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INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

The reason for comparing ethnic and gender differences in skeletal mass, size, and architecture is to define the structural basis underlying the differences in fracture rates seen between these groups. Han et al. have examined histomorphometric and biochemical measurements of bone turnover in premenopausal and postmenopausal white and black women in this, and the December 1996, edition of the Journal.(1,2) The authors take us on a journey across ethnic groups, across age, and across menopause, exploring the static and dynamic parameters of bone resorption and formation on the surfaces of the iliac crest—on the endosteal surface of its trabeculae, and on the endocortical, intracortical, and periosteal surfaces of its cortex. The studies are a contribution because they answer and raise questions concerning ethnic differences in bone fragility and show us a way of thinking about the skeleton that is a little different.

The main observations presented in these two manuscripts are: (i) the higher trabecular bone density in blacks is due to greater trabecular thickness not trabecular numbers; (ii) the lower bone turnover in blacks is likely to be due to the lower bone surface-to-volume ratio of their cancellous bone; (iii) the increase in bone remodeling associated with aging is similar in blacks and whites; (iv) despite the thicker trabeculae and lower bone turnover, blacks are not spared the loss of bone and the architectural disruption that accompanies advancing age.

The work of Han et al. is a contribution in the broader context of the study of bone remodeling: the surface phenomenon that forms the morphological basis of bone turnover and bone loss. These studies, and a great deal of research by the senior investigator of the group, Michael Parfitt, emphasize the need to study the surfaces of the skeleton. The purpose of this review is to amplify this message by (i) drawing attention to several misconceptions regarding the earlier gain and later loss of bone that have developed because of reliance on bone densitometry as the investigative method of choice or convenience in the study of skeletal health and disease, and by (ii) demonstrating that the behavior of each of the surfaces of the skeleton, during both growth and aging, differ from one ethnic group to another and in men and women. The comparison of the remodeling behavior of these surfaces during growth and aging in women of different ethnic groups, in men of different ethnic groups, and women and men of the same ethnic group may be a step toward identifying the structural components responsible for the differing fracture patterns seen in the groups.

DENSITY AND CONFUSION

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

In this computerized era, we seem to have forgotten that bone biology is the study of the behavior of the surfaces of the skeleton. In the almost 3 years from October 1993 to August 1996, there have been approximately 2438 peer-reviewed manuscripts and 511 reviews in the main English-language medical journals dealing directly or closely with osteoporosis.(3) Of the peer-reviewed manuscripts, 1428 (approximately 60%) were clinical studies in humans, of which 696 (50%) involved densitometry as the main investigative tool. Bone histomorphometry appeared in 37 papers (2.6%). Of the 633 papers published in 34 issues of the Journal in the last 3 years, 302 were studies in humans, of which 165 (55%) involved densitometry while 58 (20%) used histomorphometry.

Densitometry has made many important contributions to the study of the definition, epidemiology, detection, pathogenesis, prevention, and treatment of osteoporosis, but this has occurred at a price. The three-dimensional world of bone is presented as a lump sum, the net integrated result of the amounts of bone added and removed on its surfaces and from within its cortices. We obtain a mineral mass measured within a projected area or derived volume of a region called an areal or volumetric apparent “density.” Areal and apparent are dropped for the sake of brevity but at the price of understanding.

Increasing and decreasing density are not changes in particle number per unit area or volume as “density” implies. The complexity of the structural basis underlying the increase in bone density during growth, and decrease in bone density during aging, is not remotely conveyed by the imagery of this term. This deceptively simple word is securely entrenched in the jargon of the field and used as if it were an indivisible, unambiguous, and universally understood unit of bone. We consider the effects of dietary calcium, exercise, and drugs on bone “density,” the genetic and environmental factors responsible for the increase in “density” during growth, and decrease in “density” during aging. The choice of the word matters because it affects the way we conceptualize the skeleton (or fail to), the way we develop our thinking (or fail to), and the way we direct (or misdirect) our research. I propose that the integrated projected image of bone mass produced by the photon attenuation of densitometry blinds us to the biology of bone.

Densitometry has taught us that: (i) density increases during growth; it does not, bone size increases(4,5); (ii) peak bone density is higher in men than women; it is not, bone size is greater(6); (iii) bone density is stable until menopause in women; it is not, trabecular bone loss occurs in the third decade(7,8); (iv) women lose more trabecular bone from the axial skeleton than men; trabecular bone loss is similar in women and men(9-14); (v) cortical bone loss is greater in women than men; net loss is greater(15); (vi) blacks have a higher bone density than whites who in turn have a higher bone density than Asians—does truth lie here?(1,2,16-22)

STRUCTURE AND CLARITY

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

Many questions emerge when the structures that comprise density are specified. For example, what are the genetic and environmental factors responsible for the changes in trabecular number, thickness, connectivity, periosteal apposition, endosteal resorption, net cortical thickness, and cortical porosity during prepubertal and pubertal growth, during aging, and following menopause? When exercise and calcium are reported to increase trabecular density, is this due to increased trabecular numbers or thickness? If cortical bone density increases, is this the result of greater periosteal apposition, reduced endocortical resorption, or increased endocortical bone formation?

