Weight-Based Bisphosphonate Administration for Multiple Myeloma Patients and the Risks of Skeletal Complications

Abstract

High-dose bisphosphonate for multiple myeloma patients might elevate risks of skeletal complications earlier than general expectations. This study aims to find incidences of atypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ), elucidate their risk factors, and suggest cut-off values for the safer dosing of high-dose bisphosphonate treatment. By using the clinical data warehouse of a single institute, retrospective cohort data of multiple myeloma-diagnosed patients with high-dose bisphosphonate (pamidronate or zoledronate) treatment from 2009 to 2019 was extracted. Among 644 patients, the incidence of prominent AFF requiring surgery was 0.93% (6/644) and MRONJ was diagnosed in 11.8% (76/644) of the study population. For both AFF and MRONJ, the total potency-weighted sum of total dose per body weight (OR = 1.010, p = 0.005) were significant on logistic regression. Cutoffs of the potency-weighted total dose (mg) per body weight (kg) for AFF and MRONJ were 77.00 and 57.70 mg/kg, respectively. After roughly one year of treatment with high-dose zoledronate (about four years for pamidronate), an earlier thorough re-evaluation of skeletal complications should be taken. Body weight adjustments for accumulative dose calculation in terms of permissible dosing should be taken into consideration.

Utilização de medicamentos que induzem osteoporose ou fratura em idosos com mieloma múltiplo: estudo transversal

“…The association between atypical fractures and BPhs was evidenced in a disproportionality analysis study conducted using the Japanese pharmacovigilance system database, where eight BPhs were associated with drug-induced atypical femur fractures 14 . Atypical BPh-induced fractures were also reported in studies with patients with MM 15,22,23,24,25 .…”

“…Therapeutic schemes with nitrogen BPhs are prescribed for long periods 2,5,22 . Impairment of bone remodeling by long-term cumulative effects of treatment with mild bisphosphonates is a hypothesis for atypical fractures 15,25 . According to studies in animal models, nitrogen BPs, used in long-term therapies, prevent bone remodeling and inhibit osteoclasts, resulting in failure to repair micro-cracks in the cortical bone, accumulation of damage and reduced cortical bone tenacity, which may result in atypical fractures 15 .…”

“…A cohort study of Korean patients with MM identified an association between high BPh doses and occurrence of atypical fractures 25 . However, despite the in vivo and in vitro studies, the induction mechanism for BPh-induced atypical fractures is not yet elucidated 15,25 .…”