Modeling normal aging bone loss, with consideration of bone loss in osteoporosis.

A physiologically based model of normal bone loss in human aging is presented. The model is a modification of an existing physiologically based model of body and bone growth from birth to maturity. To account for loss of bone after peak bone mass is reached between ages 25 and 30 years, a slow first-order loss of bone is incorporated into the existing model. The rate constants for this first-order loss are the same for men and women but differ with the type of bone, being 3%/decade for cortical bone and 7-11%/decade for trabecular bone. In women, a 10-year period of more rapid loss of both cortical and trabecular bone is superimposed on the slow loss, beginning at the time of menopause. The superimposed loss occurs at the same relative rate in cortical and trabecular bone. Alterations in parameter values allow simulation of bone mass in osteoporotic men and women. The model is calibrated to quantitative estimates of cortical and trabecular bone mass as functions of age; in particular, to data sets of fractional vertebral bone volume as functions of age, and it is compared to the International Commission on Radiological Protection trend curves for skeletal mass in men and women to age 60. It is also applied to the question of whether loss of bone in women after menopause could create a hazard related to the return to blood of lead previously stored in bone. In agreement with observations made during 1976-1980, the model simulates an increase due to bone resorption of approximately 1 microg/dl in blood lead concentration in a postmenopausal (60-year-old) woman compared with a premenopausal (50-year-old) woman with typical lifetime ambient lead exposure.

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title: Quantitative computed tomography assessment of spinal trabecular bone. I. Age-related regression in normal men and women.
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title: Regional differences in bone density of young men involved in different exercises.
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title: Pathogenesis of osteoporosis.
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title: Determinants of bone density in normal women: risk factors for future osteoporosis?
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title: The Influence of Age, Height, and Weight on the Bone Mineral Content of Lumbar Vertebrae
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title: Bone mineral content of the lumbar spine in normal and osteoporotic women: cross-sectional and longitudinal studies.
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title: Rates of bone loss in normal women: evidence of accelerated trabecular bone loss after the menopause
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title: Age and activity effects on rate of bone mineral loss.
abstract: It has been postulated that the rate of mineral loss in postmenopausal women remains constant with aging and that the decreased activities of daily living associated with aging contribute to mineral loss. These hypothese were examined by measuring the bone mineral content at the midshaft of the radius with the photon absorption technique. The estimated rate of loss was calculated in a cross-sectional study as the regression coefficient of bone mineral content vs. age and in a longitudinal study as the regression coefficient of bone mineral content vs. time. In the cross-sectional study, Group A, which consisted of 264 women aged 50-72 yr, had an estimated rate of loss of -0.0114 +/- 0.0014 (SE) g/cm per yr. Group B, which consisted of 266 women aged 73-96 yr, had an estimated rate of loss of -0.0055 +/- 0.0017 g/cm per yr. In the longitudinal study, Group C consisted of 33 women aged 51-65 yr who were followed for an average of 4.5 yr with a mean number of 16 visits per subject; they were found to have a mean rate of loss of -0.00990 +/- 0.00107 g/cm per yr. Group D consisted of 38 women aged 70-91 yr who were followed for an average of 3.8 yr with a mean number of 31 visits per subjects; they were found to have a mean rate of loss of -0.00020 +/- 0.00236 g/cm per yr. The estimated and directly measured rates of loss were more rapid in the younger groups than in the older groups (A vs. B, P less than 0.001; C vs. D, P less than 0.001). These data demonstrate that the mean rate of mineral loss is not constant with aging and that in elderly subjects it is significantly slower than that of the earlier postmenopausal years. Since the elderly women were the less active, these findings suggest that factors other than decreased physical activity are more important in determining the rates of mineral loss.

title: On aging bone loss.
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title: Spine and femur density using dual-photon absorptiometry in US white women.
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title: Lead and osteoporosis: mobilization of lead from bone in postmenopausal women.
abstract: Although it has been known that humans accumulate lead in bone, mineralized tissue has been considered primarily as a sequestering compartment and not as a site of toxic action for lead. However, experimental data indicate that bone lead can be released during conditions of demineralization, such as pregnancy and lactation. We have examined lead status in women, before and after menopause, using the NHANES II dataset compiled between 1976 and 1980. In 2981 black and white women there was a highly significant increase in both whole blood and calculated plasma lead concentration after menopause. The results indicate that bone lead is not an inert storage site for absorbed lead. Moreover, lead may interact with other factors in the course of postmenopausal osteoporosis, to aggravate the course of the disease, since lead is known to inhibit activation of vitamin D, uptake of dietary calcium, and several regulatory aspects of bone cell function. The consequences of this mobilization may also be of importance in assessing the risks of maternal lead exposure to fetal and infant health.

