Weibo Xia

Correction to: Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing

SummaryThe achievement of more accurate diagnosis would greatly benefit the management of patients with osteogenesis imperfecta (OI). In this study, we present the largest OI sample in China as screened by next generation sequencing. In particular, we successfully identified 81 variants, which included 45 novel variants. We further did a genotype-phenotype analysis, which helps make a better understanding of OI.IntroductionThis study aims to reveal the gene mutation spectrum and the genotype-phenotype relationship among Chinese OI patients by next generation sequencing (NGS).MethodsWe developed a NGS-based panel for targeted sequencing of all exons of 14 genes related to OI, and performed diagnostic gene sequencing for a cohort of 103 Chinese OI patients from 101 unrelated families. Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis.ResultsOf the 103 patients from 101 unrelated OI families, we identified 79 mutations, including 43 novel mutations (11 frameshift, 17 missense, 5 nonsense, 9 splice site, and 1 chromosome translocation) in 90 patients (87.4%). Mutations in genes encoding type I collagen, COL1A1 (nxa0=xa037), and COL1A2 (nxa0=xa029) accounts for 73.3% of all molecularly diagnosed patients, followed by IFITM5 (nxa0=xa09, 10%), SERPINF1 (nxa0=xa04, 4.4%), WNT1 (nxa0=xa04, 4.4%), FKBP10 (nxa0=xa03, 3.3%), TMEM38B (nxa0=xa03, 3.3%), and PLOD2 (nxa0=xa01, 1.1%). This corresponds to 75 autosomal dominant inherited (AD) OI patients and 15 autosomal recessive (AR) inherited patients. Compared with AD inherited OI patients, AR inherited patients had lower bone mineral density (BMD) at spine (Pxa0=xa00.05) and less frequent blue sclera (Pxa0=xa00.001). Patients with type I collagen qualitative defects had lower femoral neck BMD Z-score (Pxa0=xa00.034) and were shorter compared with patients with type I collagen quantitative defects (Pxa0=xa00.022).ConclusionWe revealed the gene mutation spectrum in Chinese OI patients, and novel mutations identified here expanded the mutation catalog and genotype and phenotype relationships among OI patients.

Establishment of a normal reference value of parathyroid hormone in a large healthy Chinese population and evaluation of its relation to bone turnover and bone mineral density

SummaryA normal reference value of parathyroid hormone (PTH) was established for the first time in a large sample of healthy Chinese subjects by completely excluding interference of vitamin D deficiency. A high PTH level correlated significantly with an elevated bone turnover and a reduced bone mineral density (BMD).IntroductionThe aims of this study are to establish a normal reference value for serum PTH and to evaluate the effect of parathyroid gland status on bone turnover and BMD.MethodsOur cross-sectional study included 1436 healthy individuals from 5 different Chinese cities. Concentrations of serum PTH, 25-hydroxyvitamin D (25OHD), procollagen I N-terminal peptide (P1NP, a bone formation marker), and carboxyl-terminal telopeptide of type I collagen (β-CTX, a bone resorption marker) were measured by electrochemiluminescence immunoassay. BMD was measured by dual-energy X-ray absorptiometry. The relation of PTH concentration to age, gender, height, and weight was examined. Reference values of PTH were established for all subjects and for subjects categorized by serum 25OHD concentrations. Correlations of PTH levels with bone turnover biomarkers and BMD were statistically analyzed.ResultsReference values of PTH were 8.84–69.95xa0pg/mL in all the subjects and 7.48–60.73 and 5.83–56.78xa0pg/mL in the subjects with serum 25OHD concentrations of ≥20 and ≥30xa0ng/mL, respectively. Serum PTH showed a negative linear correlation with 25OHD, and the breakpoint was 18.21 ng/mL, below which the PTH level rapidly increased. The increase in PTH levels with age showed a positive linear correlation with P1NP and β-CTX concentrations and a negative linear correlation with BMD at the lumbar spines and the femoral neck.ConclusionsA reference value of PTH was established in a large sample of healthy Chinese subjects according to 25OHD status, gender, and age. A high PTH level correlated significantly with an elevated bone turnover and a reduced BMD.

Longitudinal increase in vitamin D binding protein levels after initiation of tenofovir/lamivudine/efavirenz among individuals with HIV.

