Epidemiology of hip fractures in Thailand.

This retrospective study examining hip fracture incidence, hip fracture trends, and the annual hospitalization costs for hip fractures in a population aged 50 years and older within the Universal Health Coverage System revealed that the incidence of hip fractures and the annual hospitalization costs for hip fractures increased significantly from 2013 to 2022. PURPOSE: To examine the annual incidence of hip fractures over 10 years (2013-2022), hip fracture trends, and the annual hospitalization costs for hip fractures in a population aged 50 years and older within the Universal Health Coverage System. METHODS: A retrospective study was conducted. Hip fracture hospitalizations were identified using ICD-10. Data on the number of hip fracture hospitalizations, population aged ≥ 50 years, and hospitalization costs were obtained. The primary outcome was the annual incidence of hip fractures. The secondary outcomes were hip fracture incidence by 5-year age group, the annual hospitalization costs for hip fractures, and the number of hip fractures in 6 regions of Thailand. RESULTS: The hip fracture incidence increased annually from 2013-2019 and then plateaued from 2019-2022, with the crude incidence (per 100,000 population) increasing from 112.7 in 2013 to 146.7 in 2019 and 146.9 in 2022. The age-standardized incidence (per 100,000 population) increased from 116.3 in 2013 to 145.1 in 2019 and remained at 140.7 in 2022. Increases in the crude incidence were observed in both sexes (34% in females and 21% in males; p < 0.05). The annual hospitalization costs for hip fractures increased 2.5-fold, from 17.3 million USD in 2013 to 42.8 million USD in 2022 (p < 0.001). The number of hip fractures increased in all six regions of Thailand across the 10-year study period. CONCLUSION: Osteoporotic hip fractures are a significant health concern in Thailand. The incidence and the annual hospitalization costs for hip fractures increased significantly from 2013 to 2022.

Global prevalence of advanced fibrosis in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) face a heightened susceptibility to advanced fibrosis, a condition linked to adverse clinical outcomes. However, reported data on liver fibrosis severity among individuals with T2DM vary significantly across studies with diverse characteristics. This meta-analysis aimed to estimate the global prevalence of advanced fibrosis among T2DM patients. METHODS: A comprehensive systematic search of the EMBASE and MEDLINE databases from inception to November 2022 was conducted to identify studies assessing advanced fibrosis in individuals with T2DM. Random-effects models were utilized to calculate point estimates of prevalence, accompanied by 95% confidence interval (CI). Meta-regression with subgroup analysis was employed to address heterogeneity. RESULTS: We identified 113 eligible studies involving 244,858 individuals from 29 countries. Globally, the prevalence of advanced fibrosis among T2DM patients was 19.5% (95% CI 16.8-22.4%). Regionally, the prevalence rates were as follows: 60.5% in West Asia (95% CI 50.3-70.4%), 24.4% in South Asia (95% CI 16.2-33.7%), 20.1% in East Asia (95% CI 14.7-26.1%), 20.0% in Europe (95% CI 15.8-24.6%), 15.8% in North America (95% CI 11.0-21.3%), and 11.3% in South America (95% CI 6.2-17.5%). The prevalence of advanced fibrosis varied notably based on the study setting and diagnostic methodology employed. Meta-regression models highlighted that 45.13% of the observed heterogeneity could be attributed to combined diagnostic modality and study setting. CONCLUSIONS: Globally, approximately one fifth of the T2DM population presents advanced fibrosis, with prevalence differing across geographical regions. Our findings underscore the need for effective strategies to alleviate its global burden.

Asia-Pacific consensus on long-term and sequential therapy for osteoporosis.

Objectives: This study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach. Methods: A panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches. Results: The panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment. Conclusions: This consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management.

Metabolic dysfunction-associated steatotic liver disease and the risk of mortality in individuals with type 2 diabetes: a systematic review and meta-analysis.

