The parathyroid hormone (parathormone) is concerned with the regulation of calcium metabolism.
Parathormone increases serum calcium by:
a. Mobilizing calcium from bone.
b. Increasing renal calcium reabsorption.
c. Promoting renal conversion of vitamin D to its active metabolite calcitriol which in turn increases calcium absorption from gastrointestinal tract.
d. Increasing phosphate excretion.
Serum calcium regulates the secretion of parathormone from the parathyroid glands by its negative feedback; hypocalcemia stimulates and hypercalcemia suppresses parathormone release. Calcium is essential for bone formation and neuromuscular function. Approximately 99% of body calcium is in bone and most of the remaining 1 % is in extracellular fluid.
Parathyroid hormone deficiency results in an increase in blood phosphorus and a decrease in blood calcium levels. Hypocalcemia results in fall of ionized (free) calcium in the serum and causes a clinical disorder tetany, which is characterized by increased irritability of muscles with spasm of the hands and feet and of the larynx. Treatment of tetany includes administration of calcium salts, parathormone and vitamin D.
Calcium:
Calcium gluconate IV is the only emergency treatment available for relieving the acute attacks of tetany. Long-term management requires oral calcium supplements in the form of calcium carbonate. It is generally given with vitamin D or its active metabolite calcitriol, which is required for the oral absorption of calcium.
Parathormone:
Parathormone is not satisfactory in the management of tetany because it is slow acting and its continuous use leads to tachyphylaxis. It has to be given parenterally and may cause allergic reactions.
Bone Metabolism:
There is a continuous remodeling of bone consisting of its breakdown and consequent reformation. The normal process of bone remodeling is controlled by a balance between osteoblasts (cells that form new bone) that secrete new bone matrix, and osteoclasts (cells that resorb bone) that break down bone matrix. This balance is controlled by the hormones calcitonin and parathyroid.
Hypercalcemia:
Hypercalcemia is almost always caused by increased entry of calcium into the extracellular fluid (from bone resorption or intestinal absorption) and decreased renal clearance. Paget’s disease of bone and malignancy, amongst others, are two causes of hypercalcemia, which results in over activity of osteoclasts leading to decalcification of skeletal system. Paget’s disease of bone is a focal skeletal disorder, characterized by marked abnormal high bone turnover resulting in bone pain, deformity, and pathologic fractures. In malignancy, tumor cells products, such as cytokines, act locally to stimulate osteoclastic bone resorption.
Drugs used to inhibit bone resorption include:
a. Calcitonin
b. Biophosphonates
a. Calcitonin:
Calcitonin is a hormone produced by C cells of the thyroid gland. It is mainly concerned with the maintenance of calcium balance. It inhibits the action of bone osteoclasts, which are concerned with bone resorption. Calcitonin lowers the concentration of calcium in the blood and increases its deposition in bone. It is mainly used in disorders where there is rapid breakdown of bone, such as Paget’s disease, or to control malignant deposits in bone, where they release excessive amounts of calcium into the blood causing hypercalcemia. The hypoglycemic effect of calcitonin wanes after several days because of tachyphylaxis.
Calcitonin is less potent than biophosphonate in inhibiting the action of osteoclasts but has no serious toxicity, is safe in renal failure and may have an analgesic effect in patients with skeletal metastases. It can be used early in the treatment of severe hypercalcemia to achieve a rapid response; concomitant use of a biophosphonate ensures a prolonged effect. Salcatonin is a synthetic or recombinant salmon calcitonin. Side effects include flushing, nausea, and rarely allergic reactions.
b. Biophosphonates:
Biophosphonates, by slowing bone marrow “turnover” relieve pain and control hypercalcemia in Paget’s disease and in malignant disease involving bone. They inhibit osteoclast activity and promote osteoblast activity in bone. They are increasingly used to treat osteoporosis in those with Paget’s disease of bone, in the elderly and in women after menopause. They are also very effective in reducing the incidence of fractures in the elderly.
Pamidronate is the most potent and is given by IV infusion for the treatment of hypercalcemia of malignancy. Etidronate, alendronate or risedronate are given orally for the treatment of Paget’s disease of bone. Side effects vary to some extent with different biophosphonates. Etidronate has been reported to cause osteomalacia in patients with osteoporosis and Paget’s disease. Alendronate is damaging to the esophagus and may cause ulceration. Minor effects include nausea and diarrhea.