Trabecular Sites Research Articles

Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study.

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46+/-4 years (mean +/- SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (- 6.6%) as well as at the femoral neck (-7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46+/-4 years (mean +/- SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below -2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by -3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation.

Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen.

Although alfacalcidol has been widely used for the treatment of osteoporosis in certain countries, its mechanism of action in bone, especially in the vitamin D-replete state, remains unclear. Here we provide histomorphometric as well as biochemical evidence that alfacalcidol suppresses osteoclastic bone resorption in an ovariectomized rat model of osteoporosis. Furthermore, when compared with 17beta-estradiol, a representative antiresorptive drug, it is evident that alfacalcidol causes a dose-dependent suppression of bone resorption, and yet maintains or even stimulates bone formation, as reflected in increases in serum osteocalcin levels and bone formation rate at both trabecular and cortical sites. 17beta-Estradiol, which suppresses bone resorption to the same extent as alfacalcidol, causes a parallel reduction in the biochemical and histomorphometric markers of bone formation. As a final outcome, treatment with alfacalcidol increases bone mineral density and improves mechanical strength more effectively than 17beta-estradiol, with a more pronounced difference in cortical bone. We conclude that estrogens depress bone turnover primarily by suppressing bone resorption and, as a consequence, bone formation as well, whereas alfacalcidol "supercouples" these processes, in that it suppresses bone resorption while maintaining or stimulating bone formation.

Cross-sectional and longitudinal assessment of pre- and postmenopausal bone loss with a portable forearm X-ray device: The Ofely study

The aim of our study was to describe cross-sectional and longitudinal bone mineral decrease in pre-, peri-, and postmenopausal healthy women using a monoenergy X-ray densitometer specifically designed for forearm assessement. Measurements were performed on the most distal part of the radius (ultradistal, 55% of trabecular bone and 45% of trabecular bone), and on the distal part (distal, 13% of trabecular bone and 87% of cortical bone). A specific trabecular-rich region of interest (nROI) comprising two trapezoids regions of interest located proximally to the endplates of the radius and ulna was also investigated. From a large prospective study (OFELY study), 455 women were measured once a year for 2 years (three measurements). The proportion of postmenopausal women classified as having osteoporosis (i.e., a T score <−2.5) was 33% for the distal region, 44% for the ultradistal region, and 45% for the nROI. No significant bone mineral decrease was found over the 2-year period in premenopausal women (n = 138). In perimenopausal (n = 48) women, a bone loss of 1% was found at the distal site. In the 269 postmenopausal women, a significant decrease was observed at all sites, ranging from 2.14% for the nROI to 2.68% for the ultradistal part. Bone loss was greater in the first 5 years after menopause in trabecular sites and decreased thereafter. For the distal site, bone loss remained stable during the postmenopausal period. We conclude that this small and portable forearm densitometer is suitable for the diagnosis of osteoporosis, and provides information on the rate of bone loss in peri- and postmenopausal women in trabecular and cortical compartments of bone.

Differential effects of menopause and metabolic disease on trabecular and cortical bone assessed by peripheral quantitative computed tomography (pQCT).

The usefulness of peripheral quantitative computed tomography (pQCT) was investigated in the diagnosis of metabolic bone diseases, including osteoporosis, and especially in the different diagnostic values in trabecular and cortical components. The subjects were 460 Japanese women aged 20-86 years, including 318 healthy volunteers, 58 osteoporotics with fracture and 84 patients with diseases including amenorrhoea, steroid-induced osteoporosis, renal osteodystrophy (ROD) and primary hyperparathyroidism. Bone mineral density (BMD) was measured for more than 4 years in 74 of the healthy volunteers. BMD was measured by spinal QCT, dual X-ray absorptiometry (DXA) of the spine, radius, and heel, and pQCT of the radius and tibia. High resolution images were obtained for geometry of the radius. Radial pQCT showed a higher correlation with radial DXA than with spinal QCT, and spinal QCT showed a higher correlation with spinal DXA than with radial pQCT. The annual bone loss rates at predominantly trabecular bone sites were accelerated in both the axial and appendicular skeleton. In the fracture study, radial pQCT showed a higher odds ratio (OR = 4.4) than radial DXA, and cortical area ratio seemed to be a good predictor of fracture risk (OR = 5.2). Amenorrhoea and steroid-induced osteoporosis predominantly affected trabecular bone, ROD predominantly affected cortical bone and hyperparathyroidism affected both components, especially the cortical component. pQCT is useful for assessing both trabecular and cortical bone, to provide information on individual bone changes in metabolic bone disease and to estimate the risk of fracture.

Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?

The role of nutritional influences on bone health remains largely undefined because most studies have focused attention on calcium intake. We reported previously that intakes of nutrients found in abundance in fruit and vegetables are positively associated with bone health. We examined this finding further by considering axial and peripheral bone mass and markers of bone metabolism. This was a cross-sectional study of 62 healthy women aged 45-55 y. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck and by peripheral quantitative computed tomography at the ultradistal radial total, trabecular, and cortical sites. Bone resorption was calculated by measuring urinary excretion of pyridinoline and deoxypyridinoline and bone formation by measuring serum osteocalcin. Nutrient intakes were assessed by using a validated food-frequency questionnaire; other lifestyle factors were assessed by additional questions. After present energy intake was controlled for, higher intakes of magnesium, potassium, and alcohol were associated with higher total bone mass by Pearson correlation (P < 0.05 to P < 0.005). Femoral neck BMD was higher in women who had consumed high amounts of fruit in their childhood than in women who had consumed medium or low amounts (P < 0.01). In a regression analysis with age, weight, height, menstrual status, and dietary intake entered into the model, magnesium intake accounted for 12.3% of the variation in pyridinoline excretion and 12% of the variation in deoxypyridinoline excretion. Alcohol and potassium intakes accounted for 18.1% of the variation in total forearm bone mass. The BMD results confirm our previous work (but at peripheral bone mass sites), and our findings associating bone resorption with dietary factors provide further evidence of a positive link between fruit and vegetable consumption and bone health.

Bone mineral density in sixty adult patients with Marfan syndrome.

Sixty adult patients (40 women, 20 men) with Marfan syndrome (MFS) according to the Berlin criteria had a full clinical examination and bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry of the hip and nondominant forearm. BMD was expressed as a Z-score and compared with the reference population of the Hologic database. In MFS men, BMD (g/cm(2)) was compared with the BMD of 45 normal tall Caucasian adults. Osteocalcin was measured by radioimmunoassay. In patients with MFS, BMD was compared between patients with and without previous fractures and according to the phenotypic severity of MFS. The mean age of the patients was 32.9 +/- 9.3 years (women 32.5 +/- 9.7, men 33.4 +/- 8.6), mean height was 180.3 +/- 10.3 cm (women 176.3 +/- 9.2, men 188.1 +/- 7.5) and mean body mass index 20.9 +/- 3.6 kg/m(2) (women 20.8 +/- 3.4, men 20.95 +/- 3.97). Hyperlaxity score (Beighton criteria) was 6.9 +/- 1. 1. Six patients (10%) had a previous fracture. Thirty per cent of patients had had at least one previous operation for scoliosis, aortic dilatation or eye problems. BMD values in the 60 patients were as follows: Z-score of the hip, -1.26 +/- 0.93, p<10(-9) (neck, -0.93 +/- 1.09, p<10(-9); trochanter, -1.31 +/- 0.85, p<10(-9); intertrochanter, -1.39 +/- 0.99, p<10(-9); Ward's triangle, -0.93 +/- 1.88, p<10(-9)); Z-score of the radius: -1.6 +/- 1.06, p<10(-9) (1/3 proximal, -1.29 +/- 1.03; mid-radius, -1.94 +/- 1.04; ultradistal, -0.68 +/- 1.1, p<10(-9)). The decrease in BMD was similar in men and women at both the hip and the radius. BMD in MFS patients was significantly decreased at cortical compared with trabecular sites (radius 1/3 proximal vs ultradistal, p<0.0001; total femur vs Ward's triangle, p<0.0005). No difference in BMD was found between MFS patients with or without previous fractures and those with severe or less severe phenotypic expression of MFS. An influence of height and weight in MFS on BMD is suspected. Osteocalcin was not increased in our group of MFS patients. Thus both men and women with MFS have a significant deficit of BMD at the hip and radius. The decrease in BMD is present equally in both sexes and is more pronounced at predominantly cortical sites. In our group of patients we found no increase in fractures and no relation between decreased BMD and phenotypic expression of the syndrome.