The systematic review aimed to assess the risks of metabolic dysfunction-associated steatotic liver disease (MASLD) on all-cause and cause-specific mortality in patients with type 2 diabetes (T2DM). EMBASE and MEDLINE were searched from inception to June 2022 for observational studies examining the relationship between MASLD and the risk of mortality among T2DM patients. Meta-analysis was conducted using random-effects models with hazard ratios (HRs) to quantify the risk of mortality. A total of 5877 articles were screened, and ultimately, 12 eligible studies encompassing 368 528 T2DM patients, with a median follow-up of 8.9 years (interquartile range, 4.7-14.5), were included. Our analysis revealed a significant association between MASLD and an increased risk of all-cause mortality in T2DM patients [HR 1.28; 95% confidence interval (CI), 1.05-1.58; I 2  = 90%]. Meta-regression analyses did not show significant effects of mean age, mean BMI, and percentage of smokers, hypertension, and hyperlipidemia on the association between MASLD and the risk of all-cause mortality. However, we found that MASLD was not significantly associated with mortality related to cardiovascular diseases (HR 1.05; 95% CI, 0.82-1.35; I2  = 0%) or cancer (HR 1.21; 95% CI, 0.41-3.51; I 2  = 79%) among patients with T2DM. No publication bias was observed. This comprehensive meta-analysis provides substantial evidence supporting a significant association between MASLD and an increased risk of all-cause mortality among the T2DM population. These findings underscore the potential benefits of screening for MASLD in T2DM patients, aiding in the early identification of high-risk individuals and enabling risk modification strategies to improve survival.

Physicians' awareness of medication-related osteonecrosis of the jaw in patients with osteoporosis.

A serious adverse effect of antiresorptive drugs, which are widely used to treat osteoporosis, is medication-related osteonecrosis of the jaw (MRONJ). Physicians can reduce the risk of MRONJ by educating patients and emphasizing the importance of good oral health. However, limited information is available regarding physicians' awareness and clinical practices associated with MRONJ. Hence, this study aimed to examine physicians' awareness related to MRONJ and associated clinical practices. This study was a cross-sectional study conducted from December 2022 to February 2023. An online self-administered questionnaire was sent to physicians in Thailand who prescribed antiresorptive drugs for osteoporosis. Most respondents agreed that antiresorptive drugs might cause MRONJ (92.3%), poor oral health increased the risk of MRONJ (84%), and MRONJ is an important consideration in patients with osteoporosis (85%). Of the respondents, 48.1% and 15.5% always referred patients to dentists before and during antiresorptive therapy, respectively. Approximately 60% of physicians informed patients of the MRONJ risk before prescribing antiresorptive drugs, and 30% inquired about patients' oral symptoms at the follow-up visit. Overall, 44% of physicians advised patients to receive oral health care; the most common reason for not advising this was that respondents did not consider themselves to be adequately knowledgeable to detect oral health problems. These findings indicate that while most physicians who prescribed antiresorptive drugs for osteoporosis were aware of and considered MRONJ in their practice, several took insufficient action to prevent it. This highlights the need to emphasize clinical practice guidelines and collaboration between physicians and dentists.

Lean non-alcoholic fatty liver disease and the risk of all-cause mortality: An updated meta-analysis.

INTRODUCTION AND OBJECTIVES: Cohort studies reported controversial results regarding the long-term prognosis of patients with lean non-alcoholic fatty liver disease (NAFLD) compared to non-lean NAFLD patients. This updated meta-analysis aimed to estimate the magnitude of the association between lean body mass index and all-cause mortality risk in NAFLD patients. MATERIALS AND METHODS: We systematically searched the EMBASE and MEDLINE databases from inception to March 2023 to identify observational studies that reported hazard ratio (HR) for all-cause mortality of patients with lean NAFLD versus those with non-lean, overweight, or obese NAFLD. Multivariable-adjusted hazard ratios (HRs) for all-cause mortality were pooled using a random effects model. RESULTS: Fourteen studies with 94,181 NAFLD patients (11.3 % with lean NAFLD) and 7,443 fatal events over a median follow-up of 8.4 years (IQR, 6.6-17.4 years) were included. Patients with lean NAFLD had a higher risk of all-cause mortality than those with non-lean NAFLD (random-effects HR 1.61, 95 % CI 1.37-1.89; I2=77 %). The magnitude of this risk remained unchanged even after stratified analysis by measures of NAFLD diagnosis, study country, cohort setting, length of follow-up, adjustment with fibrosis stage/cirrhosis, and the Newcastle-Ottawa Scale. The risk was independent of age, sex, and cardiometabolic risk factors. Sensitivity analyses did not alter these findings. The funnel plot and Egger's test revealed no significant publication bias. CONCLUSIONS: This meta-analysis revealed that lean NAFLD is associated with an approximately 1.6-fold increased mortality risk. Further studies are needed to unravel the existing but complex link between lean NAFLD and an increased risk of death.

Familial clustering of nonalcoholic fatty liver disease in first-degree relatives of adults with lean nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD. METHODS: This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms. RESULTS: The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD. CONCLUSIONS: Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.

