YEARBOOK OF PHYSICAL ANTHROPOLOGY 33:151-194 (1990)

Osteoporosis: Etiologies, Prevention, and Treatment

WILLIAM A. STINI Department of Anthropology, University of Arizona, Tucson. Arizona 85721

KEY WORDS Bone, calcium homeostasis, industrialized countries

ABSTRACT W-ith the steady increase in life expectancies occurring in industrialized countries have come major changes in the causes of morbidity and mortality. The greatest burden on the health care delivery systems in these countries has shifted from the treatment of infectious diseases to extended care of degenerative conditions. One such condition of increasing widespread concern is osteoporosis. Chronic bone loss leading to fractures and secondary infections has become a major problem in the United States, and has been estimated to cost $6 to $8 billion annually.

The etiology of osteoporosis is complex, depending upon the interaction of nutritional, endocrinological, and local factors that are subject to a variety of genetic and environmental influences. The stringent requirement of maintaining calcium homeostasis places heavy demands on the primary reservoir of calcium, the skeleton, when intake andlor absorption are inad- equate. Inactivity, depriving bone of its weight-bearing function, also ini- tiates bone resorption. Under normal circumstances in the young adult, bone is maintained through continual, balanced turnover of mineral and calcium. When this balance is upset, loss of bone can be slow or rapid, reversible or irreversible. The trabecular compartment with its high sur- face-to-volume ratio is most rapidly mobilized, but cortical bone is ulti- mately resorbed as well.

Involationaf osteoporosis is conventionally designated as either type i I postmenopauqali or type I1 senile:. Women are affected by both and, be- cause of a generally less-robust skeleton, experience risk of fracture earlier than men on the average.

The hormonal and physiological factors involved in the regulation of nor- mal bone physiology and the factors leading to loss of bone mass constitute an area of active research that is casting light on the fundamental mecha- nisms underlying bone growth and maintenance in the search for new av- enues of prevention and treatment of osteoporosis.

Currently the fastest growing segment of the population of the United States is the age group 85 years old and older (United Nations, 1986). The increasing num- bers of elderly citizens of both sexes have changed the countrys demographic profile but the proportion of women living to advanced age has had singular im- pact. In North America in 1984, males outnumbered females by about 1 million (29 million to 28 million) up to the age of 15 years, but in the age group 65 years old and older, females outnumbered males by 6 million (18 million women, 12 million men) (Stini, 1987). Beyond age 65 years, the disparity in survival continues to grow. In the age group 80 to 84 years, the death rate is currently 107.0 per 1,000 for males and 66.9 per 1,000 for females. Thus, the population of the United States

0 1990 Wiley-Liss, Inc.

152 YEARBOOK OF PHYSICAL ANTHROPOLOGY [Vol. 33, 1990

is not simply aging, but is composed increasingly of aging women. The impact of these demographic changes on the health care delivery system is already of wide- spread concern (Phillips et al., 1988).

Discussions of prioritization and rationing of medical services often center on the degree to which society can afford to allocate scarce resources to the maintenance of patients who are chronically impaired with little hope of recovery (Aaron and Schwartz, 1990). As the demographic trends cited above produce a steady increase in numbers of postmenopausal women in the population, the costs of care and treatment of patients afflicted with one or another form of bone loss will increase dramatically. The impact of this increase is already being felt in the United States where the direct costs of the various forms of bone loss broadly subsumed under the heading of osteoporosis were estimated to be in the range of 6-8 billion in 1986 dollars (Heaney, 1989a,b). In terms of the worldwide impact of the increased size of populations at risk for osteoporosis, we are only seeing the tip of the iceberg. The demographic trends pmdwing tbe high proportion of post:::eaopauaal wuiiieii iri the Western industrialized nations are also being manifested in developing coun- tries such as India. In the third world, the health care infrastructure is much less prepared to cope with the problems of large numbers of patients suffering from chronic and disabling conditions such as osteoporosis and hip fractures (Stini, 1987).

Why does the aging process produce increased risk of fractures? In order to understand the relationship between aging and bone loss it is necessary to appre- ciate the dynamic nature of bone and its continual interaction with other tissues. While the skeleton is most readily perceived as a rigid structural framework that protects and supports the bodys soft tissues, its role as a reservoir of mineral and as a buffer of the body fluids is equally important. In fact, the physiology and biochemistry of bone are intimately linked to such important processes as the immune response, muscle contraction, and nerve impulse transmission in a variety of ways. A major component of this interaction is ionic calcium, which is a major secondary intracellular messenger and a regulator of muscle contraction. Calci- ums physiological importance preceded the evolution of bone and, not surpris- ingly, its physiological functions still hold a higher priority than its structural role. Thus, the requirements of other systems are often met a t the expense of bone. Osteoporosis, broadly defined as the loss of bone, is best viewed as the result of a perturbation of the dynamic equilibrium through which bone and other systems satisfy their needs for calcium. It is therefore essential to approach the problem of osteoporosis by the ascertainment of the role of calcium in human physiology and the means hy which normal physiolagical levels of calcium are maint.ained. Ey using this approach, i t can bc scen how Lhe cells aid tissues of bone are cxqnisite!:s- attuned to the task of maintaining mineral homeostasis. It is also clear that there are many etiologies by which osteoporosis can occur and, therefore, a range of potential interventions. The present review will attempt to integrate the biochem- ical and physiological aspects of calcium metabolism with the cytological and his- tological characteristics of bone. The goal is to relate structure to function and, ultimately, malfunction. If this is done successfully, the apparent contradictions concerning the etiology of osteoporosis found in the rapidly expanding literature on the subject will, to some degree, be less confusing.

CALCIUM Physiological role

The calcium ion is now widely accepted as the most fundamental regulator of intracellular processes of all living organisms (Ebashi, 1988). The normal calcium concentration in human blood is 10 mg%. The tolerable range is generally stated as 7-13 mg%. Below 7 mg% there is danger of tetany and above 13 mg% soft tissue calcification can occur. The physiological importance of calcium derives from a number of essential functions that depend upon its presence in its ionic form.

Calcium deficiency inhibits cardiac excitation-contraction coupling. The result is

Stini I Osteoporosis: Causes and Treatment 153

a decline in contractile force without major change in single fiber action potentials (Fleckenstein, 1988). Calcium-dependent myofibrillar adenosine triphosphatase (ATPase) transforms phosphate bond energy into mechanical work. Channels in the surface membranes of many cells are formed by integral membrane proteins forming pores that allow calcium to enter the cell. The number and types of chan- nel are associated with particular kinds of tissue. The more rapid T channels and the slower L channels are both found in smooth, cardiac, and skeletal muscle. Activation or blockage of these channels can have profound effects on heart rate and blood pressure (Bolton et al., 1988). Neurons display three types of channels (Nowycky et al., 1985). In muscle contraction as well as in cytoplasmic streaming of cells, calcium acts as a regulator through its interaction with contractile pro- teins. In skeletal muscle, the attraction of calcium to a specific site on the troponin molecule potentiates the movement of tropomyosin that in turn allows actin and myosin to interart, hydrolying adenosine triphosphate (-4TP) to re!czsc ccergy during the contraction cycle.

Calcium ions play a major role as an intracellular messenger, often acting in concert with cyclic adenosine monophosphate (AMP) to determine the reactions of glandular cells that influence a wide range of physiological mechanisms (Rasmus- sen, 1989). Cytotoxic T-cells also use calcium ions in the mechanisms leading up to the lysis of target cell membranes (Young and Cohn, 1988).

Maintenance of a calcium reservoir Commensurate with the importance of calcium in so many essential processes,

the creation and mobilization of a calcium reservoir has a high priority. Short- and long-term withdrawals of calcium to maintain normal serological concentrations are facilitated by a series of responses beginning with the freeing of protein-bound calcium circulating in the blood and ultimately progressing to the resorption of calcium from the lamellae of cortical bone. Endocrine hormones emanating from the thyroid, parathyroids, adrenals, ovaries, and testes all participate under var- ious circumstances in the movement of calcium from one tissue compartment to another. When the dietary intake of calcium is adequate and when absorption is normal, bone turnover occurs a t a relatively low rate. When calcium intake, bio- availability, or absorption fall below normal levels, when perturbations in endo- crine function occur, and when inactivity or a variety of physiological malfunctions upset serum calcium balance, turnover rates increase and bone mineral is re- sorbed.

The calcium content of an adult, human body will range from 1,200 g ti? 1,500 g (Norman, 1990). Ninety-eight percent, of total calcium i s found in t.he skeletor?: which weighs from 2.8 to 4.0 kg, organic and inorganic components combined. Womens values cluster near the low end of this range and mens near the upper end although there is a substantial zone of overlap of male and female distribu- tions. In order to attain adult skeletal mass, it is necessary to maintain a net positive balance of 100 mg per day from birth to the onset of puberty (Garn, 1981; Norman, 1990). The rate of retention during puberty climbs to about 200 mg per day in females and about 280 mg per day in males. Since absorptive efficiency for calcium varies, the amount of dietary calcium needed to sustain these rates of retention could require an intake of as little as 400 mg per day for an adolescent male with an absorptive efficiency of 7596, to as much as 1,200 mg per day for an adolescent male with a n absorptive efficiency of 25% (Garn, 1981). In most in- stances, the latter value is not sustained. It is generally believed, however, that the efficiency of absorption declines with increasing dietary intake and therefore the higher efficiencyllow intake example may be the more realistic one.

Calcium turnover If a normal adult male consumes 1,000 mg of dietary calcium per day, approx-

imately 700 mg will be absorbed in the intestine. However, 600 mg will normally be secreted into the intestinal lumen resulting in a net uptake of only 100 mg.

