Understanding the physiology of calcium and phosphate homeostasis informs the physician confronted with a patient who exhibits the pathophysiology of this homeostatic system. Disorders of calcium, phosphate, and skeletal metabolism are among the most common group of diseases that the practicing physician will encounter (1). They can involve abnormalities in the serum concentrations of the two minerals, especially calcium; abnormalities of bone; and abnormalities of the major regulating organ systems, especially the parathyroid gland, kidney and gastrointestinal (GI) tract (Table 1). The serum calcium concentration can be abnormally high, as in malignancy and primary hyperparathyroidism, or abnormally low as it is in renal failure and hypoparathyroidism. The skeleton can have low bone density, as occurs in osteoporosis and osteomalacia, or high bone density as Paget's disease of bone and osteopetrosis. The GI tract can exhibit low calcium absorption, as in malabsorptive states, or high calcium absorption, as in vitamin D intoxication and the milk-alkali syndrome. The kidneys can fail to excrete calcium, as occurs in some hypercalcemic disorders; overexcrete calcium, as in some cases of nephrolithiasis; underexcrete phosphorus, as in renal failure; and overexcrete phosphorus, as in some renal tubular disorders. Corresponding events occur for magnesium, but they will not be discussed in this chapter. The goal of this chapter is to discuss the normal regulation of bone mineral metabolism in order to provide the clinician a basis for diagnosis and management of patients with the common disorders that involve this homeostatic system.
Table 1. Regulation of Calcium and Skeletal Metabolism
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As detailed in other chapters, disorders of mineral and skeletal metabolism can be due to a primary disease of one of the involved organ systems, as in primary hyperparathyroidism due to a tumor of the parathyroid gland; secondary hyperparathyroidism, due to a compensatory response of the parathyroid gland to a low serum calcium; perturbations in serum calcium due to malignancy and bone metastases; and the complex mineral and skeletal complications of renal failure. A basis for understanding the pathogenesis of the primary and secondary diseases of bone and its minerals that are discussed in this text is an appreciation of the interplay among hormones, minerals, and organ systems that the regulates normal bone and bone mineral metabolism (Figure 1).
The skeleton is the reservoir of calcium for many physiological functions, and it serves a similar but not so unique role for phosphorus and magnesium (Table 2) (2,3). Skeletal calcium is controlled through the regulatory pathways of the gastrointestinal (GI) tract and the kidney, and this regulation is mediated in bone by the osteoblast, the bone-forming cell, and the osteoclast, the bone-resorbing cell. Calcium reaches the skeleton by being absorbed from the diet in the GI tract. Unabsorbed calcium passes into the feces, which also contains the small amount of calcium secreted into the GI tract. Minor losses occur through perspiration and cell sloughing. In pregnancy, substantial losses can occur across the placenta to the developing fetus and through breast milk. Absorbed dietary calcium then enters the extracellular fluid (ECF) space and becomes incorporated into the skeleton through the process of mineralization of the organic matrix of bone, osteoid. ECF calcium is also filtered by the kidney at a rate of about 6 grams per day, where up to 98 percent of it is reabsorbed (Figure 1).
Figure 1. Schematic Representation of Calcium and Skeletal MetabolismAbbreviations: A, absorption; S, secretion; ECF, extracellular fluid; GF, glomerular filtration; TR, tubular reabsorption.The dark vertical line between bone and ECF represents bone surface and bone-lining cells. Shaded area represents labile skeletal calcium. The various calcium compartments are not to scale. See text for discussion. (see Acknowledgements)
The regulation of bone and bone mineral metabolism results from the interactions among three hormones - parathyroid hormone (PTH), calcitonin (CT), and Vitamin D (VD) - at these three target organs - bone, kidney, and GI tract - to regulate three bone minerals – calcium, magnesium, and phosphorus. Other hormones and mineral also play a role, and skin is a participating organ system (Table 1). The deviations from this normal regulatory scheme that occur in disease states can be appreciated, addressed, and, in most cases, effectively managed by the clinician when considered in the light of skeletal homeostasis (1-3).
