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.

Association of osteoporosis and sarcopenia with fracture risk in transfusion-dependent thalassemia.

Patients with transfusion-dependent thalassemia (TDT) have an increased risk of osteoporosis and fractures. They also have several potential factors associated with sarcopenia. There has been currently no study on sarcopenia and its association with falls and fractures in TDT. This study aims to determine the prevalence of and factors associated with osteoporosis, fragility fractures, and sarcopenia in adults with TDT. A cross-sectional study was conducted at the hematologic clinic at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Clinical data and laboratory testing were collected. Bone mineral density and morphometric vertebral fracture were assessed. Sarcopenia was defined using the 2014 and 2019 Asian Working Group for Sarcopenia (AWGS) criteria. We included 112 TDT patients aged 35.1 ± 12.5 years. The prevalence of osteoporosis was 38.4%. Fragility fractures were found in 20.5% of patients. Lower BMI (OR 0.29; 95% CI 0.12-0.72, P = 0.007) and hypogonadal state (OR 3.72; 95% CI 1.09-12.74, P = 0.036) were independently associated with osteoporosis. According to the 2014 AWGS criteria, the prevalence of overall sarcopenia and severe sarcopenia was 44.6% and 13.4%, respectively. Severe sarcopenia was strongly associated with fragility fractures (OR 4.59, 95% CI 1.21-17.46, P = 0.025). In conclusion, osteoporosis, fragility fractures, and sarcopenia were prevalent in adults with TDT. Severe sarcopenia was associated with fragility fractures. Early osteoporosis and sarcopenia screening and prevention may reduce fracture risk and its complications in these patients.

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.

Association of Phenotypic Aging Marker with comorbidities, frailty and inflammatory markers in people living with HIV.

BACKGROUND: Aging characteristics in people living with HIV (PLWH) are heterogeneous, and the identification of risk factors associated with aging-related comorbidities such as neurocognitive impairment (NCI) and frailty is important. We evaluated predictors of novel aging markers, phenotypic age (PhenoAge) and phenotypic age acceleration (PAA) and their association with comorbidities, frailty, and NCI. METHODS: In a cohort of PLWH and age- and sex-matched HIV-negative controls, we calculated PhenoAge using chronological age and 9 biomarkers from complete blood counts, inflammatory, metabolic-, liver- and kidney-related parameters. PAA was calculated as the difference between chronological age and PhenoAge. Multivariate logistic regression models were used to identify the factors associated with higher (>median) PAA. Area under the receiver operating characteristics curve (AUROC) was used to assess model discrimination for frailty. RESULTS: Among 333 PLWH and 102 HIV-negative controls (38% female), the median phenotypic age (49.4 vs. 48.5 years, p = 0.54) and PAA (- 6.7 vs. -7.5, p = 0.24) was slightly higher and PAA slightly less in PLWH although this did not reach statistical significance. In multivariate analysis, male sex (adjusted odds ratio = 1.68 [95%CI = 1.03-2.73]), current smoking (2.74 [1.30-5.79]), diabetes mellitus (2.97 [1.48-5.99]), hypertension (1.67 [1.02-2.72]), frailty (3.82 [1.33-10.93]), and higher IL-6 levels (1.09 [1.04-1.15]), but not HIV status and NCI, were independently associated with higher PAA. PhenoAge marker discriminated frailty better than chronological age alone (AUROC: 0.75 [0.66-0.85] vs. 0.65 [0.55-0.77], p = 0.04). In the analysis restricted to PLWH, PhenoAge alone predicted frailty better than chronological age alone (AUROC: 0.7412 vs. 0.6499, P = 0.09) and VACS index (AUROC: 0.7412 vs. 0.6811, P = 0.34) despite not statistically significant. CONCLUSIONS: While PLWH did not appear to have accelerated aging in our cohort, the phenotypic aging marker was significantly associated with systemic inflammation, frailty, and cardiovascular disease risk factors. This simple aging marker could be useful to identify high-risk PLWH within a similar chronological age group.

Bone mineral density among virologically suppressed Asians older than 50 years old living with and without HIV: A cross-sectional study.

