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Endogenous and nutritional factors affecting bone
Bone Vol. 18, No. 1, Supplement January 1996:11S-13S
ELSEVIER
Endogenous and Nutritional Factors Affecting Bone R. M A R C U S Aging Study Unit, VA Medical Center, Palo Alto, CA, USA
epiphyseal fusion, even for men.z° Even so, androgens do have independent effects on bone mass in both men and women.
Introduction
Although the particular focus of this gathering is the role of exercise on bone, it is inappropriate to model bone mass regulation in terms of a single regulator. Bone is a bifunctional organ with primary structural roles (gravitational resistance and locomotion) sometimes in conflict with its function as a mineral reservoir. Changes in activity, diet, and hormonal status occur with age, and all contribute to skeletal health. Professor Robert Heaney has likened skeletal health to a three-legged chair. Functional integrity of all legs is required for the chair to stand. If two legs receive lavish attention and buttressing but the third leg is weak, the chair falls. In this brief review, I shall follow this analogy to discuss the two legs of skeletal health that are otherwise unrepresented at this meeting, reproductive hormone adequacy and nutritional status. In addition, I shall describe skeletal health in terms of bone acquisition and loss during the life cycle.
Adult Bone Loss The final common pathway through which bone mass is altered once epiphyseal closure and linear growth have stopped is bone remodeling--a continuous cycle of destruction and renewal of bone that occurs throughout life. It is carried out by individual, independent "bone remodeling units." Remodeling is initiated by hormonal or physical signals that cause marrow precursor cells resembling mononuclear phagocytes to cluster at discrete loci on the bone surface and fuse to become multinucleated osteoclasts. Osteoclasts then dig a cavity into the bone. In cortical bone this appears as a resorption tunnel within a haversian canal. On the trabecular surface it is a scalloped area called a Howship's lacuna. Coupled to resorption, bone formation ensues when local release of chemical mediators attracts osteoblast precursors to the base of the resorption cavity. These mature into osteoblasts that begin to replace the missing bone by secreting new collagen and matrix constituents. Matrix production is initially rapid, the new osteoid seam approaching 10-20 lxm in thickness before mineral deposition begins. With time, mineralization catches up to matrix deposition, and the new bone becomes fully mineralized. Resorptive and formation phases are complete within 8-12 weeks, several additional weeks being required to complete mineralization. Remodeling is not completely efficient. On completion of each cycle a small deficit in bone persists. Because remodeling occurs throughout life, agerelated bone loss may properly be viewed as a predictable event beginning shortly after cessation of linear growth. Alterations in overall bone remodeling rate can reflect distinct alterations in the components of the remodeling cycle. These include a change in the activation, or birth rate, of remodeling units, in the resorptive capacity of individual units, or in the magnitude of bone formation response. The factors influencing adult bone loss are identical to those influencing bone acquisition, although there is apparently little residual genetic effect. Thus, hormonal and dietary factors become dominant.
Bone Acquisition and Peak Bone Mass Abundant data now indicate that about 60% of final adult bone mass is acquired during the pubertal growth spurt. I'H Although these data are generally expressed in terms of bone mineral density (BMD, grams per sq. centimeter), most of the acquired bone is accounted for by increases in bone size rather than in its volumetric mineral density.11 Adolescent bone acquisition begins and stops about 2 years earlier in girls than in boys. Crosssectional and longitudinal data indicate that 95% of bone acquisition is complete by age 18 in females, with continued accrual of -5% over the next decade. 16 Genetic factors account for >70% of peak bone mass. Strong genetic influences affect body and bone size and bone geometry. These all influence bone strength in a manner that is independent of mineral density. A polymorphism in the Vitamin D receptor gene has been described that appears to influence bone density,14 although confh-mation of this relationship has been inconsistent. It may be that sensitivity to Vitamin D could influence bone density more powerfully in communities that are marginal in Vitamin D status, but that in countries with extensive Vitamin D fortification programs, Vitamin D repletion could negate the effect of this polymorphism. Nongenetic factors influencing bone acquisition include exercise, dietary calcium, growth hormone, and reproductive hormones. In adult males, the primary reproductive hormone is testosterone. However a fascinating case report establishes the dominant and critical role for estrogen in bone acquisition and
Hormonal Factors Influencing Bone Health
Gonadal Steroids Formidable evidence supports a critical role for gonadal function in the acquisition and maintenance of bone mass. Not only do hypogonadal boys and girls show deficits in both cortical and trabecular bone mineral, but loss of endogenous sex steroids during adult life regularly leads to accelerated loss of bone mineral, an effect that is particularly striking when it occurs at an
Address for correspondence and reprints: Dr. Robert Marcus, Director, Aging Study Unit, VA Medical Center, Palo Alto, CA 94301. © 1996 by Elsevier Science Inc. All rights reserved.
