Bone and Gastric Bypass Surgery: Effects of Dietary Calcium and Vitamin D

Objective:To examine bone mass and metabolism in women who had previously undergone Roux‐en‐Y gastric bypass (RYGB) and determine the effect of supplementation with calcium (Ca) and vitamin D. Research Methods and Procedures: Bone mineral density and bone mineral content (BMC) were examined in 44 RYGB women (≥3 years post‐surgery; 31% weight loss; BMI, 34 kg/m²) and compared with age‐ and weight‐matched control (CNT) women (n = 65). In a separate analysis, RYGB women who presented with low bone mass (n = 13) were supplemented to a total 1.2 g Ca/d and 8 μg vitamin D/d over 6 months and compared with an unsupplemented CNT group (n = 13). Bone mass and turnover and serum parathyroid hormone (PTH) and 25‐hydroxyvitamin D were measured. Results:Bone mass did not differ between premenopausal RYGB and CNT women (42 ± 5 years), whereas postmenopausal RYGB women (55 ± 7 years) had higher bone mineral density and BMC at the lumbar spine and lower BMC at the femoral neck. Before and after dietary supplementation, bone mass was similar, and serum PTH and markers of bone resorption were higher (p < 0.001) in RYGB compared with CNT women and did not change significantly after supplementation. Discussion: Postmenopausal RYGB women show evidence of secondary hyperparathyroidism, elevated bone resorption, and patterns of bone loss (reduced femoral neck and higher lumbar spine) similar to other subjects with hyperparathyroidism. Although a modest increase in Ca or vitamin D does not suppress PTH or bone resorption, it is possible that greater dietary supplementation may be beneficial.     

In vivo administration of 1,25-dihydroxyvitamin D3 suppresses the expression of RANKL mRNA in bone of thyroparathyroidectomized rats constantly infused with PTH

It is known that pharmacological or toxic doses of vitamin D induce bone resorption both in vivo and in vitro, whereas physiological doses of the vitamin have a protective effect on bone in vivo. To investigate the discrepancies of the dose-dependent effect of vitamin D on bone resorption, we examined the in vivo effect of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] on the expression of the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and osteoprotegerin (OPG) mRNAs in bone of thyroparathyroidectomized (TPTX) rats infused with or without parathyroid hormone (PTH). Continuous infusion of 50 ng/h of PTH greatly increased the expression of RANKL mRNA in bone of TPTX rats. Expression of OPG mRNA was not altered by PTH infusion. When graded doses of 1,25(OH)(2)D(3) was daily administered orally for 14 days to normocalcemic TPTX rats constantly infused with PTH, 0.01 and 0.1 microg/kg of 1,25(OH)(2)D(3) inhibited the PTH-induced RANKL mRNA expression, but 0.5 microg/kg of the vitamin did not inhibit it. Regulator of G protein signaling-2 (RGS-2) gene expression was suppressed by 1,25(OH)(2)D(3) dose-dependently, but PTH/PTHrP receptor mRNA expression was not altered. Bone morphometric analyses revealed that 1,25(OH)(2)D(3) suppressed PTH-induced osteoclast number in vivo. These results suggest that pharmacological or toxic doses of 1,25(OH)(2)D(3) stimulate bone resorption by inducing RANKL, but a certain range of physiological doses of the vitamin inhibit PTH-induced bone resorption, the latter mechanism appeared to be mediated, at least in part, by the suppression of the PTH/PTHrP receptor-mediated signaling.     

Role of Slit/Robo Signaling pathway in Bone Metabolism

Slit/Robo signals were initially found to play an essential role in nerve development as axonal guidance molecules. In recent years, with in-depth study, the role of Slit/Robo in other life activities, such as tumor development, angiogenesis, cell migration, and bone homeostasis, has gradually been revealed. Bone is an organ with an active metabolism. Bone resorption and bone formation are closely related through precise spatiotemporal coordination. There is much evidence that slit, as a new bone coupling factor, can regulate bone formation and resorption. For example, Slit3 can promote bone formation and inhibit bone resorption through Robo receptors, which has excellent therapeutic potential in metabolic bone diseases. Although the conclusions of some studies are contradictory, they all affirm the vital role of Slit/Robo signaling in regulating bone metabolism. This paper reviews the research progress of Slit/Robo signaling in bone metabolism, briefly discusses the contradictions in the existing research, and puts forward the research direction of Slit/Robo in the field of bone metabolism in the future.     

Increased bone turnover markers after renal transplantation

Bone remodeling is a process that occurs continuously in a seemingly inactive tissue like bone. Because of decreased vitamin D synthesis, phosphorus retention and decreased calcium blood concentration, patients with chronic renal failure (CRF) develop secondary hyperparathyroidism. Elevated PTH levels shifts balance between osteoblast and osteoclast activity in favor of osteoclast activity and, therefore, bone resorption. Bone metabolic disorder that affects patients with CRF is called renal osteodystrophy (ROD). We presume that renal transplantation reverses bone metabolism disorder and our goal was to establish whether osteoblast and osteoclast activity returns to the levels of healthy individuals.     

Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage.

The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.     

Bone effects of vitamin D - Discrepancies between in vivo and in vitro studies

Vitamin D was discovered as an anti-rachitic agent, but even at present, there is no direct evidence to support the concept that vitamin D directly stimulates osteoblastic bone formation and mineralization. It appears to be paradoxical, but vitamin D functions in the process of osteoclastic bone resorption. In 1952, Carlsson reported that administration of vitamin D(3) to rats fed a vitamin D-deficient, low calcium diet raised serum calcium levels. Since the diet did not contain appreciable amounts of calcium, the rise in serum calcium was considered to be derived from bone. Since then, this assay has been used as a standard bioassay for vitamin D compounds. Osteoclasts, the cells responsible for bone resorption, develop from hematopoietic cells of the monocyte-macrophage lineage. Several lines of evidence have shown that the active form of vitamin D(3), 1α,25-dihydroxyvitamin D(3) [1α,25(OH)(2)D(3)] is one of the most potent inducers of receptor activator of NF-κB ligand (RANKL), a key molecule for osteoclastogenesis, in vitro. In fact, 1α,25(OH)(2)D(3) strongly induced osteoclast formation and bone resorption in vitro. Nevertheless, 1α,25(OH)(2)D(3) and its prodrug, Alfacalcidol (1α-hydroxyvitamin D(3)) have been used as therapeutic agents for osteoporosis since 1983, because they increase bone mineral density and reduce the incidence of bone fracture in vivo. Furthermore, a new vitamin D analog, Eldecalcitol [2β-(3-hydroxypropoxy)-1α,25(OH)(2)D(3)], has been approved as a new drug for osteoporosis in Japan in January 2011. Interestingly, these beneficial effects of in vivo administration of vitamin D compounds are caused by the suppression of osteoclastic bone resorption. The present review article describes the mechanism of the discrepancy of vitamin D compounds in osteoclastic bone resorption between in vivo and in vitro.     

VDR gene polymorphisms are overrepresented in german patients with type 1 diabetes compared to healthy controls without effect on biochemical parameters of bone metabolism.

Type 1 diabetic individuals are known to develop disorders of bone metabolism resulting in osteopenia. Previous studies have suggested an influence of vitamin D receptor alleles on bone metabolism and susceptibility for type 1 diabetes mellitus. The present study was initiated to investigate the distribution of vitamin D receptor alleles in Caucasian type 1 diabetic patients and their relation to bone turnover parameters. 75 patients were included and compared to 57 healthy controls. Three vitamin D receptor alleles were examined (BsmI, TaqI and FokI); serum levels of intact osteocalcin, parathyroid hormone, bone specific alkaline phosphatase, the carboxy terminal extension peptide of type I procollagen, 25-OH-vitamin D levels, HbA1c and urinary deoxypyridinoline excretion were measured. We observed a higher frequency of the TT genotype in diabetic patients, but no difference in markers of bone turnover between diabetics and non-diabetics in either sex. Bone turnover was different in men and in women without any association with vitamin D receptor genotype. No association was found between diabetes duration, age of onset or metabolic control and bone turnover parameters. In summary, our results show an association between the TT genotype and diabetes in Germans, but no difference in bone turnover markers between diabetics and non-diabetics.     

Potential role of vitamin D receptor gene polymorphism in determining bone phenotype in young male athletes.

The genetic difference among individuals partly explains variance in adaptive response to exercise through gene-environment interaction. The aim of this cross-sectional study was to evaluate the role of the vitamin D receptor (VDR) gene polymorphism, which locates at the translation initiation site, in the adaptations of bone to long-term impact loading. The VDR genotypes, as detected by endonuclease Fok I, and bone phenotypes of the lumbar spine and femoral neck were examined in 44 highly trained young male athletes and 44 age-matched nonathletic controls. As a whole, the athletes had a significantly higher bone mineral content resulting from a combination of increased volume and density at both sites than the controls. When the athletes were compared with the controls within each VDR genotype, however, the increased spinal volume was found only in the athletes with the FF but not in those with the Ff genotype("F" for the absence of the endonuclease Fok I restriction site and "f" for its presence). Differences in bone mineral content in the lumbar spine and femoral neck between the controls and the athletes were greater in subjects with FF than those with Ff. Our results suggest a gene-environment interaction in that the bone phenotypes in individuals with FF adapt to impact loading by producing stronger bone structure than those with the Ff do.     

