Dorothy A. Nelson

Effects of Ethnicity and Age or Menopause on the Remodeling and Turnover of Iliac Bone: Implications for Mechanisms of Bone Loss

We measured histologic indices of bone remodeling and turnover separately on the cancellous, endocortical, and intracortical subdivisions of the endosteal envelope, and on the combined total surface, in transiliac bone biopsies obtained after double tetracycline labeling in 142 healthy women, aged 20–74 years, 34 black and 108 white, 61 premenopausal and 81 postmenopausal. The data were analyzed by two‐way analysis of variance of the four groups defined by age/menopause and ethnicity and by linear regression of the major variables on age. None of the interaction terms was significant and none of the regression slopes on age differed between blacks and whites, indicating that, as for the previously reported structural indices, the effects of ethnicity and of age/menopause are independent. Accordingly, the data were also analyzed separately for the effect of ethnicity (pre‐ and postmenopausal combined) and age/menopause (blacks and whites combined). The analyses led to the following conclusions. (1) The geometric mean bone formation rate on the combined total surface was 25% lower in blacks than in whites; other histologic differences between ethnic groups were inconsistent between surfaces. (2) Serum osteocalcin (OC) but not bone‐specific alkaline phosphatase (BSAP) was lower by about 15% in blacks than in whites. (3) The lower bone turnover in blacks is most likely in the directed rather than in the stochastic component because of a higher bone mass and consequent reduced susceptibility to fatigue damage. (4) All Class 1 bone formation variables and the three resorption indices were significantly higher in the postmenopausal compared with the premenopausal subjects, reflecting a 33% increase in activation frequency. (5) BSAP, but not OC, was increased relatively more (66%) than the bone formation rate (BFR). Consequently, BSAP is more sensitive to the effects of menopause than OC, but OC is more sensitive to the effects of ethnicity than BSAP. (6) There were highly significant differences between the three subdivisions of the endosteal envelope for every non–cell‐related variable. All Class 1 formation variables were highest on the endocortical surface, but the magnitude and pattern of the differences otherwise was inconsistent between variables. The contributions of the different subdivisions to the total bone formation rate were cancellous 54%, endocortical 13%, and intracortical 33%. (7) The previously reported changes in bone surface location, together with the presently reported changes in activation frequency and wall thickness indicated that there was no significant effect of age/menopause on erosion depth on the cancellous and intracortical surfaces but a large increase in erosion depth on the endocortical surface. (8) The increase in bone turnover that results from hormonal changes is most likely in the stochastic rather than in the directed component because it serves no purpose but has harmful effects on skeletal integrity.

A Randomized Trial of Sodium Fluoride as a Treatment for Postmenopausal Osteoporosis

The anti-fracture efficacy of sodium fluoride (NaF) was evaluated in 84 postmenopausal white women with spinal osteoporosis. The dose of NaF used was 75 mg/day and all patients in this prospective, randomized, double-blind, placebo-controlled clinical trial received calcium supplements (carbonate salt) 1500 mg/day in addition to participating in a structured physical therapy program. For each of the outcome measures (change in stature, change in cortical bone mass in the forearm and development of new vertebral fractures determined by change in vertebral morphometry and by scintigraphy) there was no significant difference between the fluoride or placebo treated groups. Side effects, predominantly gastrointestinal symptoms and the development of the painful lower extremity syndrome, occurred significantly more frequently in the fluoride group (P<0.05). Peripheral fractures were not more frequent in the fluoride group. We conclude that, in the dose and manner used in this study, NaF is no more effective than placebo in retarding the progression of spinal osteoporosis. There is no role for NaF in the treatment of osteoporosis outside the confines of clinical research.

The accumulation of whole body skeletal mass in third- and fourth-grade children: Effects of age, gender, ethnicity, and body composition

