Alendronate inhibits hyperalgesia and suppresses neuropeptide markers of pain in a mouse model of osteoporosis

Background: Chronic back pain is one of the most important complications of postmenopausal osteoporosis. The aim of this study was to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of bisphosphonates (BPs) on pain in ovariectomized (OVX) mice. The mechanism of osteoporotic pain in OVX mice was evaluated through an examination of pain-related behavior, as well as immunohistochemical findings. In addition, the effects of alendronate (ALN), a potent osteoclast inhibitor, on these parameters were assessed. Methods: 8-week-old female ddY mice were ovariectomized and assigned to 3 groups: SHAM-operated mice treated with vehicle (SHAM; n ¼ 8); OVX mice treated with vehicle (OVX-V; n ¼ 8); and OVX mice treated with ALN (OVX-ALN; n¼8). Starting immediately after surgery, vehicle or 40 mg/kg ALNwas injected subcutaneously twice a week for 4 weeks. The bilateral distal femoral metaphyses and proximal tibial metaphyses were analyzed three-dimensionally by mCT. Mechanical sensitivity was tested using von Frey filaments. Transient receptor potential channel vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) expressions in L3-5 dorsal root ganglion (DRG) neurons were examined immunohistochemically. Results: Ovariectomy induced bone loss and mechanical hyperalgesia in hindlimbs with upregulation of TRPV1 and CGRP expressions in DRG neurons innervating hindlimbs. ALN prevented bone loss and mechanical hyperalgesia in ovariectomized mouse hindlimbs, and it suppressed upregulation of pain markers. Conclusions: ALN prevented ovariectomy-induced bone loss and mechanical hyperalgesia in hindlimbs, and it suppressed TRPV1 and CGRP expressions in DRG neurons. The results suggest that bone resorption with upregulation of TRPV1 and CGRP expressions is one of the causes of postmenopausal osteoporotic pain.本文 / Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Japan7p博士(医学)三重大