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23—
Osteoporosis

Osteoporosis is a multifactorial, complex disorder characterized by an asymptomatic reduction in the quantity of bone mass per unit volume. When bone mass becomes too low, structural integrity and mechanical support are not maintained and fractures occur with minimal trauma. The most common sites of osteoporotic fracture are the proximal femur, distal radius (Colles' fracture), vertebrae, humerus, pelvis, and ribs. In clinical research, the diagnosis of osteoporosis is frequently applied only to patients in whom one or more fractures have already occurred (NIH, 1984), even though it can now be detected by measuring bone mass with single- or dual-photon absorptiometry (Mazess and Barden, 1987) or with quantitative computed tomography (Genant et al., 1987).

Osteoporosis occurs most frequently in postmenopausal white women and in the elderly of both sexes (Cummings et al., 1985). Approximately 20% of women in the United States suffer one or more osteoporotic fractures by age 65, and as many as 40% sustain fractures after age 65.

Osteoporosis is not frequently observed in men and black women until after age 60, after which fracture rates progressively increase in these groups. For additional information on the distribution and importance of osteoporosis in the population, see Chapter 5.

Bone and Mineral Metabolism

Bone is composed primarily of calcium and phosphorus, in the form of hydroxyapatite crystals deposited in a collagen matrix (Veis and Sabsay, 1987). Adult humans have two types of bone—cortical and trabecular. Cortical bone provides rigidity and is the major component of tubular bones (the appendicular skeleton). Trabecular bone is spongy in appearance, provides strength and elasticity, and constitutes at least 50% of the vertebrae (the axial skeleton) (Arnaud and Kolb, 1986).

Bone is a metabolically active tissue that is constantly being replaced. This process is regulated by cellular activities that resorb (osteoclastic) and form (osteoblastic) bone (Baron et al., 1984). In normal adult bone, resorption and formation are in balance. When one of these activities increases or decreases, the other shifts in degree and direction so that there is no net change in the total amount of bone (Frost, 1964, 1977).

Since the driving force for changing net bone mass is intrinsic to the cellular processes that govern bone resorption and formation, functional uncoupling of these cellular processes is required to either increase or decrease bone mass. The major mineral ions of bone (calcium, phosphorus, and magnesium) must be present at physiological concentrations in extracellular fluids for bone miner-



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Page 615 23— Osteoporosis Osteoporosis is a multifactorial, complex disorder characterized by an asymptomatic reduction in the quantity of bone mass per unit volume. When bone mass becomes too low, structural integrity and mechanical support are not maintained and fractures occur with minimal trauma. The most common sites of osteoporotic fracture are the proximal femur, distal radius (Colles' fracture), vertebrae, humerus, pelvis, and ribs. In clinical research, the diagnosis of osteoporosis is frequently applied only to patients in whom one or more fractures have already occurred (NIH, 1984), even though it can now be detected by measuring bone mass with single- or dual-photon absorptiometry (Mazess and Barden, 1987) or with quantitative computed tomography (Genant et al., 1987). Osteoporosis occurs most frequently in postmenopausal white women and in the elderly of both sexes (Cummings et al., 1985). Approximately 20% of women in the United States suffer one or more osteoporotic fractures by age 65, and as many as 40% sustain fractures after age 65. Osteoporosis is not frequently observed in men and black women until after age 60, after which fracture rates progressively increase in these groups. For additional information on the distribution and importance of osteoporosis in the population, see Chapter 5. Bone and Mineral Metabolism Bone is composed primarily of calcium and phosphorus, in the form of hydroxyapatite crystals deposited in a collagen matrix (Veis and Sabsay, 1987). Adult humans have two types of bone—cortical and trabecular. Cortical bone provides rigidity and is the major component of tubular bones (the appendicular skeleton). Trabecular bone is spongy in appearance, provides strength and elasticity, and constitutes at least 50% of the vertebrae (the axial skeleton) (Arnaud and Kolb, 1986). Bone is a metabolically active tissue that is constantly being replaced. This process is regulated by cellular activities that resorb (osteoclastic) and form (osteoblastic) bone (Baron et al., 1984). In normal adult bone, resorption and formation are in balance. When one of these activities increases or decreases, the other shifts in degree and direction so that there is no net change in the total amount of bone (Frost, 1964, 1977). Since the driving force for changing net bone mass is intrinsic to the cellular processes that govern bone resorption and formation, functional uncoupling of these cellular processes is required to either increase or decrease bone mass. The major mineral ions of bone (calcium, phosphorus, and magnesium) must be present at physiological concentrations in extracellular fluids for bone miner-

