Novel mutations in FKBP10 in Chinese patients with osteogenesis imperfecta and their treatment with zoledronic acid.

Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. OI cases of autosomal recessive inheritance are rare, and OI type XI is attributable to mutation of the FKBP10 gene. Here, we used next-generation sequencing and Sanger sequencing to detect mutations in FKBP10 and to analyze their relation to the phenotypes of OI type XI in three Chinese patients. We also evaluated the efficacy of zoledronic acid treatment in these patients. Two of the affected patients had novel compound heterozygous mutations, one patient with c.343C>T (p.R115X) in exon 2 and c.1085delC (p.A362fsX1) in exon 7, and the other patient with c.879C>G (p.Y293X) in exon 5 and c.918-3C>G in intron 5. In the third proband, we identified a homozygous single base-pair duplication, c.831dupC (p.G278RfsX95) in exon 5. In conclusion, we report for the first time that these novel pathogenic mutations of FKBP10 can lead to the extremely rare type XI OI without contractures, which expands the genotypic spectrum of OI. The phenotypes of these patients are similar to patients with types III or IV OI, and zoledronic acid is effective in increasing BMD, inhibiting bone resorption biomarkers and reducing fractures of these patients.

THE CLINICAL CHARACTERISTICS AND EFFICACY OF BISPHOSPHONATES IN AUDLT PATIENTS WITH OSTEOGENESIS IMPERGECTA.

OBJECTIVE: Osteogenesis imperfecta (OI) is characterized by low bone mass and recurrent fractures. Adults with OI are often treated with oral or intravenous bisphosphonates (BPs). We investigated the clinical phenotypes of adult OI patients and prospectively compared the efficacy of oral alendronate (ALN) with intravenous zoledronic acid (ZOL) in OI patients. METHODS: This 24-month, observational, randomized clinical study included 60 adult patients with OI. We compared the differences in bone mineral density (BMD) and bone turnover biomarkers between OI adults and healthy subjects. Thereafter, OI patients were randomized at a 2:1 ratio to receive either weekly oral ALN 70 mg or once-yearly infusion of ZOL 5 mg. The efficacy outcomes were changes in BMD, bone turnover biomarkers, and fracture incidence. RESULTS: Adult OI patients had significantly lower BMD and significantly higher cross-linked C-telopeptide of type I collagen (ß-CTX) levels than age-/sex-/BMI-matched healthy subjects. A total of 52 patients completed the 24-month clinical study. BMD at lumbar spine, femoral neck, and total hip were equivalently elevated in the ALN (10.5, 13.2, and 14.7%, respectively) and ZOL (11.3, 13.7, and 11.7%, respectively; all P>.05) groups. Serum alkaline phosphatase decreased by 30.3% in the ALN group and 37.3% in the ZOL group (P = .12), and ß-CTX decreased by 58.0% in the ALN group and 63.6% in the ZOL group (P = .48). Compared to the prior fracture rates, clinical fracture incidences were decreased in the ALN and ZOL groups (both P<.05). CONCLUSION: Adults with OI present significantly lower bone mass and higher bone resorption biomarkers than healthy populations. Oral ALN and intravenous ZOL are equally effective at increasing BMD and inhibiting bone turnover in adults with OI. The treatment may reduce fractures in this study, but further efforts are still needed to demonstrate the anti-fracture efficacy of BPs. ABBREVIATIONS: 25OHD = 25-hydroxyvitamin D ALN = alendronate ALP = alkaline phosphatase BMD = bone mineral density BMI = body mass index BP = bisphosphonate ß-CTX = cross-linked C-telopeptide of type I collagen FN = femoral neck LS = lumbar spine OI = osteogenesis imperfecta RCT = randomized controlled trial TH = total hip ZOL = zoledronic acid.

Association Between Geranylgeranyl Pyrophosphate Synthase Gene Polymorphisms and Bone Phenotypes and Response to Alendronate Treatment in Chinese Osteoporotic Women.

Objective To investigate the relationship between geranylgeranyl pyrophosphate synthase (GGPPS) gene polymorphisms and bone response to alendronate in Chinese osteoporotic women.Methods A total of 639 postmenopausal women with osteoporosis or osteopenia were included and randomly received treatment of low dose (70 mg per two weeks) or standard dose (70 mg weekly) of alendronate for one year. The six tag single nucleotide polymorphisms of GGPPS gene were identified. Bone mineral density (BMD), serum cross-linked C-telopeptide of type I collagen (ß-CTX), and total alkaline phosphatase (ALP) were measured before and after treatment. GGPPS gene polymorphisms and the changes of BMD and bone turnover markers after treatment were analyzed.Results rs10925503 polymorphism of GGPPS gene was correlated to serum ß-CTX levels at baseline, and patients with TT genotype had significantly higher serum ß-CTX level than those with TC or CC genotype (all P<0.05). No correlation was found between polymorphisms of GGPPS gene and serum total ALP levels, as well as BMD at baseline. After 12 months of treatment, lumbar spine and hip BMD increased and serum bone turnover markers decreased significantly (P<0.01), and without obvious differences between the low dose and standard dose groups (all P>0.05). However, GGPPS gene polymorphisms were uncorrelated to percentage changes of BMD, serum total ALP, and ß-CTX levels (all P>0.05).Conclusion GGPPS gene polymorphisms are correlated to osteoclasts activity, but all tag single nucleotide polymorphisms of GGPPS gene have no influence on the skeletal response to alendronate treatment.

