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.

The prevalence of sarcopenic obesity in community-dwelling healthy Indian adults - The Sarcopenic Obesity-Chandigarh Urban Bone Epidemiological Study (SO-CUBES).

OBJECTIVES: To determine the prevalence of sarcopenia obesity (SO) in healthy Indian adults and delineate the relative impact of the 3 indices of obesity [body mass index (BMI), waist circumference (WC), fat mass percent (FM%)] with regards to inter-definitional agreement and their relationship with usual gait speed (GS). METHODS: Apparently healthy adults (aged ≥ 20 years) with no background history of comorbidities were enrolled from the community by door-to-door survey. Following blood investigations, individuals with biochemical abnormalities were excluded. Enrolled participants underwent dual-energy X-ray absorptiometry (DXA). Sarcopenia was defined according to EWGSOP2 consensus based on indigenous cut-offs obtained from the Sarcopenia-Chandigarh Urban Bone Epidemiological Study (Sarco-CUBES). Obesity was defined based on BMI (≥ 25.0 kg/m2) or WC (> 90 cm in men, > 80 cm in women) or DXA-derived FM% (> 32% in men, > 40% in women). RESULTS: Data of 804 participants were analyzed after exclusion. The mean ± SD for BMI, WC, and FM% were 26.5 ± 2.7 kg/m2, 86.8 ± 9.6, and 34.7 ± 7.3%, respectively. Prevalence of sarcopenia was 3.2%. Based on BMI, WC, and FM%, the prevalence of SO in elderly subjects (≥65 years) was 5.4%, 5.4%, and 6.3%, respectively. Using Cohen's kappa, inter-definitional agreement between the 3 groups was 'almost perfect'. FM%, and not BMI/WC, emerged as a significant predictor of GS on multiple linear regression analysis. CONCLUSIONS: The prevalence of SO in healthy elderly Indian adults is 5.4%-6.3%. Either BMI/WC/FM% can be used to correctly identify individuals with SO.

Metabolic Bone Profile of Healthy Adult North Indian Population from Chandigarh Urban Bone Epidemiological Study (CUBES).

We aimed to estimate metabolic bone profile in a large cohort of healthy, adult Indian population to generate reference standards of serum calcium, phosphate and alkaline phosphatase (ALP), 25 (OH) Vitamin D and iPTH, and also to find out the prevalence of Vitamin D deficiency in healthy population. Apparently healthy people in the age group of 20-80 years, residing in the union territory of Chandigarh were chosen. Fasting samples for serum calcium, phosphate, albumin, alkaline phosphatase (ALP), 25 (OH) D and iPTH were collected and were processed on the same day. We recruited 930 healthy subjects from different subsectors of Chandigarh. Final analysis was done for 915 subjects. Out of this, 530 (58%) were women and 385 (42%) were men. The study participants were divided into two groups, less than and more than 50 years for the men and pre and post-menopausal for the women. The serum calcium, phosphate, ALP and iPTH were significantly higher in the post-menopausal women compared to the pre-menopausal women. The median plasma 25 (OH) D in men and women was 12.5 ng/mL and 14.3 ng/mL, respectively. 25 (OH) D deficiency was seen in 65.4% of individuals. 25 (OH) D levels co-related negatively with iPTH levels (r = - 0.4, p < 0.0001), and showed an increasing trend with age. We have thus presented metabolic bone profile of healthy, adult north Indian population. These reference values can be used for diagnosis and monitoring of various MBDs. Vitamin D deficiency is still rampant in our population in spite of increasing awareness.

Bone mineral density in healthy adult Indian population: the Chandigarh Urban Bone Epidemiological Study (CUBES).