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Page 616 alization (formation) to occur normally (Marel et al., 1986) and play a passive role in any mass changes that occur. They help to replace minerals lost by obligatory processes (in urine, feces, and sweat) or those normally distributed to bone and soft tissues (Heaney, 1986). Maximum bone mass is achieved by about 25 to 30 years of age, is maintained without much change until 35 to 45 years of age, and is lost at a constant rate of 0.2 to 0.5% per year in men and women thereafter (Heaney, 1986; Marcus, 1982; Parfitt, 1983). About 8 to 10 years immediately before and after menopause, women lose bone at a rate of 2 to 5% per year. Subsequently, bone loss returns to the slower rate shared by the sexes. Those few men who also lose sex hormone function usually very late in life (>70 years) also lose bone mass at rates similar to postmenopausal women (Odell and Swerdloff, 1976). Evidence Associating Dietary Factors with Osteoporosis Epidemiologic and Clinical Studies Calcium Absorption and Balance Calcium balance generally reflects the degree to which bone formation is coupled with resorption (see Chapter 13). Thus, negative balances are recorded when bone resorption exceeds formation, and positive balances occur when bone formation exceeds bone resorption. Since 99% of the body's calcium is located in bone, it is not possible to build bone without positive calcium balance or to be in negative balance without losing bone. The metabolic technique used to determine calcium balance has important theoretical and practical limitations that can result in inaccuracies in determining the amount of dietary calcium needed to achieve zero balance—data that are key to determining nutritional requirements for calcium. Calcium balance depends on such factors as the amount of calcium in the diet, the efficiency of calcium absorption by the intestine, and the losses of calcium in the urine, feces, and sweat. Intestinal absorption decreases with age (Gallagher et al., 1979; Ireland and Fordtran, 1973). This may be due to the age-related decrease in serum levels of 1,25-dihydroxy vitamin D [1,25(OH)2D3] (Tsai et al., 1984)—the biologically active metabolite of vitamin D produced by the kidney that regulates intestinal absorption of calcium (DeLuca, 1983; Norman, 1985). The age-related decrease in calcium absorption may lead to secondary hyperparathyroidism. That this endocrine adaptive response occurs is supported by the observation that serum immunoreactive and bioactive parathyroid hormone increases with age (Forero et al., 1987). Whether this response to decreased calcium absorption contributes to the decreased skeletal mass and increased incidence of fractures in the elderly is not known. Relationship of Dietary Calcium to Bone Mass, Osteoporosis, and Fracture There are two major methodological problems involved in evaluating the evidence relating dietary calcium to bone mass (see Chapter 13). First are the inaccuracies inherent in determining dietary calcium by historical recall. Second are the different methods used to measure bone mass—some measure predominantly cortical bone and others measure predominantly trabecular bone. Decreased skeletal mass is the most important risk factor for bone fracture without significant trauma (Heaney, 1986; Heaney et al., 1982; Parfitt, 1983; Riggs and Melton, 1986). It is important to achieve genetically programmed peak bone mass, because the greater the mass attained before age-related loss, the less likely bone loss will reach the level at which fracture will occur (Heaney, 1986; Marcus, 1982; Parfitt, 1983). The quantity of dietary calcium  required to achieve peak bone mass is greater than that required to replace obligatory losses of this ion in urine, feces, and sweat (approximately 200 to 300 mg/day). Thus, as described in Chapter 13, people under the age of 25 years need to ingest sufficient calcium to ensure that they absorb more calcium from their intestines than they excrete and thus achieve positive balance. Many published reports have shown either no relationship or only a modest positive relationship between dietary calcium and cortical bone mass (see Chapter 13). The most widely cited of the papers showing a positive effect of calcium is that of Matkovic et al. (1979), who reported a 5 to 10% greater metacarpal cortical volume in the inhabitants of a Yugoslavian district with a high calcium intake as compared with the inhabitants of a Yugoslavian district with a low calcium intake. The population in the high-calcium district also consumed more calories, fats, and protein and fewer carbohydrates than did the population in the low-calcium district. People in the high-calcium district had a 50% lower incidence of hip fractures and a significantly greater metacarpal cortical bone