Histomorphometry and ashing provide more explicit information than the word density. The bone calcium concentration (grams per 100 g of fat-free tissue) is established in early intrauterine life and is constant from early gestation to old age.(23-25) The failure of densitometric methods to account for size has led to the erroneous view that bone density increases during growth. This view is prevalent because of the conventional graphic display of areal bone density increasing with age as shown in the upper panels of Figure 1. Cortical areal bone density increases during growth because bone size increases.(4,5) When size is taken into account, the amount of bone in the enlarging long bone is constant; volumetric bone density is independent of age because the growth bone mineral mass and bone size are proportional (lower panels). If this is true, then the genetic and environmental factors that determine whether an individual has a higher or lower volumetric density of a long bone must act early in development, perhaps before birth.

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Figure FIG. 1. Areal and volumetric femoral shaft bone mineral density (BMD) plotted against age for males and females (Lu et al.[5]).

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The data for trabecular bone are different. Volumetric bone density of the spine increases with advancing growth when measured by quantitative computed tomography (QCT).(26) The amount of trabecular bone increases out of proportion to the increase in the enlarging bone. Whether this increase is due to increasing numbers of trabeculae or increasing thickness of existing trabeculae is uncertain. Interestingly, the increase in trabecular density is similar in white girls and boys(26); they have the same trabecular numbers and thickness. The increase in trabecular density in black girls is greater than in white girls at puberty,(27) presumably because thickness increases, not numbers.(1)

THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

The population variance in volumetric density is large; 1 standard deviation (SD) is approximately 10%, double the variance in height. Persons with volumetric density in the 5th percentile have 30–40% lower volumetric bone density relative to the 95th percentile. This deficit is greater than the deficit found in women with fractures relative to age-matched controls. What is the structural basis for this difference across the extremes of population distribution in men and women of different ethnic groups? Although histomorphometric data are available across age, in most studies the sample sizes within a decade are small so that little is known about the heterogeneity of trabecular architecture in women of the same age. Do women with volumetric trabecular bone density at the 5th percentile have fewer trabeculae, thinner trabeculae, or both relative to the 95th percentile?

Within a given percentile, the way the structural components are fashioned may determine bone strength at maturity and the rate and magnitude of bone loss that will occur with advancing age and following menopause. Consider two women with identical volumetric bone density (irrespective of the percentile, gender, or ethnic group). If one has double the number of trabeculae of half the thickness, the trabecular surface area will be twice that of the woman with half the number of trabeculae of double the thickness. Do these two women with the same volumetric density have the same bone strength? As bone remodeling, the replacement of old bone with new, is a surface phenomenon, will the women with twice the number of trabeculae and double surface (upon which remodeling may occur) lose more bone at menopause when remodeling intensity increases? Will the woman with thinner trabeculae develop greater bone fragility after menopause due to the thinner trabeculae being more susceptible to perforation? If there is remodeling imbalance, this woman would be predicted to lose bone more rapidly than the woman with the same volumetric density but thicker trabeculae with less surface. Could differences in the surface/bone volume ratio be partly responsible for the variance in rates of bone loss with age? Do so-called “rapid” and “slow” bone losers with identical volumetric bone density differ by the former having a higher surface/bone volume ratio?

Whether the variance or “scatter” in volumetric density about the mean increases with age or puberty is uncertain. If the variance does increase at puberty, this implies that sex steroids may increase trabecular number and/or thickness more greatly in some individuals than others (with the same prepubertal starting value). Are there “greater trabecular bone gainers”? Why do black girls gain more trabecular thickness than white girls at puberty?(27) Comparable studies in black and white males have not been done. Are there “greater cortical bone gainers” at puberty—individuals who gain more periosteal and endocortical bone compared with individuals with the same starting cortical mass and size? Greater “bone gainers” at puberty will then have a greater proportion of their total peak bone mass accrued during puberty. If so, could “greater gainers” become “rapid bone losers” at menopause? These surfaces behave differently because they are regulated differently. Are there androgen or estrogen receptor polymorphisms associated with a greater skeletal growth response to puberty and greater bone loss at menopause? Thus, many questions arise when we specify the structures comprising “density.”

ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

From the clinical point of view, the reason for comparing ethnic and gender differences in skeletal growth and aging is to study the structural basis for the greater bone strength thought to be responsible for the lower incidence of fractures in blacks than whites and men compared with women. Blacks have higher areal bone density than whites, whites have higher areal bone density than Asians.(16-22) Men are reported to have higher areal bone density than women in most, but not all, studies. However, these differences may be artifactual because size is not taken into account when bone mass is expressed in absolute terms (g), only partly so when expressed as areal density (g/cm2), and completely so only when expressed as the amount of bone in bone–volumetric density (g/cm3).11

Ethnic and gender differences in areal density are largely, but not entirely, explained by differences in bone size.(29-34) However, corrections for differences in size were made in these studies using height and weight, imprecise surrogates of bone size, rather than by measuring the external dimensions and volume of the region scanned (a difficult task given the irregularity of structures such as the vertebral body or proximal femur). Thus, residual differences in volumetric density may disappear entirely if volume were accurately measured. If volumetric density is the same in these groups, are ethnic and gender differences in fracture rates largely accounted for by differences in bone size, shape, or microarchitecture (determinants of bone strength that are independent of its mass)?

