Review of Medical Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Hormonal Regulation of Calcium Metabolism and Bone Physiology
Bone Physiology

Structure

In adults and children, bones consist of two types: compact (or cortical) bone, which forms the outer layer of most bones (Fig. 21-2) and accounts for 80% of skeletal mass; and cancellous (or trabecular) bone, located inside the compact bone and making up the remaining 20% in The Human Body. Compact bone has a low surface area-to-volume ratio, and its bone Cells—osteocytes—exhibit low metabolic activity. They reside in lacunae and obtain nutrients via canaliculi branching throughout the compact bone (Fig. 21-3). Trabecular bone is composed of spicules or plates with a high surface area-to-volume ratio and A large number of cells located on the plate surfaces, conferring high metabolic activity. In spongy bone, nutrients diffuse from the bone extracellular fluid into the trabeculae, whereas in compact bone, they are supplied by Haversian canals (see Fig. 21-3) containing Blood Vessels. Surrounding each Haversian canal, Collagen is arranged in concentric layers forming cylinders known as osteons, or the Haversian system.

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Fig. 21-2. Structure of a typical long bone before (left) and after (right) epiphyseal plate closure.

Bone is a specialized form of Connective Tissue composed of microscopic calcium phosphate crystals embedded within a collagen matrix. The collagen itself is organized into a complex three-dimensional system. Due to its high calcium and phosphate content, bone plays a vital role in Calcium Homeostasis. It protects vital Organs, and its structural strength enables locomotion and weight-bearing against gravity. Old bone is continually resorbed and replaced by new bone (see below), allowing the Skeleton to adapt to applied stresses and strains. It is a living, highly vascularized tissue with a total blood flow of 200–400 mL/min in healthy adults.

The predominant protein of the bone matrix is type I collagen, which is also the major structural protein in tendons and Skin. As strong as steel, collagen consists of a triple helix tightly wound from three polypeptide chains. Two of these are identical a₁ Polypeptides encoded by one Gene, and the third is an a₂ polypeptide encoded by a different gene. Collagens represent a family of structurally related Proteins that ensure the integrity of numerous organs. To date, 15 distinct types have been identified, encoded by 20 different genes.

Maintaining a normal Bone Structure requires an adequate intake of proteins and minerals. Bone crystals measure 20±(3-7) nm and consist primarily of hydroxyapatites with the general formula Са₁₀(РО₄)₆(ОН)₂. Sodium and trace amounts of magnesium and carbonates are also present in bone. Additionally, one of the bone

minerals is amorphous calcium phosphate, which lacks an ordered structure capable of X-Ray Diffraction.

Osteoblasts and Osteoclasts

The cells directly responsible for Bone Formation and resorption are osteoblasts and osteoclasts, both of which originate from the Bone Marrow. Osteoblasts are bone-forming cells derived from bone marrow stromal stem cells. They secrete large amounts of type I collagen, other bone matrix proteins, and alkaline phosphatase. These cells eventually differentiate into osteocytes.

Osteoclasts are multinucleated cells that break down and resorb previously formed bone. They develop from hematopoietic stem cells via monocytes (see Chapter 27). These stem cells attach to the bone surface using Integrins within a specialized membrane extension termed the sealing zone. This zone creates an isolated microenvironment between the bone and a portion of the osteoclast (Fig. 21-4). Subsequently, H⁺-dependent ATPases (proton pumps) translocate from endosomes to The Cell membrane facing the isolated area, acidifying the microenvironment to pH 4. Similar proton pumps are found in the endosomes and Lysosomes of all Eukaryotic cells (see Chapter 1), but they are recruited to The Plasma Membrane in only a few specialized cell types. Notably, the secluded extracellular compartment created by osteoclasts resembles a giant lysosome. The acidic pH dissolves hydroxyapatite, while acid proteases secreted by the cell degrade collagen, carving out a small cavity in the bone. The degradation products are then endocytosed and transported across the osteoclast via transcytosis (see Chapter 1), ultimately being released into the interstitial fluid. Collagen breakdown products include pyridinoline cross-links, which can be measured in urine as an indicator of bone resorption rate.

Bone Growth

Skull bones develop through intramembranous ossification (direct ossification of connective tissue membranes). Long bones initially form as Cartilage models and are subsequently converted into bone via ossification starting in the bone shaft (endochondral ossification).