Human lead metabolism: Chronic exposure, bone lead, and physiological models

Exposure to lead is associated with a variety of detrimental health effects. After ingestion or inhalation, lead may be taken up from the bloodstream and retained by bone tissue. X‐ray fluorescence was used to make in vivo measurements of bone lead concentration at the tibia and calcaneus for 367 active and 14 retired lead smelter workers. Blood lead levels following a labor disruption were used in conjunction with bone lead readings to examine the endogenous release of lead from bone. Relations between bone lead and a cumulative blood lead index differed depending on time of hiring. This suggests that the transfer of lead from blood to bone has changed over time, possibly as a result of varying exposure conditions. A common polymorphism in the δ‐aminolevulinate dehydratase (ALAD) enzyme may influence the distribution of lead in humans. Blood lead levels were higher for smelter workers expressing the more rare allele. Bone lead concentrations, however, were not significantly different. This implies that a smaller proportion of lead in blood is distributed to tissue for individuals expressing the allele. The O'Flaherty physiological model of lead metabolism was modified slightly and tested with input from the personal exposure histories of smelter workers. The model results were consistent with observation in terms of endogenous exposure to lead and accumulation of lead in cortical bone. Modeling the calcaneus as a trabecular bone site did not reproduce observed trends. Variations in lead metabolism between different trabecular sites may therefore be significant. The model does not incorporate a genetic component, and its output did not reflect observed differences in this respect. This result provides further support for the influence of the ALAD polymorphism on lead metabolism. Experimental trials with a digital spectrometer revealed superior energy resolution and count throughput relative to the conventional x‐ray fluorescence system. The associated reduction in the uncertainty of lead measurement has the potential to benefit future surveys and modeling efforts.

The Addition of a Raloxifene Analog (LY117018) Allows for Reduced PTH(1–34) Dosing During Reversal of Osteopenia in Ovariectomized Rats

To test the hypothesis that an antiresorptive agent might reduce the dosing requirement for an anabolic drug during reversal of osteopenia due to estrogen deficiency, the following experiment was conducted in 6-month-old female rats. Ovariectomy or sham surgery was performed and the following six experimental groups were studied. Untreated (SHAM) or ovariectomized (OVX) animals served as control groups. Four weeks post-OVX, osteopenic rats (now 7 months old), were treated in one of four experimental protocols: human parathyroid hormone (hPTH(1-34)), 80 microg/kg/day, given by subcutaneous injection 5 days/week; a selective estrogen receptor modulator (SERM), raloxifene analog LY117018 (RA), 3 mg/kg/day, given by gavage 5 days/week; and two combinations of LY117018 at the same dose and frequency with hPTH(1-34) (same dose, 5 times/week) and a reduced dosing interval of hPTH(1-34) (same dose, 2 times/week). After 12 weeks of treatment, the four experimental groups were sacrificed at age 10 months. SHAM and OVX controls were also studied at 7 and 10 months of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at four skeletal sites: two mixed cortical/trabecular sites (femur and tibia) and two predominantly trabecular sites (lumbar spine and pelvis). The differences in BMD were consistent at all four sites. RA alone maintained BMD at all skeletal sites, but the results were not significantly improved over OVX controls, at age 10 months. hPTH(1-34) injections given 5 days/week resulted in BMD increments significantly higher than in either OVX or SHAM controls (p < 0.001). While the RA did not enhance the anabolic effects of full doses of hPTH(1-34), the addition of RA treatment to twice-weekly hPTH(1-34) dosing resulted in BMD increments at all four skeletal sites that were similar to the more intensive anabolic regimen of hPTH(1-34) therapy given 5 times/week. Therefore, an antiresorptive agent such as SERMs may potentially reduce the pharmacologic doses of PTH needed to reverse estrogen deficiency-induced osteopenia.

LY353381 x HCl: an improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34).