1 IS
8756-3282/96/$15.00 SSDI 8756-3282(95)00374-6
12S
R. Marcus Endogenous and nutritional factors affecting bone
early age. 1713-Estradiol is of particular importance for bone acquisition. A mutation in the estradiol receptor in a young man resulted not only in continued linear growth well into the third decade, but also in a bone mineral density that was several standard deviations below predicted values. 20 In women, loss of estrogen has dual effects. Decreased efficiency of intestinal and renal calcium handling increases the level of calcium necessary to maintain neutral calcium balance, s In addition, estrogen directly affects bone cell function. In animal models, strong evidence indicates estrogen directly regulates osteoblast production of intedeukin-6, a potent regulator of osteoclast recruitment. 7 The precise details of estrogen regulation of skeletally active cytokines in humans are not clear, but such interactions are thought to underlie the accelerated bone loss of early estrogen deficiency. Estrogen deficiency permits osteoclasts to resorb bone with greater efficiency. This may lead to perforation and elimination of entire trabecular elements, so that no scaffold remains for initiation of bone formation. Bringing to mind the three-legged stool, estrogen deficiency may exert an overwhelming influence on bone mass even when adequate attention is given to other important influences on bone health. For example, women endurance athletes who experience interruption of menstrual function lose bone despite regular exercise at high intensity.15 For women at menopause, the most important influence on bone mass is clearly estrogen deprivation. No amount of exercise or dietary excess can likely overcome the accelerated loss of bone due specifically to estrogen withdrawal. Menopausal estrogen replacement conserves bone mass and, if continued for 5 years or more, results in - 6 0 % reduction in risk for osteoporotic fracture. 21 Thus, menopausal hormone replacement is viewed as a long-term treatment strategy. The skeletal role of androgens for men is less well understood. Testosterone deficiency is an important contributor to osteoporosis in men, in whom replacement therapy partially restores bone mass. Whether direct actions on bone cells fully account for the effects of androgen on bone mass remains to be established. Androgens also increase muscle mass, so it is possible that androgen effects on bone reflect secondarily the increased mechanical loading that would occur if muscle bulk were increased.
Growth Hormone/IGF-1 Although this review concentrates on reproductive hormones, other endogenous factors retain interest. Age-related deficits in the somatotrophic axis (growth hormone/IGF-I) are welldescribed, and have been related to the characteristic changes in body composition of normal human aging, including the loss of bone. 19 Patients with deficient growth hormone (GH) secretory function show low bone mass, and recent studies indicate that GH replacement of such patients promotes significant increases in both axial and peripheral BMD. Because healthy elderly men and women also show low circulating levels of GH and IGF-I as well as deficient GH responses to physiologic stimuli, there has been considerable interest in the possibility that GH replacement would restore bone mass in such individuals as well. Sustained treatment with either GH or IGF-I clearly does initiate bone remodeling activity. 2'5'12 Disappointingly, however, GH has not yet proven capable of stimulating significant gain in bone mass in elderly subjects. 9 Moreover, because bone remodeling in the elderly is clearly an inefficient process, it is not obvious why an agent that promotes remodeling activity would necessarily increase bone density!