Alternatively, if volumetric density is higher in blacks than whites than Asians, and higher in men than women, what is the structural basis for these differences? Han et al., using histomorphometry, show that greater trabecular thickness, not trabecular numbers,(1) account for the higher trabecular density reported using quantitative computed tomography.(17) The investigators showed that the greater trabecular thickness was present in young adulthood.(1) Similarly, South African blacks have greater trabecular thickness, not numbers, compared with South African whites.(18) It is likely that this difference is established around puberty. Using quantitative computed tomography, Gilsanz et al. showed that volumetric trabecular density at the spine was no higher in black than white girls until puberty.(27) Fugii et al., using quantitative computed tomography, showed that Japanese men and women have lower trabecular bone density than white men and women.(35) The authors suggest that the differences were greater than can be explained by differences in the methods of measurement. Whether the Japanese have thinner or fewer trabeculae than whites is unknown.

Do these structural differences exist between genders? Peak bone mass is higher in white men than women because they have bigger bones, partly because prepubertal longitudinal growth continues for 2 years longer than in females.(36-39) Consequently, the prepubertal:pubertal contribution to peak bone mass is 80:20 in males and 50:50 in females,(39) suggesting that illnesses interfering with pubertal development may have a worse effect in females than males.

Peak trabecular bone density at the spine and iliac crest is no higher in white men than white women: they have the same trabecular number and thickness.(6,9-14,18) Likewise, neither trabecular number nor thickness differs in South African black men and women,(18) nor in Japanese men and women.(35) Thus, trabecular numbers are similar in blacks and whites of either gender. Trabecular thickness is the same in black men and women and in white men and women, but trabecular thickness is greater in blacks than whites. (Histomorphometric data in other groups are not available.) What are the genetic and environmental determinants of trabecular number and thickness? What is the biomechanical advantage of greater numbers or thicker trabeculae?

ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

It seems established that blacks have greater cortical thickness than whites. Stature varies from ethnic group to ethnic group and is, on average, greater in men than women. These size considerations complicate the comparison among ethnic groups and between genders of areal density of predominenty cortical structures such as the radius. If blacks have higher areal bone density than whites (with long bones of the same external diameter), blacks must have thicker cortices and/or cortices with fewer or smaller Haversian canals. Likewise, if men have higher cortical areal bone density than women (with long bones of the same external diameter), then men must have greater cortical thickness and/or cortices with fewer or smaller Haversian canals.

Han et al. reported that black and white women had the same iliac bone width and numerically (not statistically) greater cortical thickness.(1) Trotter et al. reported 10–14% higher volumetric densities in blacks than whites based on their study of skeletons from 40 whites and 40 blacks.(40) Similarly, Luckey et al. found approximately 7% higher radial areal bone density in black and white women with comparable radial width.(41) Similarly again, Garn et al. studied 4379 whites and 1589 blacks.(42) Black men had 7% higher subperiosteal and 30% higher medullary areas than white men. Black women had 14% higher subperiosteal and 49% higher medullary areas than white women. Blacks did have higher resultant cortical areas than whites (3% in men, 7% in women); whether differences of this magnitude account for the ethnic and gender differences in fracture rates is unknown. By contrast, Weinstein and Bell found no differences in iliac crest cortical width in 12 black and 13 white men and women of similar height and weight.(43) Likewise, Bloom and Pogrund found that combined cortical thickness of the humerus in female Bantus was no different than British whites.(44) By contrast again, in a study of 950 South African blacks and 782 whites, Solomon found that peak cortical area (measured by metacarpal morphometry) was higher in white women than white men and higher in black women than black men.(45) Blacks had lower cortical area (and have a lower fracture incidence) than whites.

What are the determinants of cortical thickness? Cortical bone thickness is the net result of periosteal and endosteal growth. Periosteal growth is responsible for 77% and endosteal growth is responsible for 23% of peak cortical thickness in white men.(46) In white females, respective contributions are 65 and 35%. Similar proportional contributions were found in children from Central and North America.(46) The proportional contributions in blacks and Asians have not been studied. These two components of cortical thickness are regulated differently in females and males.(47) Medullary contraction at puberty occurs in girls but less so in boys and is likely to be estrogen dependent, at least in girls. This mechanism may explain the observation by Odita et al. in a study of 695 Nigerian boys and 583 girls. They found higher cortical thickness in girls than boys until the age of 15 years.(48) The temporal sequence of growth may differ from ethnic group to ethnic group. A slower incremental rise in peak cortical area was reported in the cross-sectional study by Solomon in South African blacks.(45)

There is also evidence that blacks may have more advanced skeletal age than whites of comparable chronological age. Garn et al., in a study of 1942 blacks and 3046 whites, showed that skeletal age was more advanced in blacks than whites by approximately 0.6 SDs in the females and approximately 0.4 SD in the males.(49) Height was more advanced in blacks of both genders by about 0.25 SD. Thus, comparisons of black and white children, males and females, must take skeletal maturation into consideration as well as chronological age and pubertal staging. Precise assessment of skeletal development may require that skeletal atlases be developed defining mass, size, and structure according to bone age, chronological age, and pubertal status. Whether bone age of each bone should be defined according to its own ossification centers or by using established methods such as described by Gruelich and Pyle or Tanner and Whitehouse is uncertain.