Glutamatergic regulation of bone remodeling

L-glutamate (Glu) is the predominant neuromediator in the mammalian central nervous system (CNS). Bone is highly innervated and there is growing evidence of a neural control of bone cell metabolism. The recent discovery of Glu-containing nerve fibers in bone and Glu receptors (GluR) and transporters in bone cells suggest that this neuromediator may also act as a signaling molecule in bone and regulate bone cell function. Our previous studies have demonstrated that ionotropic N-Methyl-D-Aspartate (NMDA) GluR are highly expressed by mammalian osteoclasts. NMDA receptors (NMDAR) are heteromers associating the NR1 subunit and one of the four types of NR2 subunits (NR2A to D). We showed that osteoclasts express NR1, NR2B and NR2D subunits, suggesting a molecular diversity of NMDAR in these cells. Electrophysiological studies have confirmed that NMDAR are functional in mature osteoclasts, and features of Glu-induced current recorded in these cells indicate a major NR2D subunit composition. Using an in vitro assay of bone resorption, we showed that several antagonists of NMDAR binding to different sites of the receptor inhibit bone resorption. In particular, the specific NMDAR channel blocker MK801 had no effect on osteoclast attachment to bone and survival while it rapidly decreased the percentage of osteoclasts with actin ring structures that are associated with actively resorbing osteoclasts. NMDAR may thus be involved in adhesion-induced formation of the sealing zone required for bone resorption. NMDAR are also expressed by osteoclast precursors isolated from mouse bone marrow. We recently confirmed the presence of NR1, NR2B and NR2D in these cells and demonstrated their expression at all differentiation stages from osteoclast precursors to mature resorbing osteoclasts. No regulation of these subunits mRNA expression levels was observed throughout the osteoclastic differentiation sequence. Activation of NMDAR may therefore represent a new mechanism for regulating osteoclast formation and activity. While the origin of Glu in bone is still unknown, the possibility of a glutamatergic neurotransmission in this tissue is suggested by the detection of Glu in nerve fibers in close contact to bone cells. Furthermore, we recently demonstrated that sciatic neurectomy in growing rats induces a bone loss associated with a reduction of nerve profiles immunostained for Glu. These results suggest that Glu may be released from glutamatergic nerve profiles present in bone and therefore contribute to the local regulation of bone cell function.     

1,25(OH)2D3 acts as a bone-forming agent in the hormone-independent senescence-accelerated mouse (SAM-P/6)

Recent studies suggest that vitamin D signaling regulates bone formation. However, the overall effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on bone turnover in vivo is still unclear. In this study, our aim was to examine the effect of 1,25(OH)2D3 on bone turnover in SAM-P/6, a hormone-independent mouse model of senile osteoporosis characterized by a decrease in bone formation. Male and female 4-mo-old SAM-P/6 mice were treated with 1,25(OH)2D3 (18 pmol/24 h) or vehicle for a period of 6 wk, and a group of age- and sex-matched nonosteoporotic animals was used as control. Bone mineral density (BMD) at the lumbar spine increased rapidly by >30 +/- 5% (P < 0.001) in 1,25(OH)2D3-treated SAM-P/6 animals, whereas BMD decreased significantly by 18 +/- 2% (P < 0.01) in vehicle-treated SAM-P/6 animals and remained stable in control animals during the same period. Static and dynamic bone histomorphometry indicated that 1,25(OH)2D3 significantly increased bone volume and other parameters of bone quality as well as subperiosteal bone formation rate compared with vehicle-treated SAM-P/6 mice. However, no effect on trabecular bone formation was observed. This was accompanied by a marked decrease in the number of osteoclasts and eroded surfaces. A significant increase in circulating bone formation markers and a decrease in bone resorption markers was also observed. Finally, bone marrow cells, obtained from 1,25(OH)2D3-treated animals and cultured in the absence of 1,25(OH)2D3, differentiated more intensely into osteoblasts compared with those derived from vehicle-treated mice cultured in the same conditions. Taken together, these findings demonstrate that 1,25(OH)2D3 acts simultaneously on bone formation and resorption to prevent the development of senile osteoporosis.     

Vitamin D receptor gene polymorphisms,bone mineral density and bone turnover: FokI genotype is related to postmenopausal bone mass

