In addition to the primary endocrine regulators of calcium balance discussed earlier, it is apparent that many other endocrine and paracrine factors influence calcium balance. Bone growth and remodeling involve a still incompletely understood interplay of local and circulating cytokines, growth factors and hormones including insulin-like growth factor-1, growth hormone (see Chapter 44), the cytokines interleukin 1 (see Chapter 40), interleukin 6, interleukin 11, TNFa, TGF^, and doubtless many others. The prostaglandins (see Chapter 40) also have calcium mobilizing activity and stimulate bone lysis. Production of prostaglandins and interleukins is increased in a variety of inflammatory conditions and can lead to systemic or localized destruction of bone.
Many of the systemic hormones directly or indirectly have an impact on calcium balance. Obviously, special demands are imposed on overall calcium balance during growth, pregnancy, and lactation. All of the hormones that govern growth, namely, growth hormone, the insulin-like growth factors, and thyroidal and gonadal hormones (see Chapter 44), directly or indirectly influence the activity of bone cells and calcium balance. The gonadal hormones, particularly estrogens, play a critical role in maintaining bone mass, which decreases in their absence, leading to osteoporosis. This condition is common in postmenopausal women. Osteoblastic cells express receptors for estrogens, which stimulate proliferation of osteoblast progenitors and inhibit production of cytokines such as interleukin-6 that activate osteo-clasts. Consequently in their absence osteoclastic activity is increased and osteoblastic activity is decreased, and net loss of bone results.
Defects in calcium metabolism are also seen in hyperthyroidism and in conditions of excess or deficiency of adrenal cortical hormones. Excessive thyroid hormone accelerates activity of both the osteoclasts and osteoblasts, which may result in net bone resorption and a decrease in bone mass. This action may produce a mild hypercalcemia and secondarily suppress PTH secretion and hence 1,25(OH)2D3 production. These hormonal changes result in increased urinary loss of calcium and decreased intestinal absorption. Excessive glucocorticoid concentrations also decrease skeletal mass. Although glucocorticoids stimulate the differentiation of osteoclast progenitors, they decrease proliferation of these progenitor cells, which ultimately leads to a decrease in active osteoblasts. Glucocorticoids also antagonize the actions and formation of 1,25(OH)2D3 by some unknown mechanism, and directly inhibit calcium uptake in the intestine. These changes may increase PTH secretion and stimulate osteoclasts. Conversely, adrenal insufficiency may lead to hypercalcemia due largely to decreased renal excretion of calcium.
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