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Page 617 volume than did the inhabitants of the low-calcium district. Because the differences in bone mass as a function of age were constant, it is possible that high life-long calcium intakes did not prevent bone loss in this population but, rather, increased peak cortical bone mass. Contrasting sharply with these results are those of Riggs et al. (1987), who found no relationship between the calcium  intakes (range, 260 to 2,003 mg/day; mean, 922 mg/day) of 106 normal women ages 23 to 84 years and the rates at which changes occurred in bone mineral density at the midradius (determined by single-photon absorptiometry) and the lumbar spine (determined by dual-photon absorptiometry) over a mean period of 4.1 years. Dietary calcium intake has been associated with bone fracture rates in two ecological studies. In a comparison of 12 countries, Nordin (1966) reported an inverse graded association between frequency of osteoporotic vertebral fracture, as determined by x-rays of the spine, and calcium intakes. Japanese women, whose calcium intake averaged 400 mg/day, had the highest frequency of fracture, whereas women in Finland, where calcium intake was highest (1,300 mg/day), had the lowest frequency of fracture. This relationship did not hold in The Gambia and Jamaica, where there were low rates of osteoporotic fractures despite relatively low calcium  intakes (Nordin, 1966). In the study described above, Matkovic et al. (1979) found that the incidence of hip fracture in the Yugoslavian district with a high-calcium intake was 50% lower than that in the low-calcium  district, but no difference was detected in the incidence of fractures around the wrist. Most clinical studies show lower calcium intakes by osteoporotic patients than by age-matched control subjects (see Chapter 13). Dietary calcium was lower than 800 mg/day for patients and controls in all these investigations. In one study of subjects with intakes greater than 800 mg/day (Nordin et al., 1979), no differences in calcium intake were found between osteoporotic patients and controls. This finding supports the view by Heaney (1986) that low dietary calcium may play a permissive rather than a causative role in the development of osteoporosis and that this role can be demonstrated best when dietary calcium is below a ''saturation" level. Effects of Supplementation on Bone Mass and Fracture There is no direct evidence that the impairment of intestinal calcium absorption observed during menopause and aging can be overcome by calcium supplementation. Moreover, the evidence that calcium supplementation prevents the trabecular bone loss associated with menopause is at best weak. There is strong evidence, however, that calcium supplementation has a modest influence on preventing cortical bone loss. The evidence relating calcium supplementation to fracture prevalence is scanty. In a nonrandomized prospective study of the effect of various treatments on reducing vertebral fractures in women with generalized osteopenia, Riggs et al. (1982) observed that eight subjects receiving calcium carbonate (1,500-2,500 mg/day) and 19 receiving calcium supplementation plus vitamin D (50,000 IU once or twice a week) had 50%  fewer vertebral fractures than did 27 placebo-treated subjects and 18 untreated controls. As discussed in Chapter 13, calcium supplementation should therefore not be used as a substitute for sex hormone replacement, which prevents postmenopausal bone loss in most patients and appears to restore intestinal calcium absorption toward normal (Gallagher et al., 1980a). There is little justification for increasing the calcium intake above the Recommended Dietary Allowance (RDA) for women on estrogen replacement therapy. However, it seems prudent to recommend a higher calcium intake (~ 1,200 mg/day) for menopausal and postmenopausal women considered to be at risk for osteoporosis, but who either refuse to take estrogen or cannot do so for medical reasons. This could delay loss of cortical bone and prevent chronic secondary hyperparathyroidism. Some men over age 60 could benefit from supplementation for the same reasons. Evidence suggests that calcium intakes up to 2,000 mg/day are safe for teenagers and adults (Heath and Callaway, 1985; Knapp, 1947). Phosphorus Increased levels of dietary phosphorus have been shown to promote fecal calcium loss while reducing urinary excretion of calcium with the usual net effect of maintaining calcium balance. This explains why calcium balance is maintained in most normal people on a high-phosphorus diet (see Chapter 13). The mechanism by which increased dietary phosphorus decreases intestinal absorption of calcium has been investigated by Portale et al. (1986). These investigators showed that increasing dietary phosphorus from a low intake of <500 mg/ day to 3,000 mg/day decreased the production rate of 1,25(OH)2D3 to the extent that its serum