There are limited data regarding bone health in older people living with HIV (PWH), especially those of Asian ethnicity. We aimed to determine whether BMD in well-suppressed HIV-infected men and women aged ≥ 50 years are different from HIV-uninfected controls. In a cross-sectional study, BMD by dual-energy X-ray absorptiometry and calciotropic hormones were measured. A total of 481 participants were consecutively enrolled (209 HIV+ men, 88 HIV- men, 126 HIV+ women and 58 HIV- women). PWH were on average 2.5 years younger [men: 55.0 vs. 57.5 yr; women: 54.0 vs. 58.0 yr] and had lower body mass index (BMI) [men: 23.2 vs. 25.1 kg/m2; women: 23.1 vs. 24.7 kg/m2] compared to the controls. The median duration since HIV diagnosis was 19 (IQR 15-21) years in men and 18 (IQR 15-21) years in women. Three-quarters of PWH had been treated with tenofovir disoproxil fumarate-containing antiretroviral therapy for a median time of 7.4 (IQR 4.5-8.9) years in men and 8.2 (IQR 6.1-10) years in women. In an unadjusted model, HIV+men had significantly lower BMD (g/cm2) at the total hip and femoral neck whereas there was a tend toward lower BMD in HIV+women. After adjusting for age, BMI, and other traditional osteoporotic risk factors, BMD of virologically suppressed older PWH did not differ from participants without HIV (P>0.1). PWH had lower serum 25(OH)D levels but this was not correlated with BMD. In conclusion, BMD in well-suppressed PWH is not different from non-HIV people, therefore, effective control of HIV infection and minimization of other traditional osteoporosis risk factors may help maintain good skeletal health and prevent premature bone loss in Asian PWH. Clinical trial registration: Clinicaltrials.gov # NCT00411983.

Prevalence of pre-sarcopenia among postmenopausal women younger than 65 years.

OBJECTIVE: Sarcopenia is associated with high morbidity and mortality in older women. Early detection and intervention during the postmenopausal period were hypothesized to help maintain muscle mass and performance. Although the Asian Working Group has developed guidelines for sarcopenia management, the condition has not been sufficiently investigated in the middle-aged cohort of the Asian population. This study aimed to measure the prevalence of pre-sarcopenia and sarcopenia in middle-aged postmenopausal women and to determine the factors associated with low muscle mass. METHODS: In this cross-sectional study conducted in the Menopause Clinic, King Chulalongkorn Memorial Hospital, we used the bioelectrical impedance analysis method to determine the appendicular muscle mass using a body composition analyzer (TANITA MC980 Plus). Appendicular muscle mass index, handgrip strength, and 6-m gait speed were measured in 340 women aged 45 to 65 years. Hormonal profiles, anthropometric data, and relevant history were recorded. RESULTS: The mean age of the study participants and time since menopause were 57.8 ±â€Š4.5 years and 9.4 ±â€Š5.5 years, respectively. The proportion of pre-sarcopenic, sarcopenic, and nonsarcopenic women were 11.8%, 2.7%, and 85.6%, respectively. A body mass index ≤ 20 kg/m2 had the strongest correlation with low muscle mass (odds ratio 7.1; 95% confidence interval 3.0-16.8, P < 0.001). CONCLUSION: Nearly 12% of Thai middle-aged postmenopausal women were pre-sarcopenic. Early detection of symptoms of pre-sarcopenia and maintenance of a healthy body mass index may reduce the burden of this condition for middle-aged and older women.

Prevalence and risk factors of morphometric vertebral fracture in apparently healthy osteopenic postmenopausal Thai women.