The purpose of this longitudinal study is to describe bone mass and body composition, and the annual changes in these measurements, among third grade students recruited from a suburban school district. Whole body bone mineral content (WBBMC), bone mineral density (WBBMD), fat, and lean mass were measured by dual-energy X-ray absorptiometry. Bone mass in the lumbar spine (LBMC) region of the whole body scan was also utilized. 773 students (38% white, 57% black, 5% other) had baseline visits; 561 had a second measurement a year later. At baseline, black children have significantly higher WBBMC, WBBMD, height, and lean mass than whites. Black males, but not black females, have a greater LBMC. There are no significant gender differences in body size, WBBMC, or WBBMD, although girls have a greater LBMC and fat mass, and boys have a higher lean mass. Most of these differences persist in visit 2. The annual change in bone and lean mass is greater in blacks. Stepwise linear regression analyses of bone mass on body size, gender, and ethnicity and their interactions indicate that log-transformed weight explains most of the variance in both WBBMC and WBBMD (multiple r2 = 0.90 and 0.64, respectively). There are significant black/white differences in intercepts and slopes. Other variables explain only another 1%-2% of the variance. The strongest Pearson correlations are between changes in bone mass and changes in lean mass and log-transformed weight (r ranging from 0.62 to 0.84, p = 0.0001). We conclude that there is a significant black/white, but not male/female difference in whole body bone mass and bone density before puberty. Ethnic and gender differences in bone and body composition suggest that the lean component may contribute to a greater peak bone mass in blacks vs. whites, and perhaps in males vs. females.

Cross-sectional geometry, bone strength, and bone mass in the proximal femur in black and white postmenopausal women

Osteoporosis is characterized by both a low bone mass and a disruption of the architectural arrangement of bone tissue, leading to decreased skeletal strength and increased fracture risk. Although there are well‐known ethnic differences in bone mass and fracture risk, little is known about possible ethnic differences in bone structure. Therefore, we studied cross‐sectional geometry in the hip in a sample of postmenopausal black and white women in order to investigate ethnic differences that might contribute to differences in bone strength and ultimately hip fracture risk. We recruited 371 postmenopausal black and white women who were entering the Womens Health Initiative (WHI) clinical trials in Detroit. Bone density measurements of the proximal femur were done by dual‐energy X‐ray absorptiometry (DXA) using a Hologic 1000 Plus bone densitometer. The DXA data were used for hip structure analysis, which treats the entire proximal femur as a continuous curved beam from the proximal shaft to the femoral neck. This permits the analysis of cross‐sectional geometric properties in two narrow regions corresponding to thin (5 mm) cross‐sectional slabs seen on edge. The results indicate significant ethnic differences in bone density, cross‐sectional geometry, and dimensional variables. Specifically, the black women have a significantly higher bone density in both locations (10.1% and 4.1% for the neck and shaft, respectively); greater cross‐sectional geometric properties in the neck (ranging from 6.1% to 11.6%), but a smaller endocortical diameter in the neck (3.6%). There are fewer significant differences in cross‐sectional geometry in the shaft location. Our data suggest that the spatial distribution of bone is arranged in the femoral neck to resist greater loading in black women compared with white women.

Calcium in evolutionary perspective.

The nutritional requirements of contemporary humans were almost certainly established over eons of evolutionary experience and the best available evidence indicates that this evolution occurred in a high-calcium nutritional environment. The exercise and dietary patterns of humans living at the end of the Stone Age can be considered natural paradigms: calcium intake was twice that for contemporary humans and requirements for physical exertion were also greater than at present. Bony remains from that period suggest that Stone Agers developed a greater peak bone mass and experienced less age-related bone loss than do humans in the 20th Century.

Effects of Ethnicity and Age or Menopause on Osteoblast Function, Bone Mineralization, and Osteoid Accumulation in Iliac Bone

We measured histologic indices of osteoblast function, bone mineralization, and osteoid accumulation separately on the cancellous, endocortical, and intracortical subdivisions of the endosteal envelope and on the combined total surface in transiliac biopsies obtained after double tetracycline labeling in 142 healthy women, aged 20–74 years, 34 who were black (19 pre‐ and 15 postmenopausal) and 108 white (42 pre‐ and 66 postmenopausal). The data were subjected to two‐way analysis of variance of the four groups defined by age/menopause and ethnicity. Also, linear regressions of selected variables on age and between functionally related but independently measured variables were examined. None of the interaction terms was significant, and none of the regression slopes on age differed between blacks and whites, indicating that, as for the previously reported structural and remodeling indices, the effects of ethnicity and of age/menopause are independent. Accordingly, the data were analyzed separately for the effects of ethnicity (pre‐ and postmenopausal combined) and age/menopause (blacks and whites combined). The analyses led to the following conclusions (1) Osteoid surface and volume were higher and adjusted apposition rate and osteoid mineralization rate lower in postmenopausal than in premenopausal subjects, but none of the indices of osteoid accumulation differed between blacks and whites. (2) Each index of osteoid accumulation was significantly correlated with its primary independently measured kinetic determinant (osteoid thickness with adjusted apposition rate, osteoid surface/bone surface with activation frequency, and osteoid volume/bone volume with bone formation rate/bone volume). None of the regression parameters differed significantly between blacks and whites. (3) The ratio of mineralizing surface to osteoid surface (MS/OS) was substantially lower in all demographic groups than could be accounted for by the later onset of mineralization than of matrix apposition at individual bone forming sites. (4) The low values for MS/OS can be explained by terminal mineralization being too slow to trap enough tetracycline molecules to produce detectable fluorescence, and do not require that mineralization be interrupted. (5) MS/OS was about 25% lower in blacks than in whites on all surfaces with corresponding differences in derived indices based on MS/OS, including adjusted apposition rate, mineralization lag time, and formation period. (6) The lower values for MS/OS in blacks are most likely due to slower terminal mineralization. This could not be accounted for by a lower serum level of calcidiol, but is consistent with the reported effect of reduced bone blood flow. (7) All differences in bone cell function between blacks and whites that we have observed could be the result of the ethnic, and presumably genetic, difference in bone accumulation during growth. Higher bone mass would result in less fatigue microdamage, less need for repair by directed bone remodeling, lower bone turnover, lower bone blood flow, and slower terminal mineralization. (8) If this explanation is correct, there are no fundamental differences in the biology of bone remodeling between ethnic groups.