154 tVo1. 33, 1990

Fig. 1. Calcium and phosphorus homeostasis. Dietary intake is 1,000 mg per day calcium and 900 mg per day phosphorus. Calcium entries are ~n rectangles and phosphorus entries are in ovals (from Nor- man, 1979).

Therefore 900 mg of ca!ciam i s lost in the feces, The newiy absorbed 700 mg will eventually enter the exrraceiiuiar fiuid e o m p a r ~ ~ e ~ t which will maintain a pooi of approximately 900 mg of calcium. Over a period of time much of the calcium in the extracellular fluid compartment will enter cells, becoming part of the 1,000 mg intracellula~~ pool of calcium. Some calcium from extracellular f h id will reenter the blood, pass through the kidney, and be lost in the urine. This loss will average 40 mg per day. About 60 mg per day will also be lost in sweat. Thus, under conditions of homeostatic balance, the 1,000 mg of calcium ingested in the diet is offset by 900 mg lost in feces, 40 rng in urine, and 60 mg in sweat (see Fig. 1).

The calcium present in bone is also in a continual state of turnover. The rapidly exchangeable component of bone mineral permits the turnover of 20,000 mg of calcium per day while the more slowly exchangeable component contributes an additional 300 mg. The total exchangeable component o f bone includes a pool of 4,000 mg of calcium present in the skeleton at any given time. The stable compo- nent of bone is also far from inert, although the proportion of turnover i s much lower than that of the exchangeable component. Of the approximately 1 kg of stable bone mineral, about 300 mg will be added each day by accretion while 300 mg is lost by resorption. The dynamic nature of the calcium pool is such that many factors can alter turnover and produce either a positive or negative imbalance.

Stinil Osteoporosis: Causes and Treatment 155

Factors that alter intestinal function either by increasing or decreasing absorption or secretion can lead to substantial alterations in the rate andlor direction of turnover. The same can be said for changes in kidney filtration and reabsorption. Increased excretory loss of calcium will result in a reduced concentration of cal- cium in the extracellular fluid which must then in most cases be compensated for by increased withdrawal from bone (Hegsted, 1986).

The entire extracellular pool turns over between 40 and 50 times per day. The glomerular filtration rate for calcium is on the order of 10,000 mg per day but renal tubular reabsorption is highly efficient accounting for the low rate of calcium loss normally occurring in the urine. Even when serum calcium levels rise excessively, compensatory excretion of urinary calcium rarely exceeds 600 mg per day. How- ever, when intake or absorption of calcium fall to very low levels, continuous loss of calcium in the urine can have a significant effect that will be reflected in loss of honc ~ ~ , i n ~ r d , the ultimate reservnir for the maintenance of calcium homeostasis (Nordin, 1986).

Calcium absorption Calcium is usually ingested in the form of one of its compounds. In some areas,

drinking water may provide some calcium in ionized form, but this is usually not a significant proportion of the overall daily requirement. The efficiency with which ingested calcium is absorbed varies for a variety of reasons. Even large quantities of ingested calcium may be insufficient (Barrett-Connor, 1989) under certain con- ditions. Lactose intolerance and maintenance of a low-cholesterol, low-calorie diet may have the side effect of limiting calcium intake so that even an efficient cal- cium absorber is unable to derive enough calcium from the diet to offset losses to sweat and urine (Griessen et al., 1989).

The presence of specific compounds in particular foods also affects calcium ab- sorption. For example, phytates present in the gut due to the digestion of bran can interfere with absorption by chelating calcium and carrying it through the intes- tine to be lost in the feces. Although considered beneficial for many reasons, high- fiber diets have the potential to reduce calcium absorption by increasing the bulk of the intestinal contents and reducing transit time during which absorption can occur. Although spinach is rich in calcium, it is poorly absorbed in the human intestine because of the simultaneous presence of oxalates (Heaney, 1988). Animal experiments have shown that the oxalates of spinach reduce calcium absorption in other species as well (Poneros-Schneier and Erdman, 1989; Weaver et al., 1987; Wien and Schwartz, 1983): On the other hand, when kale? a low-oxalate vegetable containing pectines and other plant. fibers typical of greens is consumed, high levels of calcium absorption occur. Heaney and Weaver (1990), using an intrinsically labeled kale were able to demonstrate fractional calcium absorption of 40%, equal or superior to that associated with milk calcium. Kale is one of the varieties of Brassica oleracea, several members of which (including broccoli) are known to be rich in calcium. Other members of the genus Brassica having greens rich in ab- sorbable calcium are turnip, collard, and mustard. All of these are characterized by low oxalate content.

Recent work suggests that interactions between different ingested foods can affect calcium absorption. For example, Heaney and Weaver (1989) found that when milk and calcium oxalate were ingested together, oxalate did not interfere with the absorption of milk calcium. The oxalate calcium was absorbed more poorly than the milk calcium but still better than spinach calcium.

In an effort to measure the effect of calcium supplements and milk on calcium balance, Lewis et al. (1989), conducted a metabolic balance study on 8 adult males over a 56-day period. They found that milk and supplements had no appreciable effect on calcium balance in their subjects. This would seem to contradict the results of a study conducted by Schuette et al. (1989), who found that lactose or its component sugars enhance jejunal calcium absorption in proportion to their effect on fluid absorption. The apparent contradiction may arise from potential differ-

156 YEARBOOK OF PHYSICAL ANTHROPOLOGY

TABLE 1 Prevalence of gastric atrophy with increasing age

[Vol. 33, 1990

Age (years) Percent atrophic 60-69 24 70-79 32 ,80 37

ences in the degree to which lactose was broken down to its constituent sugars, glucose and galactose. The enhancement of calcium absorption by glucose in the human intestine has been reported by a number of investigators (Monnier e t al., 1978; Norman et al., 1980; Wood, 19871. Wood (1987) also noted that glucose polymers enhance calcium bioavailability, confirming the role of glucose while not necessarily excluding dii eiilidixiug effecL by galactose.

It is generally accepted that calcium supplements are best absorbed when taken with a meal. In a recent study, Heaney et al. (1989~) found that the co-ingestion of calcium supplement and a light meal of varied composition enhanced calcium absorption efficiency by 10% to 30%. The solubility of the calcium supplement will of course affect its absorption efficiency. Calcium carbonate, the most-frequently used form of calcium supplement, is not the most soluble. Nor are calcium phos- phate, calcium gluconate, calcium fluoride, or calcium chloride. The most avail- able calcium is that taken in the form of calcium citrate or calcium pidolate (Bel- lony et al., 1989; Harvey et al., 1988). There is also evidence that the presence of certain amino acids, one of them L-lysine, enhances calcium absorption (Civitelli e t al., 1989).

The role of the gastrointestinal tract Because the solubilization of calcium compounds is essential for absorption, the

normally acid environment of the stomach is an important component of calcium digestion. Thus, conditions such as achlorhydria, quite common in older people, have the affect of reducing absorption efficiency. The use of aluminum-based ant- acids can simulate or aggravate this reduction in stomach acidity.

The absorptive capacity of the intestine declines in old age for a number of reasons, not all affecting the absorptive efficiency relating to calcium, but none- theless of importance in bone maintenance. Gastric secretion of both hydrochloric acid and of pepsin decline with age. Also, the secretion of intrinsic factor decreases. reducing the absorpkon of vitamin BIZ. Pancreatic secretion also diminishes. re- sulting in lower concentrations of severai important digestive enzymes in the small intestine. Liver size and blood flow decline, additionally reducing the rate of absorption and utilization of nutrients. Although fat absorption does not appear to decrease substantially with age, i t does appear that the ability to cope with very high intakes of fat is reduced. Similarly, normal protein intake is absorbed as well by the older intestine as in early adulthood, but at intakes exceeding 1.5 gikg, nitrogen secretion increases. Lactase production declines and consequently lactose intolerance increases. The beneficial effects of glucose in calcium absorption are therefore reduced in many older people. There are indications that diets containing mixtures of carbohydrates are absorbed less effectively in the older intestine, pos- sibly indicating a change in gut flora. The rise in pH of the proximal intestine following reduction in gastric acidity potentiates bacterial overgrowth. The in- creasing prevalence of gastric atrophy producing these changes with increasing age is shown in Table 1.

As a result of the changes taking place in the intestine, the ability to increase absorptive efficiency when calcium is present in low concentrations in the gut is lost in old age. Consequently, the minimum quantity of ingested calcium needed to maintain homeostasis rises with age. The system of calcium absorption is satura- ble a t all ages, there being an upper limit to the amount absorbed when very large amounts are ingested. It is estimated that in a normal young adult 400-500 mg

Stinil Osteoporosis: Causes and Treatment 157

LACTATION 400

PREGNANCY . .

1100

Ca INTAKE ( W d a y ) -200

Fig. 2. Calcium absorption as related to calcium intake and physiological states (from Norman, 1990).

must be ingested per day to effect a net absorption of 100-150 mg (Norman, 1990). Because several factors lead to decline in absorption in older people, the amount of calcium ingested should be increased in compensation.

Calcium absorption rates also undergo changes at other stages in human life. The most dramatic shifts occur during puberty and again during pregnancy and lactation (Nordin, 1988). These changes indicate an adaptive capacity to alter absorption efficiency when the need is greatest (see Fig. 2).

Population differences in calcium intake Comparison of populations show that there is a broad range of calcium intake in

different parts of the world. Sustained intakes ranging from a low of -300 mg!day in parts of Japan and India to as high as 1.300 mglday in Finland demonstrate that the human intestine is capable of adjusting absorption rates not only in response to changing needs experienced at different stages of the life cycle but also in response to sustained demands imposed by environmental factors (Food and Ag- ricultural Organization, 1961, 1976). Much still remains to be learned about the extent to which the aging intestine can make adaptive changes to maintain cal- cium homeostasis.