Osteoporosis is a disease with a high burden of morbidity. For its accurate diagnosis, using indigenous data as reference standards is needed. However, normative data on bone density is lacking in India. Therefore, we aimed to determine the reference range for bone density for the healthy population of north India. INTRODUCTION: Osteoporosis is a major public health problem around the globe including India, resulting in significant morbidity, mortality, and health care burden. However, the reference values used for its diagnosis are largely based on data from the western population, which may lead to over- or underdiagnosis of osteoporosis in Indians. Our study aimed to determine the reference range for bone mineral density for the healthy population of India. METHODS: This is a cross-sectional study of 825 subjects (men 380, women 445) (median age: 41 years, IQR 32-55 years), recruited by a house-to-house survey. The population was stratified into decade-wise groups and biochemical measurements including renal and liver function tests, glycated hemoglobin, serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density were performed in all the subjects. The T-scores for men aged > 50 years and post-menopausal women were calculated based on the data generated from this study in young men and women aged 20-40 years. RESULTS: According to the BMD manufacturer's data, which is based on the western population, 70% of the Indian men (> 50 years) and 48% of the post-menopausal Indian women had osteopenia while 18% of the men and 25% of the women had osteoporosis. However, according to the re-calculated T-scores from the current study, only 56% and 7.2% of men and 33% and 5% of women had osteopenia and osteoporosis, respectively. An age-related decline in bone mineral density, as seen in the western population, was also seen in both Indian men and women. CONCLUSION: We have established a reference database for BMD in healthy Indian adult population, which may have clinical implications for the diagnosis and intervention strategies for the management of osteoporosis.

Age- and sex-specific concentrations of bone remodeling markers in healthy Indian adults with and without vitamin D deficiency.

Bone remodeling markers exhibit marked inter-ethnic variation; hence, population-specific data are required. Herein, we have established age- and sex-specific concentrations of serum PINP and CTX in healthy Indian adults with and without vitamin D deficiency that can be used in clinical practice for monitoring response to anti-osteoporotic therapy. OBJECTIVE: The present study was undertaken to generate data on age- and sex-specific concentrations of serum procollagen type I N-propeptide (PINP) and type I collagen C-telopeptide (CTX) in healthy Indian adults with and without vitamin D deficiency. METHODS: Apparently, healthy subjects aged ≥ 20 years with no prior co-morbidities were recruited from the community by door-to-door surveys. Provisionally eligible participants underwent blood sampling after overnight fast. Individuals with biochemical abnormalities that could potentially affect bone remodeling were excluded. However, subjects with vitamin D deficiency were not excluded. Serum total PINP and ß-CrossLaps (CTX) were measured using electro-chemiluminescence immunoassay. RESULTS: After exclusion, 677 subjects were enrolled (M:F = 2.5:4.2, mean age = 45.0 years). Median serum PINP and CTX were 55.78 ng/ml (40.27-71.70) and 0.356 ng/ml (0.238-0.499), respectively. There was no difference in PINP/CTX between men and women or between premenopausal and postmenopausal women. Decade-wise distribution of PINP/CTX showed that maximum values were attained in 3rd decade; subsequently, in men, levels declined with age while in women, there was a peak in the 6th decade coinciding with the early years of menopause. Vitamin D deficiency and severe vitamin D deficiency were seen in 417 (61.5%) and 259 subjects (38.2%), respectively. There was no significant difference in PINP/CTX in subjects with and without vitamin D deficiency. CONCLUSIONS: The present study has allowed us to generate data on serum concentrations of PINP/CTX in a diverse group of healthy community-dwelling Indian adults with varying serum vitamin D levels. It might aid in monitoring response to anti-osteoporotic therapy amongst native Indians.

Secondary diabetes as a rare complication of glycogen storage disease 1a: case report and review of literature.

Glycogen storage diseases (GSDs) are disorders of carbohydrate metabolism and hypoglycemia is their hallmark. Secondary diabetes with glycogen storage disease, which seems rather paradoxical, has been rarely reported. A 13-year-old girl previously diagnosed to have GSD 1a presented to the emergency with multiple episodes of vomiting and loss of consciousness. She had hyperglycemia, ketonuria, hyperlactatemia and metabolic acidosis, suggestive of diabetic ketosis with acidosis possibly contributed by both high serum lactate and serum ketones. Her glycated hemoglobin was high, with detectable serum insulin levels, which suggested secondary diabetes in the background of GSD Ia. Her management posed a therapeutic challenge. She was managed with insulin and achieved good glycemic control. We wish to conclude that GSD may rarely lead to secondary diabetes as a complication and the management is complex owing to the nature of the disease. Insulin remains the mainstay of the treatment.

