Bones

Bone is a tissue in which cells make up only 2% to 5% of the volume, and nonliving material make up 95% to 98%. It is the nonliving material that gives the bone its basic mechanical properties of hardness, stiffness, and resiliency. This nonliving material consists of a mineralencrusted protein matrix (also called osteoid), with the mineral comprising about half the volume and the organic matrix the other half. Unlike other connective tissues, virtually no free water is present in the bony material itself. Embedded in this solid material are cells, called osteocytes, residing in lacunae in the matrix and communicating with one another through an extensive network of long cellular processes lying in channels called canaliculi, which ramify throughout the bone. As a consequence of this arrangement, virtually no volume of normal bone is more than a few micrometers from a living cell.

The mineral of bone is a carbonate-rich, imperfect hydroxyapatite with variable stoichiometry. Calcium comprises 37% to 40%, phosphate 50% to 58%, and carbonate 2% to 8% of this mineral. These values vary somewhat from species to species, and the carbonate component is particularly sensitive to systemic acid–base status ( decreasing in acidosis and increasing in alkalosis). In addition, bone mineral contains small amounts of sodium, potassium, magnesium, citrate, and other ions present in the extracellular fluid (ECF) at the time the mineral was deposited, adsorbed onto the crystal surfaces, and trapped there, as the water in the recently deposited matrix is displaced by the growing mineral crystals.

The protein matrix of bone, as for tendons, ligaments, and dermis, consists predominantly of collagen, which comprises approximately 90% of the organic matrix. For bone, the collagen is type I. Collagen is a long, fibrous protein, coiled as a triple helix. For the molecules of the protein to coil tightly, no side chains can project from the peptide backbone on the side facing inward. Hence, every third amino acid in the body of the collagen molecule is glycine, which has no side chain. However, projecting outward are the side chains of various other amino acids, such as

lysine, which allow the posttranslational formation of tight, covalent bonds between collagen fibers. This cross-linking helps to prevent fibers from sliding along one another when bone is stressed along the axis of the fibers.

The four principal bone cells are lining cells, osteoblasts, osteoclasts, and osteocytes. They are responsible both for maintaining the mechanical properties of bone and mediating the calcium homeostatic function of bone. Lining cells are flat, fibrocyte-like cells covering free surfaces of bone. They are most probably derived from, or closely related to, the osteoblast cell line. They form a membrane that completely covers free bone surfaces and insulates bone from the cells and hormones in the general circulation. They demarcate a virtual compartment between the lining cells on one side and mature bone on the other. This compartment is continuous with the space in canaliculi surrounding osteocyte processes and may well have different ionic composition from that of the ECF located outside, that is, between the lining cells and the capillaries of bone. It is possible that lining cells, by adjusting ion fluxes between the ECF and the bone compartment, may contribute to the maintenance of calcium ion concentrations in the ECF.

Osteoblasts are derived from marrow stromal cells; they are the cells that lay down bone, first by synthesizing, depositing, and orienting the fibrous proteins of the matrix, and then by initiating changes that render the matrix capable of mineralization. Osteoblasts deposit this matrix between and beneath themselves on a preexisting bone surface, thereby pushing themselves backward as they add new bone.

Bone consists of a dense outer shell, or cortex, and an internal, chambered system of interconnected plates, rods, and spicules called cancellous or trabecular bone. In the shafts of the long bones, the cortical component predominates, creating a hollow tube, whereas nearer the joints, the cortex becomes thinner and the interior is made up of an extensive latticework of cancellous bone. Bones such as the vertebrae, pelvis, sternum, and shoulder blades possess a thin outer rind of cortex and a more or less even distribution of cancellous bone on the inside. The internal, three-dimensional architecture of cancellous bone is arranged along the lines of force that a particular bone experiences and hence provides maximum structural strength with minimum material.

The end segments of bones are called epiphyses. The shafts of long bones are called diaphyses, and the flared portion of the shaft merging with the region of the growth plate is called a metaphysis. The lining cells on the outside of the bone form a tough sheet or membrane, called the periosteum, whereas the cells on the inside surfaces of both cortical and trabecular bone are called the endosteum.

The spaces between the trabecular plates and spicules are filled with bone marrow. Early in life, much of that marrow is hemopoietic, but later the blood-producing marrow is confined to the bones of the trunk, and the peripheral skeletal marrow spaces are filled mostly with fat.