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Page 618 concentrations fell from a level 80% higher than normal to the low-normal range. This observation strongly suggests that the ability to adapt to decreases or increases in dietary phosphorus depends on the ability of the kidney to respond by increasing or decreasing its production of 1,25(OH)2D3. There is therefore a question whether increases in dietary phosphorus might adversely influence calcium economy in people whose kidneys have a limited capacity to produce 1,25(OH)2D3 or in people who need to be in positive calcium balance. Portale et al. (1984) reported that normal dietary phosphorus levels were sufficient to suppress plasma concentrations of 1,25(OH)2D3 in children with moderate renal insufficiency. No studies of the influence of dietary phosphorus on calcium and bone metabolism have been reported in other populations that may be unduly sensitive to increments in dietary phosphorus above the RDA (e.g., young people who are building bone or those such as the elderly who have a decreased ability to absorb or conserve calcium), even though there has been concern (Bell et al., 1977; Lutwak, 1975) that high phosphorus intakes may contribute to age-related bone loss in humans. Vitamin D Numerous studies during the past two decades suggest that elderly people in the United States, Israel, Great Britain, and Europe are at increased risk for developing vitamin D deficiency (see Chapter 11). Prolonged and severe deficiency of vitamin D results in osteomalacia-a disorder characterized by an increased proportion of bone matrix that is not mineralized (Frame and Parfitt, 1978; Parfitt et al., 1982). Many recent studies show a progressive decline in the serum concentrations of the major circulating form of vitamin D—25-hydroxy vitamin D—with aging, but there is no convincing evidence that the incidence of osteomalacia is increased in the elderly. Poskitt et al. (1979) speculated that these decreased serum levels of 25-hydroxy vitamin D result from the tendency for older people to remain indoors and thus to have less exposure to the sun. However true this might be, MacLaughlin and Holick (1985) have provided data supporting an alternative and possibly complementary explanation. They have found an age-dependent decrease in the epidermal concentrations of 7-dehydrocholesterol (provitamin D3). Skin biopsies showed that elderly subjects had as much as a twofold lower capacity to produce vitamin D3 than did young adults. It is likely, therefore, that the elderly have a decreased capacity to synthesize vitamin D in the skin. Protein Few epidemiologic investigations have assessed whether high levels of protein in natural mixed diets are a risk factor for osteoporosis (Marsh et al., 1980; Mazess and Mather, 1974). Studies conducted over most of the past half century have established that purified protein, taken in increased quantities as an isolated nutrient, dramatically increases the renal excretion of calcium (see Chapter 8). However, protein is not normally ingested as an isolated and purified nutrient; most protein-rich foods contain many other nutrients that could aggravate or counteract the calciuric effect of protein per se. For example, if phosphorus intake increases with protein intake, as it does in typical U.S. diets, the calciuric effect of protein is minimized (Hegsted et al., 1981; Schuette and Linkswiler, 1982). Heaney and Recker (1982) evaluated the influence of a 50% increase in the protein content of natural whole foods on urinary calcium and calcium balance in 170 perimenopausal women who were given diets containing their usual individual intakes of calcium, phosphorus, nitrogen, and caffeine. These investigators found that the calciuric effect of natural protein was much smaller than that produced by purified proteins. Using a series of regression equations generated from the dietary intake and calcium balance data recorded in their study, they calculated that a 50% increase in natural protein intake would lead to a negative calcium balance of 32 mg/day—an amount that approaches the 40 mg/day negative balance needed to account for the mean 1 to 1.5% loss in skeletal mass per year observed in postmenopausal women. It is thus possible that increases in dietary protein exceeding 66 g/day contribute to the negative calcium balance frequently observed in perimenopausal women. In the United States, many perimenopausal women consume diets containing considerably more protein than this (Christakis and Frankle, 1974). The effects of high-protein diets on the elderly have not been systematically studied. Fiber Investigations over the past five decades (Dobbs and Baird, 1977; Ismail-Beigi et al., 1977; McCance et al., 1942; Reinhold et al., 1976) show that fiber chelates calcium (and other minerals) in the gastrointestinal tract and is therefore a poten-

