Growth in Bone Mass and Size—Are Racial and Gender Differences in Bone Mineral Density More Apparent than Real?

Ego Seeman and M. D.

Austin and Repatriation Medical Centre University of Melbourne Melbourne, Australia 3084

Address correspondence and requests for reprints to: E. Seeman, M.D., Department of Endocrinology, Austin and Repatriation Centre, Heidelberg, Melbourne, 3084, Australia. E-mail: ego{at}austin.unimelb.edu.au


    Introduction
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
In this issue of JCEM, Gilsanz and colleagues (1) (see page 1420) present data that give us insight into the racial differences in bone mass, bone size, and bone mineral density (BMD), which may partly contribute to the lower incidence of fractures in blacks than in whites. The work is refreshing reading because of the meticulous attention to study design and the resultant credibility of the observations.

The investigators matched 80 black females and males with 80 whites of the same gender, age, bone age, pubertal stage, height, and weight, and report that: (i) blacks have higher volumetric apparent BMD of the cancellous (trabecular) bone of the vertebral body; (ii) there are no racial differences in femoral midshaft cortical thickness or its true BMD; (iii) blacks have longer legs and a larger femoral midshaft cross-sectional area, but shorter trunk length and vertebral height (despite having the same vertebral cross sectional area).


    Apparent and true bone mineral density
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
Many insights arise from this work, but few can be appreciated unless the difference between "true" and "apparent" BMD is understood. "True" (or material) BMD is the mass of a substance per unit volume of its own uniform bulk; the true BMD of a single trabecula, or the true BMD of cortical bone itself—devoid of its canals, canaliculae and spaces. Noninvasive methods such as dual x-ray absorptiometry, measure "apparent" BMD—the mass of mineral in a skeletal region, not all of which is bone. These regions (eg. the vertebra or femur) are composed of mineral fashioned into cortical bone and trabecular bone within a central medullary cavity containing marrow.

The measurement provided by bone densitometry is commonly expressed as an apparent bone mineral content (BMC, g) or as an areal apparent BMD (g/cm2). "Areal" apparent BMD is derived by dividing the region’s BMC by its projected area in the coronal plane—the region’s depth is not "seen" by the technology. Thus, bone size is not taken into account in the apparent BMC measurement and only partly taken into account in the areal apparent BMD measurement—the bigger the bone, the higher the apparent BMC or areal apparent BMD.

The terms "apparent" and "areal" are almost universally dropped from the literature for brevity and convenience, but at the price of understanding that the size of the bone influenced the reported "density" measurement. Larger bones in older children compared with younger children, in blacks compared with whites, or males compared with females, will be reported as having a higher (apparent) BMC or (areal apparent) BMD, even though the amount of bone contained within the periosteal envelope of the bone—its volumetric BMD—may not be higher (2, 3).

Quantitative computed tomography (QCT) measures volumetric BMD (g/cm3)—a measurement often mistakenly called "true" BMD because it is volumetric. (Unstated, but implicit in the subtle misuse of the word "true" is the unsubstantiated notion that this is the better predictor of fracture than BMC or areal BMD.) QCT-derived volumetric BMD is also an apparent BMD, or the amount of bone mineral within a unit volume of bone, not all of which is mineral. Although independent of external bone size, an increase in volumetric apparent BMD during growth or a higher volumetric apparent density in blacks than in whites, still tells us nothing about the morphological basis of this increase in volumetric apparent BMD (3).

In trabecular bone, volumetric apparent BMD may increase during growth, or it may be higher in blacks than in whites, in men than in women, in any one or more of three ways: by increasing trabecular numbers, by increasing trabecular thickness, or by increasing the true (material) density of the trabeculae within this cubic volume of bone comprised of trabecular mineral plates and sheets and marrow (Fig. 1Go).



