Reacciones adversas musculoesqueléticas a bifosfonatos

Abstract

Prior grounds: Through Spontaneous Reporting Programmes in several countries, adverse musculoskeletal reactions have been identified, related to the use of bisphosphonates. Although most reactions are already known, their frequency, severity, and risk factors are yet unknown, as specific factors -linked with higher severity of reactions- also are. Focus: Getting to know the plausible causal relationship between bisphosphonates exposure and adverse musculoskeletal reactions emersion. Identifying the diverse musculoskeletal reactions associated with bisphosphonates, their ratios, risk issues, severity and determining factors of such severity. Knowing the reported risks of the concerned adverse reactions. Drawing up a hypothesis of the etiopathogenesis to these reactions. Evaluating official datum on musculoskeletal reactions involving bisphosphonates, as well as the risk-benefit liaison of these drugs, considering derived consequences. Approach To determine likely causal associations between bisphosphonates exposure and adverse musculoskeletal reactions appearance, the Spanish Pharmacovigilance System (FEDRA) databases have been used, in addition to the ones from the WHO-Uppsala Monitoring Centre (VigiBase). Both descriptive ("case series") and also analytical ("case-by-case study") retrospective observational studies have been carried out. A logistic regression analysis has been performed to determine those factors, collateral with the severity of the cases. Results: Over querying the FEDRA database, (descriptive observational study), 18.273 notifications (registrations) of musculoskeletal and connective-tissue disorders where identified; the total amount of notifications contained in the database at that time was 237.077 (10 April 2017). Notifications of these musculoskeletal disorders represented 7,71% of the total. Out of a sum of 2.959 reports of identified adverse reactions to bisphosphonates in FEDRA, 992 reports were for musculoskeletal reactions; these reactions accounted for 33,52% of the total for this group of drugs. The case series of the reactions of interest are presented, analysing age, latency, severity, outcome, other medication or diseases, for each of the selected reactions; the possible discrepancies between the different bisphosphonates are also reviewed. In the disproportionality analysis, ROR (Reporting Odds Ratio) values above 1 are obtained for all the adverse reactions analyzed except for paresthesia; for muscle spasms the value of the estimator was not statistically relevant. The close look of the survival curves shows that reactions considered as severe occur with longer exposure periods than non-severe ones. Logistic regression analysis shows that only the exposure period above 30 days is significantly associated with severity. Concerning the VigiBase search carried out, cases of carpal tunnel syndrome where specifically investigated. A total of 6.006 cases were identified until October 2.017; on the same date, the total number of notifications registered in the database was 15.521.955. Among the 121.264 reported cases related to bisphosphonates, 457 were cases of carpal tunnel syndrome (377 per 100.000); 226 cases of synovitis (186 per 100.000) were also identified, mainly referred to the elderly and women. Most of the reported cases where about alendronic acid; it was appraised a statistically significant association between different bisphosphonates exposure and the development of carpal tunnel syndrome. Conclusions: Adverse musculoskeletal reactions -not forewarned in the information on bisphosphonate products- have been detected; this would be the case with carpal tunnel syndrome. Other reactions such as muscular rigidity, or also -so appointed- arthritis, do not feature in the official information. The severity involved by these reactions has also been assessed and some of the risk factors such as time of exposure have been identified. The information on the safety of bisphosphonates provided by this work, together with that provided by publications in the literature, would require a reassessment and updating of the risk-benefit balance of these substances. The results endorse the inclusion of new data in the information of these products and the generation of a signal, and its verification, on carpal tunnel syndrome.