Experimental Gerontology, Vol. 26. pp. 171-187. 1991 Printed in the USA. All rightsreserved.

0531-5565/91 $3.00 + .00 Copyright© 1991 PergamonPress plc

AGE-RELATED BONE CHANGES

GARY M. KIEBZAK Science Applications International Corporation, 626 Towne Center Drive, Suite 201, Joppa, Maryland 21085

Abstract -- Bone changes occur during normal aging in both men and women. Changes are both quantitative and qualitative in nature, and include: 1) alterations in the dynamics of bone cell populations, resulting in uncoupling of the normal process of bone resorption and formation; 2) changes in bone architecture (e.g., rearrangement of trabecular struts) and cross-sectional geometry (characterized by subperiosteal expansion and enlargement of the medullary cavity); 3) accumulation of microfractures; 4) localized disparity in the concentration of deposited minerals, with hypomineralization in some areas and hypermineralization in others; 5) changes in the crystalline properties of mineral deposits; and 6) changes in the protein content of matrix material. In addition, there are age-related changes in the status of calcium and phosphate regulating hormones: parathyroid hormone increases, and production of the most active metabolites of vitamin D 3 decreases. These hormonal changes undoubtedly affect the maintenance of normal bone homeostasis. Other important factors which can profoundly influence bone status in the elderly are decreased physical activity and dietary inadequacies. Bone tissue is particularly responsive to mechanical loading, and the magnitude of bone mass loss as a consequence of decreased physical activity may not be fully appreciated. Interactions of the above mentioned changes are not completely understood, and the degree to which these changes have been documented in humans varies considerably. Clearly, however, the overall net result is the occurrence of age-related loss of bone tissue and bone strength. This process is accelerated after menopause in women, resulting in the clinical condition commonly known as osteoporosis. In addition to loss of bone mass (usually reported as a decrease in bone mineral content), osteoporosis is accompanied by bone pain, spinal deformity, loss of height, and fractures. Key Words: aging, homeostasis, bone loss, bone mineral, bone matrix, biomechanics, remodeling of bone, bone cells, bone strength, osteoporosis

A G E - R E L A T E D BONE C H A N G E S 1 BOTIJ QUANTITATIVEand qualitative changes in bone tissue and in bones themselves occur not only during growth and development but also during normal aging. The net result of these

Correspondence to: G.M. Kiebzak, Ph.D., Section of Publications, Mayo Clinic, 200 First Street SW, Rochester, M N 55905. 1There are many comprehensive reviews which discuss various aspects of bone physiology and biochemistry, osteopomsis, and age-related bone changes. This paper is an overview, outlining the bone changes that occur with aging. From this perspective, references are not all-inclusive;rather, an attempt was made to cite very recent publications and (especially)to cite review papers which, together, would provide the reader with a comprehensive and serviceable listof the published literature.

171

172

G M. KIEBZAK

changes in the elderly is the loss of bone mass and bone strength. The magnitude of loss mav be striking: by age 90, a woman may lose 50% of her peak trabecular bone mass. while a man may lose 10-25% (for further discussion see Sharpe, 1979; Mazess, 1982: Duncan and Parfitt. 1984: Tonna, 1985; Melton et al., 1988). As noted by Parfitt (1988), age-related bone loss is "'a universal phenomenon of human biology that occurs regardless of sex, race, occupation. habitual physical activity, dietary habits, economic development, geographic location, or historical epoch." A curve depicting loss of bone mass with age will typically show that both men and women lose bone beginning about the middle of the third decade of life ( Newton-John and Morgan, 1970; Duncan and Parfitt, 1984: Parfitt, 1988), although loss of vertebral trabecular bone may occur even earlier (Gilsanz et al., 1988). However, there is tremendous individual variation in the age at which significant bone loss becomes evident and in the degree of bone loss which ultimately occurs (Newton-John and Morgan, 1970: Duncan and Parfitt, 1984; Parfitt, 1988). The rate and magnitude of loss will vary among bones of the axial and appendicular skeleton, among different types of bone tissue, between males and females, and even among different races (Duncan and Parfitt, 1984: Melton et al., 1988; Nilas et al., 1988; Parfitt, 1988). It is notable that at any given age after puberty, total bone mass/relative to body size) is always greater in men than in women (see reviews: Duncan and Parfitt, 1984: Tonna. 1985; Melton et al., 1988; Parfitt, 1988). Specific age-related bone changes known to occur in humans or experimental animals include: 1. alterations in the dynamics of bone cell populations, and in those factors which regulate the balance between bone resorption and bone formation; 2. adjustments in bone architecture and cross-sectional geometry: 3. accumulation of microfractures: 4. localized disparity in the concentration of deposited minerals; 5. changes in the crystalline properties of mineral deposits; and 6. changes in the protein content and organization of matrix material. These changes are not necessarily mutually exclusive; in fact, an alteration in one property of bone tissue may command a compensatory response in another. Further, in the course of this discussion, it will become clear that age-related changes in adult bone represent a combined effect of the normal progression of "'developmental" alterations (e.g., subperiosteal expansion), pathologic effects of altered cell dynamics (e.g., loss of trabeculae and appearance of porosities as a result of the imbalance between bone resorption and bone formation), and loading fatigue (e.g., accumulation of microfractures).

ORGANIZATION OF BONE TISSUE In order to better understand the processes underlying age-related bone changes, including bone atrophy, it is necessary to appreciate the levels and heterogeneity of bone structure and function. Bone is a composite material, made up of matrix (which is comprised of bone cells, collagen and other proteins, accounting for about one-third of the dry, fat-free weight of bone), and mineral deposits (which account for about two-thirds of the weight and one-half of the volume of bone) (Jowsey, 1977). Adult bone tissue is arranged primarily as either dense cortical bone (also known as compact bone) or as a latticework of trabecular bone (also known as spongy or cancellous bone).