During growth, specialized regions at the ends of each long bone (epiphyses) are separated from the shaft by a plate of actively proliferating cartilage—the epiphyseal plate (see Fig. 21-2). Bones elongate as this plate deposits new bone inward at the diaphyseal margins. The width of the epiphyseal plate is proportional to the growth rate and is influenced by several Hormones, most notably pituitary Growth Hormone and IGF-I (see Chapter 22).

Linear bone growth can continue as long as the epiphysis remains separated from the bone shaft, but it ceases when the epiphyses fuse with the diaphysis (epiphyseal plate closure). Epiphyses of different bones close in a precise chronological sequence, with the final closures occurring after Puberty. Because the normal age of closure for each epiphysis is well established, a young person's skeletal or "bone age" can be determined radiographically by assessing which epiphyses are open versus closed.

Fig. 21-3. Structure of compact and trabecular bone. Compact bone is shown in horizontal (top) and vertical (left) cross-section (reproduced with permission from Williams PL et al [editors]: Gray’s Anatomy, 37th edition, Churchill Livingstone, 1989).

Bone Formation and Resorption

Throughout human life, bone is continuously resorbed and replaced by newly formed tissue. Bone calcium is replaced at a rate of 100% per year in newborns and about 18% per year in adults. Bone remodeling is predominantly a local process occurring in small packets mediated by basic multicellular units (BMUs). Osteoclasts resorb bone first, followed by osteoblasts that deposit new bone in the same cavity, a cycle lasting roughly 100 days. However, remodeling can be coupled with drift, wherein bone shape changes because resorption occurs at one site and deposition at another. Osteoclasts tunnel through cortical bone, followed by osteoblasts; in trabecular bone, remodeling takes place On the surface. Approximately 5% of adult bone mass is remodeled at any given moment by two million skeletal remodeling units throughout the human body. The annual bone turnover rate is about 4% for cortical bone and 20% for trabecular bone. Remodeling is partly responsive to mechanical stresses (such as gravity and weight-bearing) and is regulated by circulating hormones, growth factors, and cytokines. Osteoblast precursors secrete factors that modulate osteoclast development—a mechanism that helps maintain the balance between bone resorption and formation. Some of the key factors acting on osteoblasts and osteoclasts are summarized in Table 21-2.

Fig. 21-4. An osteoclast resorbing bone. The cell borders are tightly sealed to the bone matrix, enabling acid secretion from the ruffled apical membrane and subsequent enzymatic breakdown of the underlying bone. Note the numerous nuclei (n) and Mitochondria (m) (courtesy of R. Baron).

Despite extensive research, the exact mechanisms responsible for the calcification of newly synthesized bone matrix are not yet fully understood. Several genes are implicated in this process, and targeted knockout of one such gene in mice results in animals with a purely cartilaginous skeleton devoid of bones. Osteoblasts secrete alkaline phosphatase, which hydrolyzes phosphate esters. The resulting local surge in free phosphate concentration near the osteoblasts likely triggers the precipitation of calcium phosphate.

Aside from collagen, several other non-collagenous bone proteins have been isolated and characterized. Bone morphogenetic proteins (BMPs) stimulate bone growth and are now known to play pivotal roles in The Development of The Nervous system and numerous other body Tissues. Matrix Gla protein (MGP) and bone Gla protein (BGP, or osteocalcin) both contain y-Carboxyglutamic acid (Gla) residues, a vitamin K-dependent post-translational modification (see Chapter 17). Although Gla residues bind Ca²⁺, vitamin K deficiency leads to skeletal abnormalities only during fetal development. Two additional proteins, osteonectin and osteopontin, are synthesized by osteoblasts; the synthesis of osteocalcin and osteopontin increases sharply at the onset of mineralization. Nevertheless, the precise physiological Functions of all these proteins in bone remain to be fully elucidated.

Uptake of Other Minerals

Lead and several other toxic heavy elements are absorbed and released by bone in a manner similar to calcium. Rapid skeletal uptake of these elements is sometimes regarded as a detoxification mechanism, as it removes them from Body Fluids and mitigates their toxic effects. Fluoride incorporated into bone stimulates new bone formation. It is also integrated into dental enamel, where trace amounts enhance resistance to dental caries; however, excessive intake causes enamel discoloration (dental fluorosis).

Table 21-2. Factors influencing osteoblasts and osteoclasts

Bone Disorders

Diseases caused by specific abnormalities in the cells and processes discussed below reflect the delicate interplay between the factors that ensure normal bone function.

