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TL Stewart and SH Ralston

Osteoporosis is a common disease with a strong genetic component characterised by low bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. Twin and family studies have shown that genetic factors play an important role in regulating bone mineral density and other determinants of osteoporotic fracture risk, such as ultrasound properties of bone, skeletal geometry and bone turnover. Osteoporosis is a polygenic disorder, determined by the effects of several genes, each with relatively modest effects on bone mass and other determinants of fracture risk. It is only on rare occasions that osteoporosis occurs as the result of mutations in a single gene. Linkage studies in man and experimental animals have defined multiple loci which regulate bone mass but the genes responsible for these effects remain to be defined. Population-based studies and case-control studies have similarly identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, including the vitamin D receptor, oestrogen receptor and collagen type IalphaI gene. The individual contribution of these genes to the pathogenesis of osteoporosis is small however, reflected by the fact that the relationship between individual candidate genes and osteoporosis has been inconsistent in different studies. An important aim of future work will be to define how the genes which regulate bone mass, bone turnover and other aspects of bone metabolism interact with each other and with environmental variables to cause osteoporosis in individual patients. If that aim can be achieved then there is every prospect that preventative therapy could be targeted to those at greatest risk of the osteoporosis, before fractures have occurred.

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T Yamashita, I Sekiya, N Kawaguchi, K Kashimada, A Nifuji, YI Nabeshima, and M Noda

Unloading induces bone loss as seen in experimental animals as well as in space flight or in bed-ridden conditions; however, the mechanisms involved in this phenomenon are not fully understood. Klotho mutant mice exhibit osteopetrosis in the metaphyseal regions indicating that the klotho gene product is involved in the regulation of bone metabolism. To examine whether the klotho gene product is involved in the unloading-induced bone loss, the response of the osteopetrotic cancellous bones in these mice was investigated. Sciatic nerve resection was conducted using klotho mutant (kl/kl) and control heterozygous mice (+/kl) and its effect on bone was examined by micro-computed tomography (microCT). As reported previously for wild-type mice (+/+), about 30% bone loss was induced in heterozygous mice (+/kl) by unloading due to neurectomy within 30 days of the surgery. By contrast, kl/kl mice were resistant against bone loss induced by unloading after neurectomy. Unloading due to neurectomy also induced a small but significant bone loss in the cortical bone of the mid-shaft of the femur in the heterozygous mice; no reduction in the cortical bone was observed in kl/kl mice. These results indicate that klotho mutant mice are resistant against bone loss induced by unloading due to neurectomy in both cortical and trabecular bone and indicate that klotho is one of the molecules involved in the loss of bone by unloading.

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Idris Mohamed and James K Yeh

Long-term aromatase inhibitor use causes bone loss and increases fracture risk secondary to induced estrogen deficiency. We postulated that alfacalcidol (A; vitamin D3 analog) could help prevent the Letrozole (L)-induced mineral bone loss. Fifty intact 1-month-old female rats were randomly divided into basal group; age-matched control group (AMC); L group: oral administration of 2 mg/kg per day; A group: oral administration of 0.1 μg/kg per day; and group L+A for a period of 8 weeks. Eight-week administration of L resulted in a significant increase in body weight, bone length, bone area, bone formation, and bone resorption activities when compared with the AMC group. However, the bone mass and bone mineral density (BMD) were significantly lower than the AMC group. Serum levels of testosterone, LH, FSH, and IGF-1 were significantly higher and serum estrone and estradiol were lower along with a decrease in ovary+uterus horn weight, when compared with the AMC groups. None of those parameters were affected by A treatment, except suppression of bone resorption activities and increased trabecular bone mass and femoral BMD, when compared with the AMC group. Results of L+A combined intervention showed that bone length, bone area, and bone formation activities were higher than the AMC group, and the bone resorption activities were lower and BMD was significantly higher than that of the L group. This study demonstrates that the combined intervention of L and A not only enhances bone growth, but also increases bone density, and the effects of L and A are independent and additive.

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Jonathan J Nicholls, Mary Jane Brassill, Graham R Williams, and J H Duncan Bassett

Euthyroid status is essential for normal skeletal development and the maintenance of adult bone structure and strength. Established thyrotoxicosis has long been recognised as a cause of high bone turnover osteoporosis and fracture but more recent studies have suggested that subclinical hyperthyroidism and long-term suppressive doses of thyroxine (T4) may also result in decreased bone mineral density (BMD) and an increased risk of fragility fracture, particularly in postmenopausal women. Furthermore, large population studies of euthyroid individuals have demonstrated that a hypothalamic–pituitary–thyroid axis set point at the upper end of the normal reference range is associated with reduced BMD and increased fracture susceptibility. Despite these findings, the cellular and molecular mechanisms of thyroid hormone action in bone remain controversial and incompletely understood. In this review, we discuss the role of thyroid hormones in bone and the skeletal consequences of hyperthyroidism.

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Joyce Emons, Bas E Dutilh, Eva Decker, Heide Pirzer, Carsten Sticht, Norbert Gretz, Gudrun Rappold, Ewan R Cameron, James C Neil, Gary S Stein, Andre J van Wijnen, Jan Maarten Wit, Janine N Post, and Marcel Karperien

In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P=0.002), height of the individual zones (P<0.001), and an increase in intercolumnar space (P<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P<0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays.