title: Physiologically based models for bone-seeking elements. IV. Kinetics of lead disposition in humans.
abstract: A model of lead disposition in humans has been developed. In addition to liver, kidney, other well-perfused and poorly perfused tissues, the model incorporates bone as an explicit compartment whose volume, composition, and metabolic activity are all age-dependent. The rates of all transfers of lead out of the blood are related to plasma lead. The relationship between plasma lead and blood lead is expressed as a capacity-limited binding associated with the erythrocyte. Interchanges of lead between plasma and bone are modeled as partially interactive events linked in series. Blood traversing the bone passes first through a surface region of rapid exchange before entering the metabolically active region of bone, where lead is incorporated with calcium into mineralizing bone and returned to the blood with resorbing bone. After leaving the larger vessels, plasma superfusate enters the canalicules that feed bulk bone, where lead diffuses radially outward into the total bone volume. Model simulations are compared with data from epidemiologic and experimental dietary and inhalation studies in adults.

title: Physiologically based models for bone-seeking elements. V. Lead absorption and disposition in childhood.
abstract: A physiologically based model of lead absorption and disposition, previously developed and validated for adults, has been tested and calibrated for children. The model was modified to incorporate additional information on the age dependence of bone formation rate and to take into account increasing localization of bone modeling activity with age. A bone volume characterized by mature bone metabolic activity increases from zero at birth to the total bone volume by young adulthood. Bone formation rate is high from childhood through adolescence, with peaks at birth and around puberty. Bone resorption rate keeps pace at a rate that allows the orderly increase of bone mass. In general, the model reproduces childhood blood lead observations well, except in instances where lead is ingested at very high concentrations. Both bone and blood lead concentration are labile during early childhood because of the high rate of bone turnover. They respond rapidly to increases in lead exposure, and decrease almost as rapidly to near-preexposure concentrations when exposure returns to background levels. As the child grows, fractional bone formation and resorption rates decline and total bone lead turnover becomes more sluggish. From the time of peak bone mineralization rate in adolescence into early adulthood, the rate of bone turnover drops dramatically and the ability to reverse bone lead accumulation relatively rapidly is lost.

title: Physiologically based models for bone-seeking elements. III. Human skeletal and bone growth.
abstract: A model of skeletal and bone growth for the human from birth to maturity has been developed. Dry and hydrated bone, bone marrow, ash, and calcium are included in the model. Growth of the skeleton and its fractions is expressed as a set of allometric equations relating fraction volume or weight to body weight. Blood flow rates to mature bone and bone marrow are scaled from experimentally determined values in smaller animals, but bone and marrow volumes and growth patterns cannot be scaled directly from measurements or models in small animals. The growth model compares well with measured bone weights, ash weights, and bone and skeletal densities in humans. Its form is adaptable to physiologically based description of the kinetics of bone-seeking elements.

title: QUANTITATIVE MICRORADIOGRAPHIC STUDIES OF NORMAL AND OSTEOPOROTIC BONE.
abstract: Quantitative microradiography has been developed for studying bone turnover and has been applied to a study of normal and osteoporotic human bone. Evidence is presented that this method is reproducible and provides an accurate measure of bone formation and resorption. It was demonstrated that bone from the majority of osteoporotic patients differs from normal bone by an increase in the amount of resorption. Bone formation levels are generally normal; however, in Cushing's syndrome, after corticosteroid therapy, and after immobilization, bone formation decreases.

title: The microanatomy of trabecular bone loss in normal aging men and women.
abstract: Histomorphometric changes in normal bone were investigated using tissue from the ilium of 86 women and 98 men, aged 20-90 years. While loss of trabecular volume was common to both sexes, the histologic basis for the loss differed. Decreased formation (expressed primarily as static indices) seemed to be the principal factor in bone loss in men; in women these features remained unchanged, suggesting that increased resorption was the principal factor. Bone loss in women was principally attributable to the total removal of individual trabeculae; conversely in men, there was generalized attenuation of trabecular bone. Similar findings in bone tissues of vertebral bodies suggest that differences in bone remodelling between the sexes produce different patterns of bone loss as a sequence of aging.

