Inhibitory effect of bisphosphonate on osteoclast function contributes to improved skeletal pain in ovariectomized mice

Abstract

The aim of this study was to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of bisphosphonate (BP) on pain in an ovariectomized (OVX) mouse model. We evaluated skeletal pain in OVX mice through an examination of pain-like behavior as well as immunohistochemical findings. In addition, we assessed the effects of alendronate (ALN), a potent osteoclast inhibitor, on those parameters. The OVX mice showed a decrease in the pain threshold value, and an increase in the number of c-Fos immunoreactive neurons in laminae I-II of the dorsal horn of the spinal cord. Alendronate caused an increase in the pain threshold value and inhibited c-Fos expression. The serum level of tartrate-resistant acid phosphatase 5b, a marker of osteoclast activity, was significantly negatively correlated with the pain threshold value. Furthermore, we found that an antagonist of the transient receptor potential channel vanilloid subfamily member 1, which is an acid-sensing nociceptor, improved pain-like behavior in OVX mice. These results indicated that the inhibitory effect of BP on osteoclast function might contribute to an improvement in skeletal pain in osteoporosis patients.

Chronic Osteoporotic Pain in Mice: Cutaneous and Deep Musculoskeletal Pain Are Partially Independent of Bone Resorption and Differentially Sensitive to Pharmacological Interventions

“…Chronic bisphosphonate administration also reverses bone loss and reduces cutaneous referred pain in the early stages of the pathology (i.e., 6–8 weeks after ovariectomy) in rodent models of ovariectomy-induced osteoporosis [5]. Therefore, we tested the efficacy of bisphosphonate therapy in mice with chronic, fully established osteoporosis, 6 months after ovariectomy.…”

“…One important observation in this study was that the decreased BMD and significant pain hypersensitivity were maintained for 6 months in OVX mice. Only a few previous studies have followed the long-term course of pain sensitivity in OVX rats [32] or mice [5, 33, 34]. …”

“…In ovariectomy-induced rodent models of osteoporosis, cutaneous pain hypersensitivity develops within 4–10 weeks and is dependent on estrogen depletion; estrogen replacement therapy prevents both bone loss and cutaneous pain in the early stages of the pathology [5–9]. Deep musculoskeletal pain is less commonly investigated, with most studies using referred cutaneous hypersensitivity as an indirect measure of deep skeletal pain.…”

Pathomechanisms and management of osteoporotic pain with no traumatic evidence

“…Osteoporotic osteoclasts degrade bone minerals by secreting protons through the vacuolar H + -ATPase, creating local acidic microenvironments by inflammation 49,50) , which should evoke the stimulation of TRPV1. Furthermore, this acidic microenvironment produced by inflammation stimulates acid-sensing ion channels (ASICs) in acid-sensing nociceptors 51,52) . These stimulations evoked by osteoporotic osteoclasts lead to the chronic increased expression of inflammatory pain-related neuropeptides, calcitonin gene-related peptides (CGRP), and DRG neurons, innervating osteoporotic vertebrae 39) .…”

“…A bisphosphonate has effects on other molecules too. Alendronate improves osteoporotic pain by inhibiting TRPV1 52) . In addition, a randomized, controlled trial showed that alendronate produced a stronger analgesic effect than calcitonin in postmenopausal osteoporotic women 64) .…”