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Page 619 tial cause of mineral deficiency. High-fiber diets may increase osteoporosis risk in such countries as Iran, where Bazari bread provides as much as 50% of the caloric needs of children. Although this bread contains more calcium  than does white bread, its high fiber and phytate content leads to decreased intestinal absorption of calcium, magnesium, zinc, and phosphorus (Reinhold et al., 1976). The effect of fiber on mineral status at the levels consumed in the United States is unclear (see Chapter 10). Kelsay et al. (1979) provided 12 adult males two different diets for 26 days (a high-fiber diet containing fruit and vegetables and a low-fiber diet containing fruit and vegetable juice) to determine their effects on calcium balance. Balance was + 72 mg/day in those on the low-fiber diet and -122 mg/day in those on the high-fiber diet. In a follow-up study in which oxalate was removed from the diet, those investigators found that calcium balance was positive and was not influenced by fiber. Sandstead et al. (1979) reported that fiber added to diets caused negative calcium balance, and they calculated that the requirement for dietary calcium is increased as much as 150 mg/day when dietary fiber is increased by 26 g. Cummings et al. (1979) showed that the addition of 31 g of wheat fiber to the diets of subjects already consuming a high-protein diet produced a greater negative balance than the high-protein diet alone, suggesting an interaction of protein and fiber that causes greater negative calcium balance than when either is given alone. Fluoride Mertz (1981) has argued that fluoride is an essential trace element responsible for growth and maintenance of bones and teeth (see Chapter 14). However, since the dietary intake of fluoride is only 0.3 to 0.5 mg/day (Jenkins, 1967) and an additional 1 to 2 mg/day provided in drinking water (1 ppm) appears to have no demonstrable effect on bone structure (Riggs, 1984), it seems unlikely that fluoride is an important factor in osteoporosis risk for most Americans. By contrast, the incidence of osteosclerosis is high in areas where the fluoride concentration in the drinking water is moderately high (5 to 10 ppm) (Leone et al., 1955), and there is a lower prevalence of osteoporosis in these areas than in low-fluoride regions (Bernstein et al., 1966; Leone, 1960). In areas with even higher fluoride intakes, such as the Punjab region of India, there is some crippling fluorosis (characterized by dense bones, exostoses, neurological complications, osteoarthritis, and ligamentous calcification) and, more commonly, asymptomatic osteosclerosis (Singh et al., 1963). In a prospective but unrandomized study, Riggs et al. (1982) observed that treatment of osteoporotic patients with pharmacological doses of fluoride and calcium reduced the vertebral fracture rate to approximately one-quarter that of untreated patients—a lower rate than was observed in patients treated with calcium alone. Alcohol Bone formation is decreased in patients who abuse alcohol. This causes a dramatic decrease in bone mass as compared with that in normal subjects (Bikle et al., 1985; Nilsson and Westlin, 1973). Since the risk of falling is increased in alcoholics, these two factors are probably responsible for the increased risk of hip and vertebral fracture reported in alcoholic men and women (see Chapter 16). Animal Studies Nordin (1960) reviewed an extensive literature describing the many species that develop decreased bone mass as a result of calcium deficiency (see Chapter 13). In all these studies, the bone disease produced by calcium  deficiency most resembles osteoporosis. Low-calcium diets cause a loss of trabecular bone in adult cats (Bauer et al., 1929) and a generalized thinning of bone in dogs (Jaffe et al., 1932). After feeding adult cats a low-calcium diet for 5 months, Jowsey and Gershon-Cohen (1964) found that the animals had decreased skeletal weight, decreased bone density as determined radiographically, and increased bone resorption as shown by microradiographic evidence. These changes were partially reversed by refeeding the animals a diet containing more calcium. At present, however, there is no completely satisfactory animal model of postmenopausal or age-related osteoporosis. This deficiency is a major impediment to future progress in osteoporosis research. In contrast to the apparent inability of rather dramatic changes in dietary phosphorus to influence calcium balance in normal human subjects, there is considerable evidence in animals that diets containing relatively larger quantities of phosphorus than calcium cause hyperparathyroidism and bone loss. Almost all the reports concern young growing or aged animals and thus differ from investigations in humans, which in general focus on young or middle-aged adults (see Chapter 13).