Comparisons of bone density in blacks and whites should also take into account upper and lower body segment lengths. Blacks have longer legs and shorter trunks than whites(50); higher femoral neck areal density in blacks may be the result of failure to adjust for the larger size. The finding of a shorter hip axis length in blacks may be a conservative error; hip axis length may have been even shorter had adjustment been made by leg length rather than total height.(51,52) Asians have similar trunk length but shorter leg length than whites.(53,54) The lower bone density and shorter hip axis length reported in Japanese after adjustment for total height compared with whites may not be observed after adjustment for leg length.(53)

There are secular trends in upper and lower body segment lengths and age at puberty in whites, blacks, and Asians.(54-59) Secular increases have been reported in upper and lower body segments in females and males. However, in some studies, secular trends were confined to one gender or one body segment. Within a community, secular trends may be found in the lower, but not the higher, socioeconomic group. Secular increases in hip axis length may parallel the changes in segment lengths.(59) The incidence of hip fractures varies markly across Europe and in different continents.(60,61) These patterns may vary more among countries than between genders. There have been secular increases and decreases in hip fracture incidence during the last 50 years, which vary from country to country.(62) We know little about the factors responsible for this perplexing epidemiological heterogeneity. Secular changes in the patterns of falls, in the magnitude of bone loss during aging, and in factors regulating peak bone mass, size, shape, volumetric density, body proportions, or age at puberty may contribute.

GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

Peak bone size, mass, and structure are important determinants of bone fragility in old age. If ethnic and gender differences in fracture rates in old age are due to structural differences established during growth then attention to the first 20 years of skeletal growth is needed with comparative studies in males and females of different ethnic groups. The studies should be designed to measure the temporal pattern of growth and maturation of the periosteal and endosteal surfaces and cortical thickness, upper and lower body growth in size and mass, and proximal and distal limb segments.

Within a gender, growth of the lower body is complete before growth of the upper body. Within a region, accrual of trabecular bone may proceed more rapidly than accrual of cortical bone and growth of distal limb segments reaches completion sooner than proximal limb segments.(56) These processes differ between genders and perhaps among ethnic groups. They differ because each component is likely to be regulated differently.(36-38) Bone age and the putative hormonal regulators of these surfaces should be measured because boys and girls of the same chronological age differ in their skeletal maturation and pubertal stage. Likewise, ethnic groups of the same chronological age are likely to differ by skeletal maturation and pubertal staging.

The clinical significance of the differing temporal sequences in growth from region to region, and in size and mass within a region, between genders and ethnic groups may be important when exposure to risk factors occurs. The effect of exposure to a risk factor during growth—unlike adulthood—may depend on the maturational level of the region exposed as well as the “dose” and duration of the exposure. Regions further from their peak at the time of exposure may be affected more than regions that have completed growth. Likewise, males and females or ethnic groups of the same chronological age but differing in skeletal age may be affected differently by the same risk factor.

The site of lowest areal bone density in the premenopausal daughters of women with spine fractures is the spine.(63) Deficits in premenopausal daughters of women with hip fractures were confined to the femoral neck and midshaft, with, if anything, slightly higher areal bone density at the spine.(64) Thus, genetic and environmental factors operating during the first 15–20 years of life may result in site-specific deficits in peak bone mass, size, or volumetric density at the spine, proximal femur, or both. These deficits, though established early in life, may find clinical expression in fractures many years later, when bone loss erodes the biomechanical competence of these structures.

ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

Contrary to the prevailing view, there is unlikely to be a period of stability where there is neither gain nor loss of bone. This purported period of stability between the attainment of peak bone mass (in the second or third decade) and menopause is likely to be the net result of bone formed on the periosteum integrated by densitometric methods of measurement with the bone lost on intracortical, endocortical, and trabecular surfaces of bone.

Cross-sectional and longitudinal studies suggest that trabecular bone loss begins soon after attainment of peak volumetric trabecular bone density. White females aged 25–35 years have approximately 8% lower volumetric trabecular bone density than girls aged 14–19 years.(8) There is a decline in volumetric bone density at the spine and areal density at the proximal femur in the third decade.(9) In a prospective study of 122 white and 121 African-American blacks, bone loss occurred before menopause in blacks and whites, but rates of loss were not greater in white women.(19) White women had more rapid bone loss at the spine and radius than black women around menopause. Rates of loss did not differ in the late postmenopausal periods in blacks and whites. Similar cross-sectionally determined “rates” of diminution in trabecular bone density are found in Japanese and whites.(35)

If the same trabecular bone mineral mass is fashioned into the same number of trabeculae of greater thickness, then blacks must have a lower surface/bone volume ratio than whites. Han et al. demonstrate that this is the case and suggest that bone turnover may be lower for this reason.(1,2) The proportion of the total surface of bone undergoing formation was 25% lower in blacks than whites while osteocalcin was 15% lower.(2) As one purpose of remodeling may be to maintain bone strength, Han et al. suggest that the component of remodeling directed to repair fatigue is less in blacks because the thicker trabeculae are likely to be less susceptible to fatigue damage. The literature is not entirely concordant since lower bone formation has been reported in blacks than whites with the same trabecular volumetric density and trabecular thickness,(43) while higher bone turnover has been reported in South Africa blacks than whites.(18)

Activation frequency, a measure of the intensity of bone remodeling, was no different in black and white women before menopause and increased in both groups by an equivalent degree.(2) The deficit in peak trabecular density present in whites relative to blacks did not increase with advancing age; the age-related cross-sectional diminution in trabecular bone was not greater in whites than blacks. The parallel decrease in trabecular bone volume in South African black and white women was also reported by Schnizler et al.,(18) and by Trotter et al.(40) Nevertheless, it may be difficult to detect a true difference in slopes when a trait has a large biological variation and the measurement method has a large coefficient of variation.