At their ends, where bones meet one another in a joint, the bony surface is covered with a layer of cartilage rather than with periosteum. In health, this cartilage, is highly hydrated and is lubricated by synovial fluid held there by a tough connective tissue sac called the joint capsule. This arrangement ensures that the bones move on one another smoothly.

In utero, most bones are formed first as cartilage models, which are gradually replaced by bone. In this process, blood vessels invade the cartilage, calcification ensues, and the calcified cartilage is then removed by osteoclasts and replaced by bone laid down by osteoblasts. In infancy and childhood, bone growth and development follow a similar pattern.

Bone serves two distinct functions: the provision of mechanical rigidity and stiffness to our bodies; and the provision of a homeostatic buffer, particularly to help our bodies maintain a constant level of calcium in the circulating body fluids and to provide a reserve supply of phosphorus. The mechanical function is necessary so that we can resist gravity and move about on dry land. The homeostatic function of bone is the older of the two, from the standpoint of evolution, and is in a sense the more fundamental, because the body will sacrifice the structural function before it will risk losing the homeostatic one. In other words, the body will weaken the bone structurally to maintain the calcium levels of the blood and ECF.

In the mechanical function of bone, nature strikes a balance between a skeleton so massive that it would resist most forces, but be too heavy to carry around, and one so flimsy that, although adequate to meet calcium homeostatic needs, it would be too fragile to sustain the mechanical forces of exertion or of minor injuries. Bone finds the middle ground by adjusting its mass using a classic negative feedback loop so it bends under routine use by approximately 0.05% to 0.10% in compression or tension and by 0.10% to 0.20% in shear (Fig. 89.5). This bending set point is a major determinant of bone size during growth and bone density during adult remodeling.

Total nutritional status influences bone cell function just as it does the function of other tissues. However, cellular malnutrition affects mainly bone currently being remodeled, whereas the strength of bony structures at any given time is dependent, not so much on current cell function, as on the mass of bony material accumulated by bone cellular activity over many years. For that reason, acute nutritional stresses or deficiencies rarely produce overt skeletal symptoms in adults, even when they severely compromise bone cell function. Children and growing animals show effects more promptly, both because they have less skeletal capital in their bone banks and because they are revising it much more rapidly. Nevertheless, a few nutrients, when deficient, are more likely than others to produce skeletal manifestations. These include calcium, phosphorus, vitamin D, and certain other trace nutrients.

In addition to buffering absorptive oscillations in blood calcium concentration, bone serves as a nutrient reserve for both calcium and phosphorus. This reserve is to the calcium (and phosphorus) functions of the body as body fat is to energy metabolism. Unlike most nutrient reserves, however, this one (bone) has acquired a distinct function in its own right, that is, mechanical and structural support. In other words, we walk around on our calcium reserve. It follows that any influence, nutritional or otherwise, that alters the size of the calcium reserve will alter bone strength.

Bone is a very rich source of calcium: Total skeletal calcium averages 1100 to 1500 g, and each cubic centimeter of bone contains more calcium than the entire circulating blood volume in an adult. Thus, in comparison with other nutrients, the calcium reserve is huge. Although lowcalcium diets usually deplete the bony reserves, they do so slowly. Thus, whereas the population-level risk of fracture rises immediately, it will take many years for bone strength to be sufficiently reduced to lead to a perceptible increase in an individual person’s risk of fracture.

Low intakes of calcium and phosphorus can both limit bone acquisition during growth and cause bone loss after maturity. Because human calcium requirements rise with age, and because calcium intakes tend to fall in elderly persons, precisely, such depletion occurs in most human

populations as they age.

Inadequate phosphorus availability also affects bone, but in a different way. The osteoblast environment is one of continuous mineralization, with the matrix extracting phosphate (as well as calcium) from the fluid bathing the bone-forming cells. Although calcium makes up approximately 40% of the bone mineral, phosphate accounts for nearly 60%. Thus, phosphorus is fully as important for bone building as is calcium. Rapid growth is not possible without a high blood phosphate concentration, a fact that explains the substantially higher blood phosphate values in children. When phosphate concentrations in the blood entering bone are low, mineralization extracts as much phosphate from the blood as it can, but in so doing, it creates a local environment severely depleted of phosphate. Osteoblasts, like all cells, need phosphate for their own metabolism. The result is serious interference with osteoblast function: matrix deposition is slowed, and osteoblast initiation of mineralization is reduced even more. These abnormalities produce the typical histologic pattern of rickets and osteomalacia in bone.