Whole Body Bone, Fat, and Lean Mass in Black and White Men

This research describes the effects of age, ethnicity, and body size and composition on whole body bone mass and bone density in healthy black and white men. We measured 79 male subjects, 42 white and 37 black, ranging in age from 33 to 64 years. Whole body bone mineral content (WBBMC) and bone mineral density (WBBMD), as well as fat and lean mass, were evaluated with a Hologic 1000W bone densitometer. We explore the utility of different methods of controlling for variations in body size in the two ethnic groups. There are statistically significant ethnic differences only in the bone mass variables. The black men had a 15% higher WBBMC (3111 vs. 2712 g, p < 0.0001) and a 8% higher WBBMD (1.25 vs. 1.16 g/cm2, p = 0.001) than the white men. Dividing WBBMD by height reduced the black/white difference to 6%. WBBMC, WBBMC/height, and WBBMD are strongly and significantly correlated with weight, body mass index (BMI), and body composition; correlations tended to be lower for WBBMD/height. Age is not significantly correlated with any of the variables in either ethnic group (p ≥ 0.10). In multivariate linear regression models for predicting WBBMC or WBBMD, the two best models contained height, weight, and an interaction of ethnicity and weight (model r2 = 0.72 for WBBMC and r2 = 0.47 for WBBMD); and height, lean mass, and an ethnicity–fat interaction (model r2 = 0.69 for WBBMC and r2 = 0.46 for WBBMD). Using analysis of covariance, we found that controlling for lean mass and height reduced the black/white difference in bone mass from 14.7 to 9.8%.

Identification of women at risk for developing postmenopausal osteoporosis with vertebral fractures: role of history and single photon absorptiometry

Putative risk factors for the development of postmenopausal osteoporosis (PMO) with vertebral fractures were examined in a retrospective study of 663 postmenopausal white females aged 45-75 years (266 women with non-traumatic vertebral compression fractures (VF+), 134 non-fractured women from a general medicine clinic (controls) and 263 non-fractured women who were evaluated when they presented specifically for osteoporosis screening (VF-]. The VF+ women differed from control women in several respects. The VF+ group reported a higher prevalence of a positive family history of osteoporosis, and a higher prevalence of a history of medical or surgical conditions known to be independently associated with metabolic bone disease, had fewer children, were smaller (weight, height) and were slightly older. The two groups, VF+ and controls, did not differ with respect to cigarette smoking, alcohol consumption, exercise habits, menstrual or menopausal history, dietary intake of milk and cheese or in amount taking calcium supplements during pregnancy. The VF+ group also differed in certain respects from the VF- group. The VF+ group were smaller (weight, height) and were older. The VF+ group had lower cortical bone mass (measured by single photon absorptiometry of the non-dominant forearm) than either the control or VF- groups. The latter two groups did not differ from each other with respect to this measurement. These markers demonstrated limited sensitivity and specificity as estimated from a confirmatory data set, particularly for the historical and anthropometric variables. We conclude that an assessment of the risk of developing PMO with vertebral fractures cannot be based on the putative risk factors as measured in our study, but must be based on measurement of bone mass.

