Mechanisms that drive bone pain across the lifespan.

Disorders of the skeleton are frequently accompanied by bone pain and a decline in the functional status of the patient. Bone pain occurs following a variety of injuries and diseases including; bone fracture, osteoarthritis, low back pain, orthopedic surgery, fibrous dysplasia, rare bone diseases, sickle cell disease, and bone cancer. In the past two decades, significant progress has been made in understanding the unique population of sensory and sympathetic nerves that innervate bone and the mechanisms that drive bone pain. Following physical injury of bone, mechanotranducers expressed by sensory nerve fibers that innervate bone are activated and sensitized so that even normally non-noxious loading or movement of bone is now being perceived as noxious. Injury of the bone also causes release of factors that; directly excite and sensitize sensory nerve fibers, up-regulate pro-algesic neurotransmitters, receptors and ion channels expressed by sensory neurons, induce ectopic sprouting of sensory and sympathetic nerve fibers resulting in a hyper-innervation of bone, and central sensitization in the brain that amplifies pain. Many of these mechanisms appear to be involved in driving both non-malignant and malignant bone pain. Results from human clinical trials suggest that mechanism-based therapies that attenuate one type of bone pain are often effective in attenuating pain in other seemingly unrelated bone diseases. Understanding the specific mechanisms that drive bone pain in different diseases and developing mechanism-based therapies to control this pain has the potential to fundamentally change the quality of life and functional status of patients suffering from bone pain.