Prevalence and genetic diversity of Echinorhynchus gymnocyprii (Acanthocephala: Echinorhynchidae) in schizothoracine fishes (Cyprinidae: Schizothoracinae) in Qinghai-Tibetan Plateau, China.

BACKGROUND: The schizothoracine fishes, an excellent model for several studies, is a dominant fish group of the Qinghai-Tibet Plateau (QTP). However, species populations have rapidly declined due to various factors, and infection with Echinorhynchus gymnocyprii is cited as a possible factor. In the present study, the molecular characteristics of E. gymnocyprii in four species of schizothoracine fishes from the QTP were explored. METHODS: We investigated the infection status of E. gymnocyprii in 156 schizothoracine fishes from the upper Yangtze River, upper Yellow River, and Qinghai Lake in Qinghai Province, China. The complete internal transcribed spacer (ITS) of the ribosomal RNA (rRNA) gene and part of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene of 35 E. gymnocyprii isolates from these fishes were sequenced and their characteristics analyzed. In addition, we inferred phylogenetic relationships of the E. gymnocyprii populations based on the rRNA-ITS and cox1 sequences. RESULTS: The total prevalence of E. gymnocyprii in schizothoracine fishes was 57.69% (90/156). However, the prevalence among different species as well as that across the geographical locations of the schizothoracine fishes was significantly different. The results of sequence analysis showed that the four E. gymnocyprii populations from different hosts and regions of Qinghai Province were conspecific, exhibiting rich genetic diversity. Phylogenetic analysis based on rRNA-ITS and cox1 sequences supported the coalescence of branches within E. gymnocyprii; the cox1 gene of E. gymnocyprii populations inferred some geographical associations with water systems. In addition, three species of schizothoracine fishes were recorded as new definitive hosts for E. gymnocyprii. CONCLUSIONS: To the best of our knowledge, this is the first molecular description of E. gymnocyprii populations in schizothoracine fishes from the Qinghai-Tibet Plateau that provides basic data for epidemiological surveillance and control of acanthocephaliasis to protect endemic fish stocks.

The analysis of DKK1 polymorphisms in relation to skeletal phenotypes and bone response to alendronate treatment in Chinese postmenopausal women.

AIM: To investigate the correlation between DKK1 polymorphisms with bone phenotypes and response to alendronate treatment. MATERIALS & METHODS: Five tag single nucleotide polymorphisms of DKK1 were analyzed in 639 Chinese postmenopausal women with osteoporosis or osteopenia. Bone mineral density (BMD), ß-CTX and ALP were measured before and after alendronate treatment. RESULTS: Genotypes at rs1896367, rs1528877 and rs2241529 correlated to baseline BMD (p < 0.05). rs1528877 and rs2241529 polymorphisms correlated to baseline ß-CTX levels (p < 0.05). rs2241529 polymorphisms of DKK1 had a small influence on the skeletal response to alendronate treatment (p < 0.05). CONCLUSION: DKK1 polymorphisms may correlate to baseline BMD and serum ß-CTX levels, but present a weak effect on the response to alendronate.

Gorham-Stout disease: radiological, histological, and clinical features of 12 cases and review of literature.

Gorham-Stout disease (GSD) is an exceedingly rare disease characterized by progressive osteolysis and angiomatosis. We investigate the features of this disease and evaluate the effects of bisphosphonates (BPs) on it. The clinical, radiological, and pathological characteristics of 12 patients diagnosed with GSD were summarized. Immunohistochemical staining with specific lymphatic endothelial markers (D2-40), vascular markers (CD 31, CD 34), and vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 3 (VEGFR-3) was performed in specimens of bone biopsy. Patients were treated with either BPs or conjunction therapy of radiation and BPs. The effects of BPs were evaluated by the change of radiological progression, bone mineral density (BMD) and bone turnover biomarkers. To further evaluate the prognosis, a literature review was done. Idiopathic massive osteolysis was found in all patients, including 11 polyostotic and one mono-ostotic osteolysis. Soft tissue lymphangioma was presented in four patents. Four patients were complicated with chylothorax. Endothelial cells lining the proliferative vessels were positive for CD31 and CD34 and D2-40. Mild expression of VEGF and VEGFR-3 was also revealed. Stabilization in osteolysis and improvement in BMD were observed after single therapy with BPs or combined with radiotherapy. High mortality rate was found in patients with chylothorax. Spontaneous, progressive osteolysis is the most typical sign of GSD. BPs and radiotherapy can contribute to the clinical stabilization in bone lesion of GSD. The complicated chylothorax possibly indicates poor prognosis.