Because of the multiplicity of factors capable of altering the amount of calcium absorbed, the recommended daily intake remains an area of considerable disagree- ment. The value of calcium supplementation is not universally accepted, especially with respect to the most widely used calcium carbonate tablets. However, there is general agreement that adequate intake of calcium is important up to the attain- ment of peak bone mineral content (Matkovic et al., 1987; Tylavsky et al., 1989). More will be said on recommended daily allowances in a later section.

The role of vitamin D in calcium absorption Vitamin D stimulates calcium absorption in the intestine at all levels of calcium

intake. Its stimulatory effect is most pronounced when calcium intake is low and i t declines when calcium is abundant (Norman, 1990). Some calcium absorption occurs even in the absence of vitamin D, but i t would not be sufficient to maintain

158 YEARBOOK OF PHYSICAL ANTHROPOLOGY IVol. 33, 1990

I- Fig. 3. Norman, 1990).

The vitamin D endocrine system and the maintenance of homeostatic calcium level (from

homeostasis on a sustained basis. Vitamin D is produced in the skin when ergos- terol is irradiated by ultraviolet light. Relatively little exposure of the skin is needed to satisfy normal physiological requirements. With ultraviolet radiation ergosterol is converted to cholecalciferol (vitamin D3), which enters the circulation and is carried to the liver (see Fig. 3 ) . There it is hydroxylated, to produce 25- OH-D,. The 25-hydroxycholecalciferol reenters the circulation and is carried to the kidney where i t is again hydroxylated. Two forms of dihydroxycholecalciferol emerge from the kidney. These are 1,25(OH),D3 and 24,25(OH),D,. Thus, at any time, four forms of vitamin D, may be present in the blood. Both of the hydroxy- lases producing the two forms of dihydroxycholecalciferol are found in mitochon- dria of proximal tubules of the kidney. They are enzymes with properties similar to other steroid hydroxylases present in adrenals, ovaries, and testes (Deluca, 1979).

Receptors for 1,25(OH),D3 have been identified in the intestine, in kidney, and in bone (Haussler, 1386, Norman, 1979.1984,1985; W-alters. 1985). More recently. the 1.25iUHr2rJ, receptor has aiso beer, foilnd in skin, brain, pancreas, pituitary, and gonadal tissue as well as in a number of cancer cell lines. Presence of receptors in this wide variety of target cells raises the suspicion that the vitamin D endo- crine system has additional, as yet unidentified functions. One such function im- plicated in the regulation of the immune system has been reported by Rigby (1988). This should perhaps come as no surprise in view of the common stem cell origins of bone and immune cells and their shared response to several cytokines. Recent cloning experiments have shown that the 1,25(OH),D, receptors of both humans and birds are members ofa family of receptors that also includes those for estrogen, progesterone, glucocorticoid, thyroxin, aldosterone, and retinoic acid (Minghetti and Norman, 1988).

The range of functions of the vitamin D endocrine system is now known to include besides the intestinal, kidney, and bone elements of calcium homeostasis, regulation of the differentiation of epidermal and hemopoietic cells, and of insulin secretion. Also, i t plays a role in oncogene expression (Nemere and Norman, 1982; Reichel e t al., 1989).

In the intestine, 1,25(OH),D, regulates calcium absorption by two different mechanisms (see Fig. 4). One mechanism is very rapid, occurring over a time span

Stinil

LUMEN

Osteoporosis: Causes and Treatment

BRUSH MUCOSAL CELL

159

I lK 111 FACILITATED INTRACELLULAR ACTIVE TRANSPORT

Active transport Mi tochondrial Energy dependent +ionic diffusion binding

DIFFUSION MOVEMENT

Fig. 4. Intestinal calcium absorption as mediated by 1,25(OH),D, (from Norman, 1990).

of minutes. The other involves gene transcription and is slower, taking place over a period of hours to days. The latter is the major mechanism; it involves direct interaction of the hormone-receptor complex with nuclear DNA resulting in pro- duction of messenger RNA that codes for proteins involved in intestinal absorption of calcium. One such calcium-building protein (CABP), calbindin-D,,, (Was- serman and Taylor, 1966) is found in the intestine in concentrations that increase proportionally with the rate of calcium absorption and in inverse proportion to the amount of calcium present m the intestine (Christakos et al., 1979; Wasserzliail and Taylor, 19681.

The cytosol of intestinal mucosal cells involved in the absorption of calcium contains receptors that are highly specific for 1,25(OH),D,. Their specificity is so well defined that they bind 1,000 times more tightly to 1,25(0H),D, than to the intermediate 25-hydroxyvitamin D,. No binding at all takes place with the parent vitamin D (Norman, 1990). The receptor-1,25(OH),D3 complex transits the nuclear membrane and interacts directly with DNA. When blood calcium levels are low, the localization of 1,25(OH),D, in the chromatin is maximal a t 2-3 hours after entering the cell. Production of messenger DNA reaches maximal levels 2-3 hours later and calcium absorption peaks 6 hours after maximal RNA production. The sequence of events can be sustained as long as low serum calcium levels stimulate the production of 1,25(0),D,-l-hydroxylase in the kidney. The continued produc- tion of 1,25(OH),D, maintains its high serum concentration and continued move- ment into the cytosol of intestinal mucosal cells. Negative feedback occurs when blood calcium concentration returns to normal physiological levels.

As mentioned earlier, in addition to the slower, gene-mediated action of 1,25(OH),D,, a rapid increase in calcium absorption with a time course measured in minutes rather than hours has also been described (Nemere et al., 1987; Nemere and Norman, 1987; Norman and Ross, 1979; Okamura et al., 1974; Wing et al.,

160 YEARBOOK OF PHYSICAL ANTHROPOLOGY IVOl 33, 1990

1974). This process, called transcaltachia, is thought to involve the interaction of 1,25(OH),D, with the cholesterol component of the target cell membrane in a manner similar to that known to occur with the antibiotic filipin. Filipins inter- action with membrane cholesterol appears to induce the formation of calcium- selective pores. In vitro experiments wherein chick intestinal membranes were treated with filipin induced calcium absorption similar to that induced by 1,25(OH),D, (Wong and Norman, 1975). Transcaltachia does not take place when blood calcium levels are high. This indicates a negative feedback system that prevents dangerously high blood calcium levels even in the presence of 1,25(OH),D, in pathologically high concentrations. The mechanisms by which transcaltachia works are thought to include microtubule reorganization, vesicle formation, and transport from the lumenal to vascular surfaces of the cell. Tran- scaltachia is inhibited by the antimicrotubular agent colchicine but is unaffected Ly d ~ ~ ~ i l W I I l y C i l i B wh:cn suppresses DNA transcription,

THE CELLS THAT FORM, MAINTAIN, AND DESTROY BONE

Adequate intake and absorption of calcium and phosphorus are necessary but not sufficient to insure calcium homeostasis. A number of factors can cause loss of calcium from the skeleton even when calcium availability is adequate. The dy- namic equilibrium that characterizes the physiology of bone can be upset in a variety of ways. The specialized cells that are responsible for bone growth (osteo- blasts), bone maintenance (osteocytes), and bone resorption (osteoclasts) must all function in a n intricate pattern of interactions that can be disrupted with patho- logical effects on bone. The regulation of these interactions involves both local and humoral factors. The important role played by factors secreted by immune cells in the regulation of balance between bone formation and resorption is becoming bet- ter understood with the availability of purified preparations of products produced by cells that influence activities of bone cells. Some of the substances that affect bone remodeling also have the ability to accelerate blood cell production in the marrow. Substances such as the colony-stimulating factors CSF-G and CSF-GM are now known to have effects on a number of target cells, the precursors of osteoclasts among them.

Osteoblasts and osteocytes and bone lining cells Osteoblasts originate from mesenchyme, undifferentiated cells of mesodermal

origin. Therefore, they share a common origin with cells of the hemopoietic and immune system (Ortner, 1976, Ustajblaats that reniairi in the iacunae o f hone continue t u Ftinctjan as osteo s i ney remain ID comrnunicat?on with t he vas- cular system via the endolymph surrounding them in the lacunae and in the canaliculi that interconnect throughout the lamellae of compact bone. They are therefore able to participate in the maintenance of serum calcium homeostasis (Shipman et al., 1985; Stern, 1988). Remodeling of compact bone occurs along the canaliculi as well a s along the borders of the marrow cavity. The transition from the status of osteoblast to that of osteocyte is marked by cessation of alkaline phosphatase synthesis (Doty, 1981). Within the lacunae, osteocytes are surrounded by a layer of more-permeable bone, 0.5-2.0 pm thick, that Frost et al. (1960) refers to as the halo volume. This bone is presumably more readily available for ex- change and its presence can only be detected in fresh samples of bone.

The relationship between osteocytes and bone lining cells, whose processes ex- tend into the canaliculi, is a matter of considerable interest. These cells are flat and in direct apposition to the surface of bone. Their cytoplasm is spread thinly over bone and their membranes form gap junctions with other bone lining cells as well as with osteocytes, thus indicating active exchange between cells. Lining cells are not in direct contact with bone crystals but maintain a narrow seam in which fluid accumulates (Miller and Jee, 1987; Vanderwell, 1981). While thought not to participate in bone turnover, these cells may act as support cells for osteocytes and act to partition bone extracellular fluid from interstitial fluid. If they play a role

-1

Stinil Osteoporosw Causes and Treatment 161

in resportion, it may be simply one of moving away from areas to be resorbed and exposing areas of bone to osteoclasts.