OBJECTIVE: To determine the prevalence of and risk factors for morphometric vertebral fracture (VF) in apparently healthy postmenopausal women with osteopenia. METHODS: This cross-sectional study included 490 postmenopausal Thai women with osteopenia. All had no known history of low-trauma fracture, no underlying diseases, or history of taking medications that affect bone metabolism. Morphometric VFs were assessed by thoracolumbar spine x-rays, using the Genant semiquantitative method, and interpreted independently by three radiologists. RESULTS: Mean age of participants was 59.9 ±â€Š7.8 years and mean body mass index was 24.3 ±â€Š3.4 kg/m2. Morphometric VFs were present in 29% (142/490) of women (grade 1: 62.0%, grade 2: 19.3%, and grade 3: 18.7%). Of these, 4.9% were aged 50 years or less, 40.1% were aged 50-59 years, 38% were aged 60-69 years, and 16.9% were aged over 70 years. Age and the Fracture Risk Assessment Tool (FRAX) scores for hip and major osteoporotic fracture, with or without bone mineral density, were positively correlated with VF. No differences in fracture prevalence among those with various degrees of osteopenia. Applying the current guidelines for VF screening results in discoveries of less than a half of osteopenic women who have had morphometric VF. CONCLUSIONS: Almost one third of apparently healthy postmenopausal women with osteopenia had morphometric VF. Advancing age and greater FRAX scores were associated with higher prevalence of morphometric VF.

Bone mineral density changes among people living with HIV who have started with TDF-containing regimen: A five-year prospective study.

There are limited data regarding long-term BMD changes over time among treatment-naïve people living with HIV (PLHIV) after initiating combined antiretroviral therapy (cART) in Asia. We aimed to study bone mineral density (BMD) changes among treatment-naïve PLHIV started treatment with tenofovir disoproxil fumarate (TDF)- or non-TDF-containing regimen and HIV-uninfected controls in an Asian setting. The study was a five-year prospective study. BMD at lumbar spine (LS) (L1 to L4), total hip (TH), and femoral neck (FN) were measured by dual energy X-ray absorptiometry (DEXA) scans at baseline, months 12, 24 and 60. Multivariate logistic regression models were used to explore factors associated with mean BMD ≥5% reduction after 5 years of cART. A total of 106 PLHIV (75 and 31 started TDF- and non-TDF-containing regimen, respectively) and 66 HIV-uninfected individuals were enrolled. The mean percent changes of BMD were significantly different longitudinally between TDF and non-TDF users (p<0.001 for LS, p = 0.006 for TH and p = 0.02 for FN). HIV-positive status and on TDF-containing regimen was independently associated with BMD loss ≥5% at month 60 (adjusted odds ratio [aOR] 7.0, 95% confidence interval [95%CI] 2.3-21.0, P = 0.001 for LS; aOR 4.9, 95%CI 1.7-14.3, P = 0.003 for TH and aOR 4.3, 95%CI 1.6-11.2, P = 0.003 for FN) compared to HIV-uninfected individuals. In a multivariate model for PLHIV only, TDF use (vs. non-TDF, P = 0.005) and pre-treatment CD4+ count <350 cells/mm3 (vs. ≥350 cells/mm3, P = 0.02) were independently associated with ≥5% BMD loss in TH at month 60. Treatment-naïve PLHIV initiating treatment with TDF-containing regimen have higher BMD loss in a Thai cohort. TDF use and low pre-treatment CD4 count were independently associated with BMD loss at month 60 at TH. Earlier treatment initiation and interventions to prevent bone loss could improve skeletal health among PLHIV. Clinicaltrials.gov: NCT01634607.

Higher Proportion of Abnormal Nutritional Status Among Well-Suppressed HIV-Infected Elderly Asians Compared to HIV-Negative Individuals.