Objective:To examine longitudinal change in vitamin D binding protein (DBP) levels during the first year after initiation of tenofovir disoproxil fumarate (TDF)/lamivudine/efavirenz and compare these findings with concurrent changes in markers of skeletal metabolism. Design:Secondary analysis of plasma samples collected from an ongoing multicenter clinical trial. Methods:Plasma samples collected at 0, 24, and 48 weeks after initiation of TDFu200a+u200alamivudineu200a+u200aefavirenz from 134 adult participants enrolled in a multicenter randomized trial were analyzed. Data regarding sociodemographic and clinical characteristics were obtained as part of the parent study. Laboratory analyses included plasma DBP, intact parathyroid hormone, total 25-hydroxy vitamin D, phosphorus, the bone resorption marker collagen type 1 cross-linked C-telopeptide, and the bone formation marker total procollagen type 1 N-terminal propeptide. Repeated measures analysis of variance was used to measure changes in biomarkers over time. Results:Our sample included 108 men and 26 women (mean age 33.6u200a±u200a9.6 years). Median levels of DBP increased significantly from baseline to 48 weeks [154 (91.8–257.4) versus 198.3 (119.6–351.9)u200a&mgr;g/ml, Pu200a<u200a0.001]. A concurrent rise in intact parathyroid hormone levels was observed over the same period [32.3 (24.4–40.9) versus 45.2 (35.1–60.4)u200apg/ml, Pu200a<u200a0.001]; however, 25-hydroxy vitamin D and phosphorus levels remained stable. Bone resorption and formation markers rapidly increased from 0 to 24 weeks, followed by a slight decline or plateau, but remained significantly elevated at 48 weeks (Pu200a<u200a0.001). Conclusion:Our study provides longitudinal data supporting a potential role for DBP in bone loss associated with TDF-based therapy. Further research to elucidate the mechanistic pathways and clinical impact of these findings is warranted.

Alendronate sodium/vitamin D3 combination tablet versus calcitriol for osteoporosis in Chinese postmenopausal women: a 6-month, randomized, open-label, active-comparator-controlled study with a 6-month extension

This study compares efficacy of ALN/D5600 versus that of calcitriol in osteoporotic Chinese postmenopausal women. ALN/D5600 produced greater bone mineral density (BMD) increases, greater bone turnover marker decreases, and less vitamin D insufficiency. This study provided detailed clinical information regarding ALN/D5600 treatment versus calcitriol 0.25xa0μg/day. The study did not evaluate fracture risk. The aim of this study is to investigate efficacy of alendronate 70xa0mg/vitamin D3 5600xa0IU combination tablets (ALN/D5600) versus calcitriol in osteoporotic Chinese postmenopausal women. This study is a 6-month, randomized, open-label, active-comparator study with 6-month extension (clinicaltrials.gov number NCT01350934) in postmenopausal women aged >55xa0years with osteoporosis (low bone mineral density (BMD) with/without prior fragility fracture). Patients were randomized to ALN/D5600 once weekly or calcitriol 0.25xa0μg daily. The primary efficacy end point of the base study was percent change from baseline in lumbar spine BMD (month 6). Hypercalcemia and hypercalciuria were safety events of special interest. A total of 219 patients (ALN/D5600 nu2009=u2009111, calcitriol nu2009=u2009108) were randomized. Baseline characteristics were similar, 30.3xa0% baseline 25-hydroxyvitamin D (25(OH)D) ≤15xa0ng/mL. At months 6 and 12, changes in lumbar spine BMD from baseline were 3.5 versus 1.6xa0% and 5.2 versus 2.3xa0% for ALN/D5600 versus calcitriol (between-group differences pu2009<u20090.001), respectively. Between-group differences for ALN/D5600 versus calcitriol were significant (pu2009<u20090.001) at months 6 and 12 for change from baseline in procollagen type 1 N-terminal propeptide (−59.1 versus −16.8xa0%, −68.1 versus −17.0xa0%) and serum C-telopeptides (−79.2 versus −27.2xa0%, −76.2 versus −24.2xa0%). Drug-related adverse events (AEs) and discontinuations due to drug-related AEs occurred in 15 (14.0xa0%) versus 8 (7.4xa0%) patients and 3 (2.8xa0%) versus 0 patients in the ALN/D5600 and calcitriol group, respectively. Hypercalciuria 12-month incidence (24-h urine Ca >300xa0mg) was 8.4 (ALN/D5600) versus 13.9xa0% (calcitriol) (pu2009>u20090.05). One patient (calcitriol) had hypercalcemia. ALN/D5600 produced greater increases in lumbar spine BMD and greater decreases in bone turnover markers versus calcitriol in osteoporotic Chinese women. It is not known whether the greater increase in BMD results in fewer fractures. ALN/D5600 was generally well tolerated in Chinese patients.