Bone Vol. 18, No. 1, Supplement January 1996:11S-13S
Parathyroid Hormone Primary regulation of extracellular fluid calcium concentration is carded out by the parathyroid glands and their peptide secretory product, parathyroid hormone (PTH). In the next section, I discuss the influence of calcium nutriture on bone health. The physiologic response to inadequate calcium is presumably an increase in PTH secretion, which subsequently restores and maintains blood calcium levels at the expense of the skeleton. Circulating levels of PTH rise during normal human aging, particularly in women. 13 Moreover, a normally observed nocturnal rise in PTH secretion is temporally associated with increased biochemical evidence for bone resorption. A new relationship between PTH and bone has recently been shown. When administered in an intermittent fashion, PTH can be shown to exert impressive anabolic effects on trabecular bone. This differs fundamentally from the loss of axial bone that is observed when hormone is administered as a continuous infusion. The mechanism for these disparate actions is not clear, but clinical trials are underway to learn whether intermittent PTH offers a means to repair bone deficits in osteoporotic patients. ~7
Calcium Nutritional State The skeleton is the repository for 99.5% of body calcium stores, and constitutes a reservoir of mineral that can support plasma calcium levels at times of need. The daily recommended dietary calcium intake for adolescent boys and girls is 1200 mg. Because 60% of final bone mass is deposited during the pubertal growth spurt, dietary inadequacy may impose far greater constraints on bone formation at this time than at other times of life. Consumption figures indicate that the calcium intake of American men corresponds reasonably well to recommended levels at most ages, but that median intakes for girls are substantially below target levels by age 11, and never recover. Thus, it is likely that calcium undernutrition has an important influence on peak bone mass in women. Randomized clinical trials now indicate that calcium supplementation of adolescent boys and girls leads to increased bone acquisition.I° Whether these short-term increases will be retained as increases in final achieved peak bone mass remains to be established. Recker et al.16 have shown a powerful influence of calcium intake on terminal bone acquisition during the third decade, although the total amount of bone accrued during this period is only - 5 % of the peak bone mass. The mechanism by which inadequate calcium intake may promote adult bone loss is thought to be via a PTH-dependent increase in bone remodeling. During the third through fifth decades, growth has stopped, and robust compensatory mechanisms permit rapid adaptation to even severe dietary restriction. Calcium nutritional state appears not to be a major influence on the rate of bone loss during this period, so it is unlikely that calcium supplementation will exert beneficial effects on bone mass at this time. It is ironic that this population receives the greatest proportion of advertising of calcium supplements. At menopause, the initial acceleration in bone loss reflects loss of endogenous estrogen, and has little relationship to dietary calcium. Calcium supplementation of early menopausal women shows only modest effects on bone lOSS.6"18 After age 60, the early effects of estrogen deficiency have dissipated, whereas the compensatory mechanisms for accommodating dietary inadequacy have become less efficient in both men and women. At this time, proper attention to calcium nutritional state, be it from dietary calcium or from supplementation with calcium and/or
Bone Vol. 18, No. 1, Supplement January 1996:11S-13S
Vitamin D, is rational, and has been s h o w n to have beneficial effects on biochemical markers o f bone turnover as well as b o n e mass. 4 In fact, a recent clinical trial s h o w e d that provision o f 1000 m g / d a y calcium and 800 I U Vitamin D to frail elderly w o m e n leads to a - 3 0 % reduction in fracture incidence, including hip fracture, as well as a decrease in total mortality. 3 Thus, calcium/Vitamin D supplementation of the frail elderly appears to be one of the m o s t powerful interventions available to reduce fracture-associated morbidity and mortality!