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Page 620 The committee found no relevant studies in animals focusing on the effects of dietary protein, fiber, and vitamin D on bone mass and rate of bone fracture. Evidence Associating Nondietary Factors with Osteoporosis Age and Sex Age is a major risk factor for fracture, because bone mass is lost progressively with aging and the strength of bone is highly correlated with its mass and mineral content (Carter and Hayes, 1976; Dalen et al., 1976; Horsman and Currey, 1983; Rockoff et al., 1969). In the United States, the incidence of hip fracture increases dramatically after age 70 in both sexes but is twice as high among white women as among white men (Farmer et al., 1984; Gallagher et al., 1980b). Gallagher et al. (1980b) estimated that an adult white woman in the United States who attains the average lifespan of 80 years has a 15% lifetime risk of suffering a hip fracture compared to 5% for a white male whose life expectancy is 75 years. The risk of Colles' fracture is 6 to 8 times greater among elderly white women than among white men. Fractures of the humerus and pelvis are also more common in the elderly; 70 to 80% of these fractures result from minimal trauma (Melton et al., 1981; Rose et al., 1982). Several investigators speculated that the lower incidence of osteoporotic fractures in men may be due to the greater bone mass in men than in women of all ages (Cummings et al., 1985; Garn, 1970). However, there are no reliable data on the influence of age, sex, or race on vertebral fractures. Race Blacks in the United States suffer fewer osteoporotic fractures than do whites, presumably because they have a higher bone mass, greater bone density, thicker bony cortex, and greater vertebral density (Cohn et al., 1977; Smith and Rizek, 1966; Trotter et al., 1960). Black women have about one-half the age-specific incidence rates of hip fractures as white women (Bollett et al., 1965; Engh et al., 1968; Iskrant, 1968), and hip fractures are unusual among blacks in Africa (Solomon, 1968). Asian-Americans have less cortical bone mass than age-matched whites (Garn et al., 1964; Yano et al., 1984). However, incidence rates of hip and other fractures have not been reported for Asian or Hispanic populations in the United States. Genetics and Familial Factors The role of heredity and family history in determining bone mass and susceptibility to fracture have not been well studied. Garn (1970) found that metacarpal dimensions of siblings were somewhat more highly correlated (R = .37) than those of parents and children (R = .23). In a study of young male twins, Smith et al. (1973) reported that there was a slightly greater variance in cortical bone mass between pairs of dizygotic twins than between pairs of monozygotic twins. Peri- and Postmenopausal Estrogens Nilas and Christiansen (1987) assessed bone mass in relation to age, menopausal status, and serum  concentrations of sex hormones in 178 healthy Danish women ages 29 to 78 years. They observed that the menopause has a greater influence on bone loss than does chronological age. Physiological doses of estrogen prevent or retard the bone loss associated with oophorectomy or menopause (Christiansen et al., 1980; Genant et al., 1982; Horsman and Currey, 1983; Horsman et al., 1977; Lindsay et al., 1976; Nachtigall et al., 1979; Recker et al., 1977; Riis et al., 1987). When estrogen therapy is discontinued, loss of cortical bone mass resumes at a rate similar to that observed immediately after the menopause (Christiansen et al., 1981; Lindsay et al., 1978). The risk of hip and vertebral fracture appears to be reduced by at least 50% as long as estrogen is taken (Paganini-Hill et al., 1981; Weiss et al., 1980). Long-term use of estrogen has been reported to reduce rates of new vertebral deformities and fractures (Ettinger et al., 1985; Gordan et al., 1973; Lindsay et al., 1980; Riggs et al., 1982). It is not clear, however, whether postmenopausal women not taking estrogen who lose cortical bone rapidly have lower serum concentrations of estrogen than those who lose cortical bone slowly (Aloia et al., 1983; Avioli, 1981; Riis et al., 1984). Treatment with estrogen unopposed by progestogen is associated with an increased risk of endometrial cancer (Hulka et al., 1980; Kelsey and Hildreth, 1983; Ziel and Finkle, 1975). Hypogonadal males develop an osteoporotic syndrome similar to oophorectomized or postmenopausal women (Odell and Swerdloff, 1976).