Osteoporosis knowledge, self-efficacy, and health beliefs among Chinese individuals with HIV

SummaryIndividuals with HIV are at increased risk for osteoporosis and fracture. Using the Health Beliefs Model, we identified key relationships between knowledge, self-efficacy and health beliefs pertaining to physical activity and dietary calcium intake, two key modifiable preventive measures for osteoporosis.PurposeIndividuals with HIV are at increased risk for osteoporosis and fracture. Few studies have systematically explored concerns related to osteoporosis prevention among this group. Applying the Health Beliefs Model (HBM), we examined associations between osteoporosis-related preventive health behaviors (i.e., physical exercise and dietary intake) and knowledge, self-efficacy and health beliefs in a large cohort of Chinese individuals with HIV.MethodsWe conducted a cross-sectional study with participants from an ongoing multi-center trial. Volunteers completed a questionnaire consisting of the International Physical Activity Questionnaire (IPAQ), a calcium and vitamin D intake assessment, the Osteoporosis Knowledge Test, Osteoporosis Self-Efficacy Scale, Osteoporosis Health Beliefs Scale, and relevant sociodemographic and clinical risk factors.ResultsA total of 263 of 297 eligible participants enrolled in this study. Mean age of participants was 38.4u2009±u20099.8xa0years, average BMI was 21.6u2009±u20092.6xa0kg/m2, and 76xa0% were men. About 30xa0% of the sample reported low physical activity. Consumption of foods from each calcium and vitamin D-rich category averaged between multiple times per month to weekly. Knowledge regarding osteoporosis was universally low and self-efficacy correlated directly with engagement in preventive behaviors. Women and individuals with lower education perceived greater barriers to adopting preventive behaviors. Multivariate logistic regression adjusted for age, sex and BMI showed that calcium and vitamin D intake was directly correlated with knowledge and self-efficacy, whereas physical activity correlated with manual labor occupation, perceived barriers to exercise and health motivation.ConclusionsBehavioral frameworks such as the HBM may provide important insight into promoting adoption and maintenance of osteoporosis-related preventive behaviors among individuals with HIV.

Increased bone resorption during tenofovir plus lopinavir/ritonavir therapy in Chinese individuals with HIV

SummaryWe sought to evaluate the effects of antiretroviral therapy on skeletal metabolism in Chinese individuals with human immunodeficiency virus. Patients switched to tenofovir/lamivudineu2009+u2009lopinavir/ritonavir after treatment failure had an increase in bone resorption marker levels by nearly 60xa0%, which is greater than the magnitude previously described in non-Chinese populations.IntroductionFew studies have evaluated the effects of antiretroviral therapy on skeletal metabolism in Asian populations infected with human immunodeficiency virus (HIV).MethodsWe performed a secondary analysis of bone turnover markers (BTM) at baseline and 2xa0years in stored plasma samples collected from 2/2009 to 1/2013 as part of a multi-center trial. Two groups were compared: (1) treatment-naïve patients initiated on zidovudine (AZT)/lamivudine (3TC) plus nevirapine (NVP) and (2) patients who failed first-line therapy and were switched to tenofovir (TDF)/3TC plus lopinavir/ritonavir (LPVr). Tests included the bone resorption marker, C-terminal cross-linking telopeptide of type-1 collagen (CTX), and the bone formation marker procollagen type 1xa0N-terminal propeptide (P1NP).ResultsIn the TDF/3TCu2009+u2009LPVr group, samples were available from 59 patients at baseline and 56 patients at 2xa0years. Of these, 36 patients had samples available from both time points. In the AZT/3TCu2009+u2009NVP group, plasma samples were analyzed from 82 participants at baseline and of those, 61 had samples at 2xa0years. Median change over 2xa0years was greater in the TDF/3TCu2009+u2009LPVr group for both CTX (+0.24xa0ng/mL, interquartile ranges (IQR) 0.10–0.43 vs. +0.09xa0ng/mL, IQR −0.03 to 0.18, pu2009=u20090.001) and P1NP (+25.5xa0ng/mL, IQR 2.4–51.3 vs. +7.11xa0ng/mL, IQR −4.3 to 21.6, pu2009=u20090.012). Differences remained after adjusting for potential confounders in the multivariable analysis.ConclusionsSwitching to TDF/3TCu2009+u2009LPVr after treatment failure resulted in greater increases in BTMs than initiation with AZT/3TCu2009+u2009NVP in Chinese patients with HIV. Following this change, bone resorption marker levels increased by nearly 60xa0%, which is greater than the 25–35xa0% increase from baseline described previously in non-Chinese populations. Further studies are warranted to elucidate these findings.

