Background/Purpose:   In animal models, cyclo-oxygenase (COX)-2 stimulates osteoclasts through prostaglandin E2 (PGE2). Therefore, non-steroidal anti-inflammatory drugs (NSAIDs) preferentially inhibiting COX-2 (ie-coxibs) should prevent bone resorption. Withdrawal of COX-2 inhibition leads to a rebound effect and excessive osteoclast stimulation which may cause fractures. There are few human studies assessing the risk of fracture with NSAID use. Thus, we examined the risk of osteoporotic fracture with NSAID use, specifically related to the duration and timing of coxib use.

Methods: We conducted a nested case control study using The Health Improvement Network, a population-based electronic medical records database from the UK. We included persons aged 40-89 with hip or knee osteoarthritis (OA). Individuals with malignancy or metabolic bone disease were excluded. NSAID use, including coxibs, was assessed using detailed prescription records. 

Incident osteoporotic fracture cases were identified using Readcodes, and the date of fracture was considered the index date. Up to 4 controls were matched to each case by age, gender, year of OA diagnosis and index date.

Fracture risk is expected to depend on the cumulative dose and how recent the drug use was. Hence coxib users were categorized as: (A) Current long term users (>6 months use, and prescription within 3 months of the index date), (B) Current short term users (<6 months use and a prescription within 3 months), (C) Remote long term users (>6 months use and no prescription within 3 months), (D) Remote short term users (<6 months use and no prescription within 3 months), (E) non-selective NSAID users and (F) NSAID non-users.  Coxibs included: celecoxib, etorocoxib, lumiracoxib, rofecoxib, and valdecoxib.

Potential confounders included BMI, smoking, alcohol use, history of falls, osteoporosis, other comorbidities and medication use. Conditional logistic regression was conducted to assess the risk associated with each of the coxib exposure categories compared to NSAID non-user. 

Results:  4153 cases and 15040 matching controls were identified.  Fracture cases had a higher prevalence of osteoporosis, anti-osteoporotic drug use and history of falls.  Other baseline demographics were similar between 2 groups (Table). Each of the coxib exposure categories was associated increased risk of fractures.  Current coxib use with <6 months of exposure had the highest risk of fracture (Table).

Conclusion: In this large OA population, risk of fracture was most increased with current use of COX-2 inhibitors.  While confounding by indication cannot be ruled out, fracture risk was also present with remote use. This topic warrants further research. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-of-osteoporotic-fractures-with-use-of-cyclooxygenase-2-inhibitors/