AGE-RELATED BONECHANGES

173

Cortical bone (which constitutes about 80% of the skeleton) is characterized by a system of longitudinally oriented, rod-like structures called osteons (also known as haversian systems), each of which consists of layers of tissue concentrically arranged around a vascular canal. Possible structural and physiologic advantages of this arrangement of osteons are: 1) osteons may represent a system for mobilization of mineral (since mineralized tissue is in close proximity to the vascular supply), 2) osteons may be important in repair mechanisms, and 3) the physical presence of osteons may limit the spread of microfractures (Currey, 1984; Lanyon, 1984; Martin and Burr, 1989). Thus, this system of osteons helps to maintain the strength and integrity of the intact bone over the course of a lifetime, particularly since the remodeling process (discussed below) involves continual formation of new (i.e., secondary) osteons. It is recognized, however, that these bundles of osteons may actually compromise the biomechanical properties of the dense cortical bone tissue itself (it is intuitively obvious that the addition of holes in a structure--in this case vascular canals--should weaken it) (Currey, 1984; Martin and Burr, 1989). In trabecular bone, arched mineralized spicules (trabeculae) arranged along the lines of weightbearing force are intersected obliquely and at right angles by other spicules which function as ties or struts. Although it constitutes only about 20% of the skeleton, trabecular bone has a greater overall surface area than does cortical bone and is considered to be more metabolically active. These characteristics may explain, at least in part, the observation that age-related trabecular bone loss, as compared to cortical loss, appears to be more pronounced and occurs at an earlier age (Newton-John and Morgan, 1970; Mazess, 1982; Riggs and Melton, 1986; Gilsanz et al., 1988; Raisz and Smith, 1989). However, this pattern of loss, often purported as dogma, has been difficult to prove and remains somewhat controversial. In addition, there may be sex differences in the relative loss of cortical versus trabecular bone at any given age (but particularly when comparing postmenopausal women and elderly men), and generalizations must be taken with caution. The dual configuration of bone tissue (as cortical and trabecular bone) is designed to provide strength in direct response to weightbearing stress. In fact, both types of bone undergo perpetual change in a process called remodeling, which involves the continual replacement of old bone with new bone (for further discussion of remodeling, see Schultheis, in this special issue, p. 205). This process allows the reconfiguration of bone architecture to accommodate weightbearing loads, and probably also participates in the maintenance of calcium homeostasis (Lanyon, 1984; Parfitt, 1988; Burr and Martin, 1989). Normally, remodeling involves a process whereby old bone resorption is balanced by new bone formation, with (at least theoretically) no net loss of bone tissue (Frost, 1963; Aaron, 1976; Paffitt, 1988). Thus, bone formation and bone resorption are coupled (Frost, 1963; Ivey and Baylink, 1981; Parfitt, 1982; Peck and Woods, 1988). Remodeling involves the recruitment and activation of the bone-resorbing cells (osteoclasts) and the bone-forming cells (osteoblasts) (Aaron, 1976; Triffitt, 1987; Parfitt, 1988; Peck and Woods, 1988). The sequence of events would be" activation (and recruitment) of bone cell populations in response to a stimulus or provocation ~ resorption of old bone ~ new bone formation. The regulation of the remodeling process is largely unknown, but undoubtedly involves local regulatory factors, a combination of physical factors as a result of weightbearing stress, and the effects of calcium-regulating hormones (i.e., systemic factors) impinging upon the different bone cell populations (Lanyon, 1984; Peck and Woods, 1988; and see discussion, Chapter 5, Martin and Burr, 1989).

174

G M KIEBZAK

ALTERATION OF BONE CELL DYNAMICS--THE UNCOUPLING OF BONE RESORPTION AND FORMATION With advanced age and various pathophysiologic conditions, the remodeling sequence becomes uncoupled, and formation does not keep pace with resorption--the ultimate result is the net loss of bone tissue. There are no satisfactory explanations for uncoupling. It is conceivable that uncoupling is the result of a primary disruption of signal transduction, which (as defined in this context) is the ability to generate and/or respond to signals which direct or initiate bone resorption and/or formation. Numerous possibilities exist to account for disrupted signal transduction, including: 1) an age-related change in the secretion or metabolism of calcium-regulating hormones (Riggs and Melton, 1986: Eastell et al.. 1988; Kiebzak et al., 1988a, b), local regulatory factors (Marks and Popoff, 1988; Thompson and Rodan, 1988: Canalis et al., 1989), or matrix chemoattractant proteins (Triffitt, 1987: Epstein, 1988: Lian and Gundberg, 1988) or, alternatively, a change in target cell sensitivity to hormones, local regulatory factors, or chemoattractant proteins; 2) decreased perfusion of bone tissue as a result of age-related changes in bone blood flow (Hruza and Wachtlova, 1969; Atkinson et al.. 1984; Brindley et al., 1988), with a resultant alteration in the delivery of blood-borne regulatory factors and/or progenitor cells; 3) changes in the crystalline properties of bone mineral (Matsushima and Hikichi, 1989) and in the content or organization of the extracellular matrix material (Vejlens, 1971; Laitinen, 1976; Klein and Rajah, 1984; Dickson and Bagga, 1985: Ferris et al., 1987; Robey, 1989) which may influence not only the biomechanical properties of bone but also the conduction and distribution of strain-generated electrical fields through bone tissue (these electrical fields may. in turn, play a role in coordinating or stimulating formation-resorption activity) (Bassett and Becker, 1962; Lanyon, 1984; Buckley et al., 1988; Rubin et al., 1989; Tabrah et al., 1990); 4) an age-related decrease in the metabolic activity of osteoblasts, the cells which produce extracellular matrix and which participate in the mineralization process (Irving et al., 1981; Nishimoto et al., 1985: Tonna, 1978, 1985: Riggs and Melton, 1986; Meunier, 1988); and 5) an age-related decrease in the population of osteoblast progenitor cells (Meunier et al., 1971; Irving et al., 1981; Nishimoto et al., 1985; Tonna, 1985). Histomorphometry has shown that the bone formation rate decreases dramatically with age (Jowsey, 1960; Aaron, 1976; Sharpe, 1979; Currey, 1984; Exton-Smith, 1985; Tonna, 1978, 1985; Meunier, 1988; Martin and Burr, 1989). In elderly people, the area of bone surfaces with no active mineralization activity increases, and osteoblasts may be totally absent from such areas (Aaron, 1976; Sharpe, 1979; Currey, 1984; Tonna, 1985). The time required for complete remodeling cycles (i.e., resorption followed by bone replacement) increases with old age. The age-related increase in cortical bone porosities is probably the result--at least in part--of incomplete "filling" of resorption spaces (Martin et al., 1980; Parfitt, 1984; Exton-Smith, 1985; Martin and Burr, 1989). The effects of the imbalance between resorption and formation are not uniform throughout the skeleton, as quantitative and qualitative differences in areas of net resorption are evident not only between weightbearing bones and nonweightbearing bones but also between the inner (endosteal) and outer (periosteal) regions of the diaphysis (shaft) of long bone cortex (specifically, the ratio of resorption to formation surfaces in the endosteal cortical bone--the inner surface, next to the marrow space, is increased in the elderly) (Thompson, 1980; Martin and Burr, 1989).