An updated hip fracture projection in Asia: The Asian Federation of Osteoporosis Societies study

Objectives Hip fracture is a major public health problem. Earlier studies projected that the total number of hip fracture will increase dramatically by 2050, and most of the hip fracture will occur in Asia. To date, only a few studies provided the updated projection, and none of them focused on the hip fracture projection in Asia. Thus, it is essential to provide the most up to date prediction of hip fracture in Asia, and to evaluate the total direct medical cost of hip fracture in Asia. Methods We provide the updated projection of hip fracture in 9 Asian Federation of Osteoporosis Societies members using the most updated incidence rate and projected population size. Results We show that the number of hip fracture will increase from 1,124,060 in 2018 to 2,563,488 in 2050, a 2.28-fold increase. This increase is mainly due to the changes on the population demographics, especially in China and India, which have the largest population size. The direct cost of hip fracture will increase from 9.5 billion United State dollar (USD) in 2018 to 15 billion USD in 2050, resulting a 1.59-fold increase. A 2%–3% decrease in incidence rate of hip fracture annually is required to keep the total number of hip fracture constant over time. Conclusions The results show that hip fracture remains a key public health issue in Asia, despite the available of better diagnosis, treatment, and prevention of fracture over the recent years. Healthcare policy in Asia should be aimed to reduce the burden of hip fracture.

Bone turnover and bone mineral density in HIV-1 infected Chinese taking highly active antiretroviral therapy -a prospective observational study.

BackgroundLow bone mass and high bone turnover have been reported in HIV-infected individuals, both as a consequence of HIV infection itself, as well as from treatment with highly active antiretroviral therapy (HAART). The purpose of this study is to evaluate the impact of HAART on bone mineral density and bone turnover in HIV-1 infected Chinese patients.MethodsForty HIV-1 infected patients were enrolled in this study; all patients were followed through 48xa0weeks, and 17 patients completed 96xa0weeks. Bone mineral density (BMD), procollagen type 1xa0N-terminal propeptide (P1NP), collagen type 1 cross-linked C-telopeptide (β-CTX), parathyroid hormone (PTH), and 25-OH vitamin D levels were measured at baseline, 48 and 96xa0weeks. Baseline measurements were compared with an age-, gender-, and BMI-matched healthy control population.ResultsAt baseline, raw BMD in the lumbar spine of HIV-1 infected patients was significantly lower than that of healthy controls (1.138u2009±u20090.112xa0g/cm2 vs. 1.195u2009±u20090.139xa0g/cm2, pu2009=u20090.047). During the first 48xa0weeks after initiating HAART, BMD of lumbar spine, femoral neck, and total hip decreased significantly in HIV-1 infected patients, with annual percent decline ranging from 1.78-3.28%. However, from week 48 to 96, BMD remained stable. Baseline levels of β-CTX (0.31u2009±u20090.16xa0ng/mL vs. 0.42u2009±u20090.19xa0ng/mL, pu2009=u20090.008) and P1NP (32.96u2009±u200914.00xa0ng/mL vs. 55.82u2009±u200926.87xa0ng/mL, pu2009=u20090.05) were lower in HIV-infected patients compared with controls, respectively. Both β-CTX and P1NP levels increased after onset of HAART until week 48, and remained elevated during the next 48xa0weeks. 25-OH vitamin D in HIV-infected patients was lower at baseline compared to healthy controls, but this difference was not statistically significant. PTH, however, was higher in HIV patients at baseline, and showed a significant increase throughout the study.ConclusionsChinese adults with HIV-1 infection have low bone turnover prior to HAART as well as lower raw BMD of the lumbar spine compared with healthy controls, with further bone loss occurring following the initiation of HAART. The long-term clinical implications of these findings remain unclear at this time.

