An intricate physiologic mechanism has evolved to prevent dangerous hypocalcemia: a reduction in calcium intake stimulates calcium absorption by the gastrointestinal tract, promotes renal calcium conservation, and stimulates net bone resorption (mineral plus matrix), thus restoring the serum calcium level to normal.

Take as an example a 30-year-old woman who begins a diet with a very low calcium intake. Let us explore the mechanisms that maintain a constant calcium level in the extracellular fluid.

In response to reduced calcium intake, net absorption decreases and serum calcium levels decline transiently. As a result, secretion of PTH increases. The target organs for PTH are the bones and the kidneys. In bone, osteoclastic activity is stimulated via a complex “coupling” mechanism involving interactions with osteoblasts. PTH stimulates osteoblasts to produce Receptor for Activation of Nuclear Factor κB ligand (RANKL), which then interacts with RANK receptors on osteoclast precursor cells. This ligandreceptor interaction leads to an activation of osteoclastic activities that result in a net resorption of both bone matrix and bone mineral. In the kidney, PTH promotes the tubular reabsorption of filtered calcium and impairs the reabsorption of P_i. In addition, via the cyclic adenosine monophosphate (cyclic AMP)–mediated pathway, PTH activates the enzyme 25-hydroxyvitamin D–1α-hydroxylase, or 25(OH)D-1α-OH_ase, in the mitochondria of the proximal tubular cells, thus promoting the conversion of the 25(OH)D substrate to the potent hormonal metabolite 1,25-dihydroxyvitamin D (1,25[OH]₂D, or calcitriol). The major target organs for 1,25(OH)₂D are the bones, the duodenum, and the jejunum. The mechanism of 1,25(OH)₂D-induced bone resorption involves a stimulation of osteoclastic precursors. It promotes calcium absorption in the duodenum and jejunum by stimulating numerous events and proteins, including the production of CBP in the enterocytes. However, the kidney’s ability to adapt to low calcium intake by the mechanisms described declines with age. An agerelated decline in 1,25(OH)₂D production by the kidneys impairs the efficiency of gastrointestinal absorption of calcium; thus, an even greater resorption of bone is required to maintain serum calcium at normal levels. This latter mechanism is thought to play a major role in the evolution of type II, or agerelated, osteoporosis.