A multidisciplinary approach to post-operative fragility hip fracture care in Thailand - a narrative review.

INTRODUCTION: Appropriate care and rehabilitation following surgery for fragility hip fractures in older adults is associated with better outcomes and a greater likelihood of achieving pre-injury functioning. Clinical guidelines specifically for the post-operative care and rehabilitation of patients with hip fractures are scarce; as such, country-specific protocols benchmarked against established guidelines are essential given the wide variation in cultures and beliefs, clinical practice and diverse healthcare systems in Asia. We aimed to provide clinically relevant recommendations for post-operative fragility hip fracture care and rehabilitation to improve patient outcomes and prevent subsequent fractures in Thailand. METHODS: A targeted literature review was conducted to identify key evidence on various elements of post-hip fracture care and rehabilitation. Further discussions at a meeting and over email correspondence led to the development of the recommendations which amalgamate available evidence with the clinical experience of the multidisciplinary expert panel. RESULTS: Our recommendations are categorized by one period domain - acute post-operative period, and five major domains during the post-operative period - rehabilitation, optimization of bone health, prevention of falls, nutritional supplementation, and prophylaxis for venous thromboembolism. A multidisciplinary approach should be central to the rehabilitation process with the involvement of orthopedists, geriatricians/internists, physiatrists, physical and occupational therapists, endocrinologists, pharmacists and nursing staff. Other key components of our recommendations which we believe contribute to better functional outcomes in older patients undergoing hip fracture surgery include comprehensive pre-operative assessments, early surgery, goal setting for recovery and rehabilitation, early mobilization, medication optimization, tailored exercise plans, adequate coverage with analgesia, assessment and appropriate management of osteoporosis with due consideration of the fracture risk, fall prevention plans, and nutritional assessment and support. Patients and their caregivers should be a part of the recovery process at every step, and they should be counseled and educated appropriately, particularly on the importance of adherence to their rehabilitation plan. CONCLUSION: We have provided guidance on the critical domains of clinical care in the post-operative setting to optimize patient outcomes and prevent fracture recurrence. Our recommendations for post-operative care and rehabilitation of older adults with hip fracture can serve as a framework for hospitals across Thailand.

Summary of the Thai Osteoporosis Foundation (TOPF) Clinical Practice Guideline on the diagnosis and management of osteoporosis 2021.

Objectives: The Thai Osteoporosis Foundation (TOPF) is an academic organization that consists of a multidisciplinary group of healthcare professionals managing osteoporosis. The first clinical practice guideline for diagnosing and managing osteoporosis in Thailand was published by the TOPF in 2010, then updated in 2016 and 2021. This paper presents important updates of the guideline for the diagnosis and management of osteoporosis in Thailand. Methods: A panel of experts in the field of osteoporosis was recruited by the TOPF to review and update the TOPF position statement from 2016. Evidence was searched using the MEDLINE database through PubMed. Primary writers submitted their first drafts, which were reviewed, discussed, and integrated into the final document. Recommendations are based on reviews of the clinical evidence and experts' opinions. The recommendations are classified using the Grading of Recommendations, Assessment, Development, and Evaluation classification system. Results: The updated guideline comprises 90 recommendations divided into 12 main topics. This paper summarizes the recommendations focused on 4 main topics: the diagnosis and evaluation of osteoporosis, fracture risk assessment and indications for bone mineral density measurement, fracture risk categorization, management according to fracture risk, and pharmacological management of osteoporosis. Conclusions: This updated clinical practice guideline is a practical tool to assist healthcare professionals in diagnosing, evaluating, and managing osteoporosis in Thailand.

Dietary Composition and Its Association with Newly Diagnosed Nonalcoholic Fatty Liver Disease and Insulin Resistance.

