The Indian Society for Bone and Mineral Research (ISBMR) position statement for the diagnosis and treatment of osteoporosis in adults.

The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India. PURPOSE: In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines, the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country. METHODS: The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians, researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guidelines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India. RESULTS: Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diagnostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice. Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential, which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy. CONCLUSIONS: Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India.

LOWER SERUM 25-HYDROXYVITAMIN D IS ASSOCIATED WITH OBESITY BUT NOT COMMON CHRONIC CONDITIONS: AN OBSERVATIONAL STUDY OF AFRICAN AMERICAN AND CAUCASIAN MALE VETERANS.

OBJECTIVE: The study examined whether vitamin D insufficiency is a predictor of prevalent and/or incident common chronic conditions in African American men (AAM) and Caucasian American men (CAM). METHODS: A total of 1,017 men were recruited at an urban VA medical center and followed prospectively for a mean of 5.4 years. Prevalent and incident chronic conditions evaluated were: obesity, type 2 diabetes, cancer, depression, dementia, and cardiovascular disease (CVD, including coronary artery disease [CAD], cerebrovascular accident [CVA], and congestive heart failure [CHF]). Univariate and multivariate regressions were performed to examine the association between 25-hydroxyvitamin D (25[OH]D) and these chronic illnesses. RESULTS: This analysis was limited to 955 men (65.5% AAM, 27.2% CAM, 6.4% Hispanic) who had at least 1 year of follow-up (range, 1.0 to 7.1 years). Univariate analysis of the entire group showed that 25(OH)D correlated negatively with body mass index (BMI). There was no correlation between 25(OH)D and prevalent CVD (including separate analyses for CAD, CVA, and CHF), cancer, depression, dementia, all-cause mortality, or incident cancer, CAD, or CVA. Independent predictors of prevalent common conditions included increasing age, BMI, smoking, alcohol and polysubstance use, but not 25(OH)D levels. CONCLUSION: The study does not support previously suggested associations of low vitamin D levels with prevalent common chronic conditions or increased risk for cancer, CAD, and CVA in a population of men with high burden of chronic disease. The finding that smoking and alcohol and polysubstance use are predictors of chronic conditions is an important reminder for addressing these risks during patient encounters. ABBREVIATIONS: AAM = African American men BMI = body mass index CAD = coronary artery disease CAM = Caucasian American men CHF = congestive heart failure CI = confidence interval CVA = cerebrovascular accident CVD = cardiovascular disease HTN = hypertension OR = odds ratio T2DM = type 2 diabetes mellitus VAMC = Veteran Administration Medical Center 25(OH)D = 25-hydroxyvitamin D.

Influence of bone mineral density measurement on fracture risk assessment tool® scores in postmenopausal Indian women.

AIM: Fracture risk assessment tool® calculations can be performed with or without addition of bone mineral density; however, the impact of this addition on fracture risk assessment tool® scores has not been studied in Indian women. Given the limited availability and high cost of bone mineral density testing in India, it is important to know the influence of bone mineral density on fracture risk assessment tool® scores in Indian women. Therefore, our aim was to assess the contribution of bone mineral density in fracture risk assessment tool® outcome in Indian women. METHODS: Apparently healthy postmenopausal Indian women (n = 506), aged 40-72 years, without clinical risk factors for bone disease, were retrospectively selected, and their fracture risk assessment tool® scores calculated with and without bone mineral density were compared. RESULTS: Based on WHO criteria, 30% women were osteoporotic, 42.9% were osteopenic and 27.1% had normal bone mineral density. Fracture risk assessment tool® scores for risk of both major osteoporotic fracture and hip fracture significantly increased on including bone mineral density (P < 0.0001). When criteria of National Osteoporosis Foundation, US was applied number of participants eligible for medical therapy increased upon inclusion of bone mineral density, (for major osteoporotic fracture risk number of women eligible without bone mineral density was 0 and with bone mineral density was 1, P > 0.05, whereas, for hip fracture risk number of women eligible without bone mineral density was 2 and with bone mineral density was 17, P < 0.0001). CONCLUSION: Until the establishment of country-specific medication intervention thresholds, bone mineral density should be included while calculating fracture risk assessment tool® scores in Indian women.

Relationship Between BMD and Prevalent Vertebral Fractures in Indian Women Older Than 50 Yr.