The Asian Federation of Osteoporosis Societies' call to action to improve the undertreatment of osteoporosis in Asia

Osteoporosis and its associated fractures lead to significant morbidity and mortality worldwide. Asia is not exempt, as it has been estimated that over 50% of all the hip fractures in the world will occur in Asia by 2050 [1]. A recent review estimated that around 30% of the hip fractures occurring worldwide will arise in Asian populations, most notably in China [2], due to an increasingly ageing population. The age-adjusted incidence of hip fracture among men and women in China [2,3], Japan [2], and Thailand [4] are increasing, with a possible stabilization of the rates in Hong Kong and Singapore [2]. The increased mortality following osteoporotic fractures has also been shown in Asian populations. A multicentre survey from mainland China found that the mortality was doubled after osteoporotic vertebral and hip fractures compared to that of the healthy population [5]. The 1-year mortality after a hip and vertebral fracture was 3.8% and 3.1% respectively, compared to 1.6% in the nonfracture population. Overall, the 5-year mortality was 16.9% [5]. In Taiwan, the 1-year mortality after a low-energy trauma hip fracture was found to be 12.4% [6]. The 1-year mortality rate after hip fracture was 23.9% in Korean nursing home residents [7]. Morbidity with impaired self-care ability was also high, with 40.6% affected after a hip fracture in the aforementioned study in mainland China [5]. The risk of a second osteoporotic fracture following the first osteoporotic fracture is increased by up to 4 times compared to those who have not yet had a fracture [8]. Thus, treating these high-risk patients should be a key priority. Despite the significant mortality and morbidity following osteoporotic fractures, there is a lack of recognition of the importance of osteoporosis, with very few Asian countries making osteoporosis one of their national health priorities [9]. The ability to diagnose osteoporosis can pose a challenge in Asia. Many countries in Asia have predominant rural populations where there is difficulty in getting access to health care professionals who are knowledgeable about osteoporosis. In addition, access to bone mineral density measurements with dual-energy X-ray absorptiometry (DXA) is highly variable, with many Asian countries having less than 1 DXA machine per million population [9], when the recommendation is 10.6 DXA units per million of the general population [10]. Antiosteoporosis medication (AOM) have been shown to be very effective in significantly reducing future osteoporotic fractures [11]. However, even when osteoporosis has been identified after a fragility fracture, a treatment gap remains. The low rate of

Consensus on best practice standards for Fracture Liaison Service in the Asia-Pacific region

SummaryThe Fracture Liaison Service (FLS) Consensus Meeting endorsed by the International Osteoporosis Foundation (IOF), Asian Federation of Osteoporosis Societies (AFOS), and Asia Pacific Osteoporosis Foundation (APOF) was hosted by the Taiwanese Osteoporosis Association on October 14, 2017. International and domestic experts reviewed the 13 Best Practice Framework (BPF) standards and concluded that all standards were generally applicable in the Asia-Pacific region and needed only minor modifications to fit the healthcare settings in the region.PurposeTo review and generate consensus on best practices of fracture liaison service (FLS) in the Asia-Pacific (AP) region.MethodsIn October 2017, the Taiwanese Osteoporosis Association (TOA) invited experts from the AP region (nu2009=u200923), the Capture the Fracture Steering Committee (nu2009=u20092), and the USA (nu2009=u20091) to join the AP region FLS Consensus Meeting in Taipei. After two rounds of consensus generation, the recommendations on the 13 Best Practice Framework (BPF) standards were reported and reviewed by the attendees. Experts unable to attend the on-site meeting reviewed the draft, made suggestions, and approved the final version.ResultsBecause the number of FLSs in the region is rapidly increasing, experts agreed that it was timely to establish consensus on benchmark quality standards for FLSs in the region. They also agreed that the 13 BPF standards and the 3 levels of standards were generally applicable, but that some clarifications were necessary. They suggested, for example, that patient and family education be incorporated into the current standards and that communication with the public to promote FLSs be increased.ConclusionsThe consensus on the 13 BPF standards reviewed in this meeting was that they were generally applicable and required only a few advanced clarifications to increase the quality of FLSs in the region.