AGE-RELATED BONE CHANGES

175

ADJUSTMENTS IN BONE ARCHITECTURE AND CROSS-SECTIONAL GEOMETRY The size and shape of bones (as organs of the skeletal system) change as the bone tissue remodels. However, with aging, formation does not keep pace with resorption, and the result is a profound effect on ultrastructure and architecture that is different from normal remodeling. Characteristic age-related architectural changes due to unbalanced resorption include both the complete loss of trabecular struts and ties and the thinning of remaining trabeculae, enlargement of the medullary cavity, increased size of the vascular canals, trabeculation of previously cortical endosteal bone, and the appearance of intracortical porosities (Delling, 1973; Dequeker, 1975; Lips et al., 1978; Sharpe, 1979; Duncan and Parfitt, 1984; Parfitt, 1984; Grynpas and Holmyard, 1988; Kiebzak et al., 1988a, b, c; Melton et al., 1988; Compston et al., 1989; Martin and Burr, 1989). From the point of view of a mechanical engineer, some age-related architectural changes may actually serve as a compensation against a decline in tissue quality (i.e., the "material property") of bone and against the loss of bone mineral (Currey 1984; Martin and Burr, 1989). This concept has been demonstrated in both rats (Kiebzak et al., 1988 a, b) and humans (Delling, 1973; Martin et al., 1980; Ruff and Hayes, 1982; Currey, 1984; Duncan and Parfitt, 1984; Parfitt, 1984; Ruff and Hayes, 1984; Ruff and Hayes, 1988; Zagba-Mongalima et al., 1988; Martin and Burr, 1989). These architectural "compensations"--that is, geometric remodeling--occur in human long bones, where the potentially detrimental effects of endosteal resorption and medullary expansion on biomechanical integrity are, to an extent, offset by concurrent subperiosteal bone (i.e., bone on the outer surface of the shaft, beneath the periosteum) opposition and expansion. It is emphasized, however, that architectural compensations cannot totally counterbalance the well-documented age-related loss of strength (Burstein et al., 1976; Martin and Atkinson, 1977; see Chapter 8, Martin and Burr, 1989) which is a combined result of changes in cell dynamics (and the associated decrease in matrix production; Jowsey, 1960; Meunier, 1988), aberrant collagen orientation and metabolism (Laitinen, 1976; Klein and Rajan, 1984), and loss of mineral (Mazess, 1982; Martin and Burr, 1989). The efficiency of compensation (with regard to preserving bone strength) seems to be greater in men than women (see discussion in Chapter 8, Martin and Burr, 1989, and in Ruff and Hayes, 1988). This finding is somewhat controversial, though, since not all studies of age-related geometric remodeling support this purported sex effect (see discussion, Ruff and Hayes, 1988). One intriguing explanation is that sex differences in the degree of age-related geometric remodeling between sample populations (e.g., rural versus urban, or archeological versus modem) may be related more to the estimated levels of physical activity during life (i.e., mechanical loading) than to aspects of sexual dimorphism (Ruff and Hayes, 1988). OTHER BONE CHANGES ASSOCIATED WITH AGE Micro fractures

Microfractures tend to accumulate in bone with increasing age (Vernon-Roberts and Pirie, 1973; Burstein et al., 1975; Sharpe, 1979; Martin et al., 1980; Frost, 1985; Melton et al., 1988; an excellent discussion of bone fatigue can be found in Chapter 7, Martin and Burr, 1989). Mineralized tissue develops tiny cracks as a consequence of critical mechanical stress. These cracks (or microfractures) usually spread only a limited distance, being interrupted by the

176

G. l',l. K I E B Z A K

heterogeneous arrangement of osteons in the bone tissue. However, continued or excessive stress and the consequent deformation results in additional microfractures until the structural properties of the bone itself become impaired, and ultimately, a major (i.e., clinically relevant) fracture occurs.

Hyper- and Hypomineralization Old bone tissue is more highly mineralized than young bone (Parfitt, 1988); thus, the density of mineral per unit volume of b o n e - - e x c l u s i v e of porosities--increases with age. Reid and Boyde (1987) have reported that the amount of low-density tissue decreases with age, while the proportion of bone with a higher mineralization density increases, being contained within a smaller fraction of the skeleton. Others have observed that areas of subperiosteal bone from elderly humans appear to be hypercalcified (Zagba-Mongalima et al., 1988). These changes probably reflect the age-related decrease in bone turnover, and may also reflect an increase in the size of hydroxyapatite crystals with time. The anatomic distribution of osteons is altered with aging; there is an increase in interstitial bone tissue (bone without osteons) and an increased number of partial osteons and overlapping osteons (Currey, 1964; Evans, 1976; Duncan and Parfitt, 1984). These areas increase also in the degree to which they are mineralized. In addition, as osteocytes (differentiated osteoblasts which have been trapped within mineralized tissue) are lost with increasing age (i.e., the number of viable osteocytes decreases with age). the osteocytic lacunae become plugged and calcified, and the canaliculi and some osteons may become occluded and mineralized (Frost, 1960; Jowsey, 1960; Evans, 1973; Duncan and Parfitt, 1984). Localized areas may actually become hypermineralized, resulting in micropetrosis, a condition which is associated with increased brittleness of the bone tissue; this results in increased susceptibility to fatigue and microfracture, especially if it occurs in areas that are porotic (Frost, 1960; Duncan and Parfitt, 1984). In summary, bone tissue density (i.e., mineral per unit volume of bone) actually increases somewhat with age. However, as noted by Parfitt (1988), Ruff and Hayes (1984, 1988), and others (e.g., Kiebzak et al., 1988c; Martin and Burr, 1989; Basle et al., 1990), bone tissue density changes much less with age than does bone volume, which is the main determinant of bone mineral content (as measured by absorptiometry methods), a parameter that is unequivocally documented to decrease with age (e.g., see discussion in Dequeker, 1975; Mazess, 1982;

IThe observationsdescribed above may seem contradictory to the common notion that bone "density" decreases with age. In part, this misconceptionstems from the fact that the term density is frequently misused by investigatorsreporting results from noninvasive procedures, such as bone scans using photon absorptiometry, which measure total bone mineral at the scan site. Strictly speaking, density means mass/unit volume, or g/cm3. However, single photon absorptiometry measures total bone mineral content (grams of mineral/centimeterof longitudinal length at the scan site) without regard for how the mineral is distributed across the existing bone tissue itself. (In an effort to compensate for this, data are often normalized to bone width at the scan site, a calculation which attempts to take bone volume into account, yielding a final expression of g/cm2.) True bone density may be more closely approximated by newer instrumentation, such as quantitative computed tomography (Johnston et al., 1989; Tothill, 1989); still, the measurement of the density of a whole bone (as an organ of the skeletal system) is obtained only by applying Archimedes' principle. (See discussion of the problems encountered with data expression and the use of the term density; Ruff and Hayes, 1984; Kiebzak et al., 1988c; Mimouni and Tsang, 1988; Parfitt, 1988; Chapter 8, Martin and ButT, 1989).

AGE-RELATEDBONE CHANGES

177

Riggs and Melton, 1986; Hedlund and Gallagher, 1989; Raisz and Smith, 1989; Rosenthal et al., 1989). It has become evident that the way in which bone mass is distributed per unit area (i.e., the bone architecture) is more important than the density of mineral per se. It is cautioned, however, that this discussion should not be misconstrued to imply that bone mineral content is not of critical importance; a strong relationship exists between total bone mineral content and strength (Burstein et al., 1975; Melton et al., 1988; Martin and Burr, 1989), and low bone mineral content is highly associated with risk of fracture (Melton et al., 1988; Johnston et al., 1989).

Crystalline properties of mineral deposits

The crystallinity of bone increases with age (Matsushima and Hikichi, 1989). This has been attributed to an increase in crystallite size and/or a decrease in lattice imperfections. It is conceivable that such alterations may influence biomechanical properties and physiochemical dynamics of bone tissue--or even the conduction of electrical fields. The significance of these changes is poorly understood, and the effects of crystaUinity changes on matrix protein and hydroxyapatite interactions have not been well-studied. Reduced crystal size has been seen in pathologic conditions, such as osteogenesis imperfecta, and may be a consequence of matrix protein defects (matrix proteins have been associated with the process of mineralization) (Robey et al., 1988; Hauschka and Wians, 1989). It is not clear whether age-related crystalline changes affect matrix protein-mineral interactions or vice versa,or if the changes in crystallinity represent merely a maturation process unrelated to other aspects of bone dynamics.

