Long-term Consequences of Traumatic Brain Injury in Bone Metabolism

Abstract

Traumatic brain injury (TBI) leads to long-term cognitive, behavioral, affective deficits, and increase neurodegenerative diseases. It is only in recent years that there is growing awareness that TBI even in its milder form poses long-term health consequences to not only the brain but to other organ systems. Also, the concept that hormonal signals and neural circuits that originate in the hypothalamus play key roles in regulating skeletal system is gaining recognition based on recent mouse genetic studies. Accordingly, many TBI patients have also presented with hormonal dysfunction, increased skeletal fragility, and increased risk of skeletal diseases. Research from animal models suggests that TBI may exacerbate the activation and inactivation of molecular pathways leading to changes in both osteogenesis and bone destruction. TBI has also been found to induce the formation of heterotopic ossification and increased callus formation at sites of muscle or fracture injury through increased vascularization and activation of systemic factors. Recent studies also suggest that the disruption of endocrine factors and neuropeptides caused by TBI may induce adverse skeletal effects. This review will discuss the long-term consequences of TBI on the skeletal system and TBI-induced signaling pathways that contribute to the formation of ectopic bone, altered fracture healing, and reduced bone mass.

Keywords: bone formation; bone resorption; fracture repair; growth hormone; heterotopic ossification; neuropeptides; osteoporosis.

Figure 1

The interaction between traumatic brain injury (TBI) and hypoxic conditions that lead to the development of heterotopic ossification (HO). TBI induces a hypoxic environment in tissue that reduces PHD2 activity, which in turn, prevents the cleavage of hypoxia-inducible factor (HIF)1α and increases angiogenesis. This pathway increases osteogenic precursor cell activity, thereby promoting chondrocyte differentiation and hypertrophy in soft tissues and leading to bone formation in HO. TBI may also directly affect pro-osteoinductive molecules that promote increased osteogenic precursor cell activity.

Figure 2

The relationship between trauma, neuropeptides, and decreased bone formation. Traumatic brain injury (TBI) induces central nervous system disruption and inflammation and causes an upregulation in leptin levels due to the compromised blood–brain barrier. TBI also causes hypothalamus–pituitary–adrenal axis (HPA) dysfunction that increases leptin and causes the release of neuropeptides such as substance P (SP), neurokinin A (NKA), neuropeptide Y (NPY), neurokinin B (NKB), and calcitonin gene-related peptide (CGRP). These neuropeptides propagate further inflammation that further increase systemic circulation of NPY and other neuropeptides that reduce bone formation via the leptin pathway.

Figure 3

Trauma-induced hypothalamus–pituitary–adrenal axis (HPA) dysfunction lead to reduced bone formation. Traumatic brain injury causes significant HPA dysfunction that leads to increased levels of adrenocorticotropin (ACTH), prolactin (PRL), and growth hormone (GH), but decreased or unchanged levels in luteinizing hormone (LH), follicle-stimulating hormone (FSH), PRL, melanocyte-stimulating hormone (MSH), and thyrotropin (TSH) levels. The altered secretion of hormones impact osteoblast function and impair bone formation.