Mechanisms that drive bone pain across the lifespan

Abstract

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 2 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 fibres 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 fibres, upregulate proalgesic neurotransmitters, receptors and ion channels expressed by sensory neurons, induce ectopic sprouting of sensory and sympathetic nerve fibres 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 nonmalignant 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.

The Intraosseous Dysfunction in the Osteopathic Perspective: Mechanisms Implicating the Bone Tissue

“…All bone compartments have somatic and sympathetic sensory innervations; however, nerve fiber density is variable -for every 100 fibers in the periosteum, two in the bone marrow, and 0.1 in the mineralized bone [34]. Sensory receptors of bone tissue are able to detect mechanical, inflammatory, and nociceptive stimuli.…”

“…It is well established in the scientific medical world that several conditions can cause bone pain, such as fractures, osteoarthritis, rheumatoid arthritis, low back pain, bone cancer, and also various genetic diseases that affect bones and joints [34]. Bone tissue has thin myelinated (A-delta) and unmyelinated (C) fibers responsive to harmful chemical and mechanical stimuli that participate in inflammatory pain signaling.…”

“…Neurogenesis related to ectopic sprouting of nerve fibers may also be involved in bone nociception. Following bone injury or pathology, several neurotrophic factors are released, inducing sprouting and increased innervation of the bone marrow, mineralized bone, and periosteum [34]. This occurs even in a fracture that is normally healing in the callus region so that it is protected until complete repair occurs.…”

“…When this happens, the callus is reabsorbed and this innervation returns to its natural state. However, in cases of bone disease or injury, in which the repair process does not take place properly, this nerve sprouting may not return to its normal state, keeping the bone hyperinervated in such a way that non-noxious mechanical loads will be perceived as nociceptive events [34].…”

Drugs for the treatment of metabolic bone diseases

“…Another important but nearly universally underserved aspect affecting patients with many different metabolic bone diseases is the potential for bone pain. In this issue, Mantyh delineates the pathophysiology of bone pain and describes recent developments for the treatment of this frequently debilitating complication.…”