Baud and Bolvin (1981) have observed that the level of osteocyte activity seems to depend upon the cells proximity to more active surfaces of bone. Boyde (1981) argues that osteocytes themselves are not involved in bone resorption and that their production of microfilaments and lysosomal vesicles may only be related to anabolic processes.

Osteoclasts The major entities of bone modeling, remodeling, and resorption, however, are

the osteoclasts. These cells are of hemopoietic origin, arising from precursor cells originating in marrow and released into the blood. They are multinuclear, some having as many as 50 nuclei. Their formation is the outcome of interaction of bone marrnw lymphocytes and cells o f the monocyteimacrnphage line The lymphokinw and cytokines secreted by these cells also appear to activate mature osteoclasts (Baron et al., 1983; Mundy, 1988). In fact, regulation of the balance between bone formation and resorption is a t least in part under the control of cells of the immune system, located in discrete regions of bone. These local factors act in concert with humoral factors circulating in the blood stream including the several forms of vitamin D,, parathyroid hormone, and calcitonin (Mundy and Roodman, 1987).

The early stages of osteoclast production appear to be in response to the presence of Colony-Stimulating Factor (CSF), which is produced by many types of cells. Although CSF appears to play an important role in the developmentof osteoclasts from their precursor cells and their migration (Barnes, 1987) i t does not appear to stimulate existing osteoclasts to resorb bone. Two types of CSF, one of which controls macrophage production (CSF-M) and the other which regulates differen- tiation of the precursors of granulocytes and macrophages (CSF-GM), stimulate proliferation of osteoclast precursors.

Mundy and Roodman postulate a collection of local factors, produced by lympho- cytes, monocytes, and macrophages in the marrow, that promote the next stage of osteoclast formation. Among these local factors they include interleukin-1, trans- forming growth factor a (TGF-a), tumor necrosis factor a, and tumor necrosis factor P (lymphotoxin) (Felix et al., 1989). Osteoclast precursors are attracted to bone surface, possibly by the presence of osteocalcin (Gla protein). There, 1,25(OH),D3 and parathyroid hormone (PTH) are thought to act synergistically to cause fusion of precursors forming mature, multinucleated osteoclasts. When they have achieved this level of maturation, osteoclasts are responsive to lyrnphokines and cytokines produced by cells in the marrow and will begin the process of re- sorption. Prostaglandin E,, which is produced by many cells of the monocyte- macrophage line as well as by osteoblasts, is also known to have a resorption- stimulating effect (Harvey et al., 1989; Lidor et al., 1989; Stewart and Stern, 1989).

It is thought that neither local factors nor systemic factors act on mature osteo- clasts directly. Instead, their presence stimulates an intermediary which in turn stimulates the osteoclast to begin the process of resorption. At present, the prime candidate for the role of intermediary is the osteoblast or an osteoblast precursor (Meghji et al., 1988). Both categories of cell are known to produce prostaglandin E,, but their stimulatory effect may be the result of other, as yet unidentified osteo- clast-activating factors (OAF) as well. Parathyroid hormone, cytokines, and growth factors all have the capability of increasing prostaglandin production while the antiinflammatory glucocorticoids, 1,25(OH),D,, epinephrine, and estradiol, can all suppress it, as can nonsteroidal antiinflammatory drugs (NSAID). Other inhibitors of osteoclastic resorption include calcitonin (CT) produced by the thy- roid, while gamma interferon (INF-7) is thought to be a potent inhibitor of osteo- clast formation, as is transforming growth factor p (TGF-P).

When activated, osteoclasts resorb bone through a combination of lysosome-like activity and formation of many low pH compartments alongside the surface of the bone. This process can be visualized as similar to the placement of a cup upside

162 YEARBOOK OF PHYSICAL ANTHROPOLOGY lV0l 33,1990

down on the surface of a table. The cup seals off an area of the surface into which are secreted protons and lysosomal enzymes. The highly acidic environment cre- ated in this compartment dissolves bone mineral, freeing ionic calcium from crys- tals of calcium hydroxypatite at the surface (de la Piedra et al., 1989; Stepan et al., 1989a,b). At the same time, lysosomal enzymes digest the organic matrix and other proteins present in the resorption compartment. The protons secreted into the compartment may be produced by the action of carbonic anhydrase, which forms bicarbonate from carbon dioxide and water. The result is the formation of a re- sorption lacuna with the transient appearance of spicules of unresorbed bone as the surface erodes.

The movement of protons across the osteoclast membrane is accomplished by two different pumping mechanisms. One requires the presence of ATP-ase which leads to the exchange of protons and potassium ions, the same mechanism that produces stomach acid. It is also possible to simply pump protons into the resorption cavity as occurs in the kidney. An additional possibility is an ATP-ase that exchanges sodium for por;assmm, setting up an ionic gradient that wouid allow the infiux of ionic calcium from bone into the resorption cavity (Barnes, 1987).

Once begun, osteoclastic resorption of bone continues for about 10 days and then stops. Calcitonin can stop it at any time before i t runs its course. But other osteo- clasts can mature and become active with the result of sustained resorption under the appropriate circumstances. Over a period of years, all bone undergoes resorp- tion and turnover is a part of the process of continual remodeling. However, prob- ably no more than 5% of total bone surface is undergoing such turnover at any one time when the system is in normal equilibrium. Trabecular bone, which consti- tutes about 20% of total bone mass, has a turnover rate eight times more rapid than cortical bone because its total exposed surface is much greater (Dodds et al., 1989; Genant et al., 198913; Kumar and Riggs, 1980). The action of osteoclasts on cortical bone is limited to the surfaces adjacent to the endosteum and the perios- teum and in canaliculi. There is also a general predominance of endosteal over subperiosteal resorption underlying the remodeling pattern seen in long bones such as the metacarpals and radius.

The role of osteoblasts in the remodeling process Under normal circumstances, bone resorption by osteoclasts has a stimulatory

effect on osteoblasts near the perimeter of the resorption cavity. Osteoblasts arise from precursors that also may differentiate to produce fibroblasts, chondrocytes, or adipocytes (Stern, 1987, 1988). Since the mature osteoblast i s active in the syn- thesis and secretmn of a number of siibatances. it 1s endowed with a large GoIgi zone and abundant rvugli endopiasrnie reticui1um 1 Wooliand St. John D:xon, 1988;. Both osteonectin and osteocalcin (Bone-Gla protein) are secreted by osteoblasts and are used as markers of bone formation (Azria, 1989; Bar-Shira-Maymon et al., 1989; Delmas, 1989; Urist, 1986; Wallach, 1989). Collagenase, which degrades collagen, removing its surface proteins and facilitating osteoclast destruction of matrix, is also produced by osteoblasts. Alkaline phosphatase, which is a regulator of the mineralization process, and prostaglandin E, are additional products of osteoblast synthesis (Azria, 1989; Bar-Shira-Maymon et al., 1989; Harvey and Bennett, 1988; Nagai, 1989; Rodin et al., 1989; Whyte, 1989).

The primary function of the osteoblasts in bone formation is the synthesis of collagen. In their earlier stages of development, osteoblasts undergo a process of development very similar to that undergone by osteoclasts. Their precursors pro- liferate and migrate to the sites where resorption has occurred. There, they dif- ferentiate into mature osteoblasts and are eventually activated to begin producing collagen and participate in the process of mineralization. It has been estimated that by the time the mature osteoblast is ready to perform its definitive functions it is 3 to 4 months past the precursor stage. A number of factors serve to modify the early stages of osteoblast development. Among the local factors is bone-derived

Stinil Osteoporosis Causes and Treatment 163

growth factor (BDGF), which stimulates an increase of DNA synthesis of about 50%.

Other local factors influencing osteoblast development are interstitial growth factor (IGF) and TGF-f3 both originating in bone cells. Cartilage-drived growth factor (CDGF), produced by cartilage along with IGF also influence osteoblastic development and activity. It is also believed that factors originating in matrix have an effect on the development and activation of osteoblasts. These include skeletal growth factor (SGF), fibroblast growth factors (FGF), and platelet-derived growth factor (PDGF). It appears that while a number of factors exert their effects on all phases of osteoblast activity others have more limited effects. TGF-P, for instance, stimulates osteoblast replication through mitogenesis but does not ap- pear to play any significant role in increasing collagen synthesis (Canalis, 1984). In fact, if TGF-P is withdrawn (in vitro ra t calvaria experiments), there is a surge nf collagen svnthesis which is presumed to be the secondary effect of earlier cell replication. Besides being produced in matrix, SGF is produced by osteoblasts themselves, most abundantly by those with the highest alkaline phosphatase lev- els. When the osteoblast is fully mature, SGF no longer exerts a mitogenic effect but does increase collagen synthesis. Somatomedin-C, also called insulin-like growth factor, stimulates development of osteoblasts, especially in the earlier phases. The long-suspected estrogen receptor has finally been shown to be present on osteoblasts (Boden et al., 1989; Colston et al., 1989), but the full range of its role in osteoblastic activity still needs to be determined.

All of the aforementioned growth factors are polypeptides which stimulate mi- togenic activity. Prostaglandin E, (PGE2), produced by a number of cells including osteoblasts can, under the appropriate circumstances, stimulate bone formation even though its best known effect is on bone resorption. It appears that PGE, stimulates resorption after chronic exposure, but in low concentrations may have the effect of stimulating bone formation. At high concentrations, formation is inhibited and resorption is stimulated by PGE,. One of the key questions to be resolved if the etiology of osteoporosis is to be fully explained is what links forma- tion and resorption and thereby moderates the range of effects that both local and systemic factors have on osteoblasts and osteoclasts. As the list of cytokines and lymphokines known to affect bone cell activity grows, it is increasingly clear that cellular events well outside the musculoskeletal system have the potential to elicit side effects affecting bone. The exquisite role played by components of the immune system in this ever-broadening network of intercellular communication may ulti- mately prove to be the key to understanding the mechanisms regulating bone turnover and the events producing disturbances in the dynamic equilibrium of bone physiology.