Vitamin D has many bony effects, such as facilitating the development of osteoclast precursors at an activated remodeling locus and augmenting osteoclast response to resorptive stimuli. The vitamin also stimulates synthesis and release of osteocalcin by osteoblasts. However, its major importance for bone is its facilitation of intestinal absorption of calcium (and to some extent phosphorus) from the diet. Severe vitamin D deficiency causes rickets and osteomalacia. Milder shortages of the vitamin reduce calcium availability to the body and produce a situation of calcium deficiency, resulting in osteoporosis. Because of the traditional identification of vitamin D deficiency with rickets and osteomalacia, it has been customary to refer to less extreme degrees of vitamin D shortage as insufficiency. This distinction is no longer useful. All degrees of vitamin D inadequacy that produce disease should be termed deficiency.

Vitamin K deficiency results both in undercarboxylation of osteocalcin and in reduced osteocalcin synthesis. The net effect of these changes on bone strength or integrity is not certain. However, low v itamin K status is associated in epidemiologic studies with low bone mass, increased hip fracture risk, and increased cardiovascular mortality.

Vitamin C and certain trace minerals (notably copper, zinc, and manganese) are important cofactors for the synthesis or cross-linking of matrix proteins. Copper is the cofactor for lysyl oxidase, the enzyme responsible for cross-linking collagen fibrils. Interference with crosslinking results in structurally weak bone. Ascorbic acid is also a required cofactor for the cross-linking of collagen fibrils; and in its absence, bone strength is impaired. In the presence of deficiencies of these micronutrients during growth, severe bone abnormalities can result. These abnormalities include stunting of growth, deformity of bones, and epiphyseal dysplasia. Whether adults can develop sufficient deficiencies of these nutrients to interfere significantly with bone integrity remains unknown.

Osteoporosis is a multifactorial condition of the skeleton in which skeletal strength is reduced sufficiently so that fractures occur on minor trauma. Generally, osteoporosis exhibits reduced bone mass (i.e., both matrix and mineral) as well as various microstructural disturbances of bony architecture. A simple decrease in quantity of bone is sometimes called osteopenia (literally, “shortage of bone”). Osteopenia is characterized by a BMD value at hip or spine between 1 and 2.5 standard deviations than 2.5 standard deviations below young adult normal are now called osteoporosis, whether or not a fracture is present. BMD is, unfortunately, a poor way to represent bone structural strength, because it explicitly eliminates the important influence of bone size. A larger bone with a lower density is usually stronger—less likely to fracture— than a smaller, denser bone.

A common feature of most cases of osteoporosis is elevated bone remodeling, particularly in postmenopausal women. Remodeling activity, although designed to repair weakened bone, actually makes it temporarily weaker during the remodeling process; and when remodeling is in excess of mechanical need, it causes only weakness. Estrogen deficiency, low calcium intake, and vitamin D deficiency all contribute to a harmful postmenopausal rise in bone remodeling.

Rickets is a disorder of the growth apparatus of bone in which the growth cartilage fails to mature and mineralize normally. Growth is stunted, and various deformities about the growth plates occur. Osteomalacia is the corresponding disorder in adults, in whom newly deposited bone matrix fails to mineralize adequately. New matrix formation is slowed in both conditions, but mineralization is retarded even more; thus, unmineralized matrix accumulates on microscopic bone surfaces. For this reason, the proportion of mineral to matrix drops. In severe cases, unmineralized bone may constitute so large a proportion of the skeleton that individual bones lose their stiffness and become severely deformed (bowed legs and misshapen pelves). The stereotypical forms of rickets and osteomalacia are those associated with vitamin D deficiency. The principal pathogenesis of these common forms follows from insufficient intestinal absorption mainly of calcium (and to some extent phosphorus) from the diet. In attempting to keep blood calcium concentrations close to normal values, the body raises PTH secretion. Rickets and osteomalacia also develop for reasons other than vitamin D deficiency, including extreme calcium deficiency, fluoride toxicity, and cadmium poisoning, as well as in association with certain rare vascular malignant diseases.