The relationship between vitamin D receptor (VDR) intragenic polymorphisms FokI, BsmI, ApaI and TaqI and bone mineral density (BMD) or biochemical markers of bone remodeling were investigated in 114 Czech postmenopausal women, on the average 62.5+/-8.9 years of age. Restriction fragment length polymorphisms in the VDR gene were assessed by PCR amplification and digestion with restriction enzymes FokI, BsmI, ApaI, and TaqI recognizing polymorphic sites in the VDR locus. Bone mineral density was measured at the lumbar spine and at the hip by dual-energy X-ray absorptiometry (DEXA, g/cm2). After adjusting for age and the body mass index (BMI), subjects with the ff genotype had 9.4% lower BMD at the hip than those with the Ff genotype (p=0.0459, Tukey's test). FF individuals had an intermediate BMD at the hip. A similar pattern of lower lumbar spine BMD was also found in ff individuals, but it did not reach statistical significance. There was no relationship between BsmI, ApaI and TaqI VDR polymorphisms and BMD at any skeletal site. Subjects with Aa (ApaI) genotypes had higher levels of propeptide of type I collagen (PICP) than homozygous AA (p=0.0459, Tukey's test). In FokI, BsmI and TaqI restriction sites the biochemical markers of bone remodeling did not differ by genotype. In addition, no significant difference was observed in VDR genotypic distribution between osteoporotic women and non-osteoporotic controls in the study group. To conclude, the FokI genotype of the vitamin D receptor gene is related to bone mass at the hip in Czech postmenopausal women, whereas the importance of remaining VDR genotypes was not evident.     

The effect of calcium and vitamin D supplementation on osteoporotic rabbit bones studied by vibrational spectroscopy

Fourier transform infrared spectroscopy is utilized to examine the effects of increased calcium, vitamin D, and combined calcium-vitamin D supplementation on osteoporotic rabbit bones with induced inflammation. The study includes different bone sites (femur, tibia, humerus, vertebral rib) in an effort to explore possible differences among the sites. We evaluate the following parameters: mineral-to-matrix ratio, carbonate content, and non-apatitic species (labile acid phosphate and labile carbonate) contribution to bone mineral. Results show that a relatively high dose of calcium or calcium with vitamin D supplementation increases the bone mineralization index significantly. On the other hand, vitamin D alone is not as effective in promoting mineralization even with high intake. Mature B-type apatite was detected for the group with calcium supplementation similar to that of aged bone. High vitamin D intake led to increased labile species concentration revealing bone formation. This is directly associated with the suppression of pro-inflammatory cytokines linked to induced inflammation. The latter is known to adversely alter bone metabolism, contributing to the aetiopathogenesis of osteoporosis. Thus, a high intake of vitamin D under inflammation-induced osteoporosis does not promote mineralization but suppresses bone resorption and restores metabolic balance.     

Immobilization on the day 14th does not disrupts the basic diurnal rhythm of bone resorption

Weight bearing and physical activity are important mechanical stimuli to bone growth and metabolism, and microgravity, such a space flight and/or bed rest, induces bone resorption and bone loss. An increased excretion of urinary Ca, an increased bone resorption and a decreased bone mineral density (BMD) have been observed in bed rest experiment of healthy subjects. Bone resorption markers show the specific circadian rhythms in human. Cross-linked carboxyl-terminal telopeptide of type I collagen (ICTP) and the urinary excretion of deoxypyridinoline (Dpy) are the highest in the early morning and the lowest late at night. Bed rest immobilization might influence these rhythms, due to no mechanical loading with loss of daily life activity. Bone resorption markers in healthy subjects had been compared between before and during bed rest to determine disruption of diurnal rhythms of bone resorption.     

维生素D与PTH相关性研究进展

维生素D是人体必需的一种脂溶性营养素,随着科学技术不断进步,维生素D对人类健康的作用逐渐被发现。已有研究表明,维生素D不仅与多种骨代谢相关疾病有关,并与心血管疾病、代谢综合征、感染、肿瘤、自身免疫疾病等关系密切。在骨代谢方面,维生素D的缺乏可能会导致软骨病、佝偻病、骨质疏松症,甚至会导致急性跌倒事件的发生和骨折的形成,而甲状旁腺激素(PTH)是骨代谢过程中的关键分子。本文综述了维生素D代谢过程及维生素D受体多样性及维生素D与甲状旁腺激素(PTH)相关性,以便有助于探究维生素D与骨代谢之间的关系。     

Effect of pinocembrin isolated from Alpinia zerumbet on osteoblast differentiation

Cytotechnology - Bone mass is regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Osteoporosis is a bone metabolism disorder in which bone mass decreases due to...     

Space flight modulates signal transduction pathway of growth factor receptors in rat osteoblasts.

Bone metabolism is regulated by the balance of bone formation and resorption. Osteoblasts serves primarily for bone formation. Microgravity deteriorates osteoblastic function and inhibit bone formation. Growth factors regulate osteoblast function via receptors. Binding of EGF and PDGF to the receptors activates receptor tyrosine kinase and rapid association of adapter proteins Shc and Grb2, and evokes the Ras/MAP kinase cascade. Signals from various chemical and physical stimuli are transmitted to the nucleus, and induce c-fos and c-jun gene expression. However, effects of microgravity on the molecular events in osteoblasts remain unknown. The purpose of this study is to investigate the mRNA levels for PDGF-beta receptor, EGF receptor, Shc, and c-fos in rat osteoblasts during space flight.