Physicians are most aware of the clinical status of calcium and skeletal metabolism in the patient as revealed by the circulating concentrations of these minerals in biological fluids, especially blood and urine, and by the structural integrity of the skeleton (1). The actions of the calcemic hormones to regulate mineral concentrations in biological fluids are well understood the target organ level. However, less well understood are the cellular and intracellular mechanisms that underlie the clinically important phenomena.
Both calcium and phosphorous, as well as magnesium, are transported to blood from bone, renal, and GI cells, and vice versa (4-6). These transport mechanisms can be through cells (transcellular) and around cells (paracellular). The cellular transport is mediated by the membrane structures illustrated in Figure 2 and by binding transport proteins (7,8). The paracellular transport is generally passive and mediated by mineral gradients. These bone mineral mechanisms also involve corresponding co-transportation and exchange-transportation with other ions, notably sodium, potassium, chloride, hydrogen, and bicarbonate, some of which are powered by ATP hydrolysis. Similar mechanisms allow for the intracellular distribution of calcium, where it partitions primarily between the mitochondria and cytosol.
The details of the regulation of these cellular and intracellular mineral transports are not as well understood as are the whole organ mechanisms that they effectuate. However, some evidence along with inferences lead to the tentative clinical conclusion that changes in ambient concentrations of mineral in extracellular fluids are mirrored by corresponding intracellular changes and redistribution (Figure 2).
Figure 2. Schematic representation of cellular transport of bone minerals. The model can be applied to transport of calcium, magnesium, and phosphorus for cells of the renal tubules, gastrointestinal tract enterocytes, and bone cells. The mineral transport can be with (downhill) or against (uphill) a gradient. Lumen refers to GI and renal tracts; for bone, it can refer to bone marrow, blood, and/or matrix space. The site of the indicated membrane transport structures is schematic. Microsomes designate other intracellular organelles such as secretory vesicles and endoplasmic reticulum. See text for details.
Figure 2 provides a simplified version of the cellular regulation of bone minerals metabolism and transport. Mineral homeostasis requires the transport of calcium, magnesium, and phosphate across their target cells in bone, intestine, and kidney. This transport can be across cells (transcellular) and around cells (pericellular). The pericellular transport is usually diffusional, down a gradient ("downhill"), and not hormonally regulated. Diffusion can also occur through cell channels, which can be gated. Transport across cells is more complex and usually against a gradient ("uphill"). This active transport is energized by either ATP hydrolysis or electrochemical gradients and involves membrane structures that are generally termed porters, exchangers, or pumps. Three types of porters have been described, uniporters of a single substance; symporters for more than one substance in the same direction; and anti-porters for more than one substance in opposite directions (7,8).
Once through the luminal cell membrane, the bone minerals can cross the cell into the extracellular fluid compartment, blood for enterocytes and urine for renal epithelium cells (5,6). For bone cells, the corresponding compartments are marrow and blood (1,2). For calcium, the transcellular transport is ferried by the interaction among a family of proteins that include calmodulin, calbindin, integral membrane protein, and alkaline phosphatase; the latter three are vitamin D dependent in their expression(6). Cytoskeletal interactions are likely important for transcellular transport as well. Exit from the cell is regulated by membrane structures similar to those that mediate entry. There do not appear to be any corresponding binding proteins for phosphorous, so diffusional gradients and cytoskeletal interactions seem to regulate its cellular transport.
The molecular details of the hormonal regulation of cellular bone mineral transport have not been fully elucidated. It is reasonable to hypothecate that PTH, CT, and Vitamin D regulate these molecular mechanisms through their biological effects on the participating membrane structures and transport proteins. For the enterocyte, vitamin D enhances the movement of calcium into the cell through its stimulation of calbindin synthesis (6). For kidney tubules, PTH is the key regulator in a corresponding manner for the transport of phosphate and calcium (5). For bone, PTH and CT are the major regulators of cellular calcium and phosphate transport, while vitamin D provides appropriate concentrations of these minerals through its renal and GI actions (1-3).
It is important to note that these mineral translocations not only mediate the organ mineral metabolism represented in Figure 2, but also the cellular effects summarized in Table 3.