LY353381 x HCl is a benzothiophene analog that is structurally related to raloxifene with potent selective estrogen receptor modulator activity in the ovariectomized rat model of postmenopausal osteoporosis. The effects of LY353381 x HCl on bones, body weight, and uterine weight were evaluated in 7-month-old rats with osteopenia that was induced by ovariectomizing animals for 1 month before initiation of treatment with several agents individually, in combination, or in sequence. LY353381 x HCl was administered daily by itself for 90 days, in combination with the amino-terminal fragment of PTH-(1-34) (PTH) for 90 days, or sequentially after PTH when PTH was discontinued after 45 days of treatment. Additionally, comparisons were made of animals treated with PTH alone, 17alpha-ethynyl estradiol alone, equine estrogens (Premarin) alone, raloxifene alone, or combinations of PTH and equine estrogens or raloxifene. Ovariectomy induced increases in the rate of bone turnover and body weight while decreasing bone mineral density, bone mineral content, bone strength, trabecular bone volume, trabecular thickness, trabecular number, and uterine weight. LY353381 x HCl at 0.01-1 mg/kg had marginal effects on body weight and no effect on uterine weight compared with those in ovariectomized controls, in contrast to 17alpha-ethynyl estradiol or equine estrogens. LY353381 x HCl prevented further bone loss due to ovariectomy in tibia, femora, and lumbar vertebra, like 17alpha-ethynyl estradiol but unlike equine estrogens. LY353381 x HCl prevented the resorption of trabecular bone spicules, like 17alpha-ethynyl estradiol, but inhibited bone formation activity to a lesser extent than 17alpha-ethynyl estradiol. In this model, 17alpha-ethynyl estradiol appeared to be more efficacious after 3 months of treatment than equine estrogens in the proximal tibia metaphysis, suggesting efficacy differences between metabolites of 17beta-estradiol in bone. PTH at 10 microg/kg had no effect on body weight or uterine weight, but significantly increased bone mass to beyond those in sham-operated controls, baseline controls, and groups receiving other individual treatments at both axial and appendicular sites. The combination of LY353381 x HCl and PTH increased bone mass at a faster rate and to a greater extent than PTH alone or the combinations of equine estrogens/PTH and raloxifene/PTH at trabecular bone sites. The LY353381 x HCl/PTH combination improved bone mass and quality beyond any agent alone in regions enriched for cancellous bone, but was not significantly better than PTH alone on cortical bone. Additionally, when PTH was discontinued at 45 days, LY353381 x HCl prevented the rapid loss of bone observed in controls. Therefore, LY353381 x HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women.

Quantitative bone mineral assessment at the forearm: a review.

Bone mineral density and geometric properties of the human forearm can be measured to determine the amount of bone or bone loss at the scanning site and to predict the risk of forearm fractures. These forearm measurements are also used to estimate bone mass at remote anatomical locations and thereby estimate the risk for spine, hip and other fractures. The peripheral location of the human forearm, with its relatively small amount of surrounding soft tissue, improves the accuracy and the precision of bone mass measurement and has made this site an early choice for the assessment of a subject's bone mineral status. Furthermore, the anatomy of the human radius enables the examination of both cortical and cancellous bone. This review describes the procedures for non-invasive bone assessment at peripheral sites including some of the more recently developed systems dedicated to assessment of the distal radius. The accuracy, precision and normative values they provide are presented. Responses to different forms of therapies as well as the ability to discriminate or predict osteoporotic fractures are also assessed. Low radiation dose, comfortable and fast handling, moderate cost, and a strong association with the risk of non-spine fractures, promote the use of forearm scanning as a widely applied screening procedure for the detection of generalised osteoporotic bone loss. However, a higher accuracy of fracture risk prediction at the spine or at the hip can be achieved by a direct bone density measurement at these sites. The monitoring of treatment at the distal forearm appears to require a longer follow-up time due to its decreased responsiveness compared with such highly trabecular load-bearing sites as the spine and the proximal femur.