Conclusions The three-legged stool is a useful model to help understand the roles o f multiple contributors to bone health, and to help investigators realize that they can no longer focus solely on one area in isolation f r o m the others. For too long the osteoporosis community has consisted o f endocrinologists, biomechanists, and nutritionists, each traveling in nonintersecting orbits. To complete the picture, however, it is important to r e m e m b e r that, like trabecular bone, the legs o f the stool are connected by horizontal connecting elements. That is, there are important interconnections and modulating influences between and a m o n g them. Although considerable information exists concerning the interactions b e t w e e n nutritional status and reproductive h o r m o n e function, very little is k n o w n about the effects o f either reproductive h o r m o n e s or nutrients on the skeletal response to mechanical loading. F o r example, it m a y be that estrogen regulates the production or organization o f cellular organelles involved with the skeletal response to exercise. One hopes that conferences such as this will p r o m o t e further exploration in this area.
References 1. Bonjour, J. P., Theintz, G., Buchs, B., Slossman, D., and Rizzoli, R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 73:555-563; 1991. 2. Brixen, K., Nielsen, H. K., Mosekilde, L., and Flyvbjerg, A. A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodelingin normal human volunteers.J Bone Miner Res 5:609618; 1990. 3. Chapuy, M. C., Arlot, M. E., Duboeuf, F., Bru, J., Crouzet, B., Amaud, S., Delmas, P.D., and Meuhier, P.J. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637-1642; 1992. 4. Dawson-Hughes,B., Dallal, G. E., Krall, E. A., Sadowski,L., Sahyoun,N., and Tannenbaum, S. A controlled trial of the effect of calcium supplementationon bone density in postmenopansalwomen. N Engl J Med 323:878-883, 1990. 5. Ebeling, P. R., Jones, J. D., O'Fallon, W. M., Janes, C. H., and Riggs, B. L. J Clin Endocrinol Metab 77:1384-1387; 1993. 6. Elders, P. J. M., Netelenbos, J. C., Lips, P., van Ginkel, F. C., Khoe, E., Leeu-
R. Marcus Endogenous and nutritional factors affecting bone
13S
wenkamp, O. R., Hackeng, W. H. L., and van der Stelt, P. F. Calcium supplementation reduces vertebral bone loss in perimenopansalwomen: a controlled trial in 248 women between 46 and 55 years of age. J Clin Endocrinol Metab 73:553-540; 1991. 7. Girasole, G., Jilka, R. L., Passeri, G., Boswell, S., Boder, G., Williams, D. C., and Manolagas, S.C. 17~estradiol inhibits interleuldn-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 89:883-891; 1992. 8. Heaney, R. P., Recker, R. R., and Saville, P. D. Calcium balance and calcium requirements in middle-aged women. Am J Clin Nutr 30:1603-1611; 1977. 9. Holloway, L., Butterfield, G., Hintz, R.L., Gesundheit, N., and Marcus, R. Effect of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. J Clin Endocrinol Metab 79:470--479; 1994. 10. Johnston, C.C., Jr., Miller, J.Z., Slemenda, C.W., Reister T. K., Huit, S., Christian, J. C., and Peacock, M. Calcium supplementation and increases in bone mineral density in children. N Engl J Med 327:82-87; 1992. 11. Katzman, D. K., Bachrach, L. K., Carter, D. R., and Marcus, R. Clinical and anthropometric correlates of bone mineral acquisition in healthy adolescent girls. J Clin Endocdnol Metab 73:1332-1339; 1991. 12. Marcus, R., Butterfield, G., Holloway, L., Gilliland, L., Baylink, D. J., Hintz, R. L., and Sherman, B. L. Effects of short-termadministration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 70:519527, 1990. 13. Marcus, R., Madvig, P., and Young, G. Age-related changes in parathyroid hormoneand parathyroidhormoneaction in normal humans.J Clin Endocrinol Metab 56:223-230; 1984. 14. Morrison,N. A., Qui, J. C., Tokita, A., Kelly, P. J., Crofts, L., Nguyen, T. V., Sambrook, P. N., and Eisman, J. A. Prediction of bone density from vitamin D receptor alleles. Nature 367:284-287; 1994. 15. Myburgh, K. H., Bachrach, L. K., Lewis, B., Kent, K., and Marcus, R. Low bone mineral density at axial and appendicular sites in amenorrheic athletes. Med Sci Sports Exere 25:1197-1202; 1993. 16. Reeker, R. R., Davies, K. M., Hinders, S. M., Heaney, R. P., Stegman, M. R., and Kimmel, D. B. Bone gain in young adult women. JAMA 268:2403-2408; 1992. 