The purpose of the study was to study the relationship of morphometric vertebral fractures with bone mineral density (BMD) in Indian women older than 50 yr. Four hundred fifteen healthy Indian women older than 50 yr (mean age: 62.8 yr) underwent lateral X-rays of the lumbar and thoracic spine. Genant's semiquantitative method was used to diagnose and classify morphometric vertebral fractures. BMD was measured by DXA at lumbar spine and total hip. Recruited subjects underwent anthropometric, biochemical, and hormonal evaluation. Vertebral fractures were present in 17.1% (95% confidence interval: 13.5, 20.8) subjects. Prevalence of osteoporosis based on BMD was 35.7%. By adding those with prevalent fractures, the number of women requiring therapy for osteoporosis would increase to 46.5%. The BMD measured at femur neck, total hip, and lumbar spine (L1eL4) was not found to be lower in women with vertebral fractures as compared with those without fractures. BMD was not found to be lower in women with vertebral fractures as compared with those without fractures. Significant number of additional subjects with BMD in the normal or osteopenic range become eligible for osteoporosis treatment when presence of vertebral fracture is used as an independent indication for such treatment.

Similarities and differences between patients included and excluded from a randomized clinical trial of vitamin D supplementation for improving glucose tolerance in prediabetes: interpreting broader applicability.

BACKGROUND: Randomized Clinical Trial (RCT) designs range from highly selective resulting in lack of external validity to more inclusive, requiring large sample sizes to observe significant results. Few publications, however, have compared excluded to enrolled participants. We aimed to assess our trial's design based on the effectiveness versus efficacy continuum using the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool and to compare included and excluded patients. METHODS: Fifteen members of endocrinology section completed PRECIS for DIVA (D-Vitamin Intervention in VA) trial; an RCT evaluating vitamin D supplementation in improving dysglycemia in patients with prediabetes. Retrospective chart review compared subjects excluded (OUT) to those included (IN) in RCT. Student's t and Chi-square tests were used to compare continuous and categorical variables. Additionally, multiple logistic regression was completed. RESULTS: PRECIS scores were nearly universally pragmatic. 178 patients enrolled in DIVA trial were compared with 178 randomly selected patients excluded from study involvement. There was no significant difference between IN and OUT for the majority of the continuous and all of the categorical variables. Multivariate logistic regression identified only the A1c, HDL and Charlson Index as significant predictors of a participant's inclusion or exclusion. There was higher HDL (51.3(13.9) versus 44.6(10.1), P = 0.001) and Charlson Index (2.85(1.6) versus 2.2(1.17), P = 0.001) for OUT versus IN groups. Subanalysis of excluded patients in A1c range 5.7 to 6.9, had lower BMI (30.7(3.4) versus 32(2.7), P = 0.002) but higher HDL (mg/l: 49.7(11.8) versus 44.6(10.1), P = 0.001) and Charlson index (2.85(1.6) versus 2.2(1.17), P = 0.001) than included participants. Additionally, there was a trend towards higher rates of cancer (22.9% versus 12.9%, P = 0.033) but less psychiatric problems (56.2% versus 72.5%, P = 0.026) and thiazide diuretic use (18.1% versus 29.8%, P = 0.034). CONCLUSION: DIVA trial design appears to favor broad clinical applicability. The majority of objectively compared variables did not different between patients included and excluded from this RCT. Advice based on the evidence from this RCT may be applicable to a larger group of patients than those fitting inclusion/exclusion criteria alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01375660 (registered 15 June 2011).

Significant differences in fecal microbiota are associated with various stages of glucose tolerance in African American male veterans.

The importance of gut microbiota in pathogenesis of diabetes remains unknown. This study investigated the relationship between microbiota and metabolic markers in African American men (AAM) with prediabetes and hypovitaminosis D. The study was ancillary to a randomized trial of vitamin D supplementation with weekly ergocalciferol (50,000 IU) conducted in AAM veterans over 12 months (D Intervention in Veterans Affairs). Glycemic groups (Gr) were characterized based on changes in oral glucose tolerance between baseline and exit. Subjects with stable normal glucose tolerance were assigned to Gr-1 and those with stable prediabetes (impaired glucose tolerance and impaired fasting glucose) to Gr-2. Microbiota composition was analyzed in stool collected at the exit (n = 115) and compared between Gr-1 and Gr-2, as well as between the lowest and highest quartiles of dietary intake of energy and fat, hemoglobin A1c, and serum 25-hydroxyvitamin D (25[OH]D) level. Differences between Gr-1 and Gr-2 included the Bacteroidetes/Firmicutes and Bacteroidales/Clostridia ratios and differences in genera such as Ruminococcus and Dialister. Changes in specific taxa associated with the lowest and highest quartiles of 25(OH)D (eg, Ruminococcus, Roseburia, Blautia, Dorea) were clearly distinct from those of dietary intake (eg, Bacteroides, Bacteroides/Prevotella ratio) or A1c (eg, Faecalibacterium, Catenibacterium, Streptococcus). These findings suggest a novel interaction between microbiota and vitamin D and a role for microbiota in early stages of diabetes development. Although results suggest that specific taxa are associated with glycemic stability over time, a causative relationship between microbiota makeup and dysglycemia is still to be demonstrated.

