Calcitonin and Calcium Homeostasis

Calcitonin and Calcium Homeostasis

The effect of calcitonin on calcium homeostasis has not been well studied and the role of calcitonin in adult mineral and bone homeostasis is not well understood. Nonetheless, calcitonin is a bone active, US Food and Drug Administration-approved, antiresorptive agent to treat but not prevent osteoporosis.  One report indicated that calcitonin therapy regulated circulating magnesium, copper, and zinc and these minerals were more useful for evaluating response to treatment in women with postmenopausal osteoporosis. Thus, calcitonin may be involved with minerals other than calcium in decreasing bone resorption. A single dose of nasal calcitonin has been shown to decrease bone resorption by 15% as evidenced by biochemical markers of bone turnover, whereas the anabolic action of calcitonin has not been clearly demonstrated. Calcitonin reduces the risk of vertebral fractures up to 40%, but does not affect nonvertebral (i.e., hip) BMD or fractures. Long-term efficacy appears to be reduced with calcitonin and thus its use is limited. However, advantages of calcitonin are that it is bone-specific, may be used as an alternative to estrogen, and may be used in men. Calcitonin is typically administered intranasally, obviating the problems of parenteral administration, and has analgesic benefits. Interestingly, calcitonin therapy for 6 months decreased serum interleukin (IL)-10 and IL-6r, but increased serum IL-2, IL-8, and tumor necrosis factor (TNF)-􀁆, illustrating that calcitonin may influence bone through the action of cytokines and that cytokines may be affected in different directions.



Potential Mechanisms for Bone Resorption and Perturbation of Calcium Homeostasis With Menopause and Hormone Therapy

Estrogen deficiency is associated with increased cytokine production. For this reason, there are numerous studies of the relative contribution of cytokines to bone loss, the potential cell sources of cytokines in the bone microenvironment, and the mechanism of action of various cytokines. The inflammatory cytokines (IL-6, IL-1, and TNF-􀁆 in particular) are thought to be involved in stimulating bone resorption. IL-1 was one of the first to be identified and most potent bone-resorbing cytokines, causing osteoclast formation, differentiation, and activation.  The effects of IL-1 are enhanced by two orders of magnitude when IL-6 is present in the medium.  Under estradioldeficient conditions (i.e., menopause), IL-6 plays a role as a local regulator of bone turnover. TNF is necessary for stimulating osteoclastogenesis and also stimulates osteoblasts such that their bone-formative action is hindered. TNF suppresses recruitment of osteoblasts from progenitor cells, inhibits the expression of matrix protein genes, and stimulates expression of genes that amplify osteoclastogenesis. Thus, TNF assails bone at many levels.  As indicated previously, many postmenopausal women experience hypercalciuria and it may very well be that cytokines play a role in this process.  The action of HT to reduce bone resorption may be mediated by inhibiting cytokines.  Further research is needed to understand the connections between HT, cytokines, and calcium homeostasis in postmenopausal women. Another area that should be investigated is that of perturbations in acid–base balance with menopause because one metabolic consequence is a rise in the venous bicarbonate concentration, which is reversed by HT.  Orr-Walker and colleagues examined the changes in acid–base metabolism in normal postmenopausal women starting on HT regimens+. Groups receiving either medroxyprogesterone acetate alone or combined with estrogen exhibited a decrease in arterialized venous blood bicarbonate and PCO2, whereas those receiving estrogen only or placebo did not change. Accompanying changes in blood pH were noted only in those who received combined therapy. With respect to calcium metabolism, only the combined therapy group showed consistent changes, with reductions in urinary calcium excretion and serum phosphate. Bone turn over indexes (i.e., bone-specific alkaline phosphatase, hydroxyproline, osteocalcin, deoxypyridinoline) decreased in both the estrogen only and combined groups, with more consistent and larger changes in the combined therapy group. Thus, the changes in acid– base balance correlated with the suppression of bone resorption, suggesting that acid– base balance may contribute to the effect of HT on bone and calcium balance.

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