Turner Syndrome and Osteoporosis: Mechanisms and Prognosis

Despite only limited reports of a greater number of fractures during childhood or adulthood, osteoporosis historically has been described as a feature in Turner syndrome, because of the frequent observation of radiographic osteopenia and the coarse trabecular pattern of the carpal bones on radiographs. The pathogenesis of the skeletal demineralization remains unclear, but the data support the concept of an intrinsic bone defect that is then exacerbated by a number of hormonal factors, including the growth-regulating hormones, the gonadal steroids, and possibly the calcium-regulating hormones. The advent of more refined methods, such as single- and dual-photon absorptiometry and dual energy x-ray absorptiometry, has led to improved insights into bone mineral density (BMD) status in Turner syndrome (TS). A major limitation of these projection methods is that they report areal and not true volumetric BMD, resulting in an underestimation of the true BMD in smaller subjects. In assessing BMD in TS, various methods have been used to eliminate the confounding effect of bone size. Some consistent patterns do emerge in persons with TS who are not treated with long-term growth hormone (GH) or estrogen therapy. A significant deficit in cortical bone commonly appears in childhood and usually is associated with a low bone-turnover state. Significant osteopenia at predominantly trabecular sites develops during mid- to late adolescence and persists into adulthood, when it is associated with increased bone turnover. Preliminary BMD data on patients after long-term GH therapy show an absence of osteopenia. With respect to the impact of long-term estrogen therapy, the BMD deficit in adults with TS who have been treated adequately with estrogen, but who have not been treated with GH, is less than it is in those who have been insufficiently treated or not treated at all with estrogen. The available data indicate that long-term GH treatment during the prepubertal and early to midpubertal years optimizes BMD and improves the prognosis for adequate peak bone mass being achieved after a puberty that, most often, has been induced with exogenous estrogen. Long-term treatment with estrogen and progestin that is initiated during mid- to late adolescence and is continued throughout adulthood appears necessary for a normal peak bone mass to be achieved and the BMD to be preserved well beyond the time of peak bone mass. Additional measures to prevent osteoporosis must be used, such as ensuring adequate calcium intake and ample weight-bearing activities, focusing on preventing injuries and avoiding overtreatment with thyroid hormones. Long-term surveillance with measurement of BMD and of bone turnover in a large TS population into their later adult years is necessary before it can be concluded that the osteopenia observed in TS is a nonprogressive asymptomatic bone defect of no clinical consequences.

Localization of estrogen receptor-alpha in human and rabbit skeletal tissues.

Estrogen is essential for the development and maintenance of optimal bone mass in women and men, and acts through activation of estrogen receptors (ER). We have examined the pathways of estrogen action on the skeleton by seeking to localize the "classical" estrogen receptor, ER alpha, to particular cells to test the hypotheses that 1) estrogen directly influences growth plate chondrocytes; and 2) estrogen has a principal action on bone tissue via osteoblasts. ER alpha messenger ribonucleic acid (mRNA) was localized by in situ hybridization in human specimens from five males (11-15 yr old), two females (9 and 11 yr old), and three growing rabbits. In all of the human material examined, ER alpha mRNA was consistently identified in chondrocytes. In all of the rabbit tissue studied, ER alpha mRNA was localized in chondrocytes of the growth plate and the subarticular epiphyseal growth center. ER alpha mRNA signals were readily observed in both active osteoblasts and lining cells on trabecular surfaces of all samples. No clear evidence of positive staining was detectable in osteoclasts or osteocytes in either species. The distribution of ER alpha mRNA coincided with immunolocalization of the ER protein in the human specimens. These data suggest a direct action of estrogen on growth plate chondrocytes that may affect longitudinal growth and subsequent fusion of the growth plate and also on osteoblasts to affect bone formation at trabecular sites.

Low bone mass and high incidence of fractures after successful simultaneous pancreas-kidney transplantation.