Han et al. report that advancing age and menopause were associated with a similar degree of complete loss of trabecular elements and increased separation in whites and blacks. Increased numbers of resorption sites associated with increased activation frequency may be anticipated to result in perforation of the thinner trabeculae in whites and greater bone fragility, particularly if erosion depth is increased. The thicker trabeculae in blacks should protect from perforation. In addition, bone resorption may thin the trabeculae, increasing bone surface. Consequently, as age advances, whites should have greater trabecular spacing and a fall in trabecular surface as trabeculae drop out. Blacks should have an increase in trabecular surfaces. These changes were not observed.

Finding a similar cross-sectionally determined “rate” of diminution in bone volume in blacks and whites, a similar degree of loss of trabecular plates, and increased trabecular separation (despite whites having thinner trabeculae and higher surface/volume ratio) may be the result of blacks having a more negative bone balance within each basic multicellular unit by having deeper resorption cavities and/or lower bone formation than whites. Although results of bone balance were not available, premenopausal black women had higher osteoclast indices than premenopausal white women on the trabecular and combined total surface.(2) This was not found in postmenopausal black women compared with postmenopausal white women. However, wall thickness was reduced in postmenopausal blacks on the cancellous and combined total surface. Erosion depth was greater on the endocortical, but not trabecular, surfaces.

What about gender differences? Convention has it that trabecular bone loss is greater in white women than white men. Evidence based on ashing, iliac crest histomorphometry, and quantitative computed tomography of the spine suggests otherwise.(9-14,18,35) The impression that women lose more trabecular bone than men at the spine is based on finding a greater diminution in lumbar spine areal bone density with advancing age.(65) This method integrates the trabecular and cortical compartments (Fig. 2).

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Figure FIG. 2. The age-related diminution in integral bone density (vertebral body plus posterior process) using dual photon absorptiometry in men and women (Riggs et al.[63]).

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Using quantitative computed tomography, trabecular bone loss with age is similar in men and women (upper panels, Fig. 3).(12) Trabecular bone loss occurs by perforation and loss of connectivity in women and predominantly thinning in men.(13,14) Increased “resorption” in women means an increased extent of resorption, the result of increased numbers of remodeling sites on the surface of bone with each being in negative bone balance. Evidence for “deeper” erosion cavities on trabecular surfaces is not compelling.

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Figure FIG. 3. The age-related diminution in vertebral body trabecular bone density (upper panels) and vertebral cortical bone density (lower panels) measured using single energy (broken lines, open symbol) and dual energy (unbroken lines, closed symbol) quantitative computed tomography in men and women (Kalender et al.[5]).

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ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

The greater “loss” of bone across age in women than men (Fig. 2) is actually the result of greater loss of cortical bone (lower panels, Fig. 3). However, just as peak cortical thickness is the net result of growth on the endosteal and periosteal surfaces, cortical thickness in the elderly is the net result of endocortical resorption and periosteal appositional growth throughout adult life. This “loss” of cortical bone is a net loss.

As depicted in Fig. 4, the greater loss of cortical bone in white women than white men is the net effect of greater loss on the endocortical surface and the less periosteal appositional growth in women than men.(9,11,15,66) The same amount of bone placed further from the long axis of bone results in a bone of greater breaking strength.(15) Bouxsein et al. showed that compared with 21 younger women, 22 older women had 7% greater ulna width, 10% lower cortical area, 10% greater total subperiosteal area, and 88% greater medullary area.(67) The maximum moment of inertia increased by 27%.

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Figure FIG. 4. Cortical bone loss is less in men than women because endocortical resorption is greater in women than men, and subperiosteal formation is greater in men than women. (Adapted from Ref. 15, Ruff and Hayes.)

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There is insufficient information concerning the role of ethnic or gender differences in the relative contribution of endosteal resorption and periosteal apposition to final cortical thickness in old age. If a greater proportion of the net cortical loss is due to reduced periosteal formation rather than endosteal resorption then this information should focus attention on formation-stimulating agents for periosteal bone growth. Han et al. found no increase in the width of the iliac bone in black or white women, perhaps because periosteal apposition with age may be site specific. However, a secular increase in stature in black and white women may have obscured a real age-related increase in periosteal appositional growth.

Han et al. showed that erosion depth increased on the endocortical surface, accounting for cortical bone thinning in both groups. Cortical thickness decreased more in black than white women. Although this did not achieve statistical significance, the decrease was double that in white women and suggests that either endosteal resorption was greater or that periosteal formation was less in blacks.