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Figure 1. Cartoon illustrating that volumetric trabecular apparent bone mineral density (BMD) may increase in one or more of three ways. The morphological basis of the increase is different, and has different biological and perhaps biomechanical implications.

 
The same mineral mass fashioned into greater trabecular numbers of half the thickness results in a structure with more surface per unit mineral mass than the same mineral mass fashioned into half the number of trabeculae of double the thickness. Thinner trabeculae may be a disadvantage at menopause when increased bone remodeling, a surface-based phenomenon, may cause perforation of trabeculae. The same mass fashioned with thicker trabeculae will have less surface per unit volume, and so less surface available for remodeling to occur upon. This is partly why bone remodeling may be slower with less of the mineral mass "turned over" annually in blacks (4, 5, 6).

In a long bone such as the midshaft of the femur, volumetric apparent BMD may be higher in blacks than in whites, or in men than in women in two ways; for long bones of the same external dimensions, either the cortex will be thicker (and the medullary cavity smaller) or the cortical bone true BMD may be higher. True BMD of the bone remains constant during life (7) or may increase in response to drug therapy (8). During aging, increased intracortical porosity will reduce cortical bone mass; apparent BMC will decrease but the true BMD of the remaining cortical bone does not change (7). Figure 2Go illustrates how intracortical porosity increases with advancing age, while apparent BMD decreases. The decline in apparent BMD is proportional to the increase in intracortical porosity, but the true BMD of the remaining cortical bone is constant (7). (QCT does not have the resolution to exclude canaliculi and canals from the true BMD measurement. Thus, true BMD of cortical bone may be underestimated when measured by QCT).



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Figure 2. In men and women, porosity (P), (the percentage of cortical bone occupied by vascular cavities) increased with age. Apparent mineral density (AMD) and ash weight per unit cortical bone volume decreased with age and correlated with porosity. The true mineral density (TMD)—ash weight per unit volume of bone free of its canals and resorption spaces remained unchanged with age (Laval-Jeantet et al. Ref 7).

 
Another level of complexity occurs during growth. Volumetric apparent BMD not only depends on the amount of cortical and trabecular bone contained within the periosteal surface of the bone during growth and its true BMD. It also depends on the growth of the external size of the bone relative to the accrual of bone taking place within the growing bone. These processes are dissociated in time (because they are regulated differently); at any age, size is nearer its peak adult value than is the mineral accrued within it (9). Illness interrupting growth may affect mineral accrual more than size (as size is nearer its peak), contributing to reduced volumetric apparent BMD. At the age of 12–13 yr, a time of increased fractures in children, growth in length and mineral accrual are most dissociated (9).

So, if the growth in external size of the bone increases, apparent BMC and areal apparent BMD increase—no surprise—the size of the bone is increasing (upper panels, Fig. 3Go) (10). However, if the increase in size is matched by a proportional increase in the mass within its periosteal envelope, volumetric apparent BMD remains constant during growth (lower panels, fig. 3Go). This appears to occur in long bones such as the midshaft of the femur and the radius; volumetric apparent BMD is independent of age during growth (10, 11). The fascinating implication of this data is that the relative position of an individual’s long bone volumetric apparent BMD in the normal distribution must be determined at birth, if not before!



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Figure 3. Areal and volumetric femoral shaft bone mineral density (BMD) plotted against age for males and females. Lu et al. (10). With permission.

 
If growth in mineral mass contained within the periosteal surface of the bone is proportionately more than the increase in its size, volumetric apparent BMD increases. This occurs in the vertebral body. As shown in Fig. 4Go, volumetric apparent BMD is constant until late puberty and then increases in boys and girls by a similar amount (12) and probably because of increasing trabecular thickness rather than numbers (4, 5, 13).



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Figure 4. Vertebral volumetric trabecular apparent bone mineral density (BMD) in white and girls is similar before puberty and independent of age until puberty when comparable increases occur. Drawn from data in the legend of Fig. 2Go, Gilsanz et al. (14).