Simultaneous pancreas-kidney transplantation successfully restores normoglycaemia and corrects uraemia in insulin-dependent diabetes mellitus patients with end-stage renal failure due to diabetic nephropathy. Low bone turnover and cortical osteopenia are often associated with the diabetic state and corticosteroid-induced bone loss, predominantly trabecular, is expected post-transplantation. Little is known, however, about the resultant long-term effects of successful simultaneous pancreas-kidney transplantation on bone mass and consequent fracture rate. We studied bone and mineral metabolism, bone densitometry (using dual X-ray absorptiometry), and fracture prevalence in a cross-sectional design in 31 IDDM patients at least 12 months (mean 40+/-23 months) after successful simultaneous pancreas-kidney transplantation. All patients were insulin-independent and mean creatinine clearance was 64 +/- 21 ml/min. Secondary hyperparathyroidism, probably multifactorial, was found in 55% of the patients. Increased bone turnover as suggested by elevated osteocalcin concentrations was present in 45% of the patients. Twenty-three per cent of patients had a significant decrease in bone mass (T score < -2.5 SD) at the predominantly trabecular lumbar spine sites. In contrast, 58% demonstrated a similarly low bone mass at the femoral neck, where cortical bone is prevalent. Forty-five per cent of patients had documented vertebral (mostly asymptomatic) and non-vertebral fractures. Our findings suggest that low bone mass is prevalent after successful simultaneous pancreas-kidney transplantation, and that this is associated with a high incidence of fractures, representing a cause for concern with regard to long-term morbidity. Contrary to the predominant trabecular bone loss expected with corticosteroid excess, cortical bone loss was prevalent in our patients, possibly due to pre-existing diabetic state and persistent hyperparathyroidism.

Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats.

For the first time, PTH (1-34) was found to significantly affect bone quality, femora length, and body weight of aged, ovariectomized rats. Specifically, we examined the effects of biosynthetic human PTH (1-34) in 9 month-old rats that were ovariectomized and dosed for the ensuing 6 months with 8 or 40 microg/kg PTH. Bone content, architecture, and quality of axial and appendicular skeletal sites were analyzed by computed tomography (QCT), histomorphometry, and biomechanical testing. The large sample size (n = 26-35) of this study was useful in confirming the anabolic, dose-dependent effects of PTH at trabecular and cortical bone sites. Longitudinal analysis of tibias by QCT confirmed a small age-dependent reduction in bone density, with further reductions observed for ovariectomized controls (OVX). Subtle but deleterious effects of ovariectomy on bone quality are described. Additionally, the strength of the femoral neck was shown not to differ between baseline, sham-operated controls, or OVX in this model, suggesting limited utility of this measurement in aged rats. Both doses of PTH induced substantial gains above OVX, in bone mass and connectivity for the proximal tibia, distal femur, proximal femur, and spine. Ovariectomy significantly decreased the toughness of vertebral bone. However, PTH at 8 microg/kg reversed this deleterious effect on bone quality, while 40 microg/kg PTH significantly improved both toughness and brittleness beyond baseline controls. Cortical bone analyses at the femoral or tibial diaphysis confirmed the PTH stimulation of endosteal and periosteal bone formation with resulting increase in cortical thickness, moment of inertia, strength, and stiffness of the femur. PTH treatment significantly improved the intrinsic properties, Young's modulus and toughness, of the femur compared with OVX. At 40 microg/kg PTH, bone mass and strength were typically greater than sham or baseline controls, confirming that PTH is functionally anabolic at trabecular and cortical bone sites. Interestingly, PTH dose-dependently increased the femora length, in the absence of differences between baseline, sham, and OVX controls. PTH slightly increased body weight above OVX. In addition, PTH did not interfere with the beneficial effects of ovariectomy on rat longevity.

Comparison of Human Osteoblasts and Osteogenic Cells from Heterotopic Bone

Heterotopic ossification is a common complication in which bone develops in soft tissues. Although frequently benign, in some patients the condition becomes painful, restricts motion, and requires surgical intervention. This condition and the cells responsible for it are poorly characterized. Using cell culture techniques, this study compares the performance of osteogenic cells obtained from heterotopic ossification with trabecular osteoblasts isolated from the same patient. Cells isolated from trabecular bone samples and heterotopic ossification sites from six patients were evaluated for osteocalcin production after exposure to 1,25-dihydroxycholecalciferol, alkaline phosphatase activity, typing and synthesis of collagen, cell proliferation, and total protein content. Samples of heterotopic ossification and trabecular bone from three of the patients were examined histologically. Heterotopic ossification derived cells were shown to produce osteocalcin, Type 1 collagen, and alkaline phosphatase activity. They also had increased rates of collagen synthesis, alkaline phosphatase activity, and cell proliferation compared with the normal osteoblasts. Initial tissue from the heterotopic ossification sites showed increased numbers of osteocytes/mm2 compared with normal trabecular bone. Although heterotopic ossification derived cells functioned qualitatively like osteoblasts, they exhibited elevated levels of activities traditionally ascribed to osteoblasts, such as collagen synthesis and alkaline phosphatase activity.