Dietary modification is essential for treating nonalcoholic fatty liver disease (NAFLD); however, the dietary components are less well defined. We enrolled 252 adults with no history of liver disease and excessive alcohol use to evaluate the relationship between macronutrients and NAFLD and insulin resistance. Participants took photographs of their meals and documented their food intake in a food diary for seven consecutive days. A dietitian estimated the type and portion size of food items and analyzed nutrients with INMUCAL-Nutrients software. Later, participants underwent transient elastography to diagnose NAFLD and blood tests to measure insulin resistance using the homeostasis model. Total energy intake and the proportion of carbohydrate, fat, and protein consumption did not differ between participants with NAFLD (n = 41) and those without NAFLD (n = 211). Using multiple logistic regression analysis, daily intake of protein < 1.0 g/kg (OR: 3.66, 95% CI: 1.41-9.52) and full-fat dairy product ≥ 50 g (OR: 0.42, 95% CI: 0.18-0.99) were associated with NAFLD. Insulin resistance was associated with a daily intake of protein < 1.0 g/kg (OR: 3.09, 95% CI: 1.59-6.05), full-fat dairy product ≥ 50 g (OR: 0.46, 95% CI: 0.25-0.82), and dietary fiber ≥ 8 g (OR: 0.41, 95% CI: 0.22-0.74). Our data show that a low protein intake increases the odds for NAFLD and insulin resistance. Contrarily, a high intake of full-fat dairy products and dietary fiber has been associated with a potential protective effect against NAFLD and insulin resistance.

Moderate-Intensity Aerobic vs Resistance Exercise and Dietary Modification in Patients With Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial.

INTRODUCTION: This randomized trial aimed to compare the effects of moderate-intensity aerobic vs resistance exercise with dietary modification in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: Patients with NAFLD were randomly assigned (1:1) to a 12-week supervised training program of moderate-intensity aerobic or resistance exercise with dietary intervention consisting of monthly individual nutritional counseling by a dietician. Transient elastography, anthropometry, body composition, cardiorespiratory fitness, biochemistries, and glucose tolerance were measured at baseline and 12 weeks. RESULTS: Eighteen subjects exercised for an average of 3.35 ± 0.30 sessions a week in the aerobic group, and 17 subjects exercised an average of 3.39 ± 0.28 sessions a week in the resistance group. After completion of the training program, hepatic fat content was similarly reduced in both groups (P < 0.001). The mean relative reduction from baseline in the aerobic group was -10.3% (95% confidence interval -18.2 to -2.40) and the resistance group was -12.6% (-20.5 to -4.69). Liver steatosis (defined as controlled attenuation parameter >248 dB/m) disappeared in 9 (50%) of the aerobic group and in 9 (53%) of the resistance group. Whole-body and muscle insulin sensitivity indexes were improved, and waist circumference was reduced comparably in both exercise groups. The number of exercise sessions per week was correlated with the absolute reduction in hepatic fat content (r = 0.52; P = 0.001). Weekly exercise training ≥3 sessions substantially attenuates liver fat accumulation independent of weight loss. DISCUSSION: Moderate-intensity aerobic training and resistance training with dietary modification are equally effective for reducing intrahepatic fat and improving underlying insulin resistance among patients with NAFLD.

The association between perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant Thai women.

CONTEXT: Thyroid hormone is critical for fetal neurodevelopment. Perchlorate and thiocyanate decrease thyroidal iodine uptake by competitively inhibiting the sodium/iodide symporter. It is clear that perchlorate and thiocyanate anions can influence thyroid function. However, as pollutants in the environment, their impact is conflicting. OBJECTIVE: The objective was to determine the effects of environmental perchlorate and/or thiocyanate exposure on thyroid function in first-trimester pregnant women. DESIGN AND PATIENTS: A cross-sectional study was conducted in 200 pregnant Thai women with a gestational age of 14 weeks or less. MEASURES: Urinary iodide, perchlorate, thiocyanate, and serum thyroid function tests were measured. RESULTS: The women were aged 28.6 ± 6.1 years and the mean gestational age was 9.6 ± 2.7 weeks. Median urinary iodide, perchlorate, and thiocyanate concentrations were 153.5 µg/L, 1.9 µg/L, and 510.5 µg/L, respectively. Using Spearman's rank correlation analyses, there were positive correlations between serum TSH and urine perchlorate to creatinine (r = 0.20, P = .005) and TSH and thiocyanate to creatinine ratios (r = 0.22, P = .001). There were negative correlations between free T4 and the perchlorate to creatinine ratio (r = -0.18, P = .01) and free T4 and the thiocyanate to creatinine ratio (r = -0.19, P = .008). In multivariate analyses adjusting for log thiocyanate to creatinine ratio, log iodide to creatinine ratio, and gestational age, log perchlorate to creatinine ratio was positively associated with log TSH (P = .002) and inversely associated with log free T4 (P = .002). Log thiocyanate to creatinine ratio was a significant positive predictor of log TSH (P = .02) in women with a urine iodide level of less than 100 µg/L. CONCLUSIONS: Low-level environmental exposure to perchlorate and thiocyanate is common in Thailand. Low-level exposure to perchlorate is positively associated with TSH and negatively associated with free T4 in first-trimester pregnant women using multivariate analyses. In multivariate analyses, thiocyanate exposure is also positively associated with TSH in a subgroup of pregnant women with low iodine excretion.