title: Physiologically based models for bone-seeking elements. II. Kinetics of lead disposition in rats.
abstract: For toxicants with long residence times in the body, body burden is determined largely by exposure history rather than by current exposure. There is a need for physiologically based toxicokinetic models capable of integrating exposure over time by incorporating growth, development, and aging. Such a model is presented for lead kinetics in the growing rat from birth to adulthood. The model incorporates age dependence of the physiologic and metabolic processes that control lead distribution to bone and soft tissues, as well as age dependence of lead absorption from the gastrointestinal tract and age dependence of elimination of lead. The essential features of bone structure and metabolism are integrated into a framework that determines bone lead kinetics. Parameter values used in the model are taken from the literature or are estimated from the best visual fit of the model to data from chronic and short-term studies of lead exposure in rats. The model accommodates any pattern of lead exposure. The uptake of lead by bone varies with the age at which exposure occurs. The predictions of the model are compared with data from a chronic study in rats in which lead exposure was discontinued after exposure periods varying from 3 to 12 months.

title: Bone mass and its relationship to age and the menopause.
abstract: To examine the influence of age and the menopause on bone loss we studied 178 healthy women, aged 29-78 yr. Bone mass was measured at 2 forearm sites, in the total spine, in the lumbar spine, and in the whole body by single and dual photon absorptiometry. Women of the same age but different menopausal status had significantly different bone masses, whereas a 5-yr difference in age had no effect on bone mass in women with the same menopausal status. At the menopause the hormone changes (low serum estrogen and high serum gonadotropin levels) occurred simultaneously with the appearance of biochemical indices of increased bone turnover. Neither biochemical values nor bone measurements indicated significant bone loss before the menopause. We conclude that the menopause has a greater effect on bone loss than does chronological age.

title: Decreased trabecular width and increased trabecular spacing contribute to bone loss with aging.
abstract: Resistance to fracture depends not only on the total amount of trabecular bone but also on the size and distribution of the trabeculae. We used an image analysis computer to make direct measurements of trabecular width and separation in 33 normal subjects, aged 20 to 80 years. Multiple regression analysis showed that an increase in the distance between adjacent trabeculae accounted for 67.6% of the reduction in trabecular bone area in normal subjects with advancing age, with an additional 23.2% attributed to decreased trabecular width (P less than 0.001). The role of trabecular atrophy in the loss of bone with age was clearly established from the direct relationship between trabecular bone area and the independently measured trabecular width (r = 0.763, P less than 0.001). Effective treatment could increase trabecular bone by thickening the remaining trabeculae. It is, however, unlikely that treatment would replace trabeculae that have been removed or would restore biomechanical strength to the skeleton.

title: Age changes in bone mineralization, cortical thickness, and Haversian canal area
abstract: SummaryAge-related changes in femoral cortical bone were quantified in an age-graded series of human cadavers. Variables included in this study were cortical thickness, bone mineral content, cortical bone density, summed Haversian canal area, Haversian canal number, and mean Haversian canal area. Females showed significant (P<0.05) decreases in cortical thickness, bone mineral content, and cortical bone density when plotted against age. Males exhibited slight nonsignificant declines for cortical thickness, bone mineral content, and cortical bone density. Both males and females exhibited significant (P<0.05) age-related increases in summed Haversian canal area values and Haversian canal number. Females as a group were found to exhibit significantly (P<0.05) larger mean Haversian canal area values compared with males, but the male group exhibited more Haversian canals per unit area of cortical bone compared with females.Intercorrelations between the bone mineral index and summed Haversian canal area and between cortical bone density and summed Haversian canal area define the role of increasing Haversian canal number and mean canal size per unit area of cortical bone as a factor in the reduction of bone mass as a function of age. Partial correlations between the bone mass variables and the variables assessing Haversian canal size and number further support this argument.

title: High accuracy (stable isotope dilution) measurements of lead in serum and cerebrospinal fluid.
abstract: The concentration of lead in blood, serum, cerebrospinal fluid, and urine was measured in patients with neurological disease and in control subjects including cases of plumbism. A plot of blood lead versus serum lead resembles the familiar curves of blood lead versus either free erythrocyte porphyrin or urinary delta-aminolaevulinic acid in that serum lead is constant up to a blood lead concentration of 40 micrograms/dl (2 mumol/l) and rises steeply thereafter. The serum lead concentrations yield renal clearances in the range 5-22 ml/min in agreement with values obtained with radiolead on man and predicted from animal studies. The lead content of cerebrospinal fluid is consistently less than that of serum, averaging 50% of the serum concentration for blood leads of less than 20 micrograms/dl (1 mumol/l) but rising to 80-90% in cases of plumbism. Patients with motor neurone disease could not be distinguished from those with other neurological diseases on the basis of the lead content of their serum or cerebrospinal fluid.

