Bone pain mechanism in osteoporosis

Bone pain mechanism in osteoporosis: a narrative review free full-text PMC5119722 Clin Cases Miner Bone Metab. 2016 May-Aug

Bone pain in elderly people dramatically affects their quality of life, with osteoporosis being the leading cause of skeletal related events.

Peripheral and central mechanisms are involved in the pathogenesis of the nervous system sensitization.

Osteoporosis in the elderly has been associated with increased density of bone sensory nerve fibers and their pathological modifications, together with an over-expression of nociceptors sensitized by the lowering pH due to the osteoclastic activity.  

The activation of N-methyl-D-aspartate (NMDA) receptors and the microglia, as a response to a range of pathological conditions, represent the leading cause of central sensitization.

Unfortunately, osteoporosis is named the “silent thief” because it manifests with painful manifestation only when a fracture occurs.

In the management of patients suffering from bone pain, both the nociceptive and the neuropathic component of chronic pain should be considered in the selection of the analgesic treatment.


Managing bone pain is a frequent challenge for clinicians, mainly observed in elderly patients. Bone pain can dramatically worsen functional capacity and quality of life of affected people.

Osteoarthritis (OA) is the main cause of chronic bone pain (1), however most of these patients are affected by metabolic disorders, such as osteoporosis (OP) (1).

Osteoporotic fractures, particularly in the hip, result in disability with reduction of performance, as measured by the activities of daily living (ADL), and are associated with increased nursing home and rehabilitation hospital admissions (23).

Severe bone pain caused by osteoporosis, when untreated or undertreated, can quickly lead to central sensitization (4); thus it can contribute to clinical manifestation of osteoporotic pain and to its chronicization (56).

The aim of this review is to investigate the mechanisms of osteoporotic pain, focusing on peripheral and central mechanisms of sensitization.

Peripheral mechanisms of bone pain

Bone is not more considered an inanimate tissue, but is a widely innervated one; moreover bone innervation has a fundamental role in the regulation of physiological phenomena as the local blood flow and bone remodelling (7, 8).

The adult skeleton is innervated largely by thinly myelinated, Tropomyosin Receptor Kinase A (TrkA)+ sensory nerve fibers (A-delta) and the peptide-rich Calcitonine-Gene Related Peptide (CGRP), and receives little if any innervation by the larger more rapidly conducting A-beta fibers or the TrkA-, unmyelinated peptide-poor C-fibers (9, 10).

It is important to underline that, whereas bone mass and strength decline with age, density of sensory nerve fibers in the tissue does not decline in older age, therefore the bone innervation “density” increases with age (10).

Previous studies have shown that sympathetic nerve fibers in bone can regulate bone destruction, bone formation, vasodilation, vasoconstriction, macrophage infiltration and bone progenitor cell function.

Thus, those nerve fibers have a central role in a great number of diseases progression in both cartilage (i.e. rheumatoid arthritis) and bone (i.e. osteoporosis – OP); for this reasons it is demonstrated that they play a significant role in the physiopathology of bone pain (1114).

The article (link) then goes into lengthy detail describing these pain processes.


Several important peripheral mechanisms are involved in this pathological process, such as:

  • sensory nerve fibers expressing TRPV1 and ASIC-3 are sensitized by lowering of pH during osteoclastic activity;
  • bone sensory nerve fibers undergo pathological modifications, such the expression of Trk A receptors;
  • a number of neuropeptides, such as SP, CGRP, VIP and NPY, synthesized in sympathetic nerve fibers and released from their peripheral terminals, are found in the bone and periosteum tissue during osteoporosis;
  • the increasing density of bone sensory nerve fibers in the elderly associated with a decreased bone mass density amplifies these mechanisms.

These new findings should be considered when a therapeutic program is established to treat OP pain, in order to avoid pain under-treatment and central sensitization.


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