 
To summarize, (i) areal apparent BMD, as measured noninvasively, is confounded by bone size; increasing areal apparent BMD during growth or higher areal apparent BMD in one individual compared with another may be the result of greater size; (ii) if size is constant, increasing areal or volumetric apparent BMD may be the result of increasing cortical thickness, trabecular number or thickness, or increasing true (material) density of these structures; (iii) if size and accrual are both increasing, apparent volumetric BMD depends on their relative changes. Thus, when we speak of higher BMD in blacks than whites, in men than women, what do we really mean? Now to the work.


    Racial and gender differences in vertebral volumetric trabecular apparent BMD
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
A glance at the figures in the paper by Gilsanz and colleagues on page 1420, shows that before puberty there were no racial or gender differences in volumetric apparent BMD of the trabecular bone of the vertebral body (1). Thus, by inference, before puberty, trabecular number, thickness, and their true (material) BMD do not differ by race or gender. Racial differences emerged at puberty; vertebral volumetric trabecular apparent BMD was approximately 250–260 mg/cm3 in Tanner stage 1 in blacks, whites, males, and females, increasing by approximately 40 mg/cm3 in white females and males and by approximately 80 mg/cm3 in black females and males by Tanner stage 5. However, within a race, the increases in boys and girls during puberty were no different. Gilsanz and colleagues have reported this race-specific, but gender-independent effect of puberty in two previous studies (12, 14). Aaron and colleagues (15) have reported no difference in trabecular number and thickness in white males and females in young adulthood.

So, in young adulthood, peak vertebral volumetric trabecular apparent BMD is higher in black than in white men, and is higher in black than in white women, but is no different in women and men of the same race. Han et al. (4, 5) report that blacks have thicker trabeculae than whites, not greater numbers. This has not been found in other studies, perhaps in part because of sample size considerations and morphological differences in African blacks and American blacks (6, 13, 16, 17). Whether the true BMD of trabeculae themselves is higher in blacks is unknown. QCT does not have the resolution to determine true BMD of a single trabecula. However, there is histomorphometric data supporting this possibility (16).


    Racial and gender differences in femoral midshaft cortical thickness and true BMD
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
Neither the width of the cortical bone of the mid-shaft of the femur, nor its true BMD (determined by QCT) differed in blacks and whites. However, the periosteal diameter of the shaft was greater in blacks. Although the cortical width was the same, the amount of cortical bone was greater (apparent BMC was greater) because the circumference of the bone was greater in blacks. This greater bone mass was placed further from the central shaft axis, conferring greater resistance to bending in blacks than whites (18).

Cortical width is determined by the growth of the endocortical surface relative to the periosteal surface. Periosteal expansion must be greater than endocortical expansion during growth, otherwise cortical width would not increase as the bone grows in length and diameter. However, cortical width was the same in blacks and whites, despite blacks having a bigger bone, suggesting that medullary expansion during growth must have been greater in blacks. Alternatively, as the direction of endocortical growth changes from expansion to contraction at puberty (19), the similar cortical width could have been the result of less endocortical contraction at puberty in blacks. Endocortical contraction did appear to occur in this study by Gilsanz and colleagues, but the changes were not significant.

These surfaces behave differently because they are regulated differently. An understanding of the hormonal regulators of periosteal and endocortical growth and remodeling in blacks and whites, and in men and women may contribute to the development of new drugs that increase periosteal growth (increasing the bending strength of cortical bone), increase endocortical apposition (increasing cortical thickness), or reduce endocortical resorption (preventing cortical thinning) (20).


    Racial and gender differences in upper and lower body segment lengths
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
Despite being matched for height, blacks had longer legs and shorter trunks than whites, longer femurs, and shorter vertebrae than whites. So, longitudinal growth of the femur must have been more rapid in blacks, while longitudinal vertebral growth must have been slower. Lower limb growth before puberty is growth hormone-dependent and procedes at a constant velocity before puberty while spine length is accelerating (Fig. 5Go) (21); both the deceleration in limb growth and acceleration in trunk growth are partly estrogen dependent, even in males (22, 23). Hypogonadism produces longer leg length and shorter trunk length.



