A meta-analysis of prior corticosteroid use and fracture risk.

Unlabelled: The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of approximately 42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD.

Introduction: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk.

Vitamin D in Australia. Issues and recommendations.

Background: A significant number of Australians and people from specific groups within the community are suffering from vitamin D deficiency. It is no longer acceptable to assume that all people in Australia receive adequate vitamin D from casual exposure to sunlight.

Objective: This article provides information on causes, consequences, treatment and prevention of vitamin D deficiency in Australia.

Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study.

Unlabelled: With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of the vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight methodological issues that need to be resolved.

7: Treatment of osteoporosis: why, whom, when and how to treat. The single most important consideration is the individual's absolute risk of fracture.

All women and men with a history of fragility fractures should be considered for treatment of osteoporosis to reduce their risk of future fracture. There is high-level evidence for the anti-fracture efficacy of treatment in women with osteoporosis, particularly if there is prevalent fracture; the evidence is less compelling for women with osteopenia, with or without a fracture, and for men. The rigorously investigated drugs reported to reduce vertebral fractures are the bisphosphonates alendronate and risedronate, the selective oestrogen-receptor modulator raloxifene, the anabolic agent parathyroid hormone and, most recently, strontium ranelate.

Incidence of hip and other osteoporotic fractures in elderly men and women: Dubbo Osteoporosis Epidemiology Study.

Unlabelled: In this prospective 12-year study in men and women 60 years of age and older, there was a 4-6% per year reduction in the incidence rate of overall osteoporotic fractures, but the study was unable to exclude any change in the hip fracture incidence rate. Approximately one-half of hip fractures occurred before 80 years in men and two-thirds before 85 years in women. The age distribution of hip fractures underlines the need for earlier intervention in osteoporosis.

Ski-interacting protein, a bifunctional nuclear receptor coregulator that interacts with N-CoR/SMRT and p300.

Ski-interacting protein (SKIP), a vitamin D receptor (VDR) coactivator, also functions as a repressor in Notch signalling in association with the corepressor SMRT. Here we show that SKIP bifunctionally modulates (activates or represses) Retinoid-X receptor (RXR)- and VDR-dependent gene transcription in a cell line-specific manner, with activation in CV-1 and repression in P19 cells. The coactivator function of SKIP in these cells appeared to correlate with the relative level and ratio of expression of N-CoR and p300, with greater SKIP activation in higher p300-expressing and lower N-CoR-expressing cell-lines.

Osteoporosis: underrated, underdiagnosed and undertreated.

Osteoporosis is: (1) Underrated. Currently costs about 7 billion dollars annually in Australia. Has high morbidity and 2-3-fold increase in risk of death after any major osteoporotic fracture.

Targeted overexpression of vitamin D receptor in osteoblasts increases calcium concentration without affecting structural properties of bone mineral crystals.

Increased cross-sectional area and strength of long bones has been observed in transgenic mice with 2-fold (OSV9) and 3-fold (OSV3) elevation of osteoblast vitamin D receptor (VDR) levels. In the present study, mineralization density distributions, including typical calcium content (Ca(Peak)) and homogeneity of mineralization (Ca(Width)) of femoral bone and growth plate cartilage, were determined by quantitative backscattered electron imaging (qBEI). Fourier-transform infrared (FTIR) microspectroscopy was used to examine mineral content, collagen and crystal maturation, and scanning small angle X-ray scattering (scanning-SAXS) for studying mineral particle thickness and alignment.

Limited utility of clinical indices for the prediction of symptomatic fracture risk in postmenopausal women.

Bone mineral density (BMD) is the primary predictor of fracture, and is utilised in the definition of osteoporosis. Mass screening for osteoporosis is, however, currently not recommended. The primary objective of this study was to develop, validate and assess a simple, non-invasive scoring system to identify women at high risk of fracture.

Genetic determination of bone mineral density: evidence for a major gene.

This study was designed to test the hypothesis of a major gene influence on the variation in bone mineral density (BMD). BMD and bone mineral content at the lumbar spine and femoral neck were measured in 330 men and 413 women, aged 18-90 yr, from 107 nuclear and complex families (including 5 large pedigrees with 194 individuals who were identified through an index case with moderately high BMD at the femoral neck (z-score, >or=1.28)).

Osteoporotic fracture: missed opportunity for intervention.

As prior fracture is consistently associated with increased risk of subsequent fracture, subjects with a history of prior fracture represent a high risk group which should be targeted for intervention to reduce future fracture rates. The aim of this study was to investigate whether prior osteoporotic fracture affected treatment patterns among subjects admitted with hip fractures. All hip fracture admissions to two major teaching hospitals of the University of New South Wales, Sydney, Australia, over the 12-month period between July 1997 and June 1998 were identified retrospectively from medical records.

Reduction of immunosuppressant therapy requirement in heart transplantation by calcitriol.

Calcitriol has been shown to have immunomodulatory effects. We examined whether heart transplant recipients, randomly assigned to receive calcitriol to reduce bone loss, required less immunosuppressive therapy or demonstrated different rejection and survival outcomes. Patients receiving low-dose calcitriol required substantially lower cumulative doses of cyclosporin (29% [95% confidence interval; 8%-50%] and 28% [7%-50%] for 1 and 2 years, respectively) for organ rejection without any detectable change in episodes of rejection, infection, or deaths.

Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium.

High-dose corticosteroids, used for many medical conditions, are associated with rapid bone loss from sites such as the vertebrae, and compression fractures can be observed within months. Recent trials suggest treatment with bisphosphonates or active vitamin D analogs can reduce bone loss and the risk of fracture associated with glucocorticoids, but few studies have directly compared such agents. We conducted a randomized, multicenter, open-label trial to compare the efficacy of alendronate, calcitriol, and simple vitamin D in prevention and treatment of glucocorticoid-induced bone loss.

Interactions of SKIP/NCoA-62, TFIIB, and retinoid X receptor with vitamin D receptor helix H10 residues.

The vitamin D receptor (VDR) is a ligand-dependent transcription factor that heterodimerizes with retinoid X receptor (RXR) and interacts with the basal transcription machinery and transcriptional cofactors to regulate target gene activity. The p160 coactivator GRIP1 and the distinct coregulator Ski-interacting protein (SKIP)/NCoA-62 synergistically enhance ligand-dependent VDR transcriptional activity. Both coregulators bind directly to and form a ternary complex with VDR, with GRIP1 contacting the activation function-2 (AF-2) domain and SKIP/NCoA-62 interacting through an AF-2 independent interface.

Skeletal lead release during bone resorption: effect of bisphosphonate treatment in a pilot study.

There has been renewed interest in impacts on physiologic systems in the middle and older age groups, especially from fractures and hypertension. Increased blood lead (BPb) levels in postmenopausal females, which are thought to arise from bone demineralization, may also relate to other health effects including hypertension. Taking advantage of natural differences in lead isotope signature between Australian sources of lead and those from other countries, a 2-year pilot study was performed in premenopausal and postmenopausal females and male partners in which the subjects were administered a bisphosphonate, alendronate, for 6 months.

Vitamin D analogue-specific recruitment of vitamin D receptor coactivators.

Synthetic ligands for the vitamin D receptor (VDR) are potential therapeutic agents for metabolic, neoplastic, and autoimmune disorders. Some of these ligands have similar or more potent antiproliferative, yet reduced hypercalcemic actions, than calcitriol. However, the mechanisms for these differential actions have not been clearly defined.

Novel N-terminal variant of human VDR.

The importance of N-terminal regions of nuclear hormone receptors in transcriptional regulation is increasingly recognized. As variant VDR gene transcripts indicated possible N-terminally extended receptors, we investigated their natural occurrence, transactivation capacity, and subcellular localization. A novel 54-kDa VDRB1 protein, in addition to the previously recognized 48-kDa VDRA form, was detected in human kidney tissue as well as in osteoblastic (MG63), intestinal (Int-407, DLD-1, and COLO 206F), and kidney epithelial (786) human cell lines by Western blots using isoform-specific and nonselective anti-VDR antibodies.

Changing RANKL/OPG mRNA expression in differentiating murine primary osteoblasts.

Osteoblast-osteoclast coordination is critical in the maintenance of skeletal integrity. The modulation of osteoclastogenesis by immature cells of the osteoblastic lineage is mediated through receptor activator of NF kappa B (RANK), its ligand RANKL, and osteoprotegerin (OPG), a natural decoy receptor for RANKL. Here, the expression of OPG and RANKL in primary mouse osteoblastic cultures was investigated to determine whether the osteoclastogenic stimulus depended on the stage of osteoblastic differentiation and the presence of the calciotrophic hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)).

Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy.

Background: Osteopenia has been associated with antiretroviral therapy, particularly with protease inhibitors. Osteopenia in HIV-uninfected men is associated with mitochondrial defects.

Methods: Bone density was assessed by dual-energy X-ray absorptiometry (DEXA) in 221 HIV-infected men (mean age 43 years) recruited to a lipodystrophy prevalence survey.

Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1alpha (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals.

Cross-talk between 1,25-dihydroxyvitamin D3 and transforming growth factor-beta signaling requires binding of VDR and Smad3 proteins to their cognate DNA recognition elements.

1,25-Dihydroxyvitamin D(3) (vitamin D) and transforming growth factor-beta (TGF-beta) regulate diverse biological processes including cell proliferation and differentiation through modulation of the expression of target genes. Members of the Smad family of proteins function as effectors of TGF-beta signaling pathways whereas the vitamin D receptor (VDR) confers vitamin D signaling. We investigated the molecular mechanisms by which TGF-beta and vitamin D signaling pathways interact in the regulation of the human osteocalcin promoter.

Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription.

Transforming growth factor-beta (TGF-beta) signaling requires the action of Smad proteins in association with other DNA-binding factors and coactivator and corepressor proteins to modulate target gene transcription. Smad2 and Smad3 both associate with the c-Ski and Sno oncoproteins to repress transcription of Smad target genes via recruitment of a nuclear corepressor complex. Ski-interacting protein (SKIP), a nuclear hormone receptor coactivator, was examined as a possible modulator of transcriptional regulation of the TGF-beta-responsive promoter from the plasminogen activator inhibitor gene-1.

Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation.

Bone loss is most rapid in the immediate period after cardiac or lung transplantation. This randomized study compared the efficacy of 6 months of treatment with either calcitriol (1,25-dihydroxyvitamin D3; 0.5 microg/day) or two cycles of etidronate plus calcium in preventing bone loss in 41 patients undergoing cardiac or lung transplantation.