Belt electrode-skeletal muscle electrical stimulation-induced attenuation of aromatase inhibitor-induced bone loss in ovariectomized rats.

Abstract

Cancer treatment-induced bone loss (CTIBL) is a clinically significant adverse effect of endocrine therapy in hormone-related cancers, including breast cancer. Pharmacological interventions, including antiresorptive agents, are widely used; however, few nonpharmacological interventions ensure preservation of bone health without imposing excessive physical burden. We investigated the preventive effects of belt electrode-skeletal muscle electrical stimulation (B-SES) on aromatase inhibitor (AI)-induced bone loss in a letrozole-administered ovariectomized rat model. Twenty-two 12-week-old female Sprague-Dawley rats were ovariectomized and allocated to a control group (n = 8) or a letrozole-administered group (n = 14); treatment administration was initiated 4 weeks post-ovariectomy, and 6-week B-SES was initiated 6 weeks post-ovariectomy in the right hindlimb of letrozole-administered rats. Tibial bone microarchitecture was evaluated using micro-computed tomography, biomechanical properties were assessed using a three-point bending test, and gene expression in tibial bone marrow fluid and gastrocnemius muscle was analyzed using real-time RT-PCR. Letrozole administration worsened trabecular bone microarchitecture and reduced biomechanical strength, consistent with skeletal deterioration associated with aromatase inhibitor administration under estrogen-deficient conditions. Prophylactic B-SES significantly improved trabecular bone volume fraction, trabecular thickness, and yield stress compared with those in the non-stimulated limbs (all p < 0.05), whereas cortical bone parameters were only modestly improved. At the molecular level, B-SES suppressed skeletal muscle myostatin expression and reduced receptor activator of nuclear factor kappa-B ligand expression in tibial bone marrow fluid. Thus, B-SES mitigated aromatase inhibitor-induced skeletal fragility predominantly through favorable effects on trabecular bone, potentially through mechanically mediated loading and muscle-bone crosstalk. B-SES may represent a feasible nonpharmacological adjunct for preserving bone health under endocrine therapy-associated skeletal conditions.