EFFECT OF HIGH-DOSE VITAMIN D REPLETION ON GLYCEMIC CONTROL IN AFRICAN-AMERICAN MALES WITH PREDIABETES AND HYPOVITAMINOSIS D.

OBJECTIVE: This double-blind, randomized, controlled trial evaluated whether 12 months of high-dose vitamin D2 supplementation improved insulin sensitivity and secretion and glycemic status. METHODS: African-American males (AAM) with prediabetes (glycosylated hemoglobin [A1C] 5.7-6.4%), hypovitaminosis D (25-hydroxyvitamin D [25OHD] 5-29 ng/mL), and prevalent medical problems were supplemented with vitamin D3 (400 IU/day) and then randomized to weekly placebo or vitamin D2 (50,000 IU). The primary outcome was the change in oral glucose insulin sensitivity (OGIS, from an oral glucose tolerance test [OGTT]) after 12 months of treatment. Secondary outcomes included other glycemic indices, A1C, and incident diabetes. RESULTS: Baseline characteristics were similar in vitamin D-supplemented (n = 87) and placebo (n = 86) subjects completing the trial with average concentrations 14.4 ng/mL, 362 mL × min(-1) × m(-2), and 6.1% for 25OHD, OGIS and A1C, respectively. After 12 months, the vitamin D-supplemented group had a change in serum 25OHD +35 versus +6 ng/mL for placebo, P<.001; OGIS +7.8 versus -16.0 mL × min(-1) × m(-2) for placebo, P = .026; and A1C -0.01 versus +0.01% for placebo, P = .66. Ten percent of subjects in both groups progressed to diabetes. A posthoc analysis of participants with baseline impaired fasting glucose (IFG) showed that more subjects in the vitamin D subgroup (31.6%) than placebo (8.3%) returned to normal glucose tolerance, but the difference did not reach significance (P = .13). CONCLUSION: The trial does not provide evidence that 12 months of high-dose D2 repletion improves clinically relevant glycemic outcomes in subjects with prediabetes and hypovitaminosis D (NCT01375660).

Relationship between glycated hemoglobin and circulating 25-hydroxyvitamin D concentration in African American and Caucasian American men.

OBJECTIVES: To examine whether (1) serum 25-hydroxyvitamin D level (25[OH]D) is a risk factor for hyperglycemia, as assessed by glycated hemoglobin (HbA1c), in African American men (AAM) and (2) 25(OH)D is a predictor of HbA1c in AAM and Caucasian American men (CAM). METHODS: We prospectively assessed 25(OH)D and HbA1c in 1,074 men, outpatients with and without diabetes, at an urban Veteran Administration Medical Center (66.8% AAM, 26.4% CAM, 6% Hispanic, 0.4% Asian, and 0.4% Native American men). Multivariate regression analyzed the determinants of HbA1c after accounting for potential confounders. RESULTS: We found high prevalence of low (< 30 ng/mL) 25(OH)D (81%) and elevated (≥5.7%) HbA1c (53.5%). The 25(OH)D was inversely associated with HbA1c in all men (r = -0.12, P<.001), in AAM (r = -0.11, P = .003), and in CAM (r = -0.15, P = .01). In the entire group the independent determinants of HbA1c included body mass index (BMI), age, 25(OH)D levels, systolic blood pressure (BP), triglycerides, high-density lipoprotein (HDL), and current alcohol use (P<.0001, .013, .009, .01, .008, .034, and .048, respectively) while glomerular filtration rate (GFR) and marital status showed borderline significance (P = .08 and .09, respectively). In AAM these determinants included BMI, 25(OH)D levels, systolic BP, and current alcohol use (P<.0001, .01, .02, and .03, respectively), while age had borderline significance (P = .06). In CAM, these included BMI, age, and triglycerides (P = .01, .03, and .004, respectively) but not 25(OH)D levels (P = .50). CONCLUSION: Circulating low 25(OH)D is a risk factor for hyperglycemia, as assessed by HbA1c, in AAM. The 25(OH)D level is an independent determinant of HbA1c in AAM, but not in CAM, including men with and without diabetes.