Look Beyond Gluten in Short Stature with Celiac Disease - A Prospective, Interventional Study.

OBJECTIVE: Short stature (SS) is a common manifestation of celiac disease (CD). After starting gluten free diet (GFD), children usually have catch-up growth (improvement in height SDS of >1 SD). However, few children in remission, even on GFD, lack catch up growth. This study was planned to assess the growth hormone (GH) axis and the prevalence of anti-pituitary antibodies in such patients. METHODS: It was a single-centre, prospective study. Patients with CD in remission for the last 1 y, having SS and lacking catch-up growth, were included after excluding other common causes of SS. GH dynamics were studied using stimulation tests: Insulin tolerance test, clonidine stimulation test, and glucagon stimulation test. GH deficiency (GHD) was defined as non-stimulable response to 2 GH stimulation tests. Anti-pituitary antibodies were analysed in these patients using rat pituitary extract as antigen. RESULTS: Ten patients (8 girls), with a mean age of 10 ± 2.8 y, in serological remission for CD and lacking catch-up growth, were enrolled. All had a height SDS of < -2. Fifteen age matched children with CD and adequate catch up growth served as controls. GHD was seen in 7 patients (70%), out of whom 2 received GH therapy and had an improvement in the height SDS from -2.7 to -1.4 and from -2.1 to 2.4 (over 1 y), respectively. Anti-pituitary antibodies were seen in significant titres in 55.5% of the cases and 40% of the controls. CONCLUSIONS: Children with CD in remission but lacking catch-up growth should be evaluated for GHD.

Carbohydrate-rich Meals Have no Impact on Post-prandial Lipid Parameters in Indians with Subclinical and Overt Primary Hypothyroidism.

BACKGROUND AND AIMS: The impact of altered cholesterol metabolism on post-prandial lipids in Indians with hypothyroidism is not known. This study evaluated the impact of overt primary hypothyroidism (OPH) and subclinical hypothyroidism (ScH) on post-prandial lipids after a standardised, carbohydrate-rich, mixed meal. METHODS: Endocrinology outpatients were screened for possible inclusion into the study. Patients >18 years of age with hypothyroidism who were not taking levothyroxine and who did not present with any comorbidities underwent biochemical evaluation following a carbohydrate-rich, mixed meal. Assessments included total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides, lipoprotein-A (Lp-A), apolipoprotein-A1 (apo-A1), apolipoprotein-B (apo-B), insulin and fasting glucose. Assessments were carried out 1 hour, 2 hours and 4 hours after the meal. Patients were compared against healthy matched controls recruited from healthcare professionals in the hospital (asymptomatic and apparently healthy nursing staff, reception staff and ward staff). RESULTS: Data from 194 patients (161 with ScH and 33 with OPH) and 40 euthyroid controls were analysed. Anthropometry, body mass index, glycaemia and insulin resistance were comparable among patients with OPH and ScH, and controls. LDL-C and Lp-A were significantly higher in those with OPH, compared with ScH and controls, at baseline, 1 hour, 2 hours and 4 hours after mixed meal consumption (all p<0.05). There was progressive and similar decline in post-prandial TC, LDL-C and Lp-A in all three groups. Triglycerides were similar among the OPH, ScH and control groups, both in fasting and post-prandial state, with a progressive and similar increase in post-prandial triglycerides in all three groups. CONCLUSION: This study demonstrated that severity of hypothyroidism had no impact on post-prandial TC, LDL-C and Lp-A. In addition, hypothyroidism had no impact on post-prandial triglycerides. Therefore, we conclude that lipid profile can be reliably estimated in a non-fasting state in individuals with ScH and OPH.

Bilateral Adrenocortical Carcinoma Presenting as Acute Adrenal Insufficiency.