Protein content of unmineralized matrix

The extracellular matrix of bone tissue contains many different types of proteins, some of which are plasma proteins which have been sequestered by the mineralized tissue fraction and some others of which are "bone-specific" proteins synthesized only by the resident bone cells (Epstein, 1988; Lian and Gundberg, 1988; Marks and Popoff, 1988; Robey et al., 1988; Hauschka and Wians, 1989; Robey, 1989). In general, it appears that most, if not all mineral-associated proteins, decrease with tissue age (Dickson and Bagga, 1985; Fisher and Termine, 1985). However, aside from the well-documented age-related changes in collagen (Laitinen, 1976; Klein and Rajan, 1984), relatively little is known about the effects of age on the protein composition of matrix (Sharpe, 1979; Dickson and Bagga, 1985; Fisher and Termine, 1985; Robey, 1989). In summary, although age-related changes in total protein content and the protein profile (i.e., the amount of each type of protein) in human bone have not been thoroughly studied, evidence exists which suggests that such changes could be associated with: 1) age-related alterations in bone ultrastructure (Klein and Rajan, 1984; Ferris et al., 1987), 2) alterations in the mineralization process and bone turnover rates (Laitinen, 1976; Sharpe, 1979; Klein and Rajan, 1984; Dickson and Bagga, 1985; Ferris et al., 1987; Epstein, 1988; Lian and Gundberg, 1988; Hauschka and Wians, 1989), and 3) alterations in the biomechanical properties of bone (Burstein et al., 1975; Burstein et al., 1976; Klein and Rajan, 1985; Chapter 8, Martin and Burr, 1989).

178

G. M KIEBZAK

ADDITIONAL FACTORS INFLUENCING BONE STATUS IN THE ELDERLY Calcemic hormones (see reviews: Exton-Smith, 1985; Riggs and Melton. 1986: Eastell et al.,

1988). Bone is a target organ for a variety of hormones. Among the important regulators of bone and calcium homeostasis are parathyroid hormone (PTH), calcitonin, and the vitamin D metabolites. PTH significantly increases with age in the normal population (some investigators report that PTH is decreased in postmenopausal osteoporosis). Production of 1,25-dihydroxycholecalciferol, the most active metabolite of vitamin D 3, decreases with age. Circulating levels of calcitonin may decrease with age and the calcitonin reserve (the amount of hormone secreted in response to a hypercalcemic challenge) may be impaired in the elderly; however, the effects of age on calcitonin secretion remain controversial. Taken together, a condition characterized by increased PTH in conjunction with decreased 1,25-dihydroxycholecalciferol (and perhaps decreased calcitonin) would be expected to favor bone resorption, especially if the osteoblast progenitor cell population was unresponsive to local and systemic regulatory, factors. Dietary deficiencies (see: Riggs and Melton, 1986; Riggs et al., 1987: Heaney, 1988).

The daily diets of the elderly are frequently deficient in vitamins and minerals (especially calcium). This may predispose the elderly population to a negative calcium balance, especially considering their declining ability to produce adequate amounts of active vitamin D 3 metabolites, which regulate intestinal calcium absorption. However, the issue of whether dietary calcium is truly an important determinant of bone status in adults and the elderly is quite unsettled. Decreased physical activin'

Mechanical loading (i.e., weightbearing stress) is perhaps the most important factor shifting the remodeling balance in favor of bone formation in adults (Heaney, 1982). However, the relationship between age-related changes in physical activity and bone mass has not been clearly delineated. Unfortunately, it is difficult to assess changes in the level of physical activity with age in the normal human population. Furthermore, if a progressive age-related decrease actually exists, it would be difficult to determine whether it was of sufficient magnitude to affect skeletal homeostasis. Only very limited data is available on this issue, but at least one study (Fried et al., 1989) indicates that the proportion of people participating in high intensity physical activity and stair climbing significantly decreases with age. Results from a number of studies suggest that even in the elderly, sustained weightbearing exercise may attenuate bone loss and in some cases actually increase bone mass (Sinaki, 1988; Marcus, 1989; Pocock et al., 1989; Sinaki et al., 1989; Smith et al., 1989; also, see LeBlanc and Schneider, in this special issue, p. 194). In contrast, immobilization due to bedrest results in significant loss of bone mineral, and in general, it is well-established that disuse results in bone atrophy (Schneider and McDonald, 1984; Weinreb et al., 1989). The loss of weightbearing stress is of practical importance during spaceflight, where it is clearly documented that astronauts lose bone mineral in the weightless environment (Schneider et al., 1989). This loss of mineral is continuous and incremental, and new steady states for

AGE-RELATED BONE CHANGES

179

calcium homeostasis have not been observed. Efforts are in progress to determine whether in-flight exercise regimens or artificial gravity would help to offset this deconditioning effect (e.g., Schneider and McDonald, 1984; Schneider et al., 1989; Schultheis et al., 1989). Currently, it is unclear how mechanical stress stimulates bone formation. Bone behaves as a mechanical-electrical transducer, and it has been hypothesized that the stress of mechanical loading induces strain-generated electrical potentials. These electrical potentials may either arise from the flow of ionic extracellular fluids through the microspaces of bone, or they may be due to stress-induced deformity of apatite crystals, collagen, or the collagen/mineral interface (the exact component of bone involved in the mechanical-electrical transduction is unknown) (Bassett and Becker, 1962; Chapter 4, Martin and Burr, 1989). These electrical fields may then serve as the signal for stimulating the remodeling process (Peck and Woods, 1988). For example, as discussed by Martin and Burr (Chapters 4 and 6, 1989), stress-generated electrical potentials may control osteoblastic and osteoclastic differentiation and activity so as to align osteons with the direction of the principal compressive strain. Electrical stimulation or mechanical deformation of bone cells in vitro has been shown to alter production of cyclic nucleotides, DNA synthesis, and synthesis of prostaglandins (the direction of the response is in part dependent on the cell type under investigation; Buckley et al., 1988; Peck and Woods, 1988; Chapter 4, Martin and Burr, 1989). Recent work, in which both animal models of disuse osteopenia and osteoporotic human volunteers have been exposed to pulsed electromagnetic fields, demonstrates the importance of strain-generated electrical potentials as regulators or coordinators of bone remodeling activity. For example, Rubin et al. (1989) performed studies with adult turkeys (turkey bone remodels in a fashion similar to that in humans) in which ulna bones were isolated from functional weightbearing by proximal and distal metaphyseal osteotomies. Examination of transverse microradiographs of the middle of the diaphyseal shaft eight weeks after surgery revealed that a treatment consisting of a pulsed electromagnetic field for one hour per day prevented the striking loss of bone seen in untreated controls. In other recent studies, Tabrah et al, (1990) provided evidence that pulsed electromagnetic fields may have clinical application in the treatment of osteoporosis. OSTEOPOROSIS The process of age-related bone loss is accelerated after menopause in women and may result in the clinical condition commonly known as osteoporosis (Newton-John and Morgan, 1970; Exton-Smith, 1985; Frost, 1985; Riggs and Melton, 1986; Burr and Martin, 1989; Raisz and Smith, 1989). In addition to loss of bone mass (usually reported as a decrease in bone mineral content), osteoporosis is accompanied by bone pain, spinal deformity, loss of height, and fractures. Strictly speaking, the term osteoporosis does not necessarily include the total spectrum of bone and endocrine changes which occur with normal aging as described in this overview. The term senile osteoporosis has been used to refer to excessive age-related bone loss with fractures in the elderly of both sexes. Postmenopausal osteoporosis may best be described as estrogen-dependent osteopenia with resultant fractures superimposed on agerelated osteopenia (Newton-John and Morgan, 1970; Heaney, 1982; Mazess, 1982; Riggs and Melton, 1986; Hedlund and Gallagher, 1989). In fact, there are many causes of clinical osteoporosis, including hyperparathyroidism; hypercortisolism; hypogonadism; and abuse or misuse of drugs, such as corticosteroids or alcohol (Newton-John and Morgan, 1970; Riggs and

180

G.M. KIEBZAK

Melton, 1986; Raisz and Smith, 1989). Thus, the term osteoporosis may best be used to denote a clinical condition rather than a unique disease process per se. Consequently, one must be cautious in equating without qualification the progressive age-related bone changes which occur over many decades with the term osteoporosis.

