Chapter 694 Bone Structure, Growth, and Hormonal Regulation

Also see Chapters 48 and 564.

Bone is constantly being formed (modeling) and re-formed (remodeling). It is a dynamic organ capable of rapid turnover, bearing weight, and withstanding the stresses of various physical activities. Bone is the major body reservoir for calcium, phosphorus, and magnesium. Disorders that affect this organ and the process of mineralization are designated metabolic bone diseases.

Bone growth and turnover rates are high during childhood; therefore, many clinical features of metabolic bone diseases are more prominent in children than in adults.

The human skeleton consists of a protein matrix, largely composed of a collagen-containing protein, osteoid, on which is deposited a crystalline mineral phase. Collagen-containing osteoid accounts for 90% of bone protein; other proteins, including osteocalcin, which contains γ-carboxyglutamic acid, are also present. Synthesis of osteocalcin depends on vitamin K and vitamin D; in states with high bone turnover, serum osteocalcin values are often elevated.

The microfibrillar matrix of osteoid permits deposition of highly organized calcium phosphate crystals, including hydroxyapatite [C₁₀(PO₄)₆·6H₂O] and octacalcium phosphate [Ca₈(H₂PO₄)₆·5H₂O], plus less organized amorphous calcium phosphate, calcium carbonate, sodium, magnesium, and citrate. Hydroxyapatite is deep within bone matrix, whereas amorphous calcium phosphate coats the surface of newly formed or remodeled bone.

Bone growth occurs in children by the process of calcification of the cartilage cells present at the ends of bone. In accord with the prevailing extracellular fluid (ECF) calcium and phosphate concentrations, mineral is deposited in chondrocytes or cartilage cells set to undergo mineralization. The main function of the vitamin D–parathyroid hormone (PTH)–endocrine axis is to maintain the ECF calcium and phosphate concentrations at appropriate levels to permit mineralization.

Other hormones also appear to regulate the growth and mineralization of cartilage, including growth hormone acting through insulin-like growth factors, thyroid hormones, insulin, leptin, and androgens and estrogens during the pubertal growth spurt. Supraphysiologic concentrations of glucocorticoids impair cartilage function and bone growth and augment bone resorption.

Phosphate homeostasis is regulated by the kidneys because intestinal phosphate absorption is nearly complete and renal excretion determines the serum level. Excessive intestinal phosphate absorption causes a fall in serum levels of ionized calcium and a rise in PTH secretion, resulting in phosphaturia, thus lowering the serum phosphate level and permitting the calcium level to rise. Hypophosphatemia blocks PTH secretion and promotes renal 1,25-dihydroxyvitamin D [1,25(OH]₂D] synthesis. This latter compound also promotes greater intestinal phosphate absorption.

Rates of bone formation are coordinated with alterations in mineral metabolism in both the intestine and kidneys. Inadequate dietary intake or intestinal absorption of calcium causes a fall in serum levels of calcium and its ionized fraction. This serves as the signal for PTH synthesis and secretion, resulting in greater bone resorption to raise the serum calcium level, enhanced distal tubular reabsorption of calcium, and higher rates of synthesis by the kidneys of 1,25(OH]₂D or calcitriol, the most active metabolite of vitamin D (Fig. 694-1). Calcium homeostasis thus is controlled by the intestine because the availability of 1,25(OH)₂D ultimately determines the fraction of ingested calcium that is absorbed.

Figure 694-1 Vitamin D metabolism. Vitamin D can be synthesized in the skin under the influence of ultraviolet irradiation, or it can be absorbed from the diet. It is converted to 25(OH)D₃ (vitamin D₃) in the liver and then further converted by the kidney. The enzyme cytochrome P450 (CYP) 27B converts 25(OH)D₃ to 1α,25-(OH)₂D₃. 1,25(OH)₂D₃ binds to vitamin D receptor (VDR), which, after transport to the nucleus, acts to induce the transcription of >200 proteins. The functions of some of the proteins are indicated. VDR activation leads to productions of fibroblast growth factor 23 (FGF23). FGF23 induces phosphaturia (not shown), upregulates CYP 24, and downregulates CYP 27B.

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