Examination of Risk Factors and Expression Patterns of Atypical Femoral Fractures Using the Japanese Adverse Drug Event Report Database: A Retrospective Pharmacovigilance Study.

Atypical femoral fracture (AFF) is a rare complication related to the use of bisphosphonates (BPs). Herein, we analyzed the risk factors and onset patterns of AFF using the Japanese Adverse Drug Event Report database and reported the findings. First, the independent risk factors for AFF were gender (female), high body mass index, and medical history of osteoporosis, arthritis, and systemic lupus erythematosus (SLE). Drug-related risk factors for AFF included BPs (i.e., alendronic acid, ibandronic acid, etidronic acid, zoledronic acid, minodronic acid, risedronic acid), denosumab, prednisolone, lansoprazole, rabeprazole, exemestane, letrozole, eldecalcitol, and menatetrenone. Therefore, it appears that AFF is influenced by a combination of patient backgrounds and drugs, and that the risk of developing AFF is particularly high in patients with fragile bones (e.g., osteoporosis, arthritis, and SLE). Second, in the analysis of AFF onset patterns, the onset of AFF from BPs and denosumab took a long time (>1 year) to develop. Analysis using a Weibull distribution showed wear-out failure-type AFF onset for BPs and denosumab, and both osteoporosis and cancer patients with long-term administration of these drugs showed a tendency to have an increased risk of onset. AFF developed earlier in osteoporosis patients with long-term administration of BPs and denosumab than in cancer patients.

Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database.

Fractures occur when bones become fragile and are subjected to external forces as occurring during falls. The use of drugs that increase bone fragility or fall risk increases the risk of fracture. This study investigates drug-induced fractures reported in the Japanese Adverse Drug Event Report (JADER) database in patients using 4892 drugs. Atypical femur fracture was the most frequently reported fracture, and 58 other fractures were also reported. Using Volcano plots and multiple logistic regression analysis, we identified the risk factors for drug-induced fractures as being female, of older age, higher body mass index, and using one of 90 drugs. The drug groups significantly associated with drug-induced fractures included bone resorption inhibitors, antiviral drugs, dopaminergic drugs, corticosteroids, and sleep sedatives. Principal component analysis was used to examine the relationship between the use of specific drugs and the site of drug-induced fracture. Bone resorption inhibitors and corticosteroids were associated with atypical femur fractures, jaw fractures, and ulna fractures through an osteoclast-mediated process. Other drugs were found to increase fracture risk via non-osteoclast-mediated mechanisms. These findings suggest that many drugs can result in drug-induced fractures through a variety of mechanisms.

Comprehensive Study of the Risk Factors for Medication-Related Osteonecrosis of the Jaw Based on the Japanese Adverse Drug Event Report Database.

Medication-related osteonecrosis of the jaw (MRONJ) is associated with many drugs, including bisphosphonates (BPs). BPs are associated with atypical femoral fractures and osteonecrosis of the external auditory canal. Thus, many drugs are reported to cause adverse effects on bone. This study aimed to investigate the effects of drugs and patient backgrounds regarding osteonecrosis-related side effects, including MRONJ. This study used a large voluntary reporting database, namely, the Japanese Adverse Drug Event Report database. First, we searched for risk factors related to MRONJ using volcano plots and logistic regression analysis. Next, we searched for bone-necrosis-related side effects using principal component and cluster analysis. Factors that were significantly associated with MRONJ included eight types of BPs and denosumab, prednisolone, sunitinib, eldecalcitol, raloxifene, letrozole, doxifluridine, exemestane, radium chloride, medroxyprogesterone, female, elderly, and short stature. Furthermore, antiresorptive agents (i.e., BPs and denosumab) tended to induce MRONJ and atypical femoral fractures by affecting osteoclasts. We believe these findings will help medical personnel manage the side effects of many medications.