SUMMARY A variety of age-related changes occur in bone which result in a net loss of bone tissue (protein matrix plus mineral) and bone strength. Interactions of inherent bone changes and alterations in regulatory systems, though not completely understood, undoubtedly exist. For example, the loss of bone strength with age is a combined function of: 1) decreased mineral content (which itself may be a consequence of age-related negative calcium balance due to decreased 1,25-dihydroxycholecalciferol and/or elevated PTH), 2) age-related changes in collagen and perhaps other bone matrix proteins as well, and 3) ultrastructural changes, such as the accumulation of microfractures and porosities (porosities result in relatively small net bone tissue loss, but have a significant impact on mechanical integrity). The degree to which age-related bone changes in humans have been documented varies considerably. For example, disrupted cellular dynamics with loss of osteoblast-like ~'lining cells" (which reside on bone surfaces) and uncoupling of formation and resorption in rodents is relatively well-documented (e.g., Tonna, 1978; Tonna, 1985), but the human data base is far less extensive. It is emphasized that the bone loss associated with aging is the result of a convergence of several pathophysiologic processes, rather than the result of a single perturbation. The skeleton fulfills both structural roles (furnishing support and providing attachment sites for muscles) and physiological roles (serving as a mineral reservoir and participating in calcium-phosphate balance)--a fact which makes the comprehension of age-related bone changes a difficult task. Whereas much is known about the morphological changes of bone which occur with aging, very little is known (relatively speaking) about physiological and metabolic changes, particularly with respect to the effects of aging on local regulatory factors, signal transduction, and cellular dynamics.

THE EVALUATION OF BONE STATUS Many so-called "aging" studies have not used laboratory animals of sufficie.ntly advanced age, and, consequently, have reported that bone loss is not significant in " o l d " animals. It is now recognized, however, that striking bone loss is indeed characteristic of at least some commonly used laboratory species, such as the rat (Kiebzak et al., 1988a, b, c) (Figs. 1 and 2). Differences in spontaneous fracture rates between humans and animals may be related more to the differences between bipedal and quadrupedal locomotion and the subsequent distribution of weightbearing loads than to the degree of actual bone loss itself. There is no universally recognized animal model with which to study age-related bone atrophy or osteoporosis. It is possible, however, to employ various manipulations which have been shown to induce bone loss in experimental animals. These include immobilization, dietary interventions (such as calcium deficiency, high phosphate or protein loading), and ovariectomy. Bone status can be evaluated on all organizational levels (cell --* tissue ~ intact organ) in

AGE-RELATED BONE CHANGES

A

181

B

C Fig. 1. The age-relateddevelopmentof cortical porosities is shown in representativecross-sectional views of the femur midshaft from 6-(A), 12-(B), and 24(C)-month-old male rats. Original magnification approximately × 24. (Reprinted from J. Bone Miner. Res. 3, 37-45, 1988, with permission.)

isolated bone specimens, using a variety of methods including histomorphometry, biomechanical measurements, determination of chemical content [chemical analysis, however, usually reveals surprisingly little change in mineral content when age comparisons are made (Dequeker, 1975; Kiebzak et al., 1988a; Basle et a l . , 1990)], and more recently developed techniques, such as backscattered electron imaging (Grynpas and Holmyard, 1988). Sophisticated noninvasive techniques also exist, such as photon absorptiometry and quantitative computed tomography,

Zig. 2. The age-related loss of trabecular bone is shown in representative cross-sectional views of the femur distal metaphysis of 6- and 24-month-old male and emale rats. Magnification, approximately × 24. (Reprinted from J. Bone Miner. Res. 3, 311 317, Iq88, with permission.)

22* J

AGE-RELATED BONE CHANGES

183

which are useful in the measurement of changes in bone mineral content in vivo (Johnston et al., 1989; Tothill, 1989). In recent years, great success has been attained in the isolation and maintenance of human osteoblasts in culture (Auf'mkolk et al., 1985; Robey and Termine, 1985; Marks and Popoff, 1988), and a variety of transformed human and animal bone cell lines are available for research. The study of bone cells in culture will enable investigators to study the mechanisms of extracellular matrix production and mineralization, hormonal regulation of cell activity, and cell interactions. When evaluating bone status it must be recognized that bones are complex composite structural materials, and the manner in which the constituents (cells, cell products, extracellular matrix, and minerals) are organized will ultimately determine overall strength; pathophysiologic factors which affect individual components of bone tissue could conceivably affect the integrity of the bone as an organ of the skeletal system. There are at least three cell types in bone tissue, and bone tissue itself is organized into different forms (cortical versus trabecular), which may have differential sensitivities to hormones and mechanical stress. It must also be recognized that bones have not only mechanical but also metabolic functions. Investigators should be aware that both age-related changes and treatment-induced changes will not be uniform throughout the skeleton, being in part dependent upon weightbearing conditions and the distribution of weightbearing loads between the axial and appendicular skeleton, on the proportion of cortical to trabecular bone, and on local turnover rates. Also, both quantitative and qualitative differences will be apparent as a function of sex and pathophysiologic disturbances in other organ systems, where, for example, a primary defect in the kidney resulting in compromised renal function could secondarily affect bone status (Kiebzak and Sacktor, 1986; Buchanan et al., 1988). Consequently, it is wise to examine more than one parameter of bone integrity when evaluating bone status in response to a treatment, to environmental or dietary conditions, or to aging. PREVENTING BONE LOSS AND RECOVERING LOST BONE: A CHALLENGE FOR ASTRONAUTS AND THE ELDERLY An increased risk of fracture of weightbearing bones (due to bone loss) is a potential consequence of both spaceflight of extended duration and normal human aging. The timeframes during which net bone loss and skeletal changes commence during spaceflight (which occur within days) and normal aging (which occur over many years) are different. The exact biochemical and physiologic mechanisms responsible for these bone changes during spaceflight and aging are also probably different. It is possible, however, that there is at least one common causative factor: decreased mechanical loading (i.e., weightbearing stress) of the musculoskeletal system, which is a function of zero-gravity in space and decreased physical activity in the elderly. (Presumably, the loss of mechanical loading has a greater role in the etiology of bone loss during spaceflight than the etiology of bone loss during aging because the magnitude of the unloading effect is greater as a result of exposure to zero-gravity conditions; the exception would be the dramatic decrease in mechanical loading in bedridden or totally immobile elderly), Regardless of the actual cause of the bone loss as a result of spaceflight and aging, there are common concerns for both astronauts and the elderly, namely: 1) is it possible to prevent the bone loss due to mechanical unloading and 2) is it possible to recover bone once it has been lost? (See LeBlanc and Schneider, this special issue, p. 189-202, for further discussion of this issue.) Clearly, there are overlapping research interests between NASA, the

