• Jasper G Steverink, Douwe Oostinga, Floris R van Tol, Mattie H P van Rijen, Claire Mackaaij, Suzanne A M W Verlinde-Schellekens, Bas J Oosterman, Albert J M Van Wijck, RoelingTom A PTAPDepartment of Anatomy, University Medical Center Utrecht, The Netherlands., and Jorrit-Jan Verlaan.
• Department of Orthopedic Surgery, University Medical Center Utrecht, The Netherlands; SentryX B.V., Woudenbergseweg 41, Austerlitz, The Netherlands. Electronic address: J.G.Steverink-4@umcutrecht.nl.
• J Pain. 2021 Nov 1; 22 (11): 1385-1395.

AbstractSkeletal 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.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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