(001) Evaluation Of The Potential Rebound Effect Of Denosumab Discontinuation: A Comparative Study Of Five Different Types Of Antiosteoporotic Medications

Publication Number: 997

Background: Discontinuation of antiosteoporotic medications (AOM), except for bisphosphonates (BPs), with a residual anti-fracture effect, is not favorable for the bone, being especially negative for Prolia® (denosumab- DMAb). DMAb discontinuation has been linked to a rebound in bone turnover markers and rapid bone loss that may lead to the occurrence of Multiple Vertebral Fractures (MVF).

Objectives: To assess the risk of MVF (≥2 VFs) after discontinuation of AOM.

Methods: A case-control analysis nested in a cohort of naïve users of DMAb, BPs, Teriparatide (TPTD), Strontium Ranelate (SrRan) or SERMs, aged ≥18 years, from 2011-2018, was performed using the Spanish Pharmacoepidemiological Research Database for Public Health Systems (BIFAP). Cases were first MVFs (index date) recorded after AOM initiation. Up to 4 controls per case, matched on age, sex, calendar time, and location, were randomly selected among non-cases from the study cohort. The association (OR; 95% CI) between discontinuation (supply of the last prescription ended >90 days before the index date) of a given AOM and occurrence of MVF was assessed by conditional logistic regression adjusting for the use of the rest of AOM and other selected confounders [e.g. previous fractures (any site) or indication of treatment]. We compared the discontinuation of each AOM with their current use (most recent prescription lasted until the index date or ended within the previous 90 days) and with BPs discontinuation, only among individuals who did not switch therapy in the study.

Results: A total of 532 incident cases of MVF were identified and matched to 2,121 controls. Most individuals (87%) were women and the median age was 75 years. The risk of MVF after DMAb discontinuation was 2.83 (1.74-4.61) compared with DMAb current use, but no increased risk was seen for the other AOM. The risk was highest for DMAb users who had discontinued 3-9 months before the index date (8.43; 3.92-18.12) and those with the longest treatments (2-5 years: 11.07; 3.39-36.20). Compared with BPs discontinuers, discontinuation of DMAb (2.84; 1.72-4.68), TPTD (2.09; 1.11-3.95) and SrRan (1.93; 1.22-3.05) showed an increased risk of MVF; current use of BP, SERMs or TPTD showed a trend to a protective effect, while DMAb did not (1.47; 0.97-2.22).

Conclusions: Discontinuation of DMAb was associated with an immediate increased risk of MVF, especially after longer treatments. Although elevated risks were also observed for other AOM discontinuers with different mechanisms of action compared with first-line AOM (BPs), these were not found when the reference was their current users. Confounding by disease (indication) prognosis across AOM users cannot be discarded nor other non-measured confounding. Lack of precision in some estimates due to low numbers was present.