Paget’s disease is a local but often multifocal disorder of the bone remodeling process of uncertain etiology. Resorption proceeds erratically, with formation filling in with new bone behind it. Bone  architecture and even external bone shape are disordered. During the early resorptive phase, the bone is excessively fragile and may fracture readily. The high level of bone remodeling is usually accompanied by high concentrations of remodeling markers, particularly serum alkaline phosphatase. When the process involves the skull, bony growths may constrict the cranial nerve passages and may lead to deafness, for example. No nutritional correlates of this disorder are known.

Osteogenesis imperfecta (OI) is a group of heritable disorders in which one of several mutations may occur in the genes encoding for the collagen molecules that comprise the bulk of bone matrix. Patients with OI have fragile skeletons with reduced bone mass. In one of the common forms of OI, long bones typically have narrow shafts as well as reduced mass. Patients with OI commonly suffer many fractures throughout life, often starting in utero. Fractures heal normally.

Patients with chronic liver disease, but especially with biliary cirrhosis, commonly have a bone disease that is basically osteoporosis. Patients who are to undergo liver transplantation often have severe osteoporosis, attributable to a combination of the underlying disease, the immobilization that inevitably accompanies the severe disability of these very sick patients, and the treatments they have received.                 

Patients with end stage renal disease often have a complex bone disease consisting of a varying mixture of osteosclerosis, osteomalacia, and hyperparathyroid bone disease. Exact expression of these varied abnormalities depends on the medical regimens the patients receive, specifically the way in which these regimens manage calcium, phosphorus, and vitamin D metabolism for the patient. Patients with a variety of disorders of the small intestine, but especially those with gluten-sensitive enteropathy, malabsorb fat-soluble vitamins and hypersecrete calcium and magnesium into the digestive juices. As a result, these patients are commonly deficient in vitamin D, calcium, and magnesium. They often have severe osteoporosis and may have osteomalacia as well. Patients who have had organ transplants commonly have osteoporosis, in part because they present for organ transplantation with already reduced bone mass and in part because the immunosuppressive therapy used to sustain the transplant itself causes bone loss.

Aluminum (Al) is not strictly speaking a nutrient, but it is extremely common in the environment, is a major component of antacids, and is widely used as cookware. Only a small fraction of ingested Al is absorbed, and absorbed Al is promptly excreted in the urine in healthy persons. However, in patients with severely compromised renal function, particularly in those treated with large doses of Al-containing antacids to block phosphorus absorption, Al accumulates at the mineralizing sites of the bone remodeling process.

As noted, the cells of bone are as dependent on total nutrition as are other cells, and bone suffers in starvation just as do other tissues. However, bone strength is not immediately affected in acute malnutrition, especially in adults. The bony effects of protein-calorie malnutrition are most obvious in two situations: one is during growth, when both growth rates and bone mass accumulation are retarded by malnutrition; and the other is in the repair of fractures, especially in elderly persons. Protein-calorie malnutrition is common among elderly persons, and when they break a bone, such as the hip, serious complications and even death may ensue. Protein supplementation has been shown to reduce these complications substantially, and it is an important and necessary component of the treatment of most patients with hip fractures. The reason for the trophic effect of protein on bone is partly that dietary protein helps to sustain normal insulinlike growth factor-I (IGF-1) concentrations, needed for bone growth and repair, and partly that, as discussed, bone formation requires fresh dietary protein.

Magnesium deficiency occurs in severe intestinal malabsorption (e.g., gluten-sensitive enteropathy, fistulas, or ileal resection, especially with high-fat diets) or with urinary losses from renal tubular defects. Initially, magnesium deficiency impairs bony responsiveness to PTH and thus leads to hypocalcemia despite a rising PTH level. As deficiency progresses, parathyroid response falters, and PTH secretion falls. The hypocalcemia of magnesium deficiency is thus the result of impairment of the calcium regulatory system and is unresponsive to calcium supplementation. Less severe degrees of magnesium deficiency in these same syndromes are associated with reduced bone mass, also unresponsive to calcium supplementation. In addition to other needed treatments (e.g., calcium), magnesium supplements are necessary in these patients. Finally, silent magnesium deficiency often accompanies low vitamin D status. The mechanism is uncertain. The deficiency manifests itself as a failure to elevate PTH secretion in response to the poor calcium absorption of vitamin D deficiency.

As noted, the effects of nutrient deficiencies on the skeleton express themselves slowly in adults. For this same reason, nutrient effects on the skeleton of any kind are difficult to detect and easy to misinterpret.