Various Mutations in collagen-encoding genes render bones brittle, resulting in Osteogenesis Imperfecta (brittle bone disease), as well as causing a variety of chondrodysplasias and at least one form of Ehlers-Danlos syndrome. It is also possible that certain cases of Osteoporosis (see below), osteoarthritis, and aortic aneurysms stem from mutations in collagen genes. In osteopetrosis, another rare and often severe disorder, osteoclasts are defective and incapable of the bone resorption they normally perform. This leads to a uniform increase in bone density, neurological deficits due to the narrowing of foramina through which nerves normally pass, and hematological abnormalities resulting from the obliteration of the marrow cavities. Mice lacking the protein encoded by the immediate-early gene c-fos develop features of osteopetrosis, a condition also observed in mice deficient in the METABOLISM/31.html">Transcription factor PU.1 and in osteocalcin-knockout mice. This suggests that all three factors play a critical role in the normal development and activity of osteoclasts.

A condition in which calcium deposition per unit of bone matrix is inadequate is called Rickets in children and Osteomalacia in adults. In osteoporosis, both matrix and minerals are lost, leading to decreased bone mass (Fig. 21-5) and diminished strength, which increases the incidence of fractures. Unlike osteopetrosis, this disorder is characterized by a net predominance of bone resorption over bone formation. While it has multiple causes, the most prevalent form is involutional osteoporosis, which is primarily associated with advanced age and menopause. Involutional osteoporosis is widespread and has become a major public health concern in the United States and Europe due to the growing elderly population.

In all normal individuals, bone mass increases during early life and growth. Following a period of stability, bone mass begins to decline with age (Fig. 21-6). When this bone loss is accelerated or exacerbated, as in osteoporosis, it leads to a higher frequency of fractures, particularly in the forearm (Colles' fractures), vertebral bodies, and femurs. All these regions contain a high proportion of trabecular bone; because trabecular bone is metabolically more active, it is lost the fastest. Compression fractures of the vertebrae cause Kyphosis, producing the characteristic "dowager's hump" common among older women with osteoporosis. Hip and joint trauma in the elderly is associated with a 12–20% mortality rate, and half of those who survive require long-term, costly care. Adult women have a lower peak bone mass than adult men and, immediately following menopause, lose bone faster than age-matched men (see Fig. 21-6), making them significantly more susceptible to severe osteoporosis. The primary cause of postmenopausal bone loss is estrogen deficiency, which is why estrogen replacement therapy can halt the progression of the disease. Estrogens inhibit the secretion of cytokines, notably IL-1, IL-6, and TNF-alpha, which promote osteoclast development. Estrogen also stimulates The production of TGF-$eta$, which in turn enhances osteoclast apoptosis. Osteoblasts possess estrogen receptors and can be directly stimulated by them. While high doses of estrogens increase the incidence of myocardial infarctions and strokes, low doses—which are effective in slowing bone loss—protect against cardiovascular disease. Estrogens also increase the risk of endometrial Cancer, though this can apparently be mitigated by co-administering progestin. On the other hand, long-term estrogen therapy may elevate the risk of breast cancer. Consequently, Treatment strategies for postmenopausal women using estrogens require a careful weighing of risks and benefits.

Fig. 21-5. Normal trabecular bone (left) compared with trabecular bone in osteoporosis (right).

Fig. 21-6. Total body calcium as an index of bone mass in males and females of various ages. Note the rapid gain in bone mass in young adults (Phase I), the steady age-related loss of bone mass in both sexes (Phase III), and the superimposed, initially accelerated bone loss in postmenopausal women (Phase II) (Reproduced by permission from Riggs BL, Melton LJ III: Involutional osteoporosis. In Evans TG, Williams TF (editors): Oxford Textbook of Geriatric Medicine. Oxford Univ Press, London, 1992).

Increased calcium intake, particularly from natural sources such as milk, and moderate Physical Exercise can also help prevent or slow the progression of osteoporosis, although their effects are modest. Bisphosphonates, such as etidronate, which inhibit osteoclastic activity, increase bone mineral density when administered in a cyclic regimen and reduce the incidence of new vertebral fractures. Fluoride stimulates osteoblasts, making bone denser, but it is not of primary importance in the Treatment of the disease.

In patients immobilized for any reason and in astronauts (see Chapter 33), bone resorption outpaces formation, leading to diffuse osteoporosis. Plasma calcium levels are not markedly elevated, yet the concentrations of Parathyroid hormone and 1,25-dihydroxycholecalciferol decrease, and large amounts of calcium are excreted in the urine. Osteoporosis also develops in patients with excess glucocorticoid secretion (Cushing's syndrome; see Chapter 20).