Reduced cortical areal bone density is also the result of increased porosity, which Han et al. show is due to increased Haversian canal number, not size. The increase occurred to a similar degree in black and white women. Bantus have a low incidence of fractures, yet the combined cortical thickness of the humerus decreased in Bantus and white British women to a similar extent.(44) Laval-Jeantet et al. showed that cortical porosity of the humerus increased from approximately 4% in white men and women aged 40 years to approximately 10% in those over 80.(66) The fall in apparent density with age correlated with porosity. True mineral density (ash weight per volume unit of bone free of vascular channels) was unchanged (Fig. 5).

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Figure FIG. 5. In men and women, porosity (P), the percentage of cortical bone occupied by vascular cavities, increased with age, apparent mineral density (AMD), ash weight per volume unit of cortical bone, decreased with age and correlated with porosity. True mineral density (TMD), ash weight per volume unit of bone freed of its canals and resorption spaces, remained unchanged with age (Laval Jeantet et al.[68]).

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GROWING OLD ON THE SURFACES OF BONE: SUMMARY

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

Thus, skeletal aging commences shortly after the attainment of peak bone density, in the third decade in white and black women and men. Early trabecular bone loss probably occurs by trabecular thinning. Cortical bone mass may still be increasing in the third decade and may reach its peak later in some ethnic groups. At midlife, perforation and loss of plates occurs to a similar degree in black and white women as bone remodeling increases across menopause. As age advances, central trabeculae and their surfaces disappear. Regions dependent on trabecular bone for strength, such as the vertebral body, may not tolerate trabecular bone loss following menopause, particularly in the face of a low peak volumetric bone density.

Endocortical resorption, trabecularization of cortical bone, canal numbers, cortical porosity, and the surface: volume ratio of cortical bone appear to increase to a similar degree with advancing age in black and white women. Cortical bone loss accelerates with age,(69,70) increasing bone fragility and making an increasing contribution to total bone loss. Cortical thinning is offset by periosteal appositional growth in white men, perhaps to a lesser extent in white women and to a variable extent from region to region. Fragility at predominantly cortical sites thus emerges later than fragility at sites with substantial amounts of trabecular bone. In the presence of fragility, the type of fracture, and the age of its occurrence depends on the age-specific pattern of trauma and falls.

Of the total bone formation, 54% is due to bone formation on trabecular surfaces and 46% is the result of bone formation on the endocortical and intracortical surfaces.(2) Han et al. suggest that the total amount of bone lost from youth to old age is equally derived from the cortical and trabecular compartments in men and women.(1) Sandor et al. suggest that 70% of the total amount of bone lost is cortical.(71) The point is, bone loss is generalized.

Thus, age-related bone loss may begin in the third decade. What is the pathogenesis of age-related bone loss? Can its causes be distinguished from mild estrogen and progestogen deficiency in women and a falling testosterone level in men? This bone loss is due to (i) increased resorptive loss due to increased numbers of remodeling sites on bone surfaces, (ii) deeper cavities, at least on the endocortical surface, (iii) reduced formation at the basic metabolic unit, and (iv) reduced formation at the periosteal surface. Secondary hyperparathyroidism is unlikely to be responsible for trabecular bone loss because primary hyperparathyroidism is associated with preservation of trabecular bone.(72) Cortical bone loss appears to be parathyroid hormone dependent. A correlation between parathyroid hormone and endosteal resorption has been reported.(73)

GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

Perry et al. provide a broad perspective.(20) From their Table 2, total body calcium (obtained by summed upper and lower body values) was 1418 and 1224 g in pre- and postmenopausal blacks, respectively, 1248 and 1018 g in pre- and postmenopausal whites, and net losses of 194 g in blacks (14%) and 230 g in whites (19%). Of the 206 g (1224–1018 g) greater mass in elderly postmenopausal blacks than whites, 170 g (1418–1248 g) was due to the greater net gain in blacks and 36 g to the greater net loss in whites. Similarly, upper body calcium was 344 and 296 g in pre- and postmenopausal blacks, 292 and 222 g in pre- and postmenopausal whites, and net losses of 48 g in blacks and 70 g in whites. Of the 74 g greater upper body bone mass in postmenopausal blacks than whites, 52 g was due to a greater net gain in blacks, and 22 g was due to greater net loss in whites. Lower body calcium was 1074 and 928 g in pre- and postmenopausal blacks, 956 g and 796 g in pre- and postmenopausal whites, and net losses of 146 g in blacks (14%) and 160 g in whites (16%). Of the 132 g greater lower body bone mass in postmenopausal blacks, 118 g was due to greater net gain in blacks and 14 g was due to greater net loss in whites.

Thus, net bone lost is greater in whites than blacks in absolute terms and as a percentage of their (lower) peaks. Net loss relative to peak at the upper body in whites (70 g, 24%) was twice that in blacks (48 g, 14%) but similar net loss occurred in the lower body. The higher bone mass in blacks than whites in the postmenopausal years (when fractures occur) is largely accounted for by the greater net gain in bone mass by blacks during growth than by the greater net loss in whites during aging. How much of the greater net loss in whites than blacks is accounted for by more endocortical resorption in whites than blacks and/or more periosteal gain in blacks than whites is unknown.

