The skeletal structure of 206 bones maintains mobility, protects internal organs, facilitates mineral homeostasis (acting as a depository for 90% of calcium and 80% of phosphorus at any given time) and houses the hematopoietic tissues in the marrow cavity of the bones.

Skeletal bone is of two types: cortical bone and trabecular bone.

Cortical bone is the outermost mineralized cortex. It is compact, strong, and densely packed as an intricate calcium matrix. Cortical bone comprises 85% of the skeleton, specifically 75% in the femoral neck, 75% in the distal radius, and 95% in the midradius. Cortical bone has no contact with marrow.

Trabecular bone is the inner spongy structure composed of the sturdy collagen matrix. It comprises 15% of the skeletal mass and has structural rigidity and elasticity to withstand mechanical stress. Trabecular bone contains hematopoietic tissue in its central cavity.

Healthy bone is maintained by a homeostatic mechanism in which bone formation is equal to bone resorption. Calcium absorption from the gut is equal to that excreted in urine.

Calcium is regulated by a negative-feedback loop in which 0.5% exists as free calcium ions and 0.5%, as protein-bound calcium; 99% is in bone stores.

Other factors help regulate bone homeostasis. Parathyroid hormone acts directly on bone/kidney and indirectly on gut, as does vitamin D, which enhances calcium absorption from the gut. Calcitonin inhibits bone resorption in response to increased serum calcium.

Impaired calcium balance results in hypercalcemia, or excess calcium, which is usually the result of malignancy. This buildup suppresses other functions. Hypocalcemia, or too little calcium, can result in tetany and hypertonia.

Bone remodeling occurs continuously throughout the lifetime, although the process slows with age. The balance of osteoclastic and osteoblastic activity results in breakdown and reconstruction, which ensures skeletal integrity and maintains mineral homeostasis. Osteoclasts and osteoblasts are interconnected and influence the activity of each other.

Osteoclasts are large multinuclear cells that develop from monocyte-macrophage precursors. They are imbedded in the bone matrix at or near the site of bone resorption and dissolve first the calcium and then the organic matrix of the bone. Osteoclasts are affected by the growth factors interleukin-1, colony-stimulating factor, tumor necrosis factor, and transforming growth factor.

Osteoblasts arise from mesenchymal cells and are found layered over the bone. They deposit calcium into the matrix that is building up cortical bone and produce collagen and other proteins to synthesize the bone matrix. Osteoclasts that are in close proximity can increase sensitivity of osteoblasts to growth factors.

Systemic hormones have a complex relation to bones in the maintenance of bone health and homeostasis. The balanced interplay of osteoclastic and osteoblastic activity depends on these hormones being delivered at the right time in the right amount. These include:

• Parathyroid hormone and parathyroid hormone-related peptide
• 1,25-(OH)2 vitamin D3
• Calcitonin
• Gonadal steroids (estrogen, androgen)
• Growth hormone
• Insulinlike growth factor

The gonadal hormones are of special interest in maintaining the integrity of the skeletal system. Premature disruption of gonadal hormones as well as the normal waning with age can have a profound and negative impact on bone health. As a woman's estrogen decreases, osteoclastic activity increases. Without the balance of osteoblastic activity, the bones begin to rapidly lose calcium and thus lose strength. Natural hormonal waning with age decreases bone strength. The loss of gonadal hormones increases bone resorption. Osteoblastic cell activity and lifespan are decreased, resulting in less new bone. Osteoclastic activity is less suppressed, increasing the rate of resorption, and osteoporosis/osteopenia becomes common.

The processes of bone resorption and bone formation are shown in the following figures.

Both systemic factors and locally acting factors induce the formation and activity of osteoclasts. Systemic hormones such as parathyroid hormone, 1.25-dihydroxyvitamin D₃ and thyroxine (T₄ ) stimulate the formation of osteoclasts by inducing the expression of receptor activator of nuclear factor-κB ligand (RANKL) on marrow stromal cells and osteoblasts. In addition, osteoblasts produce interleukin-6, interleukin-1, prostaglandins, and colony-stimulating factors (CSFs), which induce the formation of osteoclasts. Accessory cells such as T cells can produce cytokines that can inhibit the formation of osteoclasts, such as interleukin-4, interleukin-18, and interferon-y.

TGF-β denotes transforming growth factor. Plus signs indicate stimulation, and minus signs inhibition.

Figure 1. Regulation of bone resorption.
Reproduced with permission from Roodman GD. NEJM. 2004;350:1655-1664.
Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Both systemic factors and locally acting factors can enhance the proliferation and differentiation of osteoblasts. These include parathyroid hormone, prostaglandins, and cytokines as well as growth factors such as platelet-derived growth factor (PDGF) produced by lymphocytes. In addition, bone matrix is a major source of growth factors, which can enhance the proliferation and differentiation of osteoblasts. These include the bone morphogenetic proteins (BMPs), TGF-β, insulin-like growth factors (IGFs), and fibroblast growth factors (FGFs). Corticosteroids can induce a poptosis of osteoblasts and block bone formation.

Figure 2. Regulation of bone formation.
Reproduced with permission from Roodman GD. NEJM. 2004;350:1655-1664.
Copyright © 2004 Massachusetts Medical Society. All rights reserved.

1.	Roodman GD. Mechanisms of bone metastasis. NEJM. 2004;350:1655-1664.