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Figure 5. The tempo of growth (centimeter/year) in femur length and trunk length differ, the former decelerates at puberty, the latter accelerates. Adapted from Tupman et al. (21).

 
Men have longer legs than women because epiphyseal fusion occurs later. They enter puberty 2 yr later, and their pubertal growth spurt reaches a higher peak velocity and continues longer (24). Whether adrenarche and puberty occur at different chronological ages in blacks than whites is uncertain. Whether the tempo of prepubertal and pubertal longitudinal and circumferential growth of the axial and appendicular skeleton is different in blacks and whites is uncertain. Whether using methods for determining bone age and pubertal staging developed in white children is appropriate for evaluating nonwhite races is questionable. There is some evidence of earlier skeletal maturation in blacks (25).

Thus, blacks have longer legs and shorter trunks than whites, Asians have longer trunks and shorter legs than whites, Hispanics have similar body proportions as whites, but they are shorter. Men have longer legs than women, but differ less in their trunk length (26, 27). Thus, we all look at each other with less obliquity when we sit than when we stand. Differing regional sensitivity to sex hormones and growth hormone or IGF-1 could partly account for these racial differences. To speculate, if long bone epiphyses and vertebral growth are less sensitive to estrogen in blacks, this might explain the longer legs and shorter trunk lengths. Could greater sensitivity to estrogens in Asians account for their shorter legs and longer trunks than whites or blacks? These hypotheses are yet to be tested and may not be entirely unprecedented; there is evidence of differing sensitivity to parathyroid hormone in blacks and whites (28).


    Racial and gender differences in BMD: more apparent than real?
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
Gender and racial differences in areal apparent BMD, reported using single and dual photon or x-ray absorptiometry, are partly, but not entirely, the result of confounding by bone size and body size. When size is taken into account many racial differences in areal apparent BMD diminish or disappear (29, 30). The longer legs in men than women, and in blacks than whites, produces the correspondingly higher proximal femoral apparent BMC and areal apparent BMD. The shorter trunk length in blacks would make the vertebral areal apparent BMD less than in whites were it not for the higher trabecular volumetric apparent BMD in blacks (because of their thicker trabeculae). Trunk length is similar in women and men, but men have wider vertebrae, producing the higher spine apparent BMC and areal apparent BMD, but volumetric apparent BMD is the same—the amount of bone in the bone is the same in men and women. The shorter legs in Asians will result in the lower apparent BMC or areal apparent BMD and a shorter hip axis length (which is purportedly associated with a lower hip fracture risk) (31). The need for locally developed controls in the use of bone densitometry rather than the manufacturers’ reference ranges is obvious.

Thus, the effect of size on BMD has misled us in many ways (3). The most compelling morphological evidence of higher BMD in blacks is the data supporting greater trabecular thickness at the spine and iliac crest (1, 4, 5, 13). Cortical thickness was no greater in blacks in the study by Gilsanz et al. (1), but there was more bone placed further from the central axis of the femur. There is little convincing evidence that either cortical thickness or its true BMD is higher in blacks when careful matching for external bone size is done. Men and women have the same peak volumetric apparent BMD at the completion of growth; the higher apparent BMC or areal apparent BMD are the result of differences in bone size. Most of the literature reporting racial and gender differences in areal BMD is not convincing because bone and body size is not adequately taken into account, and when taken into account, is adjusted for by statistical methods using height, weight, or body mass index. These are poor surrogates for the actual size of the bone being measured, particularly given that racial and gender differences in body segment lengths will produce over- or underestimates depending on which regions and races are compared.