Similarly, between genders, peak total body calcium is 1200 g in white men and 900 g in white women. Net bone loss from youth to old age is 100 g in men and 250 g in women. The gender difference in bone mass between elderly white men and women is approximately 400 g, of which approximately 300 g is due to the greater net gain in men during growth and approximately 150 g is due to the greater net loss in women. How much of the 150 g greater net loss is accounted for by more endocortical resorption in women than men and more periosteal gain in men than women is uncertain.

Looker et al. present comprehensive data on bone area, mass, and areal density of the proximal femur in white, black, and Mexican-American women and men.(74) Confining this discussion to comparisons of total bone mass of the proximal femur, first, comparing men and women, in blacks the higher bone mass in old age in men was the result of the greater net gain during growth in men than women, which was partly, but not entirely offset by the greater net loss in men than women. By contrast, in whites and Mexican-Americans, men had higher bone mass than women because of the greater net gain during growth in men and the greater net loss in women. Second, comparing women across ethnic groups, blacks had higher bone mass in old age than whites or Mexican-Americans because the net gain during growth was greater, and the net loss during aging was less in blacks. Whites had the same bone mass as Mexican-Americans in old age because the greater net gain in whites than Mexican-Americans was offset by the greater net loss across age in whites. Third, comparing men across ethnic groups, blacks had higher bone mass than whites because the net gain was greater in blacks than whites and the net loss was similar. Blacks had higher bone mass than Mexican-Americans because the net gain was greater in blacks but the net loss was also greater, attenuating, but not abolishing, the greater difference in peak bone mass. White men gained more bone than Mexican-Americans but lost more so their advantage at peak was lost; Mexican American men had higher bone mass than whites in old age. “Net” is emphasized repeatedly. The relative contributions of the endosteal and periosteal surface modeling and remodeling to both peak bone mass and to bone loss are unknown and require study. The studies are cross sectional and deal with total bone mass so that size is not taken into account and secular effects may result in bias. Nevertheless, the differing contributions of the earlier gain and later loss to bone mass in old age within and between ethnic groups and genders are apparent.

BONE FRAGILITY—THE BOTTOM LINE

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

Returning to the question, the reason for comparing ethnic and gender differences in skeletal growth and aging was to study the structural basis for the lower fracture incidence in blacks than whites and men compared with women. Lower bone fragility in black compared with white women may be due to (i) their larger peak bone size, (ii) greater trabecular thickness, (iii) possible greater cortical thickness, (iv) less bone loss relative to their higher starting value, (v) reduced bone turnover, and (v) possible reduced perimenopausal bone loss. The lower fragility in white men than white women may be due to (i) their larger peak bone size, (ii) trabecular loss by thinning rather than perforation, (iii) greater periosteal appositional growth, and (iv) less endosteal resorption. Factors that may account for lower bone fragility in black men compared with black women and black men compared with white men are poorly defined.

Whether these differences in bone size, mass, or structure, or bone turnover among ethnic groups, or between men and women even partly account for the corresponding group differences in fracture rates is unknown. There is no direct experimental evidence to show that the difference in fracture rates among these groups diminish when the difference in one or more of these traits are taken into account. Even in drug trials, the increase in areal bone density associated with treatment is assumed to be responsible for the lower fracture rate; an association between the change in areal bone density and the change in fracture rates has never been documented.12 In current practice, osteoporosis and low bone density are synonymous and are used interchangeably. The sense and meaning of osteoporosis is bone fragility. The “microarchitectural deterioration” in the definition of osteoporosis has not achieved clinical application.(76) The view that the architecture is “captured” by the bone mass measurement is unproven. On the contrary, trabecular bone specimens from younger and older donors chosen to have the same apparent density differ in strength; specimens from older donors have a 40% lower yield stress.(77) Older women matched by areal bone density with younger women have 8% lower mean frequency of resonance in ulnar cortical bone, consistent with an age-related deterioration in a property of bone independent of areal bone density.(78)

Histomorphometry, metacarpal morphometry, peripheral quantitative computed tomography, ultrasound, densitometry, fractal signature analysis, and nuclear magnetic resonance spectroscopy(79,80) have a role in quantifying the macro- and microarchitecture of bone mass, size, shape, structure, and quality, characteristics responsible for the strength of bone. The clinical relevance of these methods is established by how well they predict bone strength initially in vitro and then in vivo, not by how well one correlates with another.

One method is “better” than another if it prospectively identifies more individuals coming to sustain fractures than another and prospectively identifies more individuals not sustaining fractures. Two methods are “better” than one if the combination shows this higher sensitivity and specificity. The only study to use this approach was published by Hui et al.(81) The lower tertile of areal bone density of the radius contained 37.5% of the cases sustaining fractures with only 1.1% of the cases in the highest tertile. The figures were 28.6 and 1.6% of cases for the lowest and highest bone mass tertiles. Few studies approach the question with this clarity. Reporting the proportion of variance in bone strength accounted for by one method, by two methods combined, the use of odds ratios, and receiver-operator curves to compare the ability of one technique to separate cases with fracture from controls retrospectively, do not convey the advantage of one method over another in the above practical manner.(82-84)

The credibility and practical utility of the measures of fragility will be determined by study design. Controls need not necessarily be age-matched. Depending on the question concerning fragility, matching by areal density, size, and comparisons within a gender across ethnic groups, or within an ethnic group across genders may be useful. Combining biochemical measurements of bone turnover with ultrasound, rates of bone loss and bone mass, and bone size and mass show promise.(85-87) Combining structural parameters such as trabecular number, connectivity with bone size, ultrasound, or densitometry awaits investigation. There are large differences in the epidemiology of fractures across continents, oceans, genders, and ethnic groups.(60) If these differing fracture patterns are due to differences in bone fragility, rather than ascertainment errors,(61) the frequency or severity of falls, or trauma, then prospective studies will have to be carried out in males and females of different ethnic groups with baseline measures of these structural determinants.

