORs were presented as incident rate ratios (IRR) with 95% confidence intervals (CI).

Results: 2011 cases of incident pseudogout were identified and successfully matched to 8013 controls (mean age 72 years; male 52%). Those with incident pseudogout were more likely than controls to have received a bisphosphonate prescription in the preceding 60 days (6.1% vs 3.8%; IRR 1.69; 95%CI 1.35, 2.11). On multivariate analysis, this association attenuated slightly (IRR 1.33; 95%CI 1.05, 1.69). A similar significant association was seen for prescription of alendronic acid (multivariate IRR 1.35; 95%CI 1.02, 1.79) but not etidronate disodium, risedronate sodium, ibandronic acid or sodium clodronate although the absolute number of prescriptions for these drugs was small. After excluding known cases of gout, multivariate associations with both any bisphosphonate (IRR 1.43; 95%CI 1.11, 1.84) and alendronic acid (IRR 1.53; 95%CI 1.14, 2.06) remained.

Conclusion: Bisphosphonate prescription appears to be a risk factor for pseudogout, independent of co-morbid conditions and medications. Prescribers should be aware of this uncommon cause of acute pseudogout.