The presentation of adrenocortical carcinoma (ACC) with bilateral adrenal masses and acute adrenal insufficiency is exceedingly rare and has only been seen in anecdotal case reports. Herein, we describe the case of a 50-year-old male who presented with a painful abdominal lump, loss of weight and appetite, several episodes of vomiting, and hypotension. Imaging studies were suggestive of bilateral adrenal masses and a lung mass. Hormonal work-up was suggestive of acute adrenal insufficiency, with the adrenal masses being non-secretory. An ultrasound-guided biopsy from one of the adrenal masses was suggestive of ACC, thus confirming the diagnosis as bilateral ACC with distant metastases. Bilateral adrenalectomy was planned for the patient, but unfortunately, he succumbed to his disease before the surgery.

Cushing's syndrome due to primary pigmented nodular adrenal disease in two brothers with Carney complex.

Two brothers (19 and 18 years old, respectively) presented with weight gain and stunted growth since the age of 10 years. They had spotty skin pigmentation over the face along with florid features of Cushing's syndrome with low bone density, renal calculi, dyslipidaemia, hypertension, and dilated cardiomyopathy. They underwent evaluation of the hypothalamic-pituitary-adrenals axis, which suggested ACTH-independent Cushing's syndrome, and the abdominal CT imaging revealed normal adrenals. The diagnosis of Familial Cushing's syndrome with primary pigmented nodular adrenal disease and Carney complex was made. Bilateral adrenalectomy was carried out in both of them with resolution of the features of hypercortisolaemia post-operatively.

Diagnostic cut-offs, prevalence, and biochemical predictors of sarcopenia in healthy Indian adults: The Sarcopenia-Chandigarh Urban Bone Epidemiological Study (Sarco-CUBES).

PURPOSE: Comprehensive data on diagnosis and prevalence of sarcopenia in India are lacking. The present study was undertaken to determine cut-offs for low muscle strength (MS) and low muscle mass (MM), and find out the prevalence of sarcopenia in Indians. METHODS: Apparently healthy individuals aged ≥ 20 years with no prior history of any co-morbidities were recruited from community by door-to-door survey. Participants eligible for study underwent blood sampling. Individuals identified as having biochemical abnormalities that could potentially affect MS and MM were excluded. Enrolled participants underwent DEXA. Muscle mass, MS, and physical performance were expressed as appendicular skeletal muscle index (ASMI), dominant handgrip strength (HGS), and usual gait speed (GS), respectively. Cut-offs for low MS and MM were defined as HGS and ASMI 2SD < mean of young reference population (20-39 years). A GS ≤ 0.8 m/s defined poor physical performance. Using them, the prevalence of sarcopenia was estimated as per EWGSOP2 recommendations. RESULTS: After exclusion, 804 participants were enrolled (mean age = 44.4 years). Peak HGS, ASMI, and GS were achieved in the 3rd/4th decades. Muscle strength/mass was lower than Caucasians. A HGS < 27.5 kg (males)/18.0 kg (females) and an ASMI < 6.11 kg/m2 (males)/4.61 kg/m2 (females) defined low MS and MM, respectively. Accordingly, prevalence of 'probable sarcopenia', 'sarcopenia', and 'severe sarcopenia' was 14.6%, 3.2%, and 2.3%, respectively. Corresponding values were higher when European cut-offs were used. Only serum testosterone positively predicted HGS/ASMI/GS in males. CONCLUSIONS: Indians have low MS/MM, and hence, indigenous and not Western cut-offs should be used to define sarcopenia in Indians.