Older adults face physiological, psychological, social, and economic changes, which may impair nutritional status, making the body vulnerable to illness and adverse clinical outcomes. Little is known regarding the nutritional status among elderly people living with HIV (PLHIV). We aimed to study the prevalence of malnutrition and the associated factors in a Thai aging cohort. A cross-sectional study was conducted among PLHIV >50 years of age on long-term antiretroviral therapy and HIV-negative controls, frequency matched by sex and age in Bangkok, Thailand. Nutritional status was assessed by the Mini Nutrition Assessment (MNA) tool. Abnormal nutritional status was defined as MNA score <24 (malnutrition and at risk of malnutrition). Body composition was measured by bioelectrical impedance analysis using Body Composition Analyzer. Demographic and disease-related factors were assessed for their association with abnormal nutrition status using multivariable logistic regression. There were 349 PLHIV and 103 HIV-uninfected controls, with median age 55 years. The majority were male (63%) with median body mass index (BMI) of 23.4 kg/m2. PLHIV had lower BMI [median, 23.1 (IQR, 20.8-25.2) vs. 25.3 (22.3-28.7) kg/m2, p < .001], lower fat percent [22.8% vs. 26.3%, p < .001] and lower fat mass [14.2 vs. 16.9 kg, p < .001] and higher abnormal nutritional status (18.05% vs. 6.8%, p = .005) than controls. In the multivariate model, older age (adjusted odds ratio [aOR], 1.06, 95% confident interval [CI]: 1.01-1.12, p = .03), positive HIV status (aOR, 2.67, 95% CI: 1.07-6.65, p = .036), diabetes mellitus (aOR, 2.21, 95% CI: 1.003-4.87, p = .049), lower fat mass (aOR, 0.70, 95%CI: 0.57-0.86, p < .001), and lower BMI (aOR, 0.63, 95% CI: 0.51-0.78, p < .001) were independently associated with abnormal nutritional status. PLHIV had higher risks for abnormal nutritional status compared with HIV-uninfected individuals. Regular screening and monitoring of nutritional status among PLHIV may promote better health outcomes.

Bone turnover markers predict type of bone histomorphometry and bone mineral density in Asian chronic haemodialysis patients.

BACKGROUND: Although the levels of intact parathyroid hormone (iPTH) are well-controlled following the Kidney Disease Outcomes Quality Initiative guideline, the incidence of osteoporosis and fracture are still high in haemodialysis (HD) patients. This study was conducted to investigate the correlation between bone turnover markers, bone mineral density (BMD), and bone histomorphometry in HD patients. METHODS: Twenty-two chronic HD patients were enrolled. Serum levels of bone turnover markers were measured. Double tetracycline-labelled iliac crest bone specimens were evaluated using specialized a computer program (Osteomeasure). The types of bone histomorphometry were classified based on turnover, mineralization and volume. BMD and coronary artery calcification were also determined. RESULTS: Bone histomorphometry revealed osteitis fibrosa (50%), adynamic bone disease (45%) and mixed uremic osteodystrophy (5%). Serum iPTH level predicted high bone turnover with area under the receiver operating characteristic (ROC) of 0.833 (95% CI = 0.665-1.000, P = 0.008). Serum TRAP-5b also had ROC of 0.733 (95% CI = 0.517-0.950, P = 0.065). In addition, when using serum iPTH (cut-off 484.50 ng/mL) or serum TRAP-5b (cut-off 1.91 pg./mL) to predict high turnover, the sensitivity was 0.917. On the other hand, when both iPTH and TRAP-5B were above these cut-off, the specificity was 1.000. Low BMD and severe vascular calcification were commonly identified. However, there were no significant correlations between bone biomarkers and BMD or severe vascular calcification. CONCLUSION: Although iPTH levels were close to the target of Kidney Disease Outcomes Quality Initiative guideline, abnormal bone histomorphometry, BMD, and severe vascular calcification are still common. Bone biopsy is still crucially required as an accurate diagnostic tool in providing optimal guide for the treatment. © 2019 Asian Pacific Society of Nephrology.

Antiretroviral-naïve HIV-infected patients had lower bone formation markers than HIV-uninfected adults.

There are limited studies regarding bone health among people living with HIV (PLHIV) in Asia. We compared bone mineral density (BMD), serum 25-hydroxyvitamin D (25(OH)D) status and bone turnover markers (serum procollagen type1 N-terminal propeptide (P1NP), osteocalcin (OC) and C-terminal cross-linking telopeptide of type1 collagen) among 302 antiretroviral therapy (ART) naive PLHIV compared to 269 HIV-uninfected controls from Thailand. People aged ≥30 years, with and without HIV infection (free of diabetes, hypertension, and active opportunistic infection) were enrolled. BMD at the lumbar spine, total hip, and femoral neck were measured using Hologic DXA at baseline and at 5 years. We analyzed BMD, serum 25(OH)D levels, and bone turnover markers at the patients' baseline visit. PLHIV were 1.5 years younger and had lower BMI. PLHIV had higher mean serum 25(OH)D level and similar BMD to the controls. Interestingly, PLHIV had significantly lower bone formation (serum P1NP and OC), particularly those with low CD4 count. Only a few participants had low bone mass. ARV naïve middle-aged PLHIV did not have lower BMD or lower vitamin D levels compared to the controls. However, PLHIV had lower bone formation markers, particularly those with low CD4 count. This finding supports the benefit of early ART.