title: Quantitative computed tomography for prediction of vertebral fracture risk.
abstract: Vertebral trabecular mineral content and peripheral cortical bone mineral were measured in 94 female and 44 male osteoporotic patients and compared to vertebral mineral values obtained for 323 control subjects in a cross-sectional study. The rate of change of spinal trabecular mineral with age (measured by quantitative computed tomography) in control females averaged 1.2% per year from age 20 to 80, with an accelerated loss demonstrated at the menopause. Trabecular bone mass in male controls declined an average 0.72% per year. Female osteoporotics had a mean decrement of 48 mg cm-3 (39%) compared to age-matched controls, whereas males were decreased 66 mg cm-3 (50%). Radial cortical bone was correlated with spinal mineral in osteoporotics for both males (r = 0.48) and females (r = 0.62). Vertebral compression fractures or wedging was generally absent in patients with vertebral mineral values above 110 mg cm-3, whereas almost all patients with values below 65 mg cm-3 had fractures. Quantitative computed tomography for measurement of vertebral trabecular bone mineral density is useful for defining those patients in whom the risk of vertebral fracture is increased.

title: Quantitative computed tomography assessment of spinal trabecular bone. II. In osteoporotic women with and without vertebral fractures.
abstract: Computed tomography was utilized to measure the bone mineral content of the spinal trabecular bone in 96 osteoporotic women. A significant overlapping was found between the values obtained for these patients and the age-matched normal values. Sixty-six percent had bone mineral content values below the fifth percentile for age-matched normals. Eighty-five percent of those with vertebral fractures had bone mineral content values below the fifth percentile for normal premenopausal women (fracture threshold). It is suggested that diagnosis of osteoporosis be made when the spinal bone mineral content value is below the fracture threshold.

title: Bone mass, bone structure and vertebral fractures in osteoporotic patients.
abstract: The clinical severity of bone disease was studied in 44 post-menopausal osteoporotic women. Spinal x-rays were assessed and compared to objective measurements of bone mass and bone structure; forearm bone mineral content (BMCarm) by single photon absorptiometry, total body bone mineral content (TBBM), and spinal bone mineral content (BMCspine) by dual photon absorptiometry, and corrected cortical width (C Cor W), trabecular bone volume (TBV), and indices of trabecular microstructure by iliac crest biopsy. For comparison data of BMCarm, TBBM and BMCspine in 25 post-menopausal normals are shown. The results showed a reduction in amount of both cortical and trabecular bone in the fracture patients compared to normals. A subdivision of the fracture patients into two groups constituting 26 patients with wedge fractures alone and 18 patients with compression (+wedge) fractures showed that the latter group had a further predominantly trabecular bone loss and a further deteriorated trabecular microstructure. On an individual basis no agreement between clinical severity of bone disease and amount and structure of bone could be demonstrated.

title: Effect of early menopause on bone mass in normal women and patients with osteoporosis.
abstract: Early menopause is widely regarded as a risk factor for osteoporosis. The aim of this study was to determine whether this risk is conferred by a lower bone mass.



Two hundred thirteen normal postmenopausal women and 55 women with postmenopausal osteoporosis (vertebral fractures) underwent bone mass measurements at the lumbar spine, femoral neck, and midshaft using dual-photon absorptiometry. To examine the effect of early menopause, postmenopausal normal women were stratified according to whether menopause occurred before or after the age of 50 years. Patients with osteoporosis were stratified in the same way.



Patients with osteoporosis had menopause at an earlier age than control subjects, but the difference in bone mass between the patients with osteoporosis and the control subjects could not be attributed to this earlier age at menopause. Furthermore, within the osteoporotic patient group, those with early menopause did not have lower bone mass than those with normal age at menopause. Similarly, within the normal subject group, those with early menopause did not have lower bone mass than those with normal age at menopause.