17. Reeve, J., Meunier, P. J., Parsons, J. A., Bernat, M., Bijvoet, O. L. M., Courpron, P., Edouard, C., Klenerman, L., Neer, R. M., Renier, J. C., Slovik, D., Visman, F. J., and Potts, J. T., Jr. Anabolic effect of human parathyroid hormone fragment (hPTH 1-34) therapy on trabecular bone in involutional osteoporosis: report of a multi-centre trial. Br Med J 280:1340-1344; 1980. 18. Riis, B., Thomsen, K., and Christiansen, C. Does calcium supplementation prevent postmenopausalbone loss? A double-blind, controlled clinical study.N Engl J Med 316:173-177; 1987. 19. Rudman, D. Growth hormone, body composition, and aging. J Am Geriatric Soc 33:800-807; 1985. 20. Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R., Specker, B., Williams, T. C., Lubahn, D. B., and Korach, K. S. Estrogen resistance caused by a mutation in the estrogen-receptorgene in a man. N Engl J Med 331:10561061; 1994. 21. Weiss, N.S., Ure, C.L., Ballard, J.H., Williams, A.R., and Daling, J.R. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Mad 303:1195-1198; 1980.
ELSEVIER
Endogenous and Nutritional Factors Affecting Bone R. M A R C U S Aging Study Unit, VA Medical Center, Palo Alto, CA, USA
epiphyseal fusion, even for men.z° Even so, androgens do have independent effects on bone mass in both men and women.
Introduction
Although the particular focus of this gathering is the role of exercise on bone, it is inappropriate to model bone mass regulation in terms of a single regulator. Bone is a bifunctional organ with primary structural roles (gravitational resistance and locomotion) sometimes in conflict with its function as a mineral reservoir. Changes in activity, diet, and hormonal status occur with age, and all contribute to skeletal health. Professor Robert Heaney has likened skeletal health to a three-legged chair. Functional integrity of all legs is required for the chair to stand. If two legs receive lavish attention and buttressing but the third leg is weak, the chair falls. In this brief review, I shall follow this analogy to discuss the two legs of skeletal health that are otherwise unrepresented at this meeting, reproductive hormone adequacy and nutritional status. In addition, I shall describe skeletal health in terms of bone acquisition and loss during the life cycle.
Adult Bone Loss The final common pathway through which bone mass is altered once epiphyseal closure and linear growth have stopped is bone remodeling--a continuous cycle of destruction and renewal of bone that occurs throughout life. It is carried out by individual, independent "bone remodeling units." Remodeling is initiated by hormonal or physical signals that cause marrow precursor cells resembling mononuclear phagocytes to cluster at discrete loci on the bone surface and fuse to become multinucleated osteoclasts. Osteoclasts then dig a cavity into the bone. In cortical bone this appears as a resorption tunnel within a haversian canal. On the trabecular surface it is a scalloped area called a Howship's lacuna. Coupled to resorption, bone formation ensues when local release of chemical mediators attracts osteoblast precursors to the base of the resorption cavity. These mature into osteoblasts that begin to replace the missing bone by secreting new collagen and matrix constituents. Matrix production is initially rapid, the new osteoid seam approaching 10-20 lxm in thickness before mineral deposition begins. With time, mineralization catches up to matrix deposition, and the new bone becomes fully mineralized. Resorptive and formation phases are complete within 8-12 weeks, several additional weeks being required to complete mineralization. Remodeling is not completely efficient. On completion of each cycle a small deficit in bone persists. Because remodeling occurs throughout life, agerelated bone loss may properly be viewed as a predictable event beginning shortly after cessation of linear growth. Alterations in overall bone remodeling rate can reflect distinct alterations in the components of the remodeling cycle. These include a change in the activation, or birth rate, of remodeling units, in the resorptive capacity of individual units, or in the magnitude of bone formation response. The factors influencing adult bone loss are identical to those influencing bone acquisition, although there is apparently little residual genetic effect. Thus, hormonal and dietary factors become dominant.