Interpretation of Absorptiometric Bone Mass Measurements in the Growing Skeleton: Issues and Limitations

There is growing awareness of the need to understand the pattern and timing and other factors that affect the accrual of peak bone mass. This interest has emanated from concern about the increasing prevalence of osteoporotic fractures in older age groups, especially the elderly. It is logical to look for ways to maximize peak bone mass in order to minimize the effect of later bone loss in adulthood. However, much of the necessary “homework” has yet to be done for designing and testing interventions in growing children and adolescents. This is due partly to the costs and difficulties associated with longitudinal studies, especially in children, but another major problem is one that is inherent in absorptiometric methods commonly used for estimating bone density. Single and dual-energy absorption methods (SPA/SXA and DPA/DXA) measure bone mass as bone mineral content (BMC). To adjust for body size differences among individuals, it is the conventional practice in adults to divide BMC by the area of the bone and express the result as areal bone mineral density (BMD). This does not take into account the depth or thickness of the bone, which cannot be determined by these absorptiometric methods. Nevertheless, BMD as a surrogate for true bone density has been shown to be useful in fracture prediction in adults [1]. In contrast, in children, the focus is not on predicting fractures but in documenting how and when peak bone mass is achieved, and what factors affect these phenomena. In children, unlike adults, the three-dimensional shape and size of bone (especially the ends of long bones) change dramatically during growth. Thus, a simple adjustment of BMC based on bone size in two dimensions (i.e., BMD) is an inadequate surrogate for bone density during growth, which somewhat limits the use of BMD as a reliable estimate of bone density in children. There are other bone mass measurement methods available that obviate some of the shortcomings of the single and dual energy (either photon or X-ray) absorption methods. For example, volumetric (three-dimensional) measurements of bone density by quantitative computed tomography (QCT) are available at some institutions [2], and have been used in a few studies of children [3, 4]. QCT’s usefulness is limited somewhat by cost and accessibility [5], and the conventionally used vertebral studies may involve more radiation than is desirable for infants and children. However, the ability to choose a region of interest of known volume within a vertebral body, while excluding regions that are changing shape during growth, offers significant advantages for assessing bone density during growth [5]. For example, Gilsanz et al. [4] used QCT in 150 African-American and white girls, ages 2–20, to describe changes in the cancellous bone density of the lumbar spine. A reasonable alternative to conventional QCT of the spine in children is peripheral QCT (pQCT) of the forearm [6], or femur [7], although there are only a few published studies of this application in children. Quantitative ultrasound (QUS) is a relatively new modality [2, 8] that is promising for use in children [9], having the advantage of not involving radiation. In addition, the ability to measure long bone shafts (e.g., tibia) by QUS would avoid the problem of adjusting for modeling changes in the epiphyseal regions of long bones commonly measured by SXA/DXA. (These comments apply also to SPA and DPA, the forerunners of the SXA/DXA methods, but the latter set of acronyms will be used generically for all four methods.) Despite the advantages of these other techniques, DXA has been and continues at present to be the most commonly used method for bone mass measurements and, more specifically, has been the method most often used for children [5]. There are many published pediatric studies utilizing SXA/DXA technology, compared with only a few using QCT/pQCT and QUS. A few of the published DXA studies are chosen to illustrate some of the issues and limitations involved in absorptiometric measurements of BMC and BMD in children. Recently, Liugi et al. [10] reported a DXA study of bone mass accumulation in fetal femora from 11.5 weeks to term. Their data affirm the knowledge of growth patterns in the femur and the normal mineralization (i.e., bone mass as BMC) of the fetal skeleton: the cortical shell forms first at the midshaft, longitudinal growth occurs at both ends of the femur (particularly the distal end), and mineralization occurs primarily during the third trimester. Given these uniCorrespondence to: D. A. Nelson, Rheumatology Division, Hutzel Hospital, 1 Lobby Center, 4707 St. Antoine, Detroit, MI 48201, USA Calcif Tissue Int (1999) 65:1–3

Menopausal changes in body composition and energy expenditure

Adult American women as a group tend to gain weight with age, and many women report that their weight gain started around the time of their menopause. Moreover, as women age, there are changes in body composition that include losses in bone mineral and body cell mass, and increases in total body fat, visceral fat, and extracellular fluid. It appears as if these body composition changes begin or accelerate during the menopausal years. The importance of weight gain and changes in body composition are their associations with an increased risk of developing some malignancies, cardiovascular disease, osteoporosis, and several other clinical conditions. This overview describes selected studies of menopause and aging-associated weight gain, changes in body composition, and alterations of energy expenditure in women. Gaps in the present understanding of these changes are highlighted, and an emphasis is placed on new research methodologies for investigating body composition and energy expenditure in vivo. A concluding section of the report summarizes areas in need of future investigation.