Bone Physiology

The skeleton is the primary structural support for the body and also provides a protected environment for hematopoiesis. It contains both a large mineralized matrix and a highly active cellular component.

A process called modeling drives the growth and development of endochondral bone. Once new bone is laid down, it is subject to a continuous process of breakdown and renewal, called remodeling, by which bone mass is adjusted throughout adult life. This remodeling is carried out by multiple independent bone remodeling units throughout the skeleton (Figure 61-6). In response to physical

figure 61-6 The bone remodeling cycle. Osteoclast precursors fuse and are activated to resorb a lacuna in a previously quiescent surface. These cells are replaced by osteoblasts that deposit new bone to restore the integrity of the tissue.

or biochemical signals, mononuclear precursors are recruited to the bone surface, where they fuse to form the characteristic multinucleated osteoclasts that excavate a cavity into the bone called the resorption lacuna.

Osteoclast production is regulated by osteoblast-derived cytokines. One particularly important factor is RANK ligand (previously called osteoclast differentiation factor), which induces osteoclast formation by activating its RANK receptor. Osteoblasts also produce osteoprotegerin, a decoy ligand that inhibits osteoclast differentiation by blocking the RANK receptor. Estrogen induces osteoprotegerin, which may be one mechanism by which estrogens inhibit osteoclast function and bone resorption in postmenopausal women.

The resorption phase is followed by ingress of preosteoblasts into the base of the resorption cavity. These cells become osteoblasts and elaborate new bone matrix constituents that help form the osteoid. Once the osteoid reaches a thickness of ~15-20 xm, mineralization begins. A complete remodeling cycle normally requires about 3-6 months.

The remodeling process is imperfect and small bone deficits persist on completion of each cycle. Lifelong accumulation of these remodeling deficits underlies the age-related bone loss that begins shortly after growth ceases. Alterations in remodeling activity represent the final pathway through which diverse stimuli—such as dietary insufficiency, hormones, and drugs—affect bone balance.

DISORDERS OF MINERAL HOMEOSTASIS AND BONE Abnormal Calcium Metabolism hypercalcemia The degree and rapidity of onset of hypercalcemia largely dictate the extent of symptoms. Chronic elevation of serum Ca2+to 12-14 mg/dL (3-3.5 mM) generally causes few manifestations, whereas an acute rise to the same level may cause marked neuromuscular manifestations by increasing the threshold for nerve and muscle excitation. Symptoms include fatigue, weakness, anorexia, depression, diffuse abdominal pain, and constipation.

The most common cause of hypercalcemia in outpatients is primary hyperparathyroidism, due either to a single adenoma or diffuse hyperplasia. Primary hyperparathyroidism is often associated with significant hypophosphatemia due to PTH effects on renal phosphate reabsorption. The diagnosis is generally apparent from the elevated serum Ca2+ associated with an inappropriately high PTH level. In contrast, secondary hyperparathyroidism is a disorder in which PTH levels are elevated in response to persistent threats to normal calcium homeostasis such as hyperphosphatemia from chronic renal disease.

Hypercalcemia in hospitalized patients is caused most often by a malignancy, either with or without bone metastases. The degree of hypercalcemia here often exceeds considerably that seen with primary hyperparathyroidism (often >13 mg/dL) and lethargy, weakness, and volume depletion may be profound. PTH-related peptide, which is produced by squamous cell and other tumors, can interact with the PTH receptor to cause humoral hypercalcemia. An assay for PTH-related peptide is often diagnostic in these patients, while the PTH level is suppressed due to feedback by the elevated serum Ca2+.

Pharmacologic overdoses of vitamin D may cause hypercalcemia if sufficient 25-OHD is present to stimulate intestinal calcium absorption. Measurement of the serum 25-OHD level is diagnostic. More often, granulomatous disorders such as sarcoidosis are associated with increased production of 1,25(OH),p due to expression of 1a-hydroxylase.

hypocalcemia Mild hypocalcemia (i.e., serum Ca2+in the range of 8-8.5 mg/dL) is usually asymptomatic. Again, the rapidity of onset affects the clinical manifestations. The signs and symptoms of hypocalcemia include tetany, paresthesias, increased neuromuscular excitability, laryngospasm, muscle cramps, and tonic-clonic seizures. Nail and tooth changes and calcification of the basal ganglia are encountered with chronic hypocalcemia due to hypoparathyroidism.