184

G. 5,1 K[EBZ~K

National Institute on Aging, and those scientists and clinicians interested in skeletal homeostasis. Consequently. coordinated research efforts would be mutually beneficial, especially with regard to: 1) the effects of exercise on maintaining and increasing bone mass. 2) hormone therapy and/or drug intervention that would prevent bone loss or promote bone tormation, and 3) the basic underlying mechanisms by which mechanical loading serves to stimulate bone formation and remodeling. .4cknowledgment,~ -- I wish to thank those colleague~ who provided helpful suggestion~ and criticisms, and Lauren Masters, Diane Ellzy, Barbara Sch~vinn, Charla BD'ant, and Joanne Brantle.~. for typing, proofreading, and editing this manuscript. REFERENCES AARON. J. Histology and micro-anatomy of bone. In: Calcium, Phosphate and Magnesium Metabolism." Clinical Physiology and Diagno.stic Procedures. Nordin, B.E.C. IEditori, pp, 298-356, Churchill Livingstone. New York. 1976. ATKINSON, M.J., SCHETTLER. T., BODENSTEIN, H.. and HESCH, R.D. Osteoporosis: A bone turnover detect resulting from an elevated parathyroid hormone concentration within the bone-marrow ca;ity? Kiln. Wochenschr. 62, 129-132, 1984. AUF'MKOLK, B., HAUSCHKA. P.V., and SCHWARTZ. E.R. Characterization of human bone cells in culture. Calc(r. Tissue Int. 37, 228-235, 1985. BASLE. M.F., MAURAS, Y., AUDRAN, M., CLOCHON, P., REBEL, A.. and ALLAIN, P. Concentration of bone elements in osteoporosis. J. Bone Miner. Res. 5, 41-47, 1990. BASSETT, C . A i . , and BECKER, R.O. Generation of electric potentials b) bone in response to mechanical ,,,tress. Science 137, 1063-1064, 1962. BRINDLEY, G.W., WILLIAMS. E.A., BRONK. J.T., MEADOWS, T.H., MONTGOMERY, R.J.. SMITH, S.R., and KELLY, P.J. Parathyroid hormone effects on skeletal exchangeable calcium and bone blood flow. Am. J. Physiol. 255, H94-HI00, 1988. BUCHANAN, J.R., MYERS, C,A., and GREER. R.B., III. Effect of declining renal function on bone density in aging women. Cah'if. Tissue htt. 43, 1-6, 1988. BUCKLEY, M,J., BANES, A.J., LEVIN, L.G., SUMPIO, B.E., SATO, M.. JORDAN, R.. GILBERT, J.. LINK, G.W., and TAY. R.T.S. Osteoblasts increase their rate of division and align in response to cyclic, mechanical tension in vitro. Bone Miner. 4, 225-236, 1988. BURR, D.B. and MARTIN, R.B. Errors in bone remodeling: Tow,ard a unified theory of metabolic bone disease. Am. J, Anat. 186, 186-216, 1989, BURSTEIN, A.H., REILLY, D.T., and MARTENS, M. Aging of bone tissue: Mechanical properties. J. Bone Joint Surg. 58-A, 82-86, 1976. BURSTEIN, A.H., ZIKA, J.M., HEIPLE. K.G.. and KLEIN, L. Contribution of collagen and mineral to the elastic~plastic properties of bone. J, Bone Joint Surg. 57-A, 956-961, 1975. CANALIS, E.. MCCARTHY, T.L., and CENTRELLA, M. Growth factors and the skeletal system. J. Emh~crinol. Invest. 12, 577-584, 1989. COMPSTON. J.E., MELLISH, R.W.E., CROUCHER, P.. NEWCOMBE, R., and GARRAHAN. N.J. Structural mechanisms of trabecular bone loss in man. Bone Miner. 6, 339-350, 1989. CURREY. J.D. Some effects of ageing in human Haversian systems. J. Anat., Lond. 98, 69-75. 1964. CURREY, J. The Mechanical Adaptations of Bones. Princeton University Press, Princeton, NJ, 1984. DELLING, G. Age-related bone changes: Histomorphometric investigation of the structure of the human cancellous bone. Curr. Top. Pathol. 58, 117-147, 1973. DEQUEKER, J. Bone and aging. Ann. Rheum. Dis. 34. 100-115. 1975. DICKSON, I.R. and BAGGA. M.K. Changes with age in the non-coilagenous proteins of human bone. Connect. Tissue Res. 14, 77-85. 1985. DUNCAN, H. and PARFITT, A.M. The biology of aging bone. In: The Aging Musculoskeleml System. Nelson, C.L. and Dwyer, A.P. (Editors), pp. 65-74, The Collamore Press. Lexington, MA, 1984. EASTELL, R., HEATH, H., III, KUMAR, R.. and RIGGS, B.L. Hormonal factors: PTH. vitamin D, and calcitonin. In: Osteoporosis: Etiology, Diagnosis. and Management, Riggs. B.L. and Melton, L.J. IEditors), pp. 373-388. Raven Press, New York, 1988.

