Pathophysiology and medical treatment of pain in fibrous dysplasia of bone

Abstract

One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The mechanism of bone pain in FD remains uncertain, but by analogy with bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of pain is highly variable and adults reports more pain than children. Bisphosphonates have been shown to reduce bone pain in uncontrolled studies. Their influence on bone strength remains unknown. In a randomized trial testing alendronate, bone pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA.

Figure 1

Most sensory nerve fibers that innervate the bone express TrkA whereas fewer than 30% of the nerve fibers that innervate the skin express TrkA. The skin is innervated by thickly myelinated A-beta fibers (TrkA^-), thinly myelinated A delta fibers (both TkA^- and TrkA⁺), unmyelinated peptide-rich C fibers (TrkA⁺) and unmyelinated peptide-poor C-fibers (TrkA^-). In contrast, the bone appears to be predominantly innervated by thinly myelinated A-delta fibers (TrkA^- but mostly TrkA⁺) and peptide-rich C-fibers (mostly TrkA⁺ and a small proportion TrkA^-). As greater than 80% of all sensory nerve fibers that innervate the bone are TrkA⁺ whereas only 30% of the sensory nerve fibers that innervate skin are TrkA⁺, these data might help explain why blocking NGF or its cognate receptor TrkA appears to be more efficacious in attenuating skeletal vs. skin pain.

Figure 2

Sprouting and formation of neuroma-like structures in chronic bone pain. Sarcoma tumor cells expressing green fluorescent protein (green) induce a marked sprouting and neuroma formation of CGRP⁺ sensory nerve fibers (red) that innervate the bone (white). These nerve fibers detect and transmit painful stimuli from periphery to the central nervous system. A) In sham bones, CGRP⁺ nerve fibers that are present in the bone appear as single nerve fibers with a liner and homogenous morphology. B) As cancer cells proliferate and grow in bone, these induce significant bone remodeling (pitted appearance) as well as a highly pathological sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers which in other conditions drives chronic pain. Confocal images from periosteal whole preparations were acquired and overlapped on a three dimensional image of the mouse femur obtained by microcomputed tomography. Images were rendered courtesy of Marvin Landis (University Information Technology Services, University of Arizona).

Figure 3

Prostate cancer cells induce sprouting of sensory nerve fibers in the bone marrow of tumor bearing femurs. High power µCT slices of bone (100 µm-thick) overlaid with confocal images (20 µm-thick) obtained from a sham femur (A) and tumor-bearing femur from mice sacrificed at early (B) and more advanced stages of the disease (C). In these images the DAPI stained nucleus of cells appear blue, the green fluorescent protein expressing (GFP) prostate cancer cells appear green, and the calcitonin gene related peptide (CGRP) sensory nerve fibers appear yellow/red. Note that in the sham mice, CGRP⁺ nerve fibers that are present in the marrow space of normal mice appear as single, nerve fibers with a highly linear morphology. As GFP⁺ prostate tumor cells proliferate and form tumor colonies (B,C), the CGRP⁺ sensory nerve fibers undergo marked sprouting which produces highly branched, disorganized and dense meshwork of sensory nerve fibers (B,C) that is never observed in the normal marrow (A).

Figure 4

Prevalence of pain at skeletal sites involved with fibrous dysplasia in adults and children. Sites at which patients reported pain was recorded. 99Tc-MDP bone scans were reviewed to confirm the presence of FD at the reported site of pain. Only those sites at which there was a concordance of pain and FD involvement were recorded. Adults had significantly more pain than children in general (p<0.05), and at both the lower extremity and the spine (p<0.05 for both).