CALCIUM METABOLISM MODIFYING AGENTS influence calcium homeostasis in the body in a variety of ways. Calcium has a central role in body function, having intracellular and extracellular roles. Intracellular function is related mainly to its role as the main second-messenger control system of the body, largely through regulation of a wide range of enzymes. Extracellular roles are mainly concerned, along with phosphate, in formation of bone and related structures. Calcium and phosphate homeostasis in the body are intimately interconnected, both being influenced by parathyroid hormone and hormones derived from vitamin D. Topics will relate to pharmacological intervention with calcium metabolism for therapy of disease states.
Parathyroid hormone (parathormone) is a polypeptide secreted by the parathyroid gland, and increases plasma concentration of calcium by mobilizing calcium from bone, by increasing reabsorption in the kidney and by stimulating production of calcitriol. Its net effect is to increase calcium concentration in plasma and to reduce that of phosphate. Secretion of parathyroid hormone from vesicles in the parathyroid gland is controlled by a Ca2+-sensor receptor of seven-transmembrane type whereby low Ca2+-concentrations stimulate secretion of the hormone, and high concentrations inhibit it. In fact parathyroid hormone is not normally used clinically except a:, a diagnostic agent. Teriparatide, a synthetic preparation of the first 34 amino acids in the parathyroid hormone sequence, is under investigation for treatment of osteoporosis. Hypoparathyroidism is most easily treated with vitamin D; or in emergencies by means of Ca2+-infusion.
Calcitriol is the main active metabolite of vitamin D, and synergizes with parathormone in mobilizing bone calcium and increasing calcium absorption from the intestine. Vitamin D occurs in a number of sterol forms. These include vitamin D3 (cholecalciferol — the form in foods and made in the skin by the action of UV); vitamin D2 (ergocalciferol — also from plants). These forms are 25-hydroxylated in the kidney, and then 1α-hydroxylated in the kidney (under the control of parathormone), to make the most active form. This is available as calcitriol. Vitamin D facilitates the absorption of calcium and to a lesser extent, phosphorus, from the intestine and promotes deposition into the bones. A deficiency of vitamin D therefore results in bone deficiency disorders, e.g. rickets in children. Therapeutic replacement of vitamin D in cases of severe deficiency requires quantities of the vitamin best provided by one of the synthetic vitamin D analogues (e.g. alfacalcidol and dihydrotachysterol).
Calcitonin is a hormone from the thyroid gland, unrelated in structure or function to the thyroxine analogues and is secreted by a different cell type (C-cells) in follicles of the gland. It is concerned with lowering calcium levels in the blood, and its action is balanced in the body by corresponding opposite action of parathyroid hormone from the anatomically adjacent parathyroid gland. Calcitonin (a calcitonin receptor agonist) is used in therapeutics to treat hypercalcaemia, Paget’s disease of the bone and for certain cancers. It works by reducing calcium uptake to bone by binding to specific receptors on osteoclasts, and acting on the kidney to decrease calcium and phosphate reabsorption. Preparations for clinical use include natural porcine calcitonin and synthetic salcatonin (salmon calcitonin). The former contains impurities and may lead to sensitization and production of neutralizing antibodies material; and the latter may cause inflammation at the injection site. Also now available is the synthetic human 32 amino acid linear sequence (it differs from the salmon form in 2 residues).
Calcium forms used therapeutically include the folinic acid supplement calcium folinate, and the mineral supplements calcium bicarbonate, calcium carbonate, calcium gluconate and calcium lactate.
Other agents used as calcium metabolism modifying agents in disorders of calcium and phosphate metabolism include bisphosphonates (diphosphonates or biphosphonates), which are enzyme-resistant analogues of pyrophosphate and natural inhibitors of bone mineralization. They are used in Paget’s disease of the bone, malignant hypercalcaemia, osteoporosis and are being evaluated in cancer metastases of the bone. The main bisphosphonates used are alendronic acid (alendronate sodium), clodronic acid (sodium clodronate), etidronic acid (sodium etidronate), pamidronic acid (pamidronate disodium) and tiludronic acid (tiludronate disodium). Also, OESTROGENS are used in prevention of post-menopausal osteoporosis. Gallium nitrate, which inhibits bone resorption, is being tested for treatment of hypercalcaemia, though there may be problems with toxicity.