Anthropometric, Lifestyle and Menstrual Factors Influencing Size-Adjusted Bone Mineral Content in a Multiethnic Population of Premenopausal Women

We report associations of anthropometric, lifestyle and menstrual characteristics with peak bone mass in a multiethnic population of premenopausal women, ages 25–34 y. Four bone sites were examined: the spine, calcaneus, and distal and proximal radius. Body mass index (BMI) was positively associated with bone mass at the spine and calcaneus, the two most trabecular sites. The calcaneus, in addition, was positively associated with an index of calf muscle mass. The distal radius was associated with an arm muscle index, grip strength and the intensity of menstrual flow (light, moderate or heavy). Menstrual flow was also associated with spine bone mass in models not adjusted for BMI; light flow was an indicator of low distal radius or spine bone mass. We hypothesize that light flow may indicate a lack of regular ovulation. The cortical proximal radius was positively associated with milk consumption and height. The magnitude of associations varied by exposure and bone site. Among the strongest associations were BMI at the spine and calcaneus (4 and 7% differences in bone mass per standard deviation), and menstrual flow at the distal radius (a 7% difference between light and heavy menstrual flow). Ethnicity was not statistically significant in multivariable models at any of the four bone sites. However, the prevalence of exposures associated with bone mass varied substantially among the ethnic groups. Ethnic differences in bone mass may have derived indirectly through differences in exposure histories. Other influences of skeletal development may also occur indirectly. Sports activity during adolescence, for instance, was not an independent predictor of bone mass, but sports activity was associated with both strength and muscle mass. Our results suggest that many factors influence peak bone mass, and that the factors vary in importance by skeletal region, possibly related to bone composition and the local intensity of exposure.

Trabecular and endocortical bone surfaces in the rat: modeling or remodeling?

There is conflicting evidence as to whether bone resorption and bone formation are coupled in the site-specific manner that is typical of bone remodeling in the rat. The aim of this study was to elucidate this controversy further by analysis of tibial and vertebral cancellous and endocortical bone in rats of different age groups with a combination of in vivo fluorochrome labeling with cement line staining. After multiple in vivo fluorochrome labeling, groups of female Fischer-344 rats were killed at 3, 6, 9, and 12 months of age, and the first lumbar vertebrae and the proximal tibiae were processed undecalcified for bone histomorphometry. By comparing fluorochrome labeling and the contour of cement lines in serial sections, cancellous and endocortical bone formation sites were classified as "remodeling," "modeling," or "uncertain." In vertebral cancellous bone, remodeling was the main turnover activity in all age groups, increasing from 70.4 +/- 2.2% (mean +/- SEM) in 3-month-old rats to 91.0 +/- 2.4% in 12-month-old rats. The percentage of modeling sites decreased from 17.1 +/- 1.7% at age 3 months to 4.67 +/- 1.84% at age 12 months. In the proximal tibial metaphysis of 3-month-old rats, 61.6 +/- 3.6% of all trabecular bone-forming sites were classified as modeling and 21.1 +/- 3.1% as remodeling sites. In the 12-month-old rats, 66.3 +/- 3.4% were classified as remodeling and 16.0 +/- 3.1% as modeling sites. A similar trend toward augmented portions of remodeling with increasing age was observed in tibial and vertebral endocortical bone-formation sites. The present study suggests that, similar to higher mammals, the prevailing activity in vertebral and tibial cancellous bone of aged rats is remodeling. In the rapidly growing proximal tibia of 3-month-old rats, however, most of the cancellous bone-forming sites were minimodeling sites.