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Page 621 Cigarette Smoking Most, but not all, studies show that smoking is associated with reduced bone mass as well as an increased risk of vertebral and hip fractures in women (Aloia et al., 1985; Cummings et al., 1985) and of vertebral fractures in men (Seeman et al., 1983). These effects may involve an alteration in  the hepatic metabolism  of estrogen (Michonovicz et al., 1986) and a reduction in the amount of adipose tissue in most smokers, both of which result in decreased concentrations of circulating estrogen. Physical Inactivity Lack of physical activity results in decreased bone mass (Dietrick et al., 1948; Donaldson et al., 1970; Whedon and Shorr, 1957). The osteoporosis produced can be localized (associated with fracture casting or painful limbs), generalized (associated with prolonged bed rest or space travel), or neurological (associated with paraplegia or quadriplegia). Its causes are unknown; the absence of stress and muscle pull on bone may be a common etiologic factor. Resumption of normal weight-bearing activity restores both trabecular and cortical bone (Mazess and Whedon, 1983; Whedon, 1984). Studies of the influence of increased physical activity on bone mass have produced mixed results. Many studies have shown that exercise of sufficient intensity and duration to produce amenorrhea can result in marked decreases in bone mineral density (Cann et al., 1984; Drinkwater et al., 1984; Lindberg et al., 1987; Marcus et al., 1985; Nelson et al., 1986). Among women who have amenorrhea from diverse causes, however, those who exercise regularly have greater bone density than those who are more sedentary (Rigotti etal., 1984). Most controlled trials suggest that moderate exercise may have a modest effect in preventing postmenopausal bone loss (Aloia et al., 1978; Krolner et al., 1983; White et al., 1984). Unfortunately, a randomized design was not used in these studies, and sample size and statistical power were inadeqate in most. The effectiveness of walking in preventing bone loss has not been well studied. Adiposity The major source of estrogen in postmenopausal women is provided by the conversion of androstenedione to estrone in adipose tissue (Grodin et al., 1973). Obese women produce more estrone than do thin women (MacDonald et al., 1978; Schindler et al., 1972). This difference has been suggested as the reason for the twofold increase in the risk of hip and Colles' fracture in thin women as compared to obese women (Cummings et al., 1985). Concentrations of sex hormone-binding globulin also tend to be lower in obese women, further increasing the availability of free estrogen (Davidson et al., 1982; Grodin et al., 1973; MacDonald et al., 1978; Schindler et al., 1972). These observations may explain why thin women have less cortical bone  mass than  obese women (Danielli, 1976; Saville and Nilsson, 1966; Smith et al., 1972). Reproductive History High parity and long lactation periods are generally associated with increased bone mass and decreased risk of fracture (Alderman et al., 1986). This may be due to the increased intestinal absorption of calcium during pregnancy and lactation. Limited data suggest that age at menarche has no effect on the later development of osteoporotic fractures (Kreiger et al., 1982). Previous Fractures The occurrence of Colles' fracture in women is associated with only a small increase in risk for hip fracture (Owen et al., 1982). However, women who have had a hip fracture have twice the risk of suffering a contralateral hip fracture (Melton et al., 1982). It has not been established that hip fracture risk is increased in patients who have suffered vertebral fractures. Other Medical Conditions Patients with  noninsulin-dependent diabetes mellitus are not at increased risk for hip fracture (Heath et al., 1980); however, some people with insulin-dependent diabetes have less bone mass than expected for their age (Hui et al., 1985). Other medical conditions that may aggravate bone loss and increase the incidence of fracture associated with aging include primary hyperparathyroidism, hyperthyroidism (spontaneous or iatrogenic), Cushing's syndrome (spontaneous or iatrogenic), chronic renal failure, hemochromatosis, vitamin C deficiency, and severe protein defi-

