Bone Structure, Growth, and Hormonal Regulation

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.

The growth pattern of bones is an acceleration of bone growth (length) of the limbs during prepubescence, increased growth (length) of the trunk (spine) during early adolescence, and increased bone mineral deposition in late adolescence. The use of dual-energy x-ray absorptiometry (DEXA) or quantitative CT permits measurement of both mineral content and bone density in healthy subjects and in children with metabolic bone disease. DEXA scanning exposes the patient to less radiation than a chest radiograph.

An understanding of the metabolism of vitamin D is necessary to appreciate metabolic bone disease and rickets. The skin contains 7-dehydrocholesterol, which is converted to vitamin D₃ [25(OH)D₃] by ultraviolet radiation; other inactive vitamin D sterols are also produced (Chapter 48). Vitamin D₃ is then transported in the bloodstream to the liver by a vitamin D–binding protein (DBP); DBP binds all forms of vitamin D. The plasma concentration of free or nonbound vitamin D is much lower than the level of DBP-bound vitamin D metabolites.

Vitamin D also can enter the metabolic pathway by ingestion of dietary vitamin D₂ (ergocalciferol) or vitamin D₃ (cholecalciferol), both of which are absorbed from the intestine because of the action of bile salts. After absorption, ingested vitamin D is transported by chylomicrons to the liver, where, along with skin-derived vitamin D₃, it is converted to 25-hydroxyvitamin D [25(OH)D] by the action of a hepatic microsomal enzyme requiring oxygen, NADPH, and magnesium to hydroxylate vitamin D at the 25th carbon atom. The 25(OH)D is next transported by DBP to the kidneys, where it undergoes further metabolism. 25(OH)D is the main circulating vitamin D metabolite in humans (Table 694-1). Because the synthesis of 25(OH)D is weakly regulated by feedback, its plasma level rises in summer and falls in winter. High vitamin D intake raises the plasma level of 25(OH)D to many times above normal, but the parent vitamin D compound itself is absorbed by adipose tissue.

Table 694-1 VITAMIN D METABOLIC VALUES IN PLASMA OF NORMAL HEALTHY SUBJECTS

In the kidneys, 25(OH)D undergoes further hydroxylation, depending on the prevailing serum concentration of calcium, phosphate, and PTH. If the calcium or phosphate level is reduced or the PTH level is elevated, the enzyme 25(OH)D-1-hydroxylase is activated and 1,25(OH)₂D is formed. This metabolite circulates at a level that is only 0.1% of the level of 25(OH)D (see Table 694-1) and acts on the intestine to increase the active transport of calcium and stimulate phosphate absorption. Because 1α-hydroxylase is a mitochondrial enzyme that is tightly feedback regulated, the synthesis of 1,25(OH)₂D declines after serum calcium or phosphate values return to normal. Excessive 1,25(OH)₂D is converted to an inactive metabolite. In the presence of normal or elevated serum calcium or phosphate concentrations, the renal 25(OH)D-24-hydroxylase is activated, producing 24,25-dihydroxyvitamin D [24,25(OH)₂D], which is a pathway for the removal of excess vitamin D; serum levels of 24,25(OH)₂D (1-5 ng/mL) increase after ingestion of large amounts of vitamin D (see Fig. 694-1). Although hypervitaminosis D and production of inactive metabolites can occur after oral dosing (Chapter 48), extensive skin exposure to sunlight does not usually produce toxic levels of 25(OH)D₃, suggesting natural regulation of the production of this metabolite in cutaneous tissue.

Serum 1,25(OH)₂D levels are higher in children than in adults, are not as subject to seasonal variability, and peak in the 1st yr of life and again during the adolescent growth spurt. These values must be interpreted in light of the prevailing serum calcium, phosphate, and PTH values and with regard to the entire vitamin D metabolite profile.

Mineral deficiency prevents the normal process of bone mineral deposition. If mineral deficiency occurs at the growth plate, growth slows and bone age is retarded, a condition called rickets. Poor mineralization of trabecular bone resulting in a greater proportion of unmineralized osteoid is the condition of osteomalacia. Rickets is found only in growing children before fusion of the epiphyses, whereas osteomalacia is present at all ages. All patients with rickets have osteomalacia, but not all patients with osteomalacia have rickets. These conditions should not be confused with osteoporosis, a condition of equal loss of bone volume and mineral (Chapter 698).

Another class of proteins important in the regulation of mineral balance and vitamin D synthesis are the phosphatonins. Among these are fibroblast growth factor (FGF)-23, sFRP-4 and MEPE. Overexpression of FGF-23 results in hypophosphatemia, phosphaturia, reduced serum 1,25(OH)₂D values, and rickets. Disorders of phosphate balance, including hyper- and hypophosphatemia, can relate to loss or gain of function of these phosphatonins (see Fig. 694-1).

The Klotho gene codes for a single-pass transmembrane protein that is an aging suppressor in mice. Klotho protein also influences interaction of FGF-23 with its receptor. FGF-23 is then able to inhibit the action of cytochrome P450 (CYP) 27b1 and the sodium-dependent phosphate transporter in the kidney. The net result of Klotho FGF-23 interaction is reduced 1,25(OH)₂D values and phosphaturia.

Rickets may be classified as calcium-deficient or phosphate-deficient rickets. Because both calcium and phosphate ions constitute bone mineral, the insufficiency of either type in the ECF that bathes the mineralizing surface of bone results in rickets and osteomalacia. The two types of rickets are distinguishable by their clinical manifestations (Table 694-2). Rickets can also occur in the face of mineral deficiency, despite adequate vitamin D stores. True dietary calcium deficiency rickets is found in some parts of Africa but rarely in North America or Europe. A form of phosphate-deficiency rickets can occur in infants given prolonged administration of phosphate-sequestering aluminum salts as a treatment for colic or gastroesophageal reflux. This results in the phosphate depletion syndrome.

Related posts:

Disorders of the Complement System Gynecologic Care for Girls with Special Needs Cardiac Development Hypothyroidism Cystic Diseases of the Biliary Tract and Liver Vesicoureteral Reflux

Nelson Textbook of Pediatrics Expert Consult