AGE-RELATEDBONECHANGES

185

,.t urinary markers of bone remodeling: Assessment of bone turnover. Endocrine Rev. 9, 43 J--449, 19~,8. EVANS, F.G. Effects of age, ~:,, race and species. In: Mechanical Properties of Bone, pp. 219-254, Charles C. Thomas, Springfield, 1973. EVANS, F.G. Mechanical properties and histology of cortical bone from younger and older men. Anat. Rec. 185, 1-11, 1976. EXTON-SMITH, A.N. Mineral metabolism. In: Handbook of The Biology of Aging, Finch, C.E. and Schneider, E.L. IEditorsL pp. 511-539, Van Nostrand Reinhold Company, New York, 1985. FERRIS. B.D., KLENERMAN, L., DODDS, R.A., BITENSKY, L., and CHAYEN, J. Altered organization of non-collagenous bone matrix in osteoporosis. Bone 8, 285-288, 1987. FISHER, L.W., and TERMINE, J.D. Purification of the noncollagenous proteins from bone: Technical pitfalls and how to avoid them. In: Current Advances in Skeletogenesis, Arnoy, A., Harell, A., and Sela, J. (Editors), pp. 467-472, Elsevier Science Publishers B.V., 1985. FRIED, L.P., FLEG, J.L., GUNDY, E., TOBIN, J.D., and FOZARD, J.L. Physical activity patterns of adults: Changes by age and sex. The Gerontologist 29 (special issue), 192A (abstract), October, 1989. FROST, H.M. Micropetrosis. J. Bone Joint Surg. 42-A, 144-150, 1960. FROST, H.M. Bone Remodelling Dynamics, Charles C. Thomas, Springfield, 1963. FROST, H.M. The pathomechanics of osteoporosis. Clin. Orthop. Rel. Res. 200, 198-225, 1985. GILSANZ, V., GIBBENS, D.T,, CARLSON, M., BOECHAT, M.I., CANN, C.E., and SCHULZ, E.E. Peak trabecular vertebral density: A comparison of adolescent and adult females. Calcif. Tissue Int. 43, 260-262, 1988. GRYNPAS, M.D. and HOLMYARD, D. Changes in quality of bone mineral on aging and in disease. Scanning Microsc. 2, 1045-1054, 1988. HAUSCHKA, P.V. and WIANS, F.H., JR. Osteocalcin-hydroxyapatite interaction in the extracellular organic matrix of bone. Anat. Rec. 224, 180-188, 1989. HEANEY, R.P. Nutritional factors in bone health. In: Osteoporosis: Etiology, Diagnosis. and Management, Riggs, B.L. and Melton, L.J. (Editors), pp. 359-372, Raven Press, New York, 1988. HEANEY, R.P. Paradox of irreversibility of age-related bone loss. In: Osteoporosis, The Proceedings of an International Symposium held at the Jerusalem Osteoporosis Center in June 1981, Menczel, J., Robin, G.C., Makin, M., and Steinberg, R. (Editors). pp. 15-20, John Wiley & Sons, New York, 1982. HEDLUND, L.R. and GALLAGHER, J.C. The effect of age and menopause on bone mineral density of the proximal femur, J. Bone Miner. Res. 4, 639-642, 1989. HRUZA, Z. and WACHTLOVA, M. Diminution of bone blood flow and capillary network in rats during aging. J. Gerontol. 24, 315-320, 1969. IRVING, J.T., LEBOLT, S.A., and SCHNEIDER. E.L. Ectopic bone formation and aging. Clin. Orthop. 154, 249-253. 1981. IVEY, J.L. and BAYLINK, D.J. Postmenopausal osteoporosis: Proposed roles of defective coupling and estrogen deficiency. Metab. Bone Disease Rel. Res. 3, 3-7, 1981. JOHNSTON, C.C., JR., MELTON, L.J., III, LINDSAY, R., and EDDY, D.M. Clinical indications for bone mass measurements. J. Bone Miner. Res. 4 (Suppl. 2), 1989. JOWSEY, J. Age changes in human bone. Clin. Orthop. Rel. Res. 17, 210-217, 1960. JOWSEY, J. Metabolic Diseases of Bone. W.B. Saunders Company, Philadelphia, 1977. KIEBZAK, G.M. and SACKTOR, B. Effect of age on renal conservation of phosphate in the rat. Am. J. Physiol. 251, F399-F407, 1986. KIEBZAK, G.M., SMITH, R., GUNDBERG, C.C., HOWE, J.C., and SACKTOR, B. Bone status of senescent male rats: Chemical, morphometric, and mechanical analysis. J. Bone Miner. Res. 3, 37-45, 1988a. KIEBZAK, G.M., SMITH, R., HOWE. J.C., GUNDBERG, C.C., and SACKTOR. B. Bone status of senescent female rats: Chemical, morphometric, and biomechanical analyses. J. Bone Miner. Res. 3, 439-446, 1988b. KIEBZAK, G.M., SMITH, R., HOWE, J.C, and SACKTOR, B. Bone mineral content in the senescent rat femur. An assessment using single photon absorptiometry. J. Bone Miner. Res. 3, 311-317, 1988c. KLEIN, L. and RAJAN, J.C. The biology of aging human collagen. In: The Aging Musculoskeletal System: Physiological and Pathological Problems, Nelson, C.L. and Dwyer, A.P. (Editors), pp. 37-48, The Collamore Press, Lexington, MA, 1984. LAITINEN, O. Relation to osteoporosis of age- and hormone-induced changes in the metabolism of collagen and bone. lsr. J. Med. Sci. 12, 620--637, 1976. LANYON, L.E. Functional strain as a determinant for bone remodeling. Calcif. Tissue Int. 36, $56-$61, 1984.

186

cJ. M. KIIz.BZAK

LIAN, J.B. and GUNDBERG, C.M. Osteocalcin: Biochemical considerations and clinical applicatl,,,~. C/re. t~rth+.:, 226, 267-291, 1988. LIPS, P., COURPRON, P., and MEUNIER, P.J. Mean wall thickness of trabecular hone packet,, in the human iliac crest: Changes with age. Calci]~ Tissue Res. 26, 13-17, 197,N. MARCUS, R. Exercise and the regulation of bone mass. Arch. Intern. Med. 149, 2170 217 I. 1980. MARKS, S.C,, JR. and POPOFF. S.N. Bone cell biology: The regulation of development, structure, and function in the skeleton. Ant. J. Anat. 183, 1-44, 1988. MARTIN, R.B. and ATKINSON, P.J. Age and ~ex-related changes in the structure and strength of the human femoral shaft. J. Biomech. 10+ 223-231, 1977. MARTIN, R.B. and BURR, D.B. Structure, Function. and Athq~tation ~f Compact Bone. Raven Press. Nev, York. 1989. MARTIN, R.B., PICKETT. J.C.. and ZINAICH, S. Studies of skeletal remodeling in aging men. Clin. Orthop. Rel. Res. 149, 268-282. 1980. MATSUSHIMA. N. and HIKICHI, K. Age changes in the crystallinity of bone mineral and in the disorder of it~ crystal. Biochim. Biophys. Aeta 992. 155-159, 1989. MAZESS, R.B. On aging bone loss. Clin. Orthop. Rel. Res. 165. 239-252+ 1982. MELTON, L.J., III. CHAO, E.Y.S., and LANE, J. Biomechanical aspects of fractures. In: O.~tec,porosis: Etiology. Diagnosis, and Management. Riggs, B i . and Melton, L.J. (Editors). pp. I I I-I 31, Raven Press, New York, 1988. MEUNIER, P., AARON, J., EDOUARD, C., and VIGNON, G. Osteoporosis and the replacement of celt populations of the marrow by adipose tissue: A quantitative study of 84 iliac bone biopsies. Clin. Orthop. Rel. Res. 80, 147-154, 1971. MEUNIER, P,J. Assessment of bone turnover by histomorphomet~ in osteoporosis. In: OstetqJorosis: Etiology, Diagnosis. and Management. Riggs, B.L. and Melton. L.J., III (Editors). pp. 317-332. Raven Press. New York. 1988. MIMOUNI, F. and TSANG. R.C. Bone mineral content: Data analysis. J. Pediatr. 113, 178-180. 1988. NEWTON-JOHN. H.F. and MORGAN. D.B. The loss of bone with age, osteoporosis, and fractures. Clin. Orthot,. Rel. Res. 71, 229-25[, 1970. NILAS, L.. GOTFREDSEN, A.+ HADBERG. A., and CHRISTIANSEN. C. Age-related bone loss in women evaluated by the single and dual photon technique. Bone Miner. 4, 95-103. 1988. NISHIMOTO, S.K.. CHANG, C.-H.. GENDLER, E., STRYKER, W.F., and NIMNI. M.E. The effect of aging on bone formation in rats: Biochemical and histological evidence for decreased bone formation capacity. Calc(f. Tis.sue Int. 37, 617-624, 1985. PARFITT, A.M. The coupling of bone formation to bone resorption: A critical analysis of the concept and of its, relevance to the pathogenesis of osteoporosis. Metab. Bone Dis. Rel. Res. 4, I-6. 1982. PARFITT, A.M. Age-related structural changes in trabecular and cortical bone: Cellular mechanisms and biomechanical consequences. Calcif. Ti,s~ue Int. 36, S123-S128. 1984. PARFITT, A.M. Bone remodeling: Relationship to the amount and structure of bone, and the pathogenesis and prevention of fractures. In: Osteoporosis." Eti~logy. Diagnosis, and Management. Riggs. B.L. and Melton, L.J. (Editors), pp. 45-94, Raven Press, New York, 1988. PECK, W.A. and WOODS, W. The cells of bone. In: Osteoporosis: Etiology, Dia~nosi.~, and Mammement, Riggs, B.L. and Melton, L.J. (Editors), pp. 1-44, Raven Press, Nev,' York, 1988. POCOCK, N., EISMAN, J., GWINN, T., SAMBROOK+ P., KELLY. P., FREUND, J.. and YEATES, M. Muscle strength, physical fitness, and weight but not age predict femoral neck bone mass. J. Bone Miner. /~e.s. 4. 441-448. 1989. RAISZ. L.G. and SMITH. J.A. Pathogenesis, prevention, and treatment of osteoporosis. Annu. Rev. Med. 40, 251-267, 1989. REID, S.A. and BOYDE, A. Changes in the mineral density distribution in human bone with age: hnage analysis using backscattered electrons in the SEM. J. Bone Miner. Res. 2+ 13-22, 1987. R1GGS, B.L. and MELTON, L.J., III. Involutional osteoporosis. N. Engl. J. Med. 314+ 1676-1686, 1986. RIGGS, B.L., WAHNER, H.W., MELTON, L.J.. III, RICHELSON, L.S., JUDD. H.L., and O'FALLON, W.M, Dietary calcium intake and rates of bone loss in women. J. Clin. Invest. 80, 979-982. 1987. ROBEY, P.G. and TERMINE+ J.D. Human bone cells in vitro. Calcif. Tissue Int. 37, 453-460. 1985. ROBEY, P.G. The biochemistry of bone. Endoerinol. Metab. Clin. North An+. 18(4), 859-902, 1989. ROBEY, P.G., FISHER, L.W., YOUNG, M.F., and TERMINE, J.D. The biochemistry of bone. In: Osteoporosi~: Etiology, Diagnosis. and Management, Riggs. B.L. and Melton, L.J. (EditorsI. pp. 05-110+ Raven Press, New York, 1988.