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Page 622 ciency (Arnaud, 1987). Hip fractures are also more frequent in patients with severe disability from rheumatoid arthritis (Hooyman et al., 1984) and neurological disorders. Summary Osteoporosis is a reduction in bone mass that is not usually apparent until minimal trauma causes a fracture. By age 65, approximately 20% of U.S. women suffer one or more osteoporotic fractures. In the elderly, secondary hyperparathyroidism, a condition that is generally associated with bone demineralization, may be caused by defects in intestinal calcium absorption. The long-term effects of increased calcium intake on bone mass after the menopause are not well established. Increased calcium intake is inferior to estrogen in slowing cortical bone loss during the period of rapid bone loss after menopause, and it has even less or no effect on the loss of trabecular bone. In contrast, estrogen prevents trabecular bone loss almost completely in most patients. Relatively small increments in dietary phosphorus could interfere significantly with intestinal calcium absorption under conditions of increased physiological need for calcium or in patients who for one reason or another have a decreased renal capacity to produce 1,25(OH)2D3 (such as patients with various degrees of renal failure). The calciuric effect of a high-protein diet is at least partially offset by the hypocalciuric effect of inorganic phosphorus, which is present in abundant quantities in most natural sources of protein. Although it is known that dietary fiber can chelate minerals and increase the fecal excretion of minerals, the effect of high dietary fiber on calcium balance is not clear. Studies in rats, mice, cats, dogs, and nonhuman primates have shown that a diet low in calcium or high in phosphorus leads to increased bone resorption typical of hyperparathyroidism as well as a generalized decrease in bone mass. White women are 2 to 3 times more likely to suffer a hip fracture than black women and men of both races. Other factors influencing osteoporosis risk are estrogen-replacement therapy, reproductive history, adiposity, cigarette smoking, alcohol intake, physical activity, previous fractures, and other medical conditions. The evidence relating dietary calcium to bone mass is at best weak. A daily intake of 800 mg is appropriate for women between the ages of 25 and 45. Intakes of 1,200 mg/day between the ages of 10 and 25 may be required to achieve peak bone mass. High calcium intakes may help to prevent loss of cortical bone in some women after age 45 and in some men after age 65. Such intakes can be acheived with a judicious diet. However, patterns of food and beverage consumption associated with low calcium intakes (e.g., diets low in milk products) may necessitate calcium supplementation in some individuals. Directions for Research · The age at which peak bone mass is achieved in men and women and the influence of calcium supplementation and exercise on peak bone mass need to be determined in prospective studies. · Dietary requirements for calcium during and immediately before menopause need to be determined in different population groups by using modem measurement techniques. If consensus on the requirements can be reached, investigations can then proceed to determine if therapeutic lowering of requirements by increasing the fraction of calcium absorbed from the diet influences the rate at which bone is lost in these subjects. · Intestinal absorption of calcium is decreased in people 65 years old and older. It is presently not known if calcium deficiency in this age group contributes to the progressive decline in skeletal mass observed with  aging. Long-term studies should be conducted to determine the effect of calcium supplementation on the rate at which bone mass is lost in this age group. · Dietary phosphorus, protein, and fiber each have separate and potentially deleterious effects on calcium economy. Studies should be conducted to determine their individual and joint effects on calcium balance in people with a diminished ability to increase the renal production of 1,25(OH)2D3 (i.e., the elderly) and in those with a need to be in positive calcium balance (i.e., adolescents). · There is a need for continued research to develop noninvasive, quantitative, analytical techniques that can accurately identify individuals at risk for osteoporotic fracture. References Alderman, B.W., N.S. Weiss, J.R. Daling, C.L. Ure, and J.H. Ballard. 1986. Reproductive history and postmenopusal risk of hip and forearm fracture. Am. J. Epidemiol. 124:262-267. Aloia, J.F., S.H. Cohn, J.A. Ostuni, R. Cane, and K. Ellis. 1978. Prevention of involutional bone loss by exercise. Ann. Intern. Med. 89:356-358.

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