Maternal vitamin D status, its associated factors and the course of pregnancy in Thai women.

CONTEXT: There are limited data on the prevalence of vitamin D inadequacy in pregnant women living in Southeast Asia and changes in their vitamin D status during pregnancy. OBJECTIVES: To determine the prevalence of vitamin D inadequacy, its predictive factors and the changes in vitamin D status during the course of pregnancy. DESIGN AND PATIENTS: A prospective study of 120 pregnant Thai women with gestational age <14 weeks. MEASUREMENTS: Serum 25 hydroxyvitamin D (25OHD) and clinical data were obtained at the first visit, in the second and third trimesters of pregnancy. Vitamin D inadequacy was defined as 25OHD <75 nm. RESULTS: The prevalences of vitamin D inadequacy were 83.3%, 30.9% and 27.4% for the first, second and third trimesters. The independent predictors of vitamin D inadequacy in the third trimester were not drinking vitamin-fortified milk (OR 11.42; 95% CI: 3.12-41.86), not taking prenatal vitamins (OR 9.70; 95% CI: 2.28-41.19) and having vitamin D deficiency in the first trimester (OR 10.58; 95% CI: 2.89-38.80). Vitamin D deficiency was not found in women taking prenatal vitamins. However, 20 women who took at least 400 IU/day of vitamin D from prenatal vitamins still had vitamin D insufficiency in the third trimester. CONCLUSIONS: Vitamin D inadequacy is common in pregnant Thai women, especially in the first trimester. Vitamin D supplementation may be needed prior to conception and during pregnancy. For areas with abundant sun exposure like Thailand, vitamin D supplementation at 400 IU/day is likely to prevent vitamin D deficiency, but is inadequate to prevent vitamin D insufficiency even at 800 IU/day.

Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1α levels in patients with MGUS.

Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, because areal bone mineral density (aBMD) measurements by dual-energy x-ray absorptiometry cannot assess bone microstructural properties critical to determining bone quality and strength. To better define the skeletal effects of MGUS, we performed aBMD and high-resolution peripheral quantitative computed tomography volumetric bone mineral density (vBMD) measurements in 50 MGUS patients (20 females, 30 males; mean ± SEM age, 70.5 ± 1.4 years) and 100 matched control subjects. Relative to controls, MGUS patients had decreased aBMD at the femoral neck (P = .05) and total femur (P < .05) but no differences at other sites. In contrast, high-resolution peripheral quantitative computed tomography showed markedly diminished cortical thickness (P < .05) and increased endocortical area (P < .01). Average vBMD (P < .01), cortical vBMD (P < .001), and trabecular thickness (P < .01) were all significantly decreased in MGUS patients, suggestive of impaired bone formation. Serum levels of the Wnt pathway inhibitor Dickkopf-related protein 1 (P < .001) and osteoclast-activating factor MIP-1α (P < .05) also were significantly elevated in MGUS patients. Our data provide the first evidence of altered bone microstructure in MGUS and suggest that cytokines elevated in osteolytic myeloma also may be associated with bone loss in MGUS.

Association of genetic variants in GABRA3 gene and thyrotoxic hypokalaemic periodic paralysis in Thai population.

BACKGROUND: Genetic predisposition has been suggested to play role in the pathogenesis of thyrotoxic hypokalaemic periodic paralysis (THPP). OBJECTIVES: In this study, we assessed the differences of single-nucleotide polymorphisms (SNP) allelic frequency between THPP patients and well-characterized controls in order to find the susceptibility genetic variants related to THPP using microarray-based assessments on pooled DNA. METHODS: Fifty cases of THPP and 50 male hyperthyroid patients without hypokalaemia as controls were recruited. Equal amounts of individual genomic DNA were pooled from each group. Estimated allele frequencies of SNPs were derived by averaging relative allele signal score obtained by Affymetrix GeneChip(R) Mapping 10K Arrays. RESULTS: Sixty-nine loci that display robust allele frequency differences between THPP and controls were identified. SNP rs750841 (A > T) in intron 3 of the gamma-aminobutyric acid (GABA) receptor alpha3 subunit (GABRA3) gene possessed the most significant difference in allele frequency (27% in THPP case and 5% in controls, P = 0.007). Actual allele frequencies obtained from genotyping in each individual were very similar to the estimated frequency from the pools (28% in THPP and 2% in controls, and P = 0.0002). Nearby DNA sequences of GABRA3 were sequenced and an additional two SNPs were found (A > C at exon 1 and G > T of rs12688128). Allele A of rs750841 and allele G of rs12688128 in intron 3 were predominantly found in THPP with significant genetic relative risk of 19 (P < 0.0002; 95%CI 2.4-151.6). CONCLUSIONS: Whole-genome scanning on pooled DNA provides an accurate, useful screening tool for elucidating genetic underpinnings of THPP. SNPs at intron 3 of GABRA3 are found to be associated with THPP.

Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women.

UNLABELLED: After acute estrogen withdrawal in postmenopausal women, administration of anakinra or etanercept, specific blockers of IL-1 and TNF-alpha, respectively, reduced the rise in bone resorption markers to about one half of that in controls. This is consistent with an important role for these immune cytokines in mediating the effect of estrogen deficiency on bone. INTRODUCTION: Studies in rodents have implicated increased production of interleukin (IL)-1 beta and TNF-alpha as mediators of bone loss after ovariectomy, but their roles are unclear in humans whose immune system differs markedly from that of rodents. MATERIALS AND METHODS: We administered transdermal estradiol, 0.1 mg/d, for 60 days to 42 early postmenopausal women. Estrogen treatment was discontinued, and subjects were randomly assigned to intervention groups receiving 3 wk of injections with 0.9% saline, anakinra 100 mg/d, or etanercept 25 mg/twice weekly. Bone turnover was assessed by measuring serum carboxyl-terminal telopeptide of type 1 collagen (CTX) and amino-terminal telopeptide of type 1 collagen (NTX), markers for bone resorption, and serum amino-terminal propeptide of type 1 collagen (P1NP), a marker for bone formation. Results were expressed as percent change in markers from baseline (last 2 days of estrogen treatment and days 20 and 21 of intervention). RESULTS: The percent changes from baseline during intervention for serum CTX, urine NTX, and serum PINP, respectively, were 43.3 +/- 8.0%, 12.0 +/- 7.1%, and -41.0 +/- 2.5% for the control group; 25.9 +/- 6.3%, 9.5 +/- 4.0%, and -37.8 +/- 3.0% for the anakinra group; and 21.7 +/- 5.0%, 0.32 +/- 3.82%, and -34.5 +/- 3.9% for the etanercept group. Compared with the control group, the blunting of the increase in serum CTX fell just below the level of significance (p=0.10) after anakinra treatment, whereas the blunting of the increase in serum CTX (p=0.034) and in urine NTX (p=0.048) were significant after etanercept treatment. Other changes were not significant. CONCLUSIONS: The data are consistent with a role for TNF-alpha, and possibly for IL-1 beta, in mediating increased bone resorption during estrogen deficiency in women. Although either cytokine blocker reduced serum CTX by about one half, the effect of combined blockade could not be tested because of concerns about toxicity. The data do not exclude direct or indirect contributory roles for RANKL or for other cytokines.

Characterization of circulating osteoblast lineage cells in humans.

We recently identified circulating osteoblastic cells using antibodies to osteocalcin (OCN) or alkaline phosphatase (AP). We now provide a more detailed characterization of these cells. Specifically, we demonstrate that 46% of OCN positive (OCN(pos)) cells express AP, and 37% also express the hematopoietic/endothelial marker CD34. Using two different anti-OCN antibodies and forward/side light scatter characteristics by flow cytometry, we find that OCN(pos) cells consist of two distinct populations: one population exhibits low forward/side scatter, consistent with a small cell phenotype with low granularity, and a second population has higher forward/side scatter (larger and more granular cell). The smaller, low granularity population also co-expresses CD34, whereas the larger, more granular cells are CD34 negative. Using samples from 26 male subjects aged 28 to 68 years, we demonstrate that the concentration of circulating OCN(pos) cells increases as a function of age (R=0.59, P=0.002). By contrast, CD34(pos) cells tend to decrease with age (R=-0.31, P=0.18); as a consequence, the ratio of OCN(pos):CD34(pos) cells also increase significantly with age (R=0.54, P=0.022). These findings suggest significant overlap between circulating cells expressing OCN and those expressing the hematopoietic/endothelial marker CD34. Further studies are needed to define the precise role of circulating OCN(pos) cells not only in bone remodeling but rather also potentially in the response to vascular injury.