Hormonal regulation of bone remodeling

Bone is a metabolically remarkably active tissue that throughout life undergoes constant remodeling by osteoclasts and osteoblasts, as described above. These cellular events are regulated by systemic and local modulators, namely parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, sex and other steroid hormones, calcitonin, prostaglandins, growth factors, and cytokines.

Bone is the most important reservoir for body calcium. Ionized plasma calcium, which represents ~50% of the total plasma calcium pool, is essential for countless metabolic functions and is therefore tightly controlled through three major circulating hormones: PTH, 1,25-dihydroxyvitamin D (calcitriol), and, to a much lesser extent, calcitonin. To keep serum ionized calcium levels stable, these regulators act on three major tissues: (1) bone; (2) the intestine; and (3) the kidney.8

6.21.2.3.1.1 PTH, vitamin D, and calcitonin

The secretion of PTH by parathyroid glands is directly stimulated through a decrease in plasma levels of ionized calcium. Within minutes, PTH increases plasma calcium by activating osteoclasts and thus mobilizing calcium from the mineral store. It also increases renal tubular reabsorption of calcium (and the excretion of phosphate). Through the activation of 1 a-hydroxylase and thereby the generation of 1,25-dihydroxyvitamin D3, PTH also helps to increase intestinal calcium absorption. In both women and men, serum levels of PTH increase with advancing age, possibly due to an age-related decrease in calcium absorption, a decline in renal 1 a-hydroxylase (CYP27B) activity, lower serum calcitriol levels, and age-associated vitamin D deficiency.8

1,25-Dihydroxyvitamin D (calcitriol) (Figure 3) is a potent secosteroid hormone that controls calcium and phosphate homeostasis by stimulating intestinal calcium absorption and bone resorption. In addition, calcitriol has pronounced effects on cell proliferation and differentiation (e.g., bone cells, bone marrow stem cells, skin basal cells, pancreatic islet cells) and on immunoregulatory functions.

The synthesis of calcitriol is usually induced through low serum calcium or inorganic phosphate levels. However, changes in active vitamin D levels occur slower than those in PTH as the 'storage form' of vitamin D, 25-hydroxyvitamin D (calcidiol), needs to be converted into the biologically active form of the hormone, i.e., 1, 25-dihydroxyvitamin D. This conversion/activation is achieved through the hydroxylation of 25-hydroxyvitamin D in its C1 position by CYP27B (a-hydroxylase). The activity of the latter enzyme, which is predominantly found in kidney parenchymal cells, is upregulated by PTH, and downregulated by plasma HPO4 levels. Conversely, calcitriol inhibits the secretion of PTH from the parathyroid glands.9 Measurement of serum 25 and 1,25 vitamin D levels may be useful in patients with osteoporosis, vitamin D deficiency, renal disease, hypercalcemia, and sarcoidosis.

Figure 3 Chemical structure of vitamin D and its metabolites. Cholecalcifol (vitamin D3) and ergocalciferol (vitamin D2) are obtained from sunlight exposure and dietary sources, respectively. These molecules are hydroxylated at carbon 25 and carbon 1 in the liver and kidney, respectively, to produce the active metabolite/hormone as shown for calcidiol (25-hydroxy-vitamin D3) and calcitriol (1,25-dihydroxyvitamin D3).

Calcidiol Calcitriol

Figure 3 Chemical structure of vitamin D and its metabolites. Cholecalcifol (vitamin D3) and ergocalciferol (vitamin D2) are obtained from sunlight exposure and dietary sources, respectively. These molecules are hydroxylated at carbon 25 and carbon 1 in the liver and kidney, respectively, to produce the active metabolite/hormone as shown for calcidiol (25-hydroxy-vitamin D3) and calcitriol (1,25-dihydroxyvitamin D3).

Vitamin D deficiency is common amongst the elderly, mainly due to decreased cutaneous vitamin D production, and an inverse relationship between serum PTH and vitamin D levels has been observed. In addition, secondary hyperparathyroidism may also be induced by renal impairment. Serum PTH levels tend to increase with age and even in people with normal or near normal glomerular filtration rate (GFR). However, the contribution of renal insufficiency to the age-related rise in serum PTH becomes increasingly important as the GFR falls. Interestingly, serum PTH has been shown to be a predictor of falls and mortality in elderly men and women independent of vitamin D status, bone mass, and measures of general health.10

Calcitonin is a product of the thyroidal C cells. Its secretion is stimulated by high serum calcium levels. The peptide has been shown to inhibit osteoclast activity rapidly and thus decreases serum calcium levels. While calcitonin is an important clinical marker of medullary thyroid cancer, its relevance in human calcium homeostasis and bone metabolism has not been well established.11

Glucocorticoids seem to have different effects on bone, depending on the dose and duration of exposure. Excessive glucocorticoid levels result in rapid and profound reductions in bone mineral density (BMD) with greatly increased fracture risk. However, the precise mechanisms of how glucocorticoids affect bone are still obscure. In vivo, markers of bone formation are clearly suppressed during glucocorticoid treatment, reflecting the profound inhibitory effects of glucocorticoids on osteoblast activity, and markers of bone resorption are often increased. Histologically, mean wall thickness is decreased, reflecting the reduced amount of bone replaced in each remodeling unit. Thus, while glucocorticoids appear to exert their effects on the skeleton through a number of pathways (e.g., suppression of sex steroids, muscle wasting, changes in renal/intestinal calcium handling), it appears that the most important catabolic skeletal actions of glucocorticoids directly target the osteoblast.12

In vitro, osteoblasts and their precursors are highly responsive to glucocorticoids. Here, the predominant effect is to promote osteoprogenitor proliferation, lineage commitment, and osteoblast differentiation, resulting in the formation of bone nodules of increased size and number. Glucocorticoids stimulate osteoblast differentiation and osteogenesis in developmental animal models. However, glucocorticoids have also been shown to inhibit type I collagen expression in rat calvarial organ cultures and primary osteoblast cell cultures, and to decrease preosteoblastic replication. Also, glucocorticoids can promote apoptosis of osteoblasts and osteocytes. The inhibitory effects of glucocorticoids on bone formation may be in part due to downregulation of insulin-like growth factor 1 (IGF-1) expression in osteoblasts. Moreover, glucocorticoids modulate factors, including receptor activator of nuclear factor kappa B (NFkB) ligand (RANKL) and osteoprotegerin (OPG), and transcription factors, NFkB and activator protein-1 (AP-1), that mediate signaling in bone, and osteoclast function and lifespan - effects that may explain the action of glucocorticoids on osteoclasts.13

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