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Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for the T575C variant, yielding an odds ratio of 1.29 ( p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value ( p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p = 0.01), as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11AA192 produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11AV192, confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations. © 2012 American Society for Bone and Mineral Research [ABSTRACT FROM AUTHOR]

Aminobisphosphonates actually represent the most common treatment for Paget disease of bone (PDB). In a previous study we demonstrated that either zoledronic acid (4 mg) or neridronate (200 mg) given as a single intravenous infusion showed a similar short-term efficacy in achieving biochemical remission in up to 90% of patient nonresponders to pamidronate. In this study we compared the long-term (36 months) effects of a same neridronate dose (200 mg) given as an intravenous (100-mg infusion for 2 consecutive days) or intramuscular (25-mg injection weekly for 2 months) regimen in 56 patients with active PDB. All patients were advised to receive calcium plus vitamin D supplementation throughout the study period. At 6 months, 92.6% and 96.5% of patients receiving intravenous and intramuscular neridronate, respectively, achieved a therapeutic response [defined as normalization of alkaline phosphatase (ALP) levels or a reduction of at least 75% in total ALP excess]. The response to treatment was significantly correlated with baseline ALP and 25-hydroxyvitamin D [25(OH)D] levels at 6 months. The decrease in ALP levels was highest in patients with higher baseline total or bone-specific ALP levels and with higher 25(OH)D levels at 6 months. Response rates were maintained at 12 months but decreased progressively at 24 and 36 months without significant differences between the two neridronate regimens. Both regimens were well tolerated. The only relevant side effect was an acute-phase response occurring in 14% of the patients. In conclusion, these results indicate that a 200-mg intramuscular neridronate course has a similar efficacy as an intravenous infusion of the same dose for the treatment of PDB and might be of particular value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusions. © 2011 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective: FSH, via its receptor (FSHR), influences bone remodeling and osteoclast proliferation and activity. The aim of this study was to evaluate the influence of two single nucleotide polymorphisms (SNPs) of the FSHR gene on bone mineral density (BMD) and bone turnover markers (bone alkaline phosphatase and type I collagen C-telopeptides) in postmenopausal women. Methods: Two hundred and eighty-nine unrelated postmenopausal women were genotyped for the SNPs rs1394205 and rs6166. BMD was estimated using dual-energy X-ray absorptiometry and quantitative ultrasound (QUS) methodologies. Results: AA rs6166 women showed a lower BMD (femoral neck and total body), lower stiffness index (calcaneal QUS), and higher serum levels of bone turnover markers compared to GG rs6166 women. The prevalence of osteoporosis was significantly higher in AA rs6166 women compared with GG rs6166 women. These results were not influenced by circulating levels of FSH and estrogens. Conclusion: The SNP rs6166 of the FSHR gene significantly influences BMD in postmenopausal women. In particular, AA rs6166 women are at increased risk of postmenopausal osteoporosis compared with GG rs6166 women, independently of circulating levels of FSH and estrogens. Previous studies have demonstrated that this SNP influences cell and tissue response to hyperstimulation of FSHR in vivo and in vitro. Our study results appear in agreement with these experimental data and with known biological actions of FSH/FSHR system in bone homeostasis. [ABSTRACT FROM AUTHOR]

The article presents a study that analyzed SQSTM1 mutations in patients afflicted with Paget's disease of bone (PDB) in the high-incidence area of Campania, Italy. The results of the study showed that patients from Campania had the highest incidence of contact with animals while a decrease in the prevalence of animal contacts related to age and a parallel increase in the incidents of SQSTM1 mutations were noted. The data suggest the importance of animal-related factors to the etiology of PDB which interact with SQSTM1 mutations.

BACKGROUND: The vitamin D receptor (VDR) gene polymorphism has been considered a factor influencing the effectiveness of the anti‐osteoporotic treatments. The aim of this study was to correlate the effectiveness of raloxifene treatment in post‐menopausal women with osteoporosis to BsmI VDR genotypes. METHODS: Between January and August 2000, 75 Italian osteoporotic women were enrolled and treated with raloxifene at a dose of 60 mg/day. At entry and after 1 year of treatment, lumbar bone mineral density (BMD), serum osteocalcin (OC) and urinary creatinine‐corrected free deoxypyridinoline (DPD) levels were evaluated. DNA was extracted from blood and analysed with restriction endonuclease BsmI for VDR gene. RESULTS: After treatment, a significant increase in lumbar BMD and a significant reduction in serum OC and urinary DPD levels were observed. The percentage of change (mean ± SD) in lumbar BMD, and in serum OC and urinary DPD levels was significantly different in homozygous bb (1.58 ± 0.80, –5.15 ± 2.36 and –7.71 ± 2.89 for BMD, OC and DPD respectively) in comparison with BB (4.13 ± 2.26, –13.59 ± 4.68 and –15.16 ± 4.65 for BMD, OC and DPD respectively) BsmI VDR genotypes. Heterozygous Bb VDR patients showed an intermediate percentage (mean ± SD) of BMD, serum OC and urinary DPD change (2.49 ± 1.54, –8.69 ± 2.60 and –10.52 ± 2.56 for BMD, OC and DPD respectively) not significantly different in comparison with homozygous BB and bb. CONCLUSIONS: In post‐menopausal women with osteoporosis the effectiveness of raloxifene treatment on bone metabolism seems to be controlled by different BsmI VDR genotypes. [ABSTRACT FROM PUBLISHER]