Sensory Innervation of Human Bone: An Immunohistochemical Study to Further Understand Bone Pain

Abstract

Skeletal diseases and their surgical treatment induce severe pain. The innervation density of bone potentially explains the severe pain reported. Animal studies concluded that sensory myelinated A@-fibers and unmyelinated C-fibers are mainly responsible for conducting bone pain, and that the innervation density of these nerve fibers was highest in periosteum. However, literature regarding sensory innervation of human bone is scarce. This observational study aimed to quantify sensory nerve fiber density in periosteum, cortical bone, and bone marrow of axial and appendicular human bones using immunohistochemistry and confocal microscopy. Multivariate Poisson regression analysis demonstrated that the total number of sensory and sympathetic nerve fibers was highest in periosteum, followed by bone marrow, and cortical bone for all bones studied. Bone from thoracic vertebral bodies contained most sensory nerve fibers, followed by the upper extremity, lower extremity, and parietal neurocranium. The number of nerve fibers declined with age and did not differ between male and female specimens. Sensory nerve fibers were organized as a branched network throughout the periosteum. The current results provide an explanation for the severe pain accompanying skeletal disease, fracture, or surgery. Further, the results could provide more insight into mechanisms that generate and maintain skeletal pain and might aid in developing new treatment strategies.Perspective: This article presents the innervation of human bone and assesses the effect of age, gender, bone compartment and type of bone on innervation density. The presented data provide an explanation for the severity of bone pain arising from skeletal diseases and their surgical treatment.

Neuronal Sprouting and Reorganization in Bone Tissue Infiltrated by Human Breast Cancer Cells

“…A recent study, investigating innervation in axial and appendicular human cadaveric bone, demonstrated that the numbers of nerve fibers significantly declined per year of age in elderly individuals (age range 66–99). Extrapolating this finding to younger individuals, it is possible that the increase in nerve profile density in MBD is even higher in magnitude due to the lower median age of the healthy controls ( 16 ). The subgroup analysis revealed a significant increase in the nerve profile density in both groups of archived cancer-infiltrated bone marrow.…”

“…Myelinated and unmyelinated fibers have been demonstrated to be mostly associated with vascular structures in human bones ( 15 , 16 , 21 ). In a recent study, examining the association of nerve profiles to vasculature in the bone marrow of iliac crest biopsies isolated from patients with primary hyperparathyroidism, we found that more than 90% of the nerve profiles were associated with vasculature ( 15 ).…”

Hallmarks of peripheral nerve function in bone regeneration

“… 76 , 77 , 92 Although there is a possibility that rodents and humans share a similar innervation pattern, 95 , 96 consistent innervation density of the bone in humans has not been shown until recently. 97 The significant predominance of CGRP + nerves relative to TH + nerves in the periosteum is reversed in bone marrow, 76 indicating the different roles/mechanisms of sensory nerves and the SNS in regulating bone hemostasis and regeneration. When running parallel with the vasculature, the sensory nerves and SNS tend to run linearly or spirally around vessels, respectively.…”

Mini review: The role of sensory innervation to subchondral bone in osteoarthritis pain

“…There is a long history of work documenting the innervation of the bone ( 9 , 54 – 61 ). Nerves can be found entering the bone through the nutrient foramina, Haversian canals, the osteochondral (OC) junction, and at the attachments of the synovial membrane ( 23 , 62 – 65 ). They branch extensively in the periosteum, bone marrow, and subchondral bone associated with synovial joints, where they end as unencapsulated, free fiber nerve endings ( 23 , 60 , 66 ).…”

“…They branch extensively in the periosteum, bone marrow, and subchondral bone associated with synovial joints, where they end as unencapsulated, free fiber nerve endings ( 23 , 60 , 66 ). The bone is a highly vascularized structure, and most nerves found within the bone run with the vasculature ( 63 , 65 , 67 ), so many authors suggested they had a vasculature function but did not comment further. The advent of retrograde tracing in combination with immunohistochemistry has provided clear evidence that nerves within the bone are of both sensory and autonomic origin, and those that are sensory predominantly function as nociceptors ( 68 , 69 ).…”