AGE-RELATEDBONECHANGES

187

ROSENTHAL, D.I., MAYO-SMITH, W., HAYES, C.W., KHURANA, J.S., BILLER, B.M.K., NEER, R.M., and KLIBANSKI, A. Age and bone mass in premenopausal women. J. Bone Miner. Res. 4, 533-538, 1989. RUBIN, C.T., MCLEOD, K.J., and LANYON, L.E. Prevention of osteoporosis by pulsed electromagnetic fields. J. Bone Joint Surg. 71-A, 411-417, 1989. RUFF, C,B. and HAYES, W.C. Subperiosteal expansion and cortical remodeling of the human femur and tibia with aging. Science 217, 945-948, 1982. RUFF, C.B. and HAYES, W,C. Bone-mineral content in the lower limb. J. Bone Joint Surg. 66-A, 1024-1031, 1984. RUFF, C,B. and HAYES, W.C. Sex differences in age-related remodeling of the femur and tibia. J. Orthop. Res. 6, 886-896, 1988. SCHNEIDER, V.S. and MCDONALD, J. Skeletal calcium homeostasis and countermeasures to prevent disuse osteoporosis. Calcif. Tissue Int. 36, S151-S154, 1984. SCHNEIDER, V.S., LEBLANC, A., and RAMBAUT, P.C. Bone and mineral metabolism. In: Space Physiology and Medicine, Nicogossian, A.E. (Editor), pp. 314-322, Lea and Febiger, Philadelphia, 1989, SCHULTHEIS, L.W., FALLON, M., KIEBZAK, G,, KAPLAN, F.; and BENOIT, R. Physiological parameters of artificial gravity. In: Space Manufacturing 7. Space Resources to Improve Life on Earth. Proceedings of the Ninth Princeton/A1AA/SSl Conference, Faughnan, B. and Maryniak, G. (Editors), pp. 312-321, American Institute of Aeronautics and Astronautics, Washington, DC, 1989. SHARPE, W.D. Age changes in human bone: An overview. Bull. NY Acad. Med. 55, 757-773, 1979. SINAKI, M. Exercise and physical therapy. In: Osteoporosis: Etiology, Diagnosis, and Management, Riggs, B.L. and Melton, L.J. (Editors), pp. 457-480, Raven Press, New York, 1988. SINAKI, M., WAHNER, H.W., OFFORD, K.P., and HODGSON, S.F. Efficacy of nonloading exercises in prevention of vertebral bone loss in postmenopausal women: A controlled trial, Mayo Clin. Proc. 64, 762-769, 1989. SMITH, E.L., GILLIGAN, C., MCADAM, M., ENSIGN, C.P., and SMITH, P.E. Deterring bone loss by exercise intervention in premenopausal and postmenopausal women. Calcif. Tissue Int. 44, 312-321, 1989. TABRAH, F., HOFFMEIER, M., GILBERT, F., JR., BATKIN, S., and BASSETT, C.A.L. Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J. Bone Min. Res. 5(5), 437--442, 1990. THOMPSON, D.D. Age changes in bone mineralization, cortical thickness, and haversian canal area. Calcif. Tissue Int. 31, 5-11, 1980. THOMPSON, D.D. and RODAN, G.A. lndomethacin inhibition of tenotomy-induced bone resorption in rats. J. Bone Miner. Res. 3, 409-414, 1988. TONNA, E.A. Electron microscopic study of bone surface changes during aging. The loss of cellular control and biofeedback. J. Gerontol. 33, 163-177, 1978. TONNA, E.A. Aging of the skeletal system and supporting tissue. In: CRC Handbook of Cell Biology of Aging, Cristofalo, V.J. (Editor), pp. 195-227, CRC Press, Inc., Boca Raton, FL, 1985. TOTHILL, P. Methods of bone mineral measurement. Phys. Med. Biol. 34, 543-572, 1989. TRIFFITT. J.T. Initiation and enhancement of bone formation. Acta Orthop. Scand. 58, 673-684, 1987. VEJLENS, L. Glycosaminoglycans of human bone tissue: I. Pattern of compact bone in relation to age. Calcif. Tissue Res. 7, 175-190, 1971. VERNON-ROBERTS, B. and PIRIE, C.J. Healing trabecular microfractures in the bodies of lumbar vertebrae. Ann. Rheum. Dis. 32, 406-412, 1973. WEINREB, M., RODAN, G.A., and THOMPSON, D.D. Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation. Bone 10, 187-194, 1989. ZAGBA-MONGALIMA, G., GORET-NICAISE, M., and DHEM, A. Age changes in human bone: A microradiographic and histological study of subperiosteal and periosteal calcifications. Gerontology 34, 264-276, 1988,