FROM DENSITY TO STRUCTURE

  1. Top of page
  2. INTRODUCTION
  3. DENSITY AND CONFUSION
  4. STRUCTURE AND CLARITY
  5. THE STRUCTURAL BASIS FOR THE POPULATION VARIANCE IN VOLUMETRIC DENSITY
  6. ETHNIC AND GENDER DIFFERENCES IN PEAK TRABECULAR NUMBER, THICKNESS, AND SURFACE
  7. ETHNIC AND GENDER DIFFERENCES IN PEAK CORTICAL THICKNESS
  8. GROWING UP ON THE SURFACES OF BONE—THE CLINICAL SIGNIFICANCE
  9. ETHNIC AND GENDER DIFFERENCES IN TRABECULAR BONE LOSS: NUMBER, THICKNESS, AND SURFACE
  10. ETHNIC AND GENDER DIFFERENCES IN CORTICAL BONE LOSS: ENDOCORTICAL RESORPTION, PERIOSTEAL APPOSITION, AND INTRACORTICAL POROSITY
  11. GROWING OLD ON THE SURFACES OF BONE: SUMMARY
  12. GROWING UP VERSUS GROWING OLD: NET GAIN VERSUS NET LOSS BETWEEN ETHNIC GROUPS AND GENDERS
  13. BONE FRAGILITY—THE BOTTOM LINE
  14. FROM DENSITY TO STRUCTURE

The term halisteresis (deprived of salt) was used by Cooke in 1955 in reference to mineral being removed from bone. It has vanished painlessly. As density is a misleading term, I recommend that it be replaced by mass with attention to the units, which convey the degree of adjustment for size: total bone mass, unadjusted for size (g), areal bone mass (g/cm2), or volumetric bone mass (g/cm3). Given the entrenched state of this misnomer, a compromise may be to reinstate apparent, for example, areal apparent bone density (AABD, g/cm2), volumetric apparent bone density (VABD, g/cm3), and the method described by Carter et al.,(88) bone mineral apparent density (BMAD, g/cm3). Apparent reinforces that density is not a real or true density but is a bone mineral mass within a region not all of which is mineral.

The many questions emerge when we replace the lump sum, density, by its parts, structure. It is during growth that: (i) ethnic and gender difference in bone size and structure develop; (ii) the variance in peak volumetric bone density develops; and (iii) the largest component of the differences in bone mass between blacks and whites, and between men and women, are established. Thus, osteoporosis has its seed sown about 9 months before birth and its pathogenesis established, in part, during in the first 20 years of life. In adulthood, bone remodeling occurs replacing old bone with new to maintain bone strength, but remodeling imbalance, the unwanted consequence of this surface-dependent phenomenon, results in bone loss and increased bone fragility earlier in the vertebral body, a structure with a large surface-to-volume ratio dependent on the trabecular connectivity for its strength. Cortical bone loss proceeds slowly then accelerates as the surface available for resorption increases on its endocortical and intracortical surfaces. Increased bone fragility occurs later at the proximal femur, at a time when falls occur with increasing frequency.

Understanding the pathogenesis of bone fragility with advancing age will require the study of the genetic and hormonal regulators of the earlier growth and later loss of bone within and between genders, within and between ethnic/racial groups, on the surfaces of bone. The papers by Han et al. asks us to broaden our thinking about bone biology and bone fragility by shifting from density to microarchitecture, surface-based bone remodeling, and surface bone volume–dependent bone turnover. We need the expertise of geneticists, evolutionary anthropologists, embryologists, pediatricians, and biomechanical engineers in the Journal and at plenary sessions to understand the pathophysiology of fractures. The Parfittian messages have been writ for some time; read them.

  • 1

    Volumetric density by QCT is mistakenly called “true” density. All noninvasive measurements are “apparent” densities—the amount of bone contained within a region not all of which is bone. Unstated, but implicit in the use of “true” is the erroneous notion that volumetric density is the “best” surrogate of strength; there is no evidence to support this view.(28) True density is the mass of a substance per unit area or volume of its own bulk.

  • 2

    Fracture rates differ greatly from trial to trial, perhaps due to varying characteristics of the participants and the varying definition of fracture.(75) Thus, valid assessment of this association requires plotting, the change in fracture rate in those treated minus the change in fracture rate in controls, against the change in bone density in those treated minus the change in bone density in controls for each trial.

  • 1
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    Han Z-H, Painitkar S, Rao DS, Nelson D, Parfitt AM 1997 Effect of ethnicity and age or menopause on the remodeling and turnover of iliac bone: Implications for mechanisms of bone loss J Bone Miner Res 12: 498508.
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