S H Ralston

..Under these circumstances it is an invaluable investigation that can be used to differentiate infiltrative disorders from primary abnormalities of osteoblast or osteoclast function...

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..Information from these studies is being used to design new drugs for osteoporosis and to develop genetic markers for fracture risk assessment...

..Our data raise the possibility that COLIA1 genotyping could be used to target etidronate therapy to those most likely to respond in terms of FN BMD, with potential benefits in terms of economic cost and clinical outcome...

..0%), weight (5.0%), and baseline BMD (2.8%). We conclude that women homozygous for the Sp1 polymorphism are at significantly increased risk of excess rates of bone loss at the spine, but this effect may be nullified by the use of HRT...

..The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk...

..We conclude that the COL1A1 Sp1 polymorphism is a functional genetic variant that predisposes to osteoporosis by complex mechanisms involving changes in bone mass and bone quality...

..CONCLUSION: Inducible NOS-mediated osteoblast apoptosis and depressed bone formation play important roles in the pathogenesis of IMO...

..We conclude that HCT1026 may be of clinical value in the prevention and treatment of inflammatory diseases such as rheumatoid arthritis, which are characterized by joint inflammation as well as periarticular and systemic bone loss...

..The association COLIAI genotype and increased femoral neck angle noted here may therefore contribute to the BMD-independent increase in hip fracture risk noted in previous studies of individuals who carry the 's' allele...

..We conclude that in our population, COLIA1 genotyping predicts fractures independently of bone mass and interacts with bone densitometry to help identify women who are at high and low risk of sustaining osteoporotic fractures...

..This raises the possibility that riboflavin intake and MTHFR genotype might interact to regulate BMD. Further work is required to determine if this association holds true for other populations and ethnic groups...

..This suggests that the increased bone fragility in carriers of the COLIA1 Sp1 allele may result in part from defects in bone mineralization...

..We conclude that the eNOS pathway plays an essential role in regulating bone mass and bone turnover by modulating osteoblast function...

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..These data indicate that the L-arginine/NO pathway represents a novel target for therapeutic intervention in the prevention and treatment of bone diseases...

..Whilst further studies will be required to confirm and extend these observations, our studies raise the possibility that A99T heterozygosity might affect lysyl hydroxylase function and regulate bone mass...

..We conclude that the COL1A1 Sp1 alleles are associated with a modest reduction in BMD and a significant increase in risk of osteoporotic fracture, particularly vertebral fracture...

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..47 at D5S2034 (187.8 cM). These data indicate the presence of several susceptibility loci for PDB and identify a strong candidate locus for the disease, on chromosome 5q35...

..We conclude that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcaemia, which should prove a useful addition to the current range of therapies available to treat this condition...

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..These results show that the iNOS pathway is essential for IL-1-induced bone resorption and suggest that the effects of NO may be mediated by modulating IL-1-induced nuclear activation of NFkappaB in osteoclast precursors...

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..These results provide the first evidence that osteoclast precursors can adhere to endothelium and suggest that endothelium could play an important role in the recruitment of osteoclast precursors to sites of bone resorption...

..A raised PTHrP concentration is a strong indicator of malignancy...

..Other drugs which may be useful in relieving back pain associated with specific circumstances include the tricyclic antidepressants, anxiolytics, antiepileptic agents, corticosteroids, colchicine and chymopapain...

..This demonstrates that HCT1026 and derivatives could represent a novel class of antiresorptive drugs with therapeutic value in the treatment of bone diseases associated with accelerated bone loss due to osteoclast activation...

..Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered...

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..The results of this study clearly show that human proximal tubular cells, in primary culture, are capable of producing nitric oxide in response to an immune challenge secondary to the induction of nitric oxide synthase...

..002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach...

..The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1...

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..Several advances have been made over recent years in understanding the genetic basis of susceptibility to osteoporosis. This paper will review recent developments in this area...

..Adoption of such an approach in other trials may yield significant improvements in recruitment and quality of participant information flow. There are, however, resource implications for both parties...

..Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia...

..The Theory of Planned Behaviour is a theoretical model that predicts behaviours from people's beliefs about the consequences, social pressures and perceived control over the behaviour, including uptake of treatment...

..Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear...

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..Polymorphisms in the apolipoprotein E (APOE) gene are associated with fracture risk, and a potential mechanism is through vitamin K transport...

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..This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage...

..006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD...

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..We observed no association in men, but a highly significant association was found in women, and this was confirmed in a population from the United Kingdom...

..They could be developed as diagnostic genetic tests or form molecular targets for design of new drugs for the prevention and treatment of osteoporosis and other bone diseases...

..In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption...

..We studied five common polymorphisms of TGFB1 in relation to osteoporosis-related phenotypes in a population-based cohort of 2975 British women, but found no significant association with bone mass, bone loss, bone markers, or fracture...

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..Illness representations are examined using Leventhal's Common Sense Self-Regulation Model while cognitions about treatment behaviours (acceptance of testing and treatment uptake) are conceptualised within the Theory of Planned Behaviour...

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..Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity...

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..In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk...

..012). Subjects with the CC genotype had significantly lower BMD (mean +/- SD: TT, 0.7 +/- 0.16; CC, 0.6 +/- 0.08 g/cm(2); P = 0.006). In conclusion, both CYP 17 and CYP 19 are candidate genes for osteoporosis in postmenopausal women...

..We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes...

..Glutamine variants and an alanine insertion were identified within the group. These data suggest that the RUNX2 alleles are associated with BMD in a menopause- and weight-dependent manner...

..The low level of nNOS expression in bone and the in vitro behavior of nNOS KO bone cells indicate that these actions are indirect and possibly mediated by a neurogenic relay...

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..This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci...

..Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin...

..Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results...

..In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD...

..High concentrations of nitric oxide generated during the course of infection do not afford significant protection against accelerated bone resorption...

..Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population...

..The conformational switch observed on binding may represent a novel mechanism that underlies specificity in regulating signalinduced protein recognition events...

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..0001). These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone...

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..Anecdotal reports indicate that osteoclast inhibitors such as bisphosphonates are effective for suppressing bone turnover and improving symptoms in these disorders, although the long-term effects on clinical outcomes are unclear...

..Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-beta1 signaling, thus causing Camurati-Engelmann disease...

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..Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects...

..We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB...

..Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin-binding properties of the mutant UBA domain peptides...

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..The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED...

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..Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner...

..In light of the molecular defects that have been identified thus far, it seems likely that these genes will also be involved in the RANK-NF-kappaB signaling pathway or its interactions with the ubiquitin-proteasome system...

..No firm evidence as yet exists to show that bisphosphonates can prevent the development of complications of Paget's disease of bone, and further work is needed to address the effects of treatment on long-term clinical outcome...