Bone Densitometry in Transgender and Gender Non-Conforming (TGNC) Individuals: 2019 ISCD Official Position.

The indications for initial and follow-up bone mineral density (BMD) in transgender and gender nonconforming (TGNC) individuals are poorly defined, and the choice of which gender database to use to calculate Z-scores is unclear. Herein, the findings of the Task Force are presented after a detailed review of the literature. As long as a TGNC individual is on standard gender-affirming hormone treatment, BMD should remain stable to increasing, so there is no indication to monitor for bone loss or osteoporosis strictly on the basis of TGNC status. TGNC individuals who experience substantial periods of hypogonadism (>1 yr) might experience bone loss or failure of bone accrual during that time, and should be considered for baseline measurement of BMD. To the extent that this hypogonadism continues over time, follow-up measurements can be appropriate. TGNC individuals who have adequate levels of endogenous or exogenous sex steroids can, of course, suffer from other illnesses that can cause osteoporosis and bone loss, such as hyperparathyroidism and steroid use; they should have measurement of BMD as would be done in the cisgender population. There are no data that TGNC individuals have a fracture risk different from that of cisgender individuals, nor any data to suggest that BMD predicts their fracture risk less well than in the cisgender population. The Z-score in transgender individuals should be calculated using the reference data (mean and standard deviation) of the gender conforming with the individual's gender identity. In gender nonconforming individuals, the reference data for the sex recorded at birth should be used. If the referring provider or the individual requests, a set of "male" and "female" Z-scores can be provided, calculating the Z-score against male and female reference data, respectively.

New-onset diabetes in HIV-treated adults: predictors, long-term renal and cardiovascular outcomes.

OBJECTIVE: To determine the incidence and risk factors for developing diabetes mellitus in a cohort of Thai HIV-infected patients on long-term combination antiretroviral therapy (cART). DESIGN: Prospective study conducted between July 1996 and 30 April 2015. METHODS: A total of 1748 patients (60% men) who did not have diabetes mellitus prior to ART were assessed twice a year. Incident diabetes mellitus was defined as either having two consecutive fasting glucose levels more than 126 mg/dl, or reporting antidiabetes mellitus medication/diabetes mellitus diagnosis after starting cART. Incidence rates were calculated per 1000 person-year follow-up. Multivariate Cox regression was used to determine risk factors for the development of diabetes mellitus. RESULTS: During a median follow-up of 9 years (16 274 person-year of follow-up), 123 patients developed new-onset diabetes mellitus, resulting in an incidence rate of 7.6 (95% confidence interval 6.3-9) per 1000 person-year of follow-up. From the multivariate models, age more than 35 years, male sex, BMI at least 25 kg/m, family history of diabetes, abnormal waist circumference, lipodystrophy and exposure to didanosine were significantly associated with incident diabetes mellitus. The diabetes mellitus group had higher mortality rate (8.1 vs. 4.1%, P = 0.04). A significantly higher proportion diabetes vs. nondiabetes patients developed cardiovascular and cerebrovascular complications (8.9 vs. 3.6%, P = 0.008) or chronic kidney disease stage III (estimated glomerular filtration rate <60 ml/min/1.73 m) (15.3 vs. 1.9%, P < 0.001) over total follow-up. CONCLUSION: In addition to traditional risk factors, lipodystrophy and use of didanosine were strongly associated with development of incident diabetes. Given the higher rate of cardiovascular-cerebrovascular complications and chronic kidney disease among patients with diabetes mellitus, careful assessment and appropriate management of diabetes mellitus are essential.

Role of Osteoblast Gi Signaling in Age-Related Bone Loss in Female Mice.