    Where are we? Where do we need to be? How do we get there?
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 
The work presented in JCEM by Gilsanz and colleagues is meritorious by virtue of the questions it answers and by the questions arising from its scholarship. The inference made from this work and other studies, is that the higher vertebral volumetric trabecular apparent BMD established during growth in blacks may be partly responsible for the lower spine fracture incidence in black than white women. This is certainly plausible, but there is no direct experimental evidence showing a correlation between the incidence of vertebral fractures and trabecular numbers or thickness in any race or either gender. There is also no experimental evidence showing that the racial or gender differences in vertebral fractures rates are explained by racial or gender difference in any morphological characteristic. The placement of the femoral midshaft cortical bone further from the central shaft axis in blacks than whites, and in men than women, may confer greater resistance to bending. Whether the lower appendicular fracture rates in blacks than whites, and males than females is attributable to these differences in bone size has not been tested by showing a correlation between hip fracture rates and the cross-sectional area of bone in blacks, whites, men, or women. Nor is there evidence that racial or gender differences in hip fracture rates are explained by corresponding racial or gender differences in bone size or bone geometry. This work is yet to be done.

Bone fragility has its seed sown early—during growth and development, and perhaps during the 9 months before birth. There is much more to growth than final height, and much more to bone than its BMD. Skeletal growth is region- surface-, gender- and race-specific. Bone size proceeds more rapidly than its mineral accrual, appendicular growth is more rapid than axial growth, periosteal surfaces grow more rapidly than endocortical surfaces and, at puberty, in different directions, so that bone size is nearer completion of growth than the mineral accrued within it. To understand the pathogenetic mechanisms responsible for the differing growth and aging of the skeleton in men and women, in blacks, whites, Asians, and other racial/ethnic groups, to understand the effects of exercise, dietary calcium intake, hormone deficiency, and excess, think surface and structure. What is the structural basis for an increase or decrease in BMD? What genetic and environmental factors contribute to the race specific, but gender independent, increase in trabecular thickness at puberty? What regulates longitudinal growth of axial and appendicular skeletons in men and women of different races? What factors regulate the absolute and relative rates of periosteal and endocortical modeling (growth) and remodeling, and so, cortical thickness? If cortical thickness is greater in blacks than whites or greater in men than women, is this the result of reduced endocortical expansion (relative to periosteal expansion) before puberty or greater endocortical contraction during puberty? Is the sensitivity to sex steroids, growth hormone or IGF-1 different in blacks? What is the basis for the secular trends in leg length and trunk length that vary by race, gender, and epoch (32, 33, 34, 35).

Noninvasive methods of measuring bone mass have made many important contributions to the study of the definition, epidemiology, detection, pathogenesis, prevention, and treatment of osteoporosis and to fracture risk prediction. However, the techniques summate the changes on the mineralized surfaces of a three-dimensional world into one or two ossified dimensions, creating flaws in the way we conceptualize the skeleton, in the way we develop our thinking and in the way we direct our research. The structural changes underlying the increase in BMD during growth are not conveyed by the imagery of density. The failure to appreciate the macro- and micro-architectural basis of a region’s volumetric apparent BMD ensures that any structural differences responsible for racial and gender differences in fracture rates will not even be thought about, much less identified and studied (3). A better understanding of the pathogenesis of osteoporosis can be gained by the comparative study of the genetic and environmental factors influencing the surface specific skeletal growth in size and mineral accrual of the axial and appendicular in men and women of different races.


    Acknowledgments
 
I would like to thank my colleagues Drs. G. Jerums and D. Roberts, Austin and Repatriation Medical Centre, University of Melbourne, Melbourne, Australia, and Professor A. M. Parfitt, University of Arkansas, city Arkansas, for their constructive criticisms of the manuscript.

Received February 5, 1998.

Accepted February 9, 1998.


    References
 Top
 Introduction
 Apparent and true bone...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Racial and gender differences...
 Where are we? Where...
 References
 

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