The prevalence of and risk factors for radiographic vertebral fractures in older Indian women and men: Delhi Vertebral Osteoporosis Study (DeVOS).

UNLABELLED: High prevalence of vertebral fractures (17.9 % over all; 18.8 % male and 17.1 % female) was observed in 808 free-living residents of Delhi, India, aged more than 50 years. The prevalence rates were comparable to that reported in Caucasian populations. While there was an increase in fracture prevalence with age in females, the same was not observed in males. INTRODUCTION: The aim of this paper is to study the prevalence of and risk factors for morphometric vertebral fractures in elderly Indian men and women over 50 years of age. METHODS: We recruited 808 healthy subjects aged 50 years or more, residing in three residential colonies in Delhi, India who voluntarily agreed to participate in this study. All subjects underwent lateral X-rays of the lumbar and thoracic spine according to a standardized protocol. All X-rays were blindly evaluated by a single trained person using an advanced semi-automated software (Optasia Medical) based on Genant's semiquantitative method. Recruited subjects underwent anthropometric, biochemical, and hormonal evaluation. RESULTS: With a mean age of 64.9 (±6.7) years, 345 males and 415 females were evaluated. Vertebral fractures were present in 17.9 % (95 % CI 15.2, 20.6) subjects [males, 18.8 % (95 % CI 14.6, 23), females 17.1 % (95 % CI 13.5, 20.8)]. Prevalence of vertebral fractures increased with age in females from 14.7 % in 50-59 years age group to 22.4 % in those ≥70 years, but not in men. Overweight subjects had significantly lower risk [OR, 0.63 (95 % CI 0.41, 0.97), p = 0.035] of vertebral fractures. Serum 25 hydroxyvitamin D levels, intake of calcium and vitamin D, or history of previous fractures were not statistically different between patients with or without prevalent vertebral fractures. CONCLUSIONS: The prevalence of vertebral fractures among older Indians was comparable to that reported in Caucasian populations. Prevalence of vertebral fractures increased with age in females, but not in males. Overweight individuals were protected against vertebral fractures.

Determinants of circulating 25-hydroxyvitamin D and bone mineral density in young physicians.

OBJECTIVE: To examine determinants of serum 25-hydroxyvitamin D [25(OH)D] and bone mineral density (BMD) in young physicians, a group not well studied previously. METHODS: We analyzed data from a questionnaire completed by young physicians as well as results of serum 25(OH)D, serum parathyroid hormone, and BMD measurements. RESULTS: Among 104 study subjects, 42% were white, 46% were Asian, 12% were "other" (10 Hispanic and 2 African American subjects), and 75% were women. The mean age and body mass index (BMI) were 28.1 years and 23.0 kg/m², respectively. White subjects had a higher mean serum 25(OH)D level (27.3 ng/mL) than did Asian subjects (15.9 ng/mL) and other subjects (22.3 ng/mL) (P<.0001). White subjects tended to have higher Z-scores than Asian subjects and other subjects for the hip (P = .06), trochanter (P = .08), and lumbar spine (P = .08). The serum 25(OH)D level was negatively associated with serum parathyroid hormone (r = -0.44; P<.01) but not with BMD. The prevalence of vitamin D insufficiency [serum 25(OH)D <30 ng/mL, 77% for the entire group] was higher (P<.01) in Asian subjects (93%) than in white subjects (61%) and other subjects (73%). Significant determinants of serum 25(OH)D included age, ethnicity, exposure to sunlight, use of vitamin D supplements, and family history of osteoporosis (P<.05 for all), and together with sex, calcium supplements, exercise, and BMI, these factors explained 49% of serum 25(OH)D level variability. Significant determinants of low BMD (osteopenia plus osteoporosis, prevalence 37.5%) included sex (P = .002) and BMI (P<.0001) but not serum 25(OH)D; Asian ethnicity reached borderline significance (P = .088). Age, sex, ethnicity, smoking, and BMI explained 20% to 30% of the Z-score variations. CONCLUSION: In young physicians with a healthful lifestyle, determinants of low serum 25(OH)D and BMD included modifiable risk factors. Vitamin D insufficiency and low BMD could be important contributors to future osteoporotic fractures in this population.