Collagen synthesis When osteoblasts are performing their primary function of bone formation,

whether during growth, modeling, or remodeling of bone, a major aspect of their activity is collagen synthesis. It is the formation of the collagen matrix that per- mits the organic framework of bone to be laid down. The type of collagen specific to bone is designated type I. Its production is regulated at the level of initial transcription (Raisz and Kream, 1983a,b). It is synthesized as a single chain, units of which are linked end to end. These long chains are then wound into a triple helix. This process, which involves the activity of two enzymes in the presence of vitamin C, results in the formation of strong cross-linkages involving covalent bonds. The two enzymes responsible for the conversion of procollagen to mature collagen are procollagen amino protease, which removes the amino peptides, and procollagen carboxyl protease, which removes carboxyl peptides. The resultant modifications allow cross-linkages to occur. It is of interest that one form of osteo- genesis imperfecta is thought to be caused by mutations that delay triple helix formation and allow modifying enzymes to act longer on collagen chains (Brenner et al., 1990).

164 YEARBOOK OF PHYSICAL ANTHROPOLOGY IVol. 33, 1990

TABLE 2. Products of osteohlnsts

Collagen I Osteonectin Osteocalcin Proteoglycans I, I1 Alkaline phosphatase TGF-f3 Sialoproteins I, I1 Prostaglandin

Albanese (1977) notes that both hydroxyproline and hydroxylysine are initially incorporated in their non-hydrosylated state. With successful modification, crys- tals form in rod-shaped arrays along the collagen fibrils, which are then laid down to form sheets. !r. matarc collagcr;, this F I - O ~ U W ~ il hrieycomb structure that facilitates mineralization. Termine et al. (1981) identify osteonectin as a bone- specific protein that links mineral to collagen (see also Robey et al., 1985; Romberg et al., 1985). The strong affinity of osteonectin to the pro-alpha 1 (I) chain of type I collagen as well as its strong affinity for hydroxyapatite (Young et al., 1990) provide the attraction that could serve as the initiator of nucleation. Attachments of mineral-binding proteins to collagen are at regular intervals that Termine et al. (1981) refer to as matrix units.

Mineralization There is disagreement among investigators concerning the degree of spontaneity

inherent in the mineralization process. Vaughan (1981) argues that the process is initiated by a booster mechanism that raises the calcium or phosphate concen- tration high enough for spontaneous mineralization of collagen to occur. The mi- tochondria of osteoblasts accumulate calcium and, under the appropriate stimulus, allow it to pass into the matrix in sufficient quantity to pass the threshold value leading to mineralization. Glimcher (1976) argues that spontaneous crystal for- mation does not occur strictly in response to high concentrations of calcium and phosphorus. Instead, a catalytic nucleation is accomplished by seeding within col- lagen. This nucleation would occur around certain nucleation sites that may be the osteonectin binding sites reported by Termine et al. According to Neuman (1980), osteoblasts facilitate deposition of crystals of calcium hydroxyapatite as well as amorphous calcium phosphates on the organic framework. Mineralization can be inhibit.ed by limiting the production of seeds iosteonectin?! or by slowing the dep- osition of mineral on the seeds zlready present. Known inhibitors of mineralization include pyrophosphate, citrate, and magnesium ions.

Frost and Villanueva (1960) characterized the mineralization process a s a grad- ual one that produces a region between the end of matrix formation and the onset of mineralization that they call the osteoid seam, made up of 95% collagen.

Non-collagenous proteins One of the most impressive aspects of osteoblast activity is the versatility of their

protein synthesis. Table 2 lists the proteins known to be produced by osteoblasts. Perturbations of synthesis of any of these products have the potential to disrupt

bone formation. The roles that the noncollagenous proteins play are varied and probably not yet

fully understood. Table 3 lists a number of known and proposed functions.

BONE AS TISSUE

Bone is connective tissue but differs from the other kinds of connective tissue in having an important mineral component. The organic component of bone makes up about 22% of its total mass and water an additional 9%. The remaining 65-70% is mineral, predominantly calcium (Triffitt, 1980). The 1,000 to 1,200 g of calcium stored in the skeleton (Mazess, 1982; Norman, 1980) represents 98% of total body

Stini] Osteoporosis: Causes and Treatment

TABLE 3 . Functions of noncollagenous proteins s.ynthesized by osteoblasts'

165

Regulations of bone mineralization reactions Signals for cell recognition and attachment Modulation o f cell differentiation and growth Determination of matrix organization and integrity Modulation of bone resorption and turnover Markers of bone metabolism

'Following Termine e t al., (1981).

calcium (Eastell et al., 1983; Kimmel, 1984). Most of the calcium in the skeleton is in the form of calcium hydroxyapatite Clo(P04)6(OH)2, although a number of other minerals may I epiace calcium 01 arlothek cuiistituerit ir: the hgdruxyapaiitx cryviai (Posner, 1987). Among the other minerals seen in bone are the fluoride which replaces the hydroxy ion, carbonate, which replaces phosphate, and magnesium or strontium, which can both replace calcium. The crystals of hydroxyapatite in re- cently formed bone differ from those that were formed earlier in that older bone is made up of larger, more regular crystals with a lower proportion of carbonate (Bonar et al., 1983; Posner and Betts, 1981; Thompson et al., 1983). Because of the resultant reduction in surface area, the larger, older crystals are less easily re- sorbed. Poor mineralization can be caused by genetic disorders (Smith, 1988) that cause amino acid substitutions in the proteins produced by osteoblasts, including collagen (Parry and Craig, 1981).

The structure of bone is conventionally designated either as trabecular (cancel- lous) or cortical (compact). However, under certain circumstances the distinction is an artificial one, as when trabecularization of the endosteal surface of a long bone occurs. About 80% of the human skeleton is compact bone (Polig and Jee, 1987). Because of its more porous structure trabecular bone is more readily resorbed. Thirty to 90% of trabecular bone is open space compared to 5% to 30% in compact bone (Carter and Spengler, 1978). Bone located at the interface of the trabecular and cortical compartments will often exhibit structural properties of both types (Kragstrup et al., 1983). Trabecular bone is most abundant in the axial skeleton which, exclusive of the skull, is 90% trabecular. The appendicular skeleton, on the other hand, is 95% compact bone by volume (Mazess, 1979). The turnover rate of trabecular bone is eight times faster than that of cortical bone. About 20% of total skeletal mass is trabecular, but up to 405 of the vertebral column is I n that category !Genant, 19871. Therefore, the effects of perturbations in the balance of' bone turnover are manifested earliest in the spine. All bone turns over, but only about 5% of total bone surface is normally exchanged over the course of a year.

Growth, modeling and remodeling Frost (1983) describes three major processes affecting bone: growth, modeling,

and remodeling. It is the last-mentioned that is of concern here although certain aspects of growth and modeling, processes generally restricted to the subadult phase of the life cycle, are of some interest as well. For instance, the formation of woven bone, which is the earliest type to appear and which is replaced by lamellar bone during the 1st year of life (Steinbock, 1976), can be induced by disease or trauma in the adult. Woven bone is not well organized to cope with mechanical stresses, but appears to be produced as an adaptive response to excessive stress and strain (Burr et al., 1989a,b; Pead et al., 1988). It is therefore not strictly a patho- logical phenomenon as claimed by Frost (1988).

When cortical bone replaces woven bone, the lamellae are formed by a process which aligns collagen fibers so that adjacent sections are oriented in opposite directions, i.e., either longitudinally or circumferentially. The adjacent lamellae combine to form Haversian systems of interconnecting lacunae and canaliculi

166 YEARBOOK OF PHYSICAL ANTHROPOLOGY Wol. 33, 1990

Fig. 5. osteon fragments (FO) (courtesy Sam Stout, 1982).

Photomicrograph of a section of human cortical bone showing intact Haversion systems (10) and

which are the primary osteons. As remodeling occurs, osteons are destroyed and replaced by secondary osteons, often leaving portions of some osteons behind (see Fig. 5). The presence of secondary osteons and the interstitial lamellae that reveal the occurrence of remodeling form the basis for a system to estimate age at death through microscopic examination of cortical bone (Frost 1974b,c; Kerley, 1965; Ker- ley and Ubelaker, 1978). Certain bony features will drift into new positions as a result of differential rates of remodeling (Enlow, 1976; Frost, 1985) providing further evidence of the destruction and replacement of cortical bone. There is considerable regional variation in the rate af remodeling. For instance, it has been estimated that a cortex half-life of 7 6 years would be normal for the femur qxhile a half-life of 24.2 years would be normal in the tibia of the same person. Neither cortical nor trabecular bone is internally homogeneous. Heterogeneity appears to be a regional phenomenon (Heaney, 1989a,b).

The remodeling of cortical bone occurs on three bone envelopes: 1) the endosteal, which is adjacent to the marrow; 2) the subperiosteal, lying under the periosteum on the external surface of the bone; and 3 ) the Haversian systems within the bone. A fourth envelope, the trabeculae, will be discussed in the context of trabecular bone loss (see Fig. 6).