Bone Acquisition and Peak Bone Mass Abundant data now indicate that about 60% of final adult bone mass is acquired during the pubertal growth spurt. I'H Although these data are generally expressed in terms of bone mineral density (BMD, grams per sq. centimeter), most of the acquired bone is accounted for by increases in bone size rather than in its volumetric mineral density.11 Adolescent bone acquisition begins and stops about 2 years earlier in girls than in boys. Crosssectional and longitudinal data indicate that 95% of bone acquisition is complete by age 18 in females, with continued accrual of -5% over the next decade. 16 Genetic factors account for >70% of peak bone mass. Strong genetic influences affect body and bone size and bone geometry. These all influence bone strength in a manner that is independent of mineral density. A polymorphism in the Vitamin D receptor gene has been described that appears to influence bone density,14 although confh-mation of this relationship has been inconsistent. It may be that sensitivity to Vitamin D could influence bone density more powerfully in communities that are marginal in Vitamin D status, but that in countries with extensive Vitamin D fortification programs, Vitamin D repletion could negate the effect of this polymorphism. Nongenetic factors influencing bone acquisition include exercise, dietary calcium, growth hormone, and reproductive hormones. In adult males, the primary reproductive hormone is testosterone. However a fascinating case report establishes the dominant and critical role for estrogen in bone acquisition and
Hormonal Factors Influencing Bone Health
Gonadal Steroids Formidable evidence supports a critical role for gonadal function in the acquisition and maintenance of bone mass. Not only do hypogonadal boys and girls show deficits in both cortical and trabecular bone mineral, but loss of endogenous sex steroids during adult life regularly leads to accelerated loss of bone mineral, an effect that is particularly striking when it occurs at an
Address for correspondence and reprints: Dr. Robert Marcus, Director, Aging Study Unit, VA Medical Center, Palo Alto, CA 94301. © 1996 by Elsevier Science Inc. All rights reserved.
1 IS
8756-3282/96/$15.00 SSDI 8756-3282(95)00374-6
12S
R. Marcus Endogenous and nutritional factors affecting bone
early age. 1713-Estradiol is of particular importance for bone acquisition. A mutation in the estradiol receptor in a young man resulted not only in continued linear growth well into the third decade, but also in a bone mineral density that was several standard deviations below predicted values. 20 In women, loss of estrogen has dual effects. Decreased efficiency of intestinal and renal calcium handling increases the level of calcium necessary to maintain neutral calcium balance, s In addition, estrogen directly affects bone cell function. In animal models, strong evidence indicates estrogen directly regulates osteoblast production of intedeukin-6, a potent regulator of osteoclast recruitment. 7 The precise details of estrogen regulation of skeletally active cytokines in humans are not clear, but such interactions are thought to underlie the accelerated bone loss of early estrogen deficiency. Estrogen deficiency permits osteoclasts to resorb bone with greater efficiency. This may lead to perforation and elimination of entire trabecular elements, so that no scaffold remains for initiation of bone formation. Bringing to mind the three-legged stool, estrogen deficiency may exert an overwhelming influence on bone mass even when adequate attention is given to other important influences on bone health. For example, women endurance athletes who experience interruption of menstrual function lose bone despite regular exercise at high intensity.15 For women at menopause, the most important influence on bone mass is clearly estrogen deprivation. No amount of exercise or dietary excess can likely overcome the accelerated loss of bone due specifically to estrogen withdrawal. Menopausal estrogen replacement conserves bone mass and, if continued for 5 years or more, results in - 6 0 % reduction in risk for osteoporotic fracture. 21 Thus, menopausal hormone replacement is viewed as a long-term treatment strategy. The skeletal role of androgens for men is less well understood. Testosterone deficiency is an important contributor to osteoporosis in men, in whom replacement therapy partially restores bone mass. Whether direct actions on bone cells fully account for the effects of androgen on bone mass remains to be established. Androgens also increase muscle mass, so it is possible that androgen effects on bone reflect secondarily the increased mechanical loading that would occur if muscle bulk were increased.