E1A oncogene expression inhibits PTHrP P3 promoter activity and sensitizes human prostate cancer cells to TNF-induced apoptosis.

In the advanced stages of prostate cancer, tumor cells can evolve to become androgen-independent and resistant to injury-induced apoptosis. Tumor cell expression of parathyroid hormone-related protein (PTHrP) may contribute to the apoptosis phenotype. Expression of the adenovirus E1A oncogene repressed PTHrP promoter and mRNA expression in human PC-3 prostate cancer cells and increased the caspase 3 activation and sensitivity of these cells to apoptosis triggered by tumor necrosis factor alpha. These results suggest that strategies aimed at modulating PTHrP expression may increase the efficacy of innate immune effector mechanisms and proapoptotic, therapeutics in prostate cancer.

Parathyroid hormone-related protein in prostate cancer.

Although originally discovered as the peptide responsible for humoral hypercalcemia of malignancy (HHM), parathyroid hormone-related protein (PTHrP) has been shown to play a major role in fetal development. In the adult, it is widely distributed in normal and various cancer tissues. In spite of the rarity of HHM in prostate cancer, PTHrP is widely distributed in prostate cancer cells. PTHrP is a precursor molecule with generation of various fragments with distinct biological activities. More recent studies have shown that there is intranuclear localization of PTHrP and that intracrine effects of the peptide are involved in promoting processes that result in tumor progression (nall proliferation, apoptosis, cell attachment and angiogenesis) in prostate cancer. PTHrP expression is controlled by three distinct promoters, with P3 being used most often in cancer cells. The factors that control PTHrP production via interaction with the promoters are growth factors, androgens, vitamin D analogs, and adenoviral proteins. TGF-beta and its effector Smad3 activate the P3 promoter through an AGAC box and an Ets binding site involving Ets1 and to some extent Ets2 proteins. In addition, TGF-beta stimulates P3 promoter activity via Smad-independent pathways that involve the p38 MAP kinase. Although the addition of PTHrP or transfection with the PTHrP gene in prostate cells results in effects that promote tumor development, studies that employ inhibition of PTHrP activity in vitro and in vivo are needed to establish a definitive role of this peptide in the pathogenesis of prostate cancer.

Frame size, ethnicity, lifestyle, and biologic contributors to areal and volumetric lumbar spine bone mineral density in Indian/Pakistani and American Caucasian premenopausal women.

Published data on the spinal bone mineral density (BMD) of premenopausal women originating from the Indian subcontinent (Indian/Pakistani) are few. We compared anteroposterior (AP) and lateral areal BMD (aBMD) using dual X-ray absorptiometry and calculated volumetric BMD (vBMD) in Indian/Pakistani (n = 47) vs American (n = 47) women with dissimilar statures and skeletal sizes. To account for differences, we "adjusted" lumbar aBMD separately for vertebral size (aBMD/the square root of the projected area), height (aBMD/height), and hip skeletal width (aBMD/hip width). We "corrected" bone mineral content (BMC), aBMD, and vBMD for frame size, collectively using height, hip width, and vertebral size. Unadjusted mean aBMD values for AP lumbar (L1-L4, p = 0.0086; L3-L4, p = 0.044) spine were higher in Americans than Indians/Pakistanis,whereas lateral vBMD (p = 0.56) or aBMD (p = 0.060) values were not different. After adjusting for height, hip width, or vertebral size, or correcting for frame size, differences in aBMD disappeared. Regression analyses indicated that the best measures to correct for frame size were: vertebral area for BMC, hip width for aBMD, and vertebral width for lateral vBMD. Height was not significant in any model. In correcting for frame size, we accounted for 73-85% of the variability in BMC, 22-28% in aBMD, and 27% in lateral vBMD. After frame size was corrected, we accounted for 34% of the variability in AP BMC and aBMD, in contrast with 6-9% in the lateral models. Five significant biologic and lifestyle factors remained in AP models; only body weight remained for lateral spine. Upon accounting for frame size using regression, much variability in BMD, aBMD, and vBMD was explained by lifestyle and biologic factors, not by ethnicity.