Age-related bone loss is an important risk factor for fractures in the elderly; it results from an imbalance in bone remodeling mainly due to decreased bone formation. We have previously demonstrated that endogenous G protein-coupled receptor (GPCR)-driven Gi signaling in osteoblasts (Obs) restrains bone formation in mice during growth. Here, we launched a longitudinal study to test the hypothesis that Gi signaling in Obs restrains bone formation in aging mice, thereby promoting bone loss. Our approach was to block Gi signaling in maturing Obs by the induced expression of the catalytic subunit of pertussis toxin (PTX) after the achievement of peak bone mass. In contrast to the progressive cancellous bone loss seen in aging sex-matched littermate control mice, aging female Col1(2.3)+/PTX+ mice showed an age-related increase in bone volume. Increased bone volume was associated with increased bone formation at both trabecular and endocortical surfaces as well as increased bending strength of the femoral middiaphyses. In contrast, male Col1(2.3)+/PTX+ mice were not protected from age-related bone loss. Our results indicate that Gi signaling markedly restrains bone formation at cancellous and endosteal bone surfaces in female mice during aging. Blockade of the relevant Gi-coupled GPCRs represents an approach for the development of osteoporosis therapies-at least in the long bones of aging women.

Osteoblast-derived FGF9 regulates skeletal homeostasis.

FGF9 has complex and important roles in skeletal development and repair. We have previously observed that Fgf9 expression in osteoblasts (OBs) is regulated by G protein signaling and therefore the present study was done to determine whether OB-derived FGF9 was important in skeletal homeostasis. To directly test this idea, we deleted functional expression of Fgf9 gene in OBs using a 2.3kb collagen type I promoter-driven Cre transgenic mouse line (Fgf9OB-/-). Both Fgf9 knockout (Fgf9OB-/-) and the Fgf9 floxed littermates (Fgf9fl/fl) mice were fully backcrossed and maintained in an FBV/N background. Three month old Fgf9OB-/- mice displayed a significant decrease in cancellous bone and bone formation in the distal femur and a significant decrease in cortical thickness at the TFJ. Strikingly, female Fgf9OB-/- mice did not display altered bone mass. Continuous treatment of mouse BMSCs with exogenous FGF9 inhibited mouse BMSC mineralization while acute treatment increased the proliferation of progenitors, an effect requiring the activation of Akt1. Our results suggest that mature OBs are an important source of FGF9, positively regulating skeletal homeostasis in male mice. Osteoblast-derived FGF9 may serve a paracrine role to maintain the osteogenic progenitor cell population through activation of Akt signaling.

Bone health and HIV in resource-limited settings: a scoping review.

PURPOSE OF REVIEW: Sub-Saharan Africa and other resource-limited settings (RLS) bear the greatest burden of the HIV epidemic globally. Advantageously, the expanding access to antiretroviral therapy (ART) has resulted in increased survival of HIV individuals in the last 2 decades. Data from resource rich settings provide evidence of increased risk of comorbid conditions such as osteoporosis and fragility fractures among HIV-infected populations. We provide the first review of published and presented data synthesizing the current state of knowledge on bone health and HIV in RLS. RECENT FINDINGS: With few exceptions, we found a high prevalence of low bone mineral density (BMD) and hypovitaminosis D among HIV-infected populations in both RLS and resource rich settings. Although most recognized risk factors for bone loss are similar across settings, in certain RLS there is a high prevalence of both non-HIV-specific risk factors and HIV-specific risk factors, including advanced HIV disease and widespread use of ART, including tenofovir disoproxil fumarate, a non-BMD sparing ART. Of great concern, we neither found published data on the effect of tenofovir disoproxil fumarate initiation on BMD, nor any data on incidence and prevalence of fractures among HIV-infected populations in RLS. SUMMARY: To date, the prevalence and squeal of metabolic bone diseases in RLS are poorly described. This review highlights important gaps in our knowledge about HIV-associated bone health comorbidities in RLS. This creates an urgent need for targeted research that can inform HIV care and management guidelines in RLS.

Undercarboxylated osteocalcin is associated with insulin resistance, but not adiponectin, during pregnancy.

