Bisphosphonate use and improved implant survival: A nation-wide cohort study

Purpose: Osteolysis and aseptic loosening are the most common cause of revision arthroplasty worldwide. Bisphosphonates might improve implant survival through their anti-osteoclast effects. We aimed to study the association between bisphosphonate use and implant survival. Methods: A retrospective cohort study was conducted within the Danish nationwide registries (5.5 million residents). We identified patients aged >=40 years undergoing total joint replacement (TJR) during the study period (1998-2007) using ICD10 codes. Patients with inflammatory arthritides, bone Paget, hip fracture and use of DMARDs were excluded. Each participant was followed up until end of study, date of emigration, revision surgery, or patient's death, whichever came first. Participants were classified as bisphosphonate users (BPU) if they had been on treatment for at least 6 months. A time-varying exposure was used to avoid immortal-time bias. Up to six BP non-users (BPNU) undergoing arthroplasty were matched to each BPU using propensity scores. Stratified Cox regression was used to model implant survival according to bisphosphonate use. Further, we studied the association between duration of use, adherence (medication possession ratio=MPR), and timing of therapy initiation (pre-op vs post-op) and implant survival. Finally, we tested for a-priori defined interactions between BP use and age, sex, joint replaced (hip/knee), and prior fracture on outcome by introducing multiplicative terms in the equation. Results: 80,342/95,392 (84.2%) subjects were eligible. We identified 1,950 (2.4%) BPU, and 1,911 (98.0%) of them were matched to 10,755 BPNU. In total, 226/12,666 (1.78%) of the participants (22/1,911 BPU and 204/10,755 matched BPNU) underwent revision surgery during study follow-up (median 1.11 years, inter-quartile range 0.43-2.29 years). Cox regression models showed reduced revision risk in BP users (propensity-matched HR 0.59; 95% Confidence Interval (CI) [0.37-0.94]) [Figure], which remained significant after multivariable adjustment for unbalanced covariates (adjusted HR 0.59; 95% CI [0.37-0.93]). This protective effect was only seen in BPU who initiated treatment postoperatively (adjusted HR 0.36 ; 95% CI [0.15-0.84]) and not in those starting pre-op (adjusted HR 0.77; 95% CI [0.44-1.35]), and who remained on treatment for at least one year: adjusted HR 0.50; 95% CI [0.27-1.00] for those treated for 1-2 years compared to adjusted HR 1.29; 95% CI (0.80-2.08) in those treated for 6-12 months. Patients with the highest adherence benefited the most (adjusted HR 0.53; 95% CI (0.30-0.95)) in BPU with MPR>0.8). The effect of BPU on implant survival was not modified by age, gender, fracture history or joint replaced (all p for interactions>0.2). Conclusions: BPU are at 40% reduced risk of revision compared to matched BPNU. These results are similar to previous findings using similar retrospective data from the UK [Prieto-Alhambra D et al. BMJ 2011]. Confirmation of these beneficial effects in formal randomized controlled trials is urgently needed.