Cortical bone turnover Under normal circumstances cortical bone turnover is coupled (Frost, 1964;

Jaworski, 1984). The process begins with activation, proceeds to osteoclastic re- sorption, and finally to reversal and formation of new bone by osteoblasts (Frost, 1980). This process, involving coordination of osteoclasts and osteoblasts, has been called the basic multicellular unit (BMU) of bone remodeling (Frost, 1973, 1980, 1986). Disturbance of the coordinated activity of the cells making up the BMU can result in excessive loss of cortical bone, ultimately leading to osteoporosis. When

Stinil Osteoporosis: Causes and Treatment 167

I I

oR1ENTATKIN L LAMELLAR NON-LAMELLAR (LAMINAE) NON-HAVERSIAN HAVERSlAN

/OSTE-\ PRIMARY SEcoNabRy OSTECNS OSTECNS

/ \ TERTIARY Q W T W A W OSTEONS OSTEONS

00 \

Fig. 6 . envelopes and the trabeculae (from Simmons, 1985).

Sites of internal remodeling showing location o f the subperiosteal, endosteal and interstitial

osteoclasts resorb cortical bone, it is usually from sites parallel to the long axis of the bone in areas where local strains of compression and tension are maximal. The reversal phase which follows resorption is marked by the presence of mononuclear cells which are thought to stimulate osteoblasts to begin new bone formation (Baron et al., 1983). The reversal phase lasts 4 to 6 times as long as the resorption phase which preceded it. After osteoblasts have deposited new organic matrix there is a delay of about 8 days before mineralization occurs. I t is, of course crucial that sufficient calcium be present a t the site of bone formation at this time or the already completed resorption will not be fully compensated by newly mineralized bone.

A steady state could be maintained if deposition and resorption occurred a t equal rates. However, this is not the usual outcome (Johnston and Slemenda, 1987). The most common pattern is one involving loss of bone in the endosteal envelope with each cycle of remodeling. Most often, the mean depth of erosion (MDE) exceeds the mean wall thickness (MWT). In other words, the amount of bone resorbed is greater than the amount formed (Jaworski, 1984; Meunier, 1983). There is no loss or gain in the intra-cortical envelope although bone quality dete- riorates with increasing age, due to the net increase in new bone as opposed to the more stable old bone. Osteoclasts resorb bone faster than osteoblasts can form it. Therefore only about one in seven BMUs is in the absorption phase tlnder normal circumstances (Lee, 1985). Replacement of small segments of bone a t any given time preserves mechanical integrity of the bone as a unit. Each remodeling event turns over 0.05-0.1 mm3 per BMU. The result is a pattern of small sections of bone that have been eroded and refilled at the endosteal surface. In the intracortical envelope, repeated remodeling results in primary osteons being replaced by sec- ondary osteons and a residue of fragmentary osteons. Osteon replacement also occurs in the periosteal, endosteal, and trabecular envelopes. However, the peri- osteal envelope usually experiences a net gain (Parfitt, 1984) with the result that long bones increase in diameter with increasing age.

Continual remodeling allows replacement of segments of bone where structural integrity may have become compromised by pathological or traumatic conditions. It also allows adaptive changes to compensate for new demands. Pressure caused by such conditions as adjacent aneurysms will lead to resorption (Kelley, 1979). The presence of marrow tissue appears to stimulate resorption of bone (Frost, 1985). Remodeling is often a response to alterations in the mechanical stresses generated by activity. Smith (1985) has proposed that osteoblasts act as receptors for tensile stress. It has also been postulated that mechanical strain can generate electrical potentials within bone that stimulate remodeling (Lanyon, 1981). Evi-

168 YEARBOOK OF PHYSICAL ANTHROPOLOGY [Vol 33,1990

dence for this form of stimulation can be seen in the close association between areas of high strain and active remodeling sites (Lanyon and Ruben, 1985). El Haj (1990) cites evidence of an osteocyte sensor network that transmits information about stresses and strains through the entire skeletal system.

Fatigue generated by mechanical stress produces microcracks in cortical bone. These also stimulate repair activity in the appropriate BMUs (Frost, 1985). The amount of damage done by mechanical stress is largely determined by the type of loading experienced. Because of its heterogeneous composition, bone is not notable for its resistance to fatigue damage (Carter et al., 1981a,b). When subjected to strong compressive forces such as experienced under weight-bearing conditions, cortical bone will exhibit shear cracks indicating substantial cellular damage. Tensile forces, while debonding osteons. do not usually cause cellular damage. Although primary bone possesses greater tensile strength than Haversian bone (Vincentelli and Griporov 1985) n+mw lim-it t h e r?xnt?gc by reduciiLg ll:e spread of cracks which would propagate widely in a more homogeneous material (Currey, 1969). Burr et al. (1985) have shown that the appearance of microcracks is followed in a few days by a substantial increase in resorptive activity, suggesting that fatigue damage stimulates Haversian remodeling.

Ninety percent of compressive strength of compact bone is determined by its density (Mazess, 1982,1987). Consequently, loss of bone mass is directly related to loss of bone strength which in turn is a determinant of fracture risk. However, compact bone can be remodeled in ways that alter its geometric properties and stress resistance. For instance, expansion of the circumference of a long bone alters its cross-sectional moment of inertia (CSMI). The CSMI is closely related to the bones resistance to bending forces (Burr, 1980; Martin and Burr, 1984). Both mass and distribution of mass relative to the neutral axis of the bone determine its resistance to bending. Mass distributed farther from the bones neutral axis makes a greater contribution to its resistance to bending stress than mass lying close to the neutral axis. Thus in a long bone with an approximately cylindrical diaphyses, bone mineral located on the periosteal surface lends greater resistance to a bend- ing force than bone mineral located on the endosteal surface. Therefore, addition of bone in the periosteal envelope can compensate for endosteal resorption even though there is a net loss of bone ova-all (Burr, 1980; Carter and Spengler, 1978; Martin and Atkinson, 1977; Ruff and Hayes, 1982).

Animal experiments in which equal force is exerted on living bone from all directions using a centrifuge result in long bones of a circular cross-section (Amt- mann, 1971). This is a pattern that would be expected if diaphysial remodeiing followed a course that would vield maximum resistance tc! the applied bending stress. Permsteal appositloll at ail points around the diaphyseal circumference would, under such experimental conditions, maximize the moment of inertia. A number of investigators are convinced that the geometric properties of bone are as important in resisting bending stress, and thus minimizing fracture risk, as is bone density (Amtmann, 1971; Ruff and Hayes, 1984). According to Burr (1980) and Sandler (1988), adaptation to loading stress requires adjustments of mass and geometry although the material properties of bone do not change.

Trabecular bone turnover Trabecular bone has a much more rapid rate of turnover than cortical bone. The

large surface area presented by the honeycomb-like structure of trabecular bone makes i t much more available for exchange. Trabecular bone is most abundant in the bodies of the vertebrae and in the ends of long bones. It is made up of a network of plates and supporting struts, the strength of which depends upon the density of its structural components as well as on the connectedness of the struts and plates (Merz and Schenk, 1970; Parfitt e t al., 1983; Parfitt, 1984; Weinstein and Hutson, 1987). Although some remodeling of trabecular bone has been reported, producing radio-opaque lines in response to prolonged stress (Kursunoglu et al., 19881, it is generally true that when trabecular bone is resorbed, it is not replaced. Thus,

Stini I Osteoporosis: Causes and Treatment

TABLE 4 . Qualitative changes in bone (after Parfitt, 19841

Unrepaired fatigue microdamage Altered architecture and distribution

Loss of connectivity in trabecular bone Thinning of cortical bone-porosities

Impaired material properties Increased brittleness Molecular disorganization Defective mineralization

169

while cortical bone undergoes extensive remodeling over the course of a lifetime, trabecular bone gradually diminishes in quantity. Heaney (1989aj hypothesizes that loss of horizontal struts eventually results in the buckling of vertical struts in what he refers to as a loss ofconnectedness. Arnold (1981) also reported an increase in the distance between vertical struts. As the connectedness of the honeycomb structure breaks down, the weight-bearing capacity of the trabeculae is compro- mised and the contribution of the trabecular component to the structural integrity of the skeleton is also compromised. Thus, in areas that are characterized by a high proportion of trabecular bone, such as the vertebral bodies, loss of internal support ultimately leads to a collapse of the cortical shell. One clinical outcome of this type of trabecular bone loss is the vertebral crush fracture. Another is the femoral neck fracture occurring in the area of Wards triangle. Early in life, trabecular bone is the primary reservoir for the maintenance of calcium homeostasis. Being the most metabolically active component of bone it is also the most vulnerable to perturba- tions in normal turnover (Jerome, 1989). Therefore, it is generally the first to exhibit osteopenia (Dodds et al., 1989; Kumar and Riggs, 1980). Trabecular thin- ning correlates positively with loss of connectedness where loss of load-bearing capability becomes clinically significant (Compston et al., 1989).

OSTEOPOROSIS: DEFINITIONS AND ETIOLOGIES

The term osteoporosis has come into wide usage to describe conditions in which bone resorption exceeds bone deposition (Nordin, 1987). Used in this way, its def- inition overlaps that of osteopenia (Pitt, 1983; Raisz and Johannesson, 1984; Mel- ton, 1989). There is general agreement that osteoporosis is a term to be reserved for conditions in which there is a reduction of bone mass per volume while the ratio of mineralized to unmineralized bone is normal (Shane, 1988). This is in contrast to disorders in which the collagen framework is present with abnormally low levels of mineralization. This latter condition is referred to as osteomalacia in adults and rachitis or rickets in children. Raisz (1987) implicates an element of osteomalacia in some fractures attributed to osteoporosis in the elderly.