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S A Lanham, A L Fowden, C Roberts, C Cooper, R O C Oreffo, and A J Forhead

Thyroid hormones are important for normal bone growth and development in postnatal life. However, little is known about the role of thyroid hormones in the control of bone development in the fetus. Using computed tomography and mechanical testing, the structure and strength of metatarsal bones were measured in sheep fetuses in which thyroid hormone levels were altered by thyroidectomy or adrenalectomy. In intact fetuses, plasma concentrations of total calcium and the degradation products of C-terminal telopeptides of type I collagen increased between 100 and 144 days of gestation (term 145±2 days), in association with various indices of bone growth and development. Thyroid hormone deficiency induced by thyroidectomy at 105–110 days of gestation caused growth retardation of the fetus and significant changes in metatarsal bone structure and strength when analyzed at both 130 and 144 days of gestation. In hypothyroid fetuses, trabecular bone was stronger with thicker, more closely spaced trabeculae, despite lower bone mineral density. Plasma osteocalcin was reduced by fetal thyroidectomy. Removal of the fetal adrenal gland at 115–120 days of gestation, and prevention of the prepartum rises in cortisol and triiodothyronine, had no effect on bodyweight, limb lengths, metatarsal bone structure or strength, or circulating markers of bone metabolism in the fetuses studied near term. This study demonstrates that hypothyroidism in utero has significant effects on the structure and strength of bone, with different consequences for cortical and trabecular bone.

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C. Wüster, F. Raue, C. Meyer, M. Bergmann, and R. Ziegler

ABSTRACT

In a cross-sectional study of 39 patients with medullary thyroid carcinoma (MTC), we have investigated the effects of long-term calcitonin excess on bone mineral density.

Bone mineral density was measured by dual X-ray absorptiometry at the lumbar spine between the second and fourth vertebra and by single photon absorptiometry at the distal forearm. The mean observation time of each patient between diagnosis of tumour and measurement of bone mineral density was 62·4 months (range 1–158 months). The mean calcitonin serum level was 14·4 μg/l at the time of measurement of bone mineral density. All patients were substituted with 150–200 μg l-thyroxine daily. At both sites, the mean bone mineral densities of all patients with MTC were not significantly different from controls. Patients with normal calcitonin levels (below 0·2 μg/l) after treatment had a normal bone mineral density of the spine but significantly (P <0·05) reduced bone mineral density values of the forearm. This was due to the decreased body surface areas of patients in this subgroup. Patients with multiple endocrine neoplasia type IIa had significantly higher bone mineral densities. Other bone-influencing factors, such as postoperative hypoparathyroidism, calcium intake, diarrhoea, menopause, tumour stage, previous anti-tumour treatment, or thyroxine substitution dose, did not affect bone mineral density.

We thus conclude that long-term excess of endogenous calcitonin in patients with MTC has no positive effect on bone mineral density.

Journal of Endocrinology (1992) 134, 141–147

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J Aerssens, S Boonen, J Joly, and J Dequeker

Skeletal site-related differences in trabecular bone composition have been studied in autopsy samples from 63 individuals (age range 23-92 years). From each individual, bone samples were excised from the iliac crest, lumbar spine, femoral neck, and calcaneus. Samples were analyzed for their content of ash, calcium, collagen, extractable proteins, osteocalcin, and IGF-I. Significant differences were found between the skeletal sites, the lumbar spine being the least mineralized site and the femur the most. The femur and lumbar spine had a higher osteocalcin and IGF-I content compared with the other skeletal sites, suggesting a higher bone turnover rate. The intercorrelations between the anatomical sites were low for minerals and collagen but high for osteocalcin and IGF-I. The latter might indicate that the presence of these proteins in the bone matrix is mainly controlled by endocrine mechanisms which may influence the osteoblast function. Finally, regression analysis showed a significant age-related decrease of skeletal IGF-I at all sites examined. This finding supports the hypothesis of an IGF-I-mediated pathogenesis of senile osteoporosis. In summary, our data imply that a global assessment of skeletal function and bone quality, based upon analyses at one anatomical site, should be applied with caution.

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P. L. Selby and R. M. Francis

In the 40 years or so since Albright & Reifenstein (1948) noted the association of osteoporosis with hypogonadism in both females and males, much has been learnt about the actions of hormones on bone and the endocrine causes of osteoporosis. Whilst subsequent work has underlined the importance of sex steroids in the maintenance of skeletal integrity, it is apparent that osteoporosis is multifactorial in origin and that non-hormonal factors are also involved in the pathogenesis of bone loss.

Osteoporosis is characterized by a reduction in bone mass in the skeleton, associated with an increased risk of fracture. The bone mass at any age, and therefore the risk of fracture, is determined by three variables: the bone mass at maturity, the age at which bone loss commences and the rate at which it proceeds (Riggs & Melton, 1986). The peak bone mass at maturity is regulated by sex, race, other genetic

Free access

Kotaro Azuma, Stephanie C Casey, Masako Ito, Tomohiko Urano, Kuniko Horie, Yasuyoshi Ouchi, Séverine Kirchner, Bruce Blumberg, and Satoshi Inoue

The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.