A multicenter study of the influence of fat and lean mass on bone mineral content: evidence for differences in their relative influence at major fracture sites. Early Postmenopausal Intervention Cohort (EPIC) Study Group

We examined the relative influence of fat and lean mass on bone mineral content (BMC) among 1600 early postmenopausal women aged 45-59 y from four geographical locations (Nottingham, United Kingdom; Portland, OR; Honolulu; and Copenhagen). Bone sites investigated included the major fracture sites: hip, spine, and radius. Body weight had strong associations at all skeletal sites examined [BMC differences of 4-6% per interquartile range (IQR) of weight]. Associations with the fat and lean components of weight were more variable. The BMC differences per IQR of lean mass were 5-7% at the hip sites, 3% at the spine, and 2% at the radial sites. The greater differences for lean mass at the hip may reflect the high physical mobility and muscular activity of this site. The BMC differences per IQR of fat mass were 4-6% at the hip sites, 4% at the spine, and 5% at the ultradistal radius. These results suggest that low fat mass or low lean mass, particularly at the extremes, may adversely affect the major fracture sites. The bone sites with the greatest differences for fat mass were the most highly trabecular sites. With only a few exceptions, the associations of BMC with fat mass and lean mass were similar in direction and comparable in magnitude across the four geographic locations. We conclude that both fat and lean mass have independent influences on bone mass, but that their relative influence may vary by bone site depending on the trabecular content, physical mobility, and muscularity of the site.

Bone mass and metabolism in women aged 45-55.

Changes in calcium homeostasis and bone mass around the climacteric are poorly understood. We examined relations between endocrine factors and indices of bone mass and metabolism in healthy women approaching the menopause. Cross-section study. Sixty-eight spontaneously menstruating women aged 45-55. Bone density measured at lumbar spine (LS) and femoral neck (FN) using dual energy X-ray absorptiometry and distal non-dominant forearm using peripheral quantitative computed tomography. We recorded menstrual history, physical activity and dietary calcium, and measured serum calcium, phosphate, alkaline phosphatase, osteocalcin, vitamin D, fT3, T4, TSH, PTH, FSH and oestradiol (E2), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) excretion. Using serum FSH level as a marker of ovarian function, 63 subjects could be classified into one of three groups: group A (serum FSH < 10 U/l, n = 29), group B (10-35 U/l, n = 27) and group C (> 35 U/l, n = 7). Bone density fell with declining ovarian function at the LS, FN and forearm trabecular (but not cortical) sites. Serum PTH was lower in group A vs B (mean (SD) 2.68 (0.97) vs 3.52 (1.17) pmol/l, P < 0.05), but similar to group C (2.90 (1.09) pmol/l, P = NS). Serum phosphate was elevated in group C compared to groups A and B (1.17 (0.15) vs 1.04 (0.11) and 1.05 (0.13) mmol/l, P < 0.05), and urinary PYD (61.1 (8.0) vs 50.4 (11.6) and 43.9 (8.1) mumol/mol creatinine) and DPD (15.9 (3.9) vs 12.0 (3.6) and 11.4 (3.6) mumol/mol creatinine) excretion were also increased. There were no significant differences in vitamin D metabolites or osteocalcin. Multivariate analysis suggested serum osteocalcin was positively related to physical activity and serum 1,25-dihydroxycholecalciferol levels. Serum free T3 was positively correlated with urinary DPD excretion, and inversely related to serum PTH. In all subjects, serum PTH was related to body weight (r = 0.38, P = 0.002). Declining ovarian function before menopause is accompanied by reductions in bone mass and altered calcium metabolism. Free T3 may regulate bone resorption and indirectly modulate PTH release.

Calcium and Vitamin D Nutritional Needs of Elderly Women

Because osteoporosis is irreversible, the most effective approach to reduce morbidity and mortality from this disease is to maximize peak bone mass and minimize bone loss. This presentation reviews the evidence that calcium and vitamin D influence rates of bone loss in postmenopausal women. In the first five or more years after menopause, women lose bone very rapidly. During this period, high dose calcium supplementation modestly reduces cortical loss from long bones but has minimal effect on more trabecular sites such as the spine. In addition, vitamin Dappears to enhance the effectiveness of supplemental calcium. Late postmenopausal women are generally more responsive to added calcium, and those with the lowest dietary calcium intakes benefit the most. In calciumreplete women, supplementation with vitamin D reduces bone loss and fracture incidence. Available evidence indicates that postmenopausal women should consume 1000–1500 mg of calcium and 400 to 800 KI of vitamin D per day to minimize bone loss.