Porth's Essentials of Pathophysiology, 4e

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Structure and Function of the Skeletal System

C h a p t e r 4 2

determines skeletal mass at any given time. The sequence of bone resorption and bone formation begins with osteoclastic resorption of existing bone, during which the organic (protein matrix) and the inorganic (mineral) components are removed. The sequence proceeds to the formation of new bone by osteoblasts. In the adult, the length of one sequence (i.e., bone resorption and forma- tion) is approximately 4 months. Ideally, the replaced bone should equal the absorbed bone. If it does not, there is a net loss of bone. In the elderly, for example, bone resorption and formation no longer are perfectly coupled, and bone mass is lost. Recently, significant progress has been made in under- standing the phenomenon of bone remodeling as it relates to the coupling of bone resorption with bone for- mation. The pivotal paracrine pathway linking these two processes consists of three factors: RANKL (for r eceptor a ctivator of n uclear factor- κ B l egend); its receptor, RANK; and a soluble inhibitor receptor for RANKL called osteo- protegerin (OPG). RANKL is expressed by osteoblasts and their immature precursors and is necessary for osteo- clast differentiation and function. RANKL activates its receptor, RANK, which is expressed on osteoclasts and their precursors, thus promoting osteoclast differentia- tion and activation and prolonging osteoclast survival by suppressing apoptosis. The fact that RANKL is expressed on osteoblasts indicates that bone resorption and bone formation are linked through RANKL. The effects of RANKL are blocked by OPG, a soluble receptor protein, which acts as a decoy receptor that binds RANKL and prevents it from binding with RANK on osteoclasts. It is now believed that dysregulation of the RANKL/ RANK/OPG pathway plays a prominent role in the pathogenesis of bone diseases such as osteoporosis (low bone density). For example, it has been shown that post- menopausal women express higher levels of RANKL on their marrow stromal cells and lymphocytes than pre- menopausal women or postmenopausal women taking estrogen. It has also been shown that estrogens and the selective estrogen receptor modulator, raloxifene, stim- ulate OPG production in osteoblasts. Glucocorticoid exposure, which can contribute to steroid osteoporo- sis, enhances RANKL expression and suppresses OPG

levels, thus elevating the RANKL-to-OPG ratio. There is also evidence linking the pathogenesis of inflammatory conditions such as rheumatoid arthritis to dysregulation of the RANKL/OPG system.

Hormonal Control of Bone Formation and Metabolism

The process of bone formation and mineral metabolism is complex. It involves the interplay among the actions of parathyroid hormone (PTH), calcitonin, and vitamin D (Table 42-2). Other hormones, such as corticosteroid hormone, growth hormone, thyroid hormone, and the sex hormones, also influence bone formation directly or indirectly. Parathyroid Hormone. Parathyroid hormone, which is produced by the parathyroid glands embedded in the thyroid gland, is one of the important regulators of calcium and phosphate levels in the blood. Parathyroid hormone prevents serum calcium levels from falling below and serum phosphate levels from rising above normal physiologic concentrations (see Chapter 8). The secretion of PTH is regulated through negative feed- back related to serum levels of ionized calcium, with decreased levels stimulating PTH release and increased levels inhibiting its release. Parathyroid hormone maintains serum calcium levels by promoting bone resorption, conserving calcium by the kidney, enhancing intestinal absorption of calcium through activation of vitamin D, and reducing serum phosphate levels (Fig. 42-5). Parathyroid hormone also increases the movement of calcium and phosphate from bone into the extracellular fluid. In the kidney, PTH stim- ulates tubular reabsorption of calcium while reducing the reabsorption of phosphate. The latter effect ensures that the increased release of phosphate frombone during mobi- lization of calcium does not produce an elevation in serum phosphate levels. This is important because an increase in calcium and phosphate levels could lead to crystallization in soft tissues. Parathyroid hormone also stimulates the activation of vitamin D by the kidney, thereby increasing the absorption of calcium from the intestine.

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TABLE 42-2 Actions of Parathyroid Hormone, Calcitonin, andVitamin D Actions Parathyroid Hormone Calcitonin

Vitamin D

Intestinal absorption of calcium Increases indirectly through increased activation of vitamin D

Probably has no effect

Increases

Intestinal absorption of phosphate Increases

Probably has no effect

Increases

Renal excretion of calcium

Decreases

Minor effect

Probably increases, but less effect than PTH

Renal excretion of phosphate

Increases Increases Decreases

Minor effect Decreases

Increases 1,25-(OH) 2 24,25-(OH) 2

Bone resorption Bone formation

D 3

increases

Uncertain

D 3

increases

Serum calcium levels

Produces a prompt increase Prevents an increase

Decreases with pharmacologic doses Decreases with pharmacologic doses

No effect

Serum phosphate levels

No effect