Combined deprivation of Ca2+ and vitamin D, as observed in malabsorption states, readily promotes hypocalcemia. Serum phosphate also will be low. Hypoparathyroidism is most often a consequence of thyroid or neck surgery, but also may be due to genetic or autoimmune disorders. Pseudohypoparathyroidism, a rare group of genetic disorders associated with decreased PTH action, results from mutations in the gene encoding the a subunit of Gs which mediates PTH action in the renal tubules. These patients can also exhibit impaired action of multiple other hormones that couple to Gs but the impaired response to PTH is most severe.

Disturbed Phosphate Metabolism

Dietary inadequacy rarely causes phosphate depletion. Sustained use of aluminum-containing antacids can severely limit phosphate absorption and cause clinically significant phosphate depletion. If severe, hypophosphatemia can cause malaise, muscle weakness, and a bone disorder termed osteomalacia that is characterized by undermineralized bone osteoid.

Hyperphosphatemia occurs commonly in chronic renal failure. The increased phosphate level directly stimulates PTH secretion and also has secondary effects due to the reduction in serum Ca2+. Because renal function is impaired, the increased PTH is unable to increase phosphate excretion sufficiently to avoid ongoing phosphate retention. The chronic secondary hyperparathyroidism may result in a bone disease called renal osteodystrophy.

Disorders of Vitamin D

hypervitaminosis d The acute or chronic administration of excessive amounts of vitamin D can cause hypervitaminosis D and hypercalcemia. The amount of vitamin D necessary to induce this condition varies widely. As an approximation, prolonged daily ingestion of 50,000 U or more can cause poisoning. The signs and symptoms are those associated with hypercalcemia.

vitamin d deficiency Vitamin D deficiency is associated with inadequate absorption of calcium and phosphate. The resulting decrease in Ca2+ stimulates PTH secretion, which acts to restore plasma Ca2+ at the expense of bone. Plasma phosphate concentration will remain low due to the phosphaturic effect of PTH. In children, the failure to mineralize newly formed bone results in rickets, a growth disorder in which the long bones may be bowed due to inadequate calcification.

In adults, vitamin D deficiency results in osteomalacia, a disease characterized by generalized accumulation of undermineralized bone matrix. Severe osteomalacia may be associated with extreme bone pain and tenderness and proximal muscle weakness. A low serum level of 25-OHD is diagnostic.

Conditions associated with abnormalities in calcitriol synthesis or response can cause rickets in children and osteomalacia in adults. Specific disorders include X-linked hypophosphatemic rickets due to mutations in the PHEX endoprotease, Vitamin D-dependent rickets due to mutations in 1a-hydroxylase, and hereditary 1,25-(OH)2D resistance due to mutations in the VDR.

SPECIFIC DISORDERS OF BONE Osteoporosis

Osteoporosis is a condition of low bone mass and microarchitectural disruption that results in fractures with minimal trauma. Characteristic sites of fracture include vertebral bodies, the distal radius, and the proximal femur, but osteoporotic individuals have generalized skeletal fragility, and fractures at sites such as ribs and long bones also occur. Fracture risk increases exponentially with age, related both to decreased bone density and to factors such as decreased muscle strength and increased risk of falls.

Osteoporosis can be categorized as primary (idiopathic) or secondary to a systemic illness or medication such as glucocorticoids or phenytoin. A major factor in the former category is the decline in estrogen levels, and the resulting sharp decrease in bone mass that accompanies menopause in women.

PAGET'S DISEASE

Paget's disease affects up to 3% of the population over age 60. It is characterized by single or multiple foci of disordered bone remodeling. The primary pathologic abnormality is increased bone resorption followed by exuberant formation of disorganized bone of poor quality. The altered bone structure can lead to bowing and stress fractures and also is associated with secondary problems such as deafness, spinal cord compression, high-output cardiac failure, and pain. Malignant degeneration to osteogenic sarcoma is a rare but potentially lethal complication.

Renal Osteodystrophy

Bone disease is a frequent consequence of chronic renal failure and dialysis. Pathologically, the lesions are typical of hyperparathyroidism, adynamic bone disease, deficiency of vitamin D (osteomalacia), or a combination of the above. The underlying defect reflects increased phosphate and decreased calcium, leading to secondary events that strive to preserve circulating levels of Ca2+ at the expense of bone.

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