In mice, undercarboxylated osteocalcin (ucOC) improves beta-cell function and insulin sensitivity through adiponectin. In humans, levels of total osteocalcin (OC) and ucOC were negatively correlated with insulin resistance (IR) indices in patients with type 2 diabetes. Whether ucOC plays a role in glucose homeostasis and whether its effect is mediated through adiponectin during pregnancy is unclear. Serum levels of total OC, ucOC, and adiponectin were measured in 130 pregnant women with varying degrees of IR [gestational diabetes mellitus (GDM), n = 74 and non-GDM, n = 56]. In all participants, total OC and ucOC levels were positively correlated with HOMA-IR and HOMA-%B, and negatively correlated with QUICKI. In contrast, adiponectin levels were negatively correlated with HOMA-IR and positively correlated with QUICKI (P < 0.01, both). However, neither total OC nor ucOC was associated with adiponectin. Although none of these markers could help distinguish women with and without GDM, total OC and ucOC levels were significantly higher in non-GDM women who had 1 abnormal OGTT value than those who had all normal OGTT values. Total OC and ucOC levels were significantly correlated with insulin secretion and IR indices, but not adiponectin levels, in pregnant women. Changes in OC might be a sensitive response to increased IR during pregnancy, which was not mediated through adiponectin.

Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive Gs-G protein signaling in osteoblasts.

G protein-coupled receptor (GPCR) signaling in osteoblasts (OBs) is an important regulator of bone formation. We previously described a mouse model expressing Rs1, an engineered constitutively active Gs-coupled GPCR, under the control of the 2.3 kb Col I promoter. These mice showed a dramatic age-dependent increase in trabecular bone of femurs. Here, we further evaluated the effects of enhanced Gs signaling in OBs on intramembranous bone formation by examining calvariae of 1- and 9-week-old Col1(2.3)/Rs1 mice and characterized the in vivo gene expression specifically occurring in osteoblasts with activated Gs G protein-coupled receptor signaling, at the cellular level rather than in a whole bone. Rs1 calvariae displayed a dramatic increase in bone volume with partial loss of cortical structure. By immunohistochemistry, Osterix was detected in cells throughout the inter-trabecular space while Osteocalcin was expressed predominantly in cells along bone surfaces, suggesting the role of paracrine mediators secreted from OBs driven by 2.3 kb Col I promoter could influence early OB commitment, differentiation, and/or proliferation. Gene expression analysis of calvarial OBs revealed that genes affected by Rs1 signaling include those encoding proteins important for cell differentiation, cytokines and growth factors, angiogenesis, coagulation, and energy metabolism. The set of Gs-GPCRs and other GPCRs that may contribute to the observed skeletal phenotype and candidate paracrine mediators of the effect of Gs signaling in OBs were also determined. Our results identify novel detailed in vivo cellular changes of the anabolic response of the skeleton to Gs signaling in mature OBs.

Increased bone mass in mice lacking the adipokine apelin.

Adipose tissue plays an important role in skeletal homeostasis, and there is interest in identifying adipokines that influence bone mass. One such adipokine may be apelin, a ligand for the Gi-G protein-coupled receptor APJ, which has been reported to enhance mitogenesis and suppress apoptosis in MC3T3-E1 cells and primary human osteoblasts (OBs). However, it is unclear whether apelin plays a physiological role in regulating skeletal homeostasis in vivo. In this study, we compared the skeletal phenotypes of apelin knockout (APKO) and wild-type mice and investigated the direct effects of apelin on bone cells in vitro. The increased fractional cancellous bone volume at the distal femur was observed in APKO mice of both genders at 12 weeks of age and persisted until the age of 20. Cortical bone perimeter at the femoral midshaft was significantly increased in males and females at both time points. Dynamic histomorphometry revealed that APKO mice had increased rates of bone formation and mineral apposition, with evidences of accelerated OB proliferation and differentiation, without significant alteration in osteoclast activity. An in vitro study showed that apelin increased proliferation of primary mouse OBs as well as suppressed apoptosis in a dose-dependent manner with the maximum effect at 5nM. However, it had no effect on the formation of mineralized nodules. We did not observed significantly altered in osteoclast parameters in vitro. Taken together, the increased bone mass in mice lacking apelin suggested complex direct and paracrine/endocrine effects of apelin on bone, possibly via modulating insulin sensitivity. These results indicate that apelin functions as a physiologically significant antianabolic factor in bone in vivo.