Growth Hormone/IGF-1 Although this review concentrates on reproductive hormones, other endogenous factors retain interest. Age-related deficits in the somatotrophic axis (growth hormone/IGF-I) are welldescribed, and have been related to the characteristic changes in body composition of normal human aging, including the loss of bone. 19 Patients with deficient growth hormone (GH) secretory function show low bone mass, and recent studies indicate that GH replacement of such patients promotes significant increases in both axial and peripheral BMD. Because healthy elderly men and women also show low circulating levels of GH and IGF-I as well as deficient GH responses to physiologic stimuli, there has been considerable interest in the possibility that GH replacement would restore bone mass in such individuals as well. Sustained treatment with either GH or IGF-I clearly does initiate bone remodeling activity. 2'5'12 Disappointingly, however, GH has not yet proven capable of stimulating significant gain in bone mass in elderly subjects. 9 Moreover, because bone remodeling in the elderly is clearly an inefficient process, it is not obvious why an agent that promotes remodeling activity would necessarily increase bone density!
Bone Vol. 18, No. 1, Supplement January 1996:11S-13S
Parathyroid Hormone Primary regulation of extracellular fluid calcium concentration is carded out by the parathyroid glands and their peptide secretory product, parathyroid hormone (PTH). In the next section, I discuss the influence of calcium nutriture on bone health. The physiologic response to inadequate calcium is presumably an increase in PTH secretion, which subsequently restores and maintains blood calcium levels at the expense of the skeleton. Circulating levels of PTH rise during normal human aging, particularly in women. 13 Moreover, a normally observed nocturnal rise in PTH secretion is temporally associated with increased biochemical evidence for bone resorption. A new relationship between PTH and bone has recently been shown. When administered in an intermittent fashion, PTH can be shown to exert impressive anabolic effects on trabecular bone. This differs fundamentally from the loss of axial bone that is observed when hormone is administered as a continuous infusion. The mechanism for these disparate actions is not clear, but clinical trials are underway to learn whether intermittent PTH offers a means to repair bone deficits in osteoporotic patients. ~7
Calcium Nutritional State The skeleton is the repository for 99.5% of body calcium stores, and constitutes a reservoir of mineral that can support plasma calcium levels at times of need. The daily recommended dietary calcium intake for adolescent boys and girls is 1200 mg. Because 60% of final bone mass is deposited during the pubertal growth spurt, dietary inadequacy may impose far greater constraints on bone formation at this time than at other times of life. Consumption figures indicate that the calcium intake of American men corresponds reasonably well to recommended levels at most ages, but that median intakes for girls are substantially below target levels by age 11, and never recover. Thus, it is likely that calcium undernutrition has an important influence on peak bone mass in women. Randomized clinical trials now indicate that calcium supplementation of adolescent boys and girls leads to increased bone acquisition.I° Whether these short-term increases will be retained as increases in final achieved peak bone mass remains to be established. Recker et al.16 have shown a powerful influence of calcium intake on terminal bone acquisition during the third decade, although the total amount of bone accrued during this period is only - 5 % of the peak bone mass. The mechanism by which inadequate calcium intake may promote adult bone loss is thought to be via a PTH-dependent increase in bone remodeling. During the