Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture

Abstract

Current therapies to treat skeletal fracture pain are extremely limited. Some non-steroidal anti-inflammatory drugs have been shown to inhibit bone healing and opiates induce cognitive dysfunction and respiratory depression which are especially problematic in the elderly suffering from osteoporotic fractures. In the present report, we developed a closed femur fracture pain model in the mouse where skeletal pain behaviors such as flinching and guarding of the fractured limb are reversed by 10mg/kg morphine. Using this model we showed that the administration of a monoclonal antibody against nerve growth factor (anti-NGF) reduced fracture-induced pain-related behaviors by over 50%. Treatment with anti-NGF reduced c-Fos and dynorphin up-regulation in the spinal cord at day 2 post-fracture. However, anti-NGF treatment did not reduce p-ERK and c-Fos expression at 20 and 90 min, respectively, following fracture. This suggests NGF is involved in maintenance but not the acute generation of fracture pain. Anti-NGF therapy did not inhibit bone healing as measured by callus formation, bridging of the fracture site or mechanical strength of the bone. As the anti-NGF antibody does not appreciably cross the blood-brain barrier, the present data suggest that the anti-hyperalgesic action of anti-NGF therapy results from blockade of activation and/or sensitization of the CGRP/trkA positive fibers that normally constitute the majority of sensory fibers that innervate the bone. These results demonstrate that NGF plays a significant role in driving fracture pain and that NGF sequestering therapies may be efficacious in attenuating this pain.

Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

“…has been shown to be efficacious at attenuating fracture pain in mice at a dose of 10 mg/ kg, i.p., when given every 5 days. 37 Therapy was initiated either before orthopedic surgery was performed or 1 day after fracture. Mice were divided into 4 groups: orthopedic surgery + anti-NGF, orthopedic surgery + vehicle, fracture + anti-NGF, and fracture + vehicle.…”

New advances in musculoskeletal pain

“…While we do not yet know the exact mechanisms that drive fracture pain, our working hypothesis, gleaned from clinical and basic science literature, is that there are at least five distinct but overlapping events that drive this pain (Jimenez-Andrade et al, 2007; Koewler et al, 2007; Freeman et al, 2008). First, within seconds of acute fracture, mechanotransducers expressed by nociceptors that innervate the bone are directly activated by mechanical distortion of the periosteum and the underlying mineralized bone.…”

“…Note that the anti-NGF anti-nociceptive effect was comparable to or greater than repeated injections (administered 15 min prior to evaluation at day 2, 8, and 12 post-fracture) of 10 mg/kg morphine sulfate (MS). Jimenez-Andrade et al 2007. Pain.…”

Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats

“…More recently, studies employing chronic anti-NGF monoclonal antibody administration or small molecule pan-tropomyosin receptor kinase (Trk) inhibitors, which block not only the NGF receptor Trk A but also Trks B and C, have shown no detrimental effects on sympathetic innervation of select target organs , Jimenez-Andrade et al, 2007, Ghilardi et al, 2011, Ghilardi et al, 2012. Additionally, in vitro studies demonstrate that, at least as far as survival is concerned, neurons isolated from rat SCG lose their dependence on NGF as they mature and remain independent of NGF in old age (Koike and Tanaka, 1991, Easton et al, 1997, Orike et al, 2001a, Orike et al, 2001b.…”