Osteoporosis can affect trabecular bone, cortical bone, or both, depending upon the stage of the condition observed. Its earliest appearance is generally in trabec- ular bone but soon both cortical and trabecular bone are involved (Wingate, 1984). Finally, in the later stages of life, the major area of bone resorption is the cortical component as the amount of available trabecular bone diminishes. Boskey (1989) and Lund et al. (1989) report involutional changes in osteoid itself that may inhibit normal mineralization. In addition, structural changes in calcium hydroxyapatite have been observed in osteoporotic patients (Lorini et al., 1989). It is evident that however osteoporosis is defined, it is a disorder of more than a single etiology. Table 4 lists qualitative changes in bone that can affect its structural integrity.

Type I osteoporosis Riggs and Melton (1983) propose a definition distinguishing two distinct syn-

dromes. The first (type I) is the form associated with menopause in women. Bone loss in this disorder is attributable to increased resorption that is most pronounced in the trabecular component. Because of the high proportion of trabecular bone in

170 YEARBOOK OF PHYSICAL ANTHROPOLOGY 1Vol. 33, 1990

the vertebrae, type I osteoporosis is associated with vertebral crush fractures (El- ders e t al., 1988; Meltzer et al., 1989). Collapse of the vertebral body may be symmetrical or may occur as wedging with the ventral (anterior) aspect of the cortex collapsing while the dorsal aspect remains intact. The eighth thoracic to the third lumbar vertebrae are most commonly involved with T-12 often being the first affected (Woolf and St. John Dixon, 1988). The result may be a dorsal kyphosis commonly called the Dowagers Hump. The obligate curvature of the spine and the loss of stature associated with this condition reduce the volume of the pulmo- nary and abdominal cavities. If the condition is sufficiently severe, i t can lead to respiratory and digestive problems of considerable potential severity (Gozzo et al., 1989; Hodkinson, 1989; Kleerekoper et al., 1989; Shane, 1988).

The distal end of the radius is another area with a large proportion of trabecular bone (60%). It is the site where the Colles fracture occurs. The occurrence of this fracture is therefore widely accepted as an indicator of type I osteoporosis. This association has been challenged on the hasis of the hi$ propsrti*-rIi .jf I&+-impact fdis associated with Colles fractures, therefore invalidating its status as a non- traumatic fracture (Aitken, 1984; Riggs and Melton, 1986). However, the rarity of Colles fractures in forearms of normal density argues for its inclusion as an indi- cator of type I osteoporosis (Eastell et al., 1989). Accelerated bone loss in the distal forearm has also been reported by other investigators (Price et al., 1989).

Vertebral crush fractures also occur in men (Frances et al., 1989; Meunier et al., 1989). Meier et al. (1984) and Orwall e t al. (1990) found that vertebral bone loss in males was far greater than that seen in the radius (2.3% vs. l%iyr). They found no correlation between rate of bone loss and age in their sample. But the rate of loss observed in their longitudinal study exceeded that which would be predicted on the basis of cross-sectional data. The time of onset of bone loss in males appears to vary widely and may reflect the degree of fitness. Castration in men is followed by bone loss (Stepan et al., 1989a). Without a threshold event such as ovarian failure to use as a baseline for comparison, studies of bone loss in males have been more incon- clusive than those focused on females to date. However, the increasing incidence of fractures in men reported by Orwall et al. (1990) points up the need for awareness of the problem of bone loss in both sexes.

It is thought that peak bone mass is attained in women by the midSOs, a little later in men. However, the vertebral bodies achieve peak mass earlier, a t about age 25 years. From the age of peak bone mass, there may be a period of perhaps 20 years of relative stability followed by decline. The relatively rapid bone loss expe- rienced by women after menopause continues for a limited amount of time: Riggs and Melton (1986) estimate 5 to 8 years Although ihe depth of resorption cavrties formed by osteoclasts generally dPdines with increasing age. there :s a period in perimenopausai wonien during tihich absorption cavities are deeper. This time of increased resorption may coincide with a period of reduced bone formation to produce the accelerated bone loss characteristic of type I osteoporosis (Riggs and Melton, 1986). Schaadt and Bohr (1988) present evidence that loss of trabecular bone in the vertebrae occurs during menopause while loss from the femoral neck is linear through adult life. Loss of compact bone from the femoral shaft is much later.

Type I osteoporosis involves cortical as well as trabecular bone loss. One aspect of the process is the trabecularization of cortical bone through absorption cavity formation on the endosteal surface of the cortex (Keshawarz and Recker, 1984; Wahner et al., 1984). The newly trabecularized bone presents a larger surface area than either cortical bone or older trabecular bone and is therefore highly suscep- tible to resorption. Moreover, there is also a decline in microfracture repair. The result is a more easily broken bone (Frost, 1980,1988,1989). A slowdown in bone turnover may also contribute to bone brittleness by allowing areas of hypermin- eralization to form (Parfitt, 1987).

As should be evident from the foregoing, the mechanisms underlying type I osteoporosis, although more often of clinical significance in females, occur in both

Stinil Osteoporosis Causes and Treatment 171

sexes (Nilas and Christianson, 1987). The predominance of trabecular bone loss and vertebral crush fractures are the usual criteria defining type I osteoporosis. However, some trabecular bone loss continues well after the postmenopausal pe- riod of accelerated involution has ended. Thus, there is considerable overlap in the symptoms used to designate type I and those used to designate type I1 (senile) osteoporosis (Johnston and Slemenda, 1987).

Type 11 osteoporosis Type I1 osteoporosis is usually associated with non-traumatic hip fractures.

However, the most-frequent site of hip fracture occurrence is in an area that contains considerable trabecular bone (Wards triangle on the femoral neck). One group of researchers (Mizrahi et al., 1984) found that the density of the trabecular core of the femoral neck is the chief determinant of its strength. The compressive strength of trabecular bone is proportional to the square of its density (Carter and Hayes, 1976). Thus a decrease of density by a iactor of Z wlii resuit in a decrease in strength of a factor of 4. However, structural factors including the geometric characteristics of the femoral neck also affect the strength of the bone under stress (Beck et al., 1990).

Despite the fact that the fracture most often cited as associated with type I1 osteoporosis may be the result of loss of trabecular bone, most investigators view type I1 osteoporosis as an extended process of cortical bone loss. Both males and females will experience erosion of cortical bone if they live long enough, and cas- trated males may experience early bone loss (Stepan et al., 1989a). But the process generally begins earlier in women, is accelerated for a time after meno- pause, and becomes clinically significant earlier in women partly because they have less bone than men at peak bone mass. Since much of the more labile tra- becular bone has been lost by the seventh decade of life, the impact of bone loss will fall most heavily on the compact bone of the skeleton thereafter. The differential rate of loss in the axial and appendicular skeleton is informative in that it closely parallels the ratio of trabecular to compact bone. For instance, the decrease in the female lumbar spine averages 47% through the adult years. The loss averages 58% for the femoral neck, 39% for the distal radius (which has up to 60% trabecular bone), and 30% for the mid radius (which is about 80% compact bone) (Riggs et al., 1981). The loss is similar in males, but occurs later and because of greater peak bone mass in males, the net loss is not as likely to result in fractures.

In a longitudinal study of bone mineral loss in old age being conducted in Sun City, Arizona, the progress of cortical bone loss in the radial diaphysis provides clear evidence of long bone remodeling which resuits in the thinning of cortical bone through what Resnick and Greenspan (1989) have described as continued endosteal resorption. Although continued periosteal deposition of bone appears to compensate to some extent for medullary cavity expansion, it does not appear to be sufficient to prevent continued declines in bone density in women and, to a lesser extent, in men (see Tables 5, 6).

To obtain the values shown in Tables 5 and 6, bone mineral content (BMC), width (WID), and bone mineral density (BMD) were all measured by single photon absorptiometry of the shaft of the radius one-third of the distance from its distal to its proximal end. The data shown were obtained from 221 women and 119 men who were scanned annually at least three times. The first three columns (BMC, WID, and BMD) show the mean values for individuals included in the designated age categories as of December 1989. The fourth, fifth, and sixth columns show the average percent change in BMC, WID, and BMD per year experienced by individ- uals in each age category.

The Sun City data shown in Tables 5 and 6 clearly reveal the sex difference in the pattern of bone remodeling. In women, although there is a continuous decline in bone mineral density from age 60 years onward, there is also a continuous increase in the width of the radius. The remodeling of the radius with the conse- quent loss of cortical bone is less notable in males. Because the width increase is

172 YEAKBOOK OF PHYSICAL ANTHROPOLOGY IVol 33,1990

TABLE 5 Average values and percent change per year in bone mineral content, uirdth, and density i n the radial dsauhysis (Sun City u'omen measured annually 3 or mow timrsi'

Age group (years) N 4 9 6 60-64 14 65-69 4 1 70-74 68 75-79 60 80-84 24 85-89 7 >90 1 Total = 221

BMC WID 0.876 1.251 0.797 1.284 0.724 1.260 0.688 1.265 0.649 1.254 0.641 1.270 0.618 1.297 0.634 1.354

BMD %Chn BMC BChe WID LicChe BMD 0.696 0.626 0.578 0.545 0.517 0.504 0.477 0.469

-0.032 --0.157 -i- 0.051 -0.941 -0.617 --1.180 --0.381

0.521

+ 0.783 -0.835 i 1.460 - 1.479 i 1.272 -- 1.084 +0.527 - 1.403 + 0.657 -1.112 +0.572 -- 1.625 + 1.284 -1.367 + 1.833 -2.059

tiometry (SPA). WID = width of the radial chg Mac.:, WiIJ, BhlD = '6 ,,,,'"I "y F l . 3 . i