Patients with osteoporosis have lower bone mass, which is independent of the age at menopause. Although a small effect (less than or equal to 5 percent) of early menopause on bone mass cannot be entirely excluded, these data suggest that the amount of bone lost following menopause is the same irrespective of the age at which menopause occurs. If early menopause is a risk factor for osteoporosis, the risk is not conferred by a bone mass substantially lower than predicted had menopause occurred later, but may be related to the duration of exposure to minimal trauma at low bone mass.

title: Absolute and relative deficit in total-skeletal calcium and radial bone mineral in osteoporosis.
abstract: cium content of the skeleton in a group of 40 osteoporotic patients as measured by total-body neutron activation analysis (TBNAA). A highly significant correlation (0.826, p < 0.001 ) was found betweenthe bone mineralcontent of the radius (measured by absorptiometric tech nique) and total-body calcium (measured by TBNAA). However, the correlation was not as high as in the group of normal subjects (0.973, p < 0.001). In order to measure the relative deficit in total-body calcium in individual patients from the absolute calcium measurement, it was nec essary to normalize the data for sex, age, and skeletal size. For this purpose an algorithm was used to predict the normal skeletal calcium in each subject based on lean-body mass, height, sex, and age. In the female osteoporotic group the mean normalized total-body calcium ratio was 0.82 compared with a mean value of 1.00

title: Ethnic and genetic differences in bone mass: a review with a hereditary vs environmental perspective.
abstract: Based on a review of the literature, ethnic and genetic factors are significant determinants of bone mass, along with such environmental factors as diet and exercise. Differences in bone density between blacks and whites remain even after adjustment for body mass. Black-white differences in bone mass appear to be related to ethnicity because blacks have not only greater skeletal calcium content, but also greater total body potassium and muscle mass. Genetic studies of twins and parent-offspring pairs reflect strong constitutional associations of both bone mineral content and bone density at commonly measured skeletal sites. At least for females, bone mass accumulation by age 20 y is highly associated with maternal bone mass; up to menopause it is enhanced by child-bearing and lactation; beyond menopause environmental factors seem to dominate. Dietary calcium and physical activity are significant in the control of bone mass. These findings are important for osteoporosis and fractures, especially in elderly people.

title: Familiality and partitioning the variability of femoral bone mineral density in women of child-bearing age
abstract: SummaryThe contributions of polygenic loci and environmental factors to femoral bone mineral density (BMD in g/cm2) variability were estimated in modified family sets consisting of women of child-bearing age. Femoral BMDs were measured in 535 women who were members of 137 family sets consisting minimally of an index, her sister, and unrelated female control. The family set could also include multiple sisters and first cousins. Women included in these family sets were all between 20 and 40 year of age to minimize the cohort effects of maturation and menopause on measures of BMD. BMDs were measured at three femoral sites using dual photon densitometry. Values were regressed on age and Quetelet Index which explained 13–15% of the variability in BMD (dependent on site). Subsequent variance components analysis on the residuals indicated that unmeasured polygenic loci accounted for substantial additional variability: 67% for femoral neck, 58% for Wards triangle, and 45% for trochanter. These results suggest that polygenic loci account for approximately half of the variability in maxmal femoral BMD.

title: Sex differences in age-related changes in vertebral body size, density and biomechanical competence in normal individuals.
abstract: Size, ash-density and biomechanical competence were investigated on whole vertebral bodies (L2) from 90 normal individuals (47 males and 43 females), aged 15-91 years. At all ages, cross-sectional area was significantly greater in males than in females. Furthermore, in males a significant increase of 25-30% in cross-sectional area was demonstrated with aging (r = 0.33, p less than 0.05). Conversely, no age-related change in cross-sectional area was detected in females (r = 0.03, n.s.). A significant and identical age-related decrease (p less than 0.001) in apparent ash-density was found for both males and females. Biomechanical compression tests revealed significant and identical decreases (p less than 0.001) in vertebral body load and stress with age in both males and females. However, because of their greater cross-sectional area and an increase in this with age, the level for the load-values was higher in men than in women up to the age of 75 years (p less than 0.05). The present study has demonstrated that in men there is a significantly greater cross-sectional area and a significant increase in vertebral body size, due to continuous periosteal growth. This could, to some extent, compensate for the unavoidable loss of vertebral bone density and stress with age. No age-related compensatory mechanism could be demonstrated in women.

title: Spine and femur density and broadband ultrasound attenuation of the calcaneus in normal Spanish women
abstract: SummaryBone density of the spine and femoral neck and broadband ultrasound attenuation of the calcaneus were measured in 111 normal Spanish women between the ages of 30 and 70 years. The cross-sectional study showed that spine and hip density decreased by 36 and 29%, respectively, and the ultrasound attenuation value decreased by 32% between 30 and 70 years of age. The rate of bone loss at the three sites was significant in women over age 50 and in postmenopausal women. These normative data will be helpful in assessing bone mass in Spanish women suspected of having osteoporosis.