third through fifth decades, growth has stopped, and robust compensatory mechanisms permit rapid adaptation to even severe dietary restriction. Calcium nutritional state appears not to be a major influence on the rate of bone loss during this period, so it is unlikely that calcium supplementation will exert beneficial effects on bone mass at this time. It is ironic that this population receives the greatest proportion of advertising of calcium supplements. At menopause, the initial acceleration in bone loss reflects loss of endogenous estrogen, and has little relationship to dietary calcium. Calcium supplementation of early menopausal women shows only modest effects on bone lOSS.6"18 After age 60, the early effects of estrogen deficiency have dissipated, whereas the compensatory mechanisms for accommodating dietary inadequacy have become less efficient in both men and women. At this time, proper attention to calcium nutritional state, be it from dietary calcium or from supplementation with calcium and/or
Bone Vol. 18, No. 1, Supplement January 1996:11S-13S
Vitamin D, is rational, and has been s h o w n to have beneficial effects on biochemical markers o f bone turnover as well as b o n e mass. 4 In fact, a recent clinical trial s h o w e d that provision o f 1000 m g / d a y calcium and 800 I U Vitamin D to frail elderly w o m e n leads to a - 3 0 % reduction in fracture incidence, including hip fracture, as well as a decrease in total mortality. 3 Thus, calcium/Vitamin D supplementation of the frail elderly appears to be one of the m o s t powerful interventions available to reduce fracture-associated morbidity and mortality!
Conclusions The three-legged stool is a useful model to help understand the roles o f multiple contributors to bone health, and to help investigators realize that they can no longer focus solely on one area in isolation f r o m the others. For too long the osteoporosis community has consisted o f endocrinologists, biomechanists, and nutritionists, each traveling in nonintersecting orbits. To complete the picture, however, it is important to r e m e m b e r that, like trabecular bone, the legs o f the stool are connected by horizontal connecting elements. That is, there are important interconnections and modulating influences between and a m o n g them. Although considerable information exists concerning the interactions b e t w e e n nutritional status and reproductive h o r m o n e function, very little is k n o w n about the effects o f either reproductive h o r m o n e s or nutrients on the skeletal response to mechanical loading. F o r example, it m a y be that estrogen regulates the production or organization o f cellular organelles involved with the skeletal response to exercise. One hopes that conferences such as this will p r o m o t e further exploration in this area.
References 1. Bonjour, J. P., Theintz, G., Buchs, B., Slossman, D., and Rizzoli, R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 73:555-563; 1991. 2. Brixen, K., Nielsen, H. K., Mosekilde, L., and Flyvbjerg, A. A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodelingin normal human volunteers.J Bone Miner Res 5:609618; 1990. 3. Chapuy, M. C., Arlot, M. E., Duboeuf, F., Bru, J., Crouzet, B., Amaud, S., Delmas, P.D., and Meuhier, P.J. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637-1642; 1992. 4. Dawson-Hughes,B., Dallal, G. E., Krall, E. A., Sadowski,L., Sahyoun,N., and Tannenbaum, S. A controlled trial of the effect of calcium supplementationon bone density in postmenopansalwomen. N Engl J Med 323:878-883, 1990. 5. Ebeling, P. R., Jones, J. D., O'Fallon, W. M., Janes, C. H., and Riggs, B. L. J Clin Endocrinol Metab 77:1384-1387; 1993. 6. Elders, P. J. M., Netelenbos, J. C., Lips, P., van Ginkel, F. C., Khoe, E., Leeu-
R. Marcus Endogenous and nutritional factors affecting bone
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