'BMC = Bone mineral content as measured by si

change per year observed in each a1 113 $it,?: RMD = h n w rn;w.ml

TABLE 6. Average values and percent change per year in bone mineral content, width, and density in the radial diaphysis (Sun City men measured an,nually 3 or m,ore times)'

Age group (years) N BMC WID BMD %ChgBMC %ChgWID W h g B M D 60-64 2 0.946 1.585 0.617 f 0.253 -1.818 + 2.325 65-69 17 1.098 1.548 0.710 +0.253 -1.818 + 2.325 70-74 28 1.038 1.467 0.707 -0.038 + 0.598 --0.536 75-79 46 1.143 1.544 0.742 -0.451 +0.345 -0.761 80-84 22 1.156 1.569 0.736 -t 0.106 -0.139 f0.291 85-89 4 1.021 1.583 0.644 -1.036 + 0.562 -1.550 >90 0 Total = 119

'BMC == Bone mineral content as measured by single-beam photon absorptiometry (SPA); WID = width of the radial shaft a t the distal 1/3 site; BMD = bone mineral density obtained by dividing BMC by WID; %' chg BMC, WID, BMD = average percent change per year observed in each age category.

accompanied by a continual decrease in bone density in the women we must con- clude that bone is being removed from the endosteal envelope while it is being added to the periosteal envelope. Failure to compensate fully for endosteal resorp- tion through continued periosteal apposition will have the effect of thinning the cortex and thereby raising the risk of fracture. Other investigators have observed similar remodeling in the 2nd metacarpal (Garn and Shaw, 1976; Plato and Norris, 1980; Plato and Purifoy, 1982; Piato et ai., 1982). For a comprehensive review of the st.udies reporting continuing periostcril apposition at a number of sites, the reader is directed to two recent articles by Lazenby (1990a,b).

Type I1 osteoporosis is a problem for both sexes and the increase in risk of clinically significant consequences accelerates beyond age 75 years. Males have more bone mineral and larger skeletons as children (Roche, 1987). Sexual dimor- phism for bone mineral content increases throughout growth and development and young adulthood (Cantatore e t al., 1989). With the onset of postmenopausal bone loss in women, this dimorphism further increases (Geusens et al., 1989). Loss of vertebral bone density in normal women begins before age 30 years (Buchanan et al., 1989), a t a time when men are still increasing spinal density (Cantatore 1989). Changes in androgenic steroid levels with increasing age are associated with loss of bone in both sexes (Nordin et al., 1985; Raisz, 1987; Vermeulen, 1985). The major concerns arising from this association have generally focused on increasing risk of hip and spine fracture. However, with increasing number of very old indi- viduals of both sexes, all parts of the skeleton are of interest. While decreased estrogen levels are associated with bone resorption, hence osteoclastic activity, androgenic deficiency appears to be associated with decreased bone formation, indicating reduced osteoblastic activity (Longcope et al., 1985). Thus, bone turn- over and remodeling can be affected by increased resorption, decreased formation, or simultaneous occurrence of both. In the last instance, a period of rapid bone loss,

Stinil Osteoporosis Causes and Treatment 173

even in the cortical component, would result. In the Sun City and Tucson longi- tudinal studies, clear evidence of such episodic acceleration of bone loss has been found. Since the site measured in these studies has been the distal one-third of the radius, the mechanism can be seen to be a combination of accelerated endosteal resorption coupled, in the more advanced ages, with a deceleration of subperiosteal apposition. In women, the width of the radius increases continually from before age 59 years through the 80s, while bone density decreases. However, the rate of increase declines sharply and bone density loss exhibits a concomitant increase in the mid-80s.

Secondary osteoporosis The foregoing descriptions of type I and type I1 osteoporosis have been concerned

with a broad category often referred to as primary osteoporosis, sometimes also designated involutional or idiopathic. This category is reserved for age-related loss ofbone. There are, however, a number of- conditions which wlli lead to bone ioss a t any age. Such conditions fall under the heading of secondary osteoporosis and may be associated with a variety of pathological, iatrogenic, and lifestyle-associated causes (Aitken, 1984; Cooper, 1989; Cummings, 1987; Gordon and Vaughan, 1976; Melton, 1989; Melton and Riggs, 1983; Shane, 1988). Surgery that alters endocrine status, such as removal of the ovaries without estrogen replacement, is an obvious example. Persistent infections, by stimulating production of lymphotoxins, inter- leukin-1, and tumor necrosis factor 01, have the potential of causing bone destruc- tion (Mundy, 1988). Smoking also is associated with increased fracture risk (He- menway et al., 1988; Pocock et al., 1989; Siemenda et al., 1989). Iatrogenic causes

Reduction in bone density is associated with medically induced hyperthyroidism (Ross et al., 1987). In addition, the use of antiinflammatory glucocorticoids are a well-known risk factor for osteoporosis (Bockman and Weinerman, 1990; Clochon, 1989; Reid, 1989a,b). The activity of these adreno-cortical hormones is the result of the conversion of cortisone to hydrocortisone (cortisol) in the body. One of the undesirable side effects of cortisone administration is increased sodium retention. In order to reduce side effects a number of synthetic analogues have been devel- oped. Among the most widely used of these analogues are prednisone, pred- nisolone, methylprednisolone, triamcinolone, dexamethasone, paramethasone, and betamethasone.

All of these analogs have longer biological half-lives than cortisone and cortisol whose biological half-lives are on the order of 8 to 12 hours. Precinisone, pred- nisolone, and ~ e t h y ~ p ~ ~ ~ ~ ~ s o n e have half-lives o f 12-36 hours and dexametha- sone, betamethasone, and paramethasone have half-lives of 36-72 hours. Conse- quently, while these analogues reduce certain undesirable side effects, their continued presence can enhance osteopenia activity, presumably resulting from a secondary hyperparathyroidism (Silve et al., 1989). One structural modification of prednisolone, deflazacort, is thought to have a reduced effect on calcium absorp- tion, collagen synthesis, and bone metabolism (Avioli, 1987). If such modifications prove to be effective and less damaging to bone, a valuable therapeutic option will be available under a wider array of circumstances than heretofore. Of course, endogenous cortisol production can be a source of bone destruction as well. Biller et al. (1989) report elevated urinary cortisol levels in bulimics, who are a known high-risk population. It appears that one of the beneficial effects of cyclosporin is its inhibition of glucocorticoid effects on bone (Kelly et al., 1989).

In order to avoid the side effects of cortisone, cortisol, and their analogs, consid- erable use has been made of a large category of nonsteroidal antiinflammatory drugs (NSAIDs). Each of these medications, although efficacious in specific in- stances, also carries with i t a risk of side effects. A number of them interfere with kidney function and may even cause serious kidney damage. Others can cause either discomfort or damage through interactions with other frequently used med-

174 YEARBOOK OF PHYSICAL ANTHROPOLOGY [Vol. 33, 1990

ications and patients must be closely monitored to avoid serious side effects in- cluding bleeding ulcers. This problem is especially acute in the older patient in whom absorption and excretion often take place at a slower rate than in youth and who is also frequently using several medications. However, since several of the NSAIDs function to reduce PGE, levels, they have the potential to slow the process of bone resorption by osteoclasts. The degree to which bone resorption is affected by one of these NSAIDs (piroxicam) is currently being monitored in a series of clinical trials being conducted a t the University of Arizona.

Diuretics have the potential of raising the urinary calcium loss and thereby the risk of osteoporosis and fractures. A number of studies implicate diuretics with increased hip-fracture incidence (LaCroix et al., 1990; Ray et al., 1989). In patients afflicted with polydipsia, increased calcium excretion has effects similar to those noted with diuretic administration (Delva et al., 1989). However, some diuretics including the frequently prescribed thiazides may actually reduce calcium loss by increasing its reabsorption in the kidnpy tubules.

Dietary factors It has long been suspected that high-protein diets reduce bone density. Some of

the earlier inferences were made on the basis of bone densitometry studies of high-protein consumers such as Eskimos (Mazess and Mather, 1974) and on com- parisons of vegetarians and omnivores (Ellis, 1972; Licata, 1981; Allen, 1982; Hunt e t al., 1989). Allen et al. (1979) suggest that the consumption of a high-protein diet inhibits calcium reabsorption in the kidney with a consequent increase in urinary calcium. Kerstetter and Lindsay (1990) cite strong evidence linking commonly consumed dietary proteins to the level of urinary calcium and calcium balance a t typical levels of calcium and phosphorus. When the intake of both calcium and phosphorus is high, as is the case with a diet containing a substantial proportion of dairy products, the effect of protein on calcium balance is less pronounced. Dietary protein increases the glomerular filtration rate and consequently, the filtered calcium load. Possibly because of the greater acidity of the filtrate and the generally higher concentration of sulfur related to high-protein diets, the reab- sorption of calcium is depressed.

The renal response to calcium intake is rapid, occurring within 4 hours of in- gestion, and it appears that calcuria associated with high protein intake is persis- tent, continuing unabated for at least 45 to 60 days. Therefore the potential for a sustained negative balance of calcium is significant and the effects on bone density can be substantial. It has also been suggested that high-salt diets increase calcium excretion in postmenopausal wonien (Zarkadas et al., 1989). Use of alcohol is associated with reduced bone density (Crilly and I)eiaquerriere-Richardson, 1936; Cummings, 198.7; Diamond et al., 19891, primarily through its depressing effect on bone formation.

Type I diabetes Type I (early onset) or insulin-dependent diabetes mellitus (IDDM) has also been

shown to have a deleterious effect on bone density. The diminished effect of insulin on osteoblasts in stimulating bone formation is the most likely mechanism under- lying the reduced bone density of early-onset diabetics (Weber e t al., 1990).

Pagets disease Pagets disease is a viral infection that causes an acceleration