Weight gain after curative parathyroidectomy predicts increase in bone mineral density in patients with symptomatic primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) results in reduction of bone mineral density (BMD) and an increased risk of pathological fractures. Curative surgery does improve BMD; however, the magnitude of rise and predictive factors are highly variable amongst the hitherto available studies. OBJECTIVES: To quantify the magnitude of improvement in BMD after curative surgery in patients with symptomatic PHPT and dissect out the possible clinical and biochemical parameters predicting the BMD rise. METHODS: We conducted a retrospective study of symptomatic PHPT patients undergoing surgery between August 2016 and July 2018. Patients achieving biochemical cure with pre- and post-operative (at least 1 year after surgery) dual-energy X-ray absorptiometry scans performed were included in the study. RESULTS: After exclusion, 63 patients were included in the study (M:F = 2:5; mean age = 44.8 years). At a median interval of 15 months, the median per cent change in BMD (ΔBMD) at lumbar spine (LS), total hip (TH), femoral neck (FN) and one-third distal radius (forearm) was 6.5%, 7.0%, 8.1% and 6.9%, respectively. Following multiple linear regression analysis, baseline BMD was found to inversely predict ΔBMD at LS, TH and forearm. Pre-operative iPTH positively predicted ΔBMD at LS and FN. Interestingly, 82.5% of the patients had a gain in body weight following curative surgery and change in body weight emerged as a significant positive predictor of ΔBMD at all sites. CONCLUSIONS: Curative surgery improves BMD at all sites in patients with symptomatic PHPT. Weight gain following surgery can be used as a positive clinical predictor of BMD rise.

Catamenial Acute Intermittent Porphyria Managed with GnRH Analogues and Estrogen and Progesterone Add-back Therapy.

BACKGROUND: Catamenial precipitation of attacks of acute intermittent porphyria (AIP) is commonly treated with gonadotropin-releasing hormone analogues (GnRHas). However, this leads to various adverse effects that might necessitate "add-back" therapy with estrogen. The literature on the efficacy and safety of such therapy is scarce. CASE: A 15-year-old girl presented to us with recurrent catamenial attacks of AIP. GnRHa therapy led to near-complete amelioration of the episodes but her bone density worsened as an adverse effect. To circumvent this, low-dose estrogen was added to her regimen as an "add-back" therapy, which was later coupled with cyclical progesterone. She continues to do well using this regimen, with no new episodes. SUMMARY AND CONCLUSION: GnRHa therapy with estrogen "add-back" is an attractive option for treating catamenial AIP episodes.

Etiological Spectrum of Precocious Puberty: Data from Northwest India.

We retrospectively analyzed clinic records of 55 children (36 girls) with precocious puberty. Majority (34, 62%) had central precocious puberty, out of which 19 were idiopathic. Peripheral precocious puberty was seen in 14 children. Congenital adrenal hyperplasia was the commonest cause of peripheral precocious puberty (6, 42.8%).

Acquired neuro-secretory defect in growth hormone secretion due to Imatinib mesylate and the efficacy of growth hormone therapy in children with chronic myeloid leukemia.

Imatinib results in growth retardation in children with chronic myeloid leukemia (CML). The study was planned to assess the GHRH-GH-IGF1 axis in children with CML, receiving Imatinib and to evaluate the efficacy of human growth hormone (hGH) therapy. Twenty children with CML, receiving Imatinib for a period exceeding 6 months, with resultant growth retardation were included. The GHRH-GH-IGF1 axis was assessed using growth hormone stimulation tests. IGF-1 generation test was performed for the evaluation of GH insensitivity. The mean age at inclusion was 15.2 years. The mean duration of treatment with Imatinib was 5.7 years. The mean decrease in height SDS since the start of Imatinib was -0.95 (p = 0.008). IGF-1 SDS was <-2 in all the patients. 71.4% of patients had a suboptimal GH response following stimulation with GHRH-Arginine. All patients had stimulable, although a delayed GH response with glucagon stimulation. 20% of patients had GH insensitivity. Four patients were treated with hGH for a mean duration of 5.75 months, achieved normalization of IGF-1 levels and improvement in growth velocity improved from 0.21 to 0.86 cm/month. Imatinib results in an acquired neurosecretory defect in GH secretion. Treatment with growth hormone leads to an improvement in growth velocity and normalization of IGF-1.

An intriguing case of precocious puberty due to an ovarian mass in an infant.

We present a rare occurrence of precocious puberty (PP) probably due to an autonomous ovarian cyst in a 15-month-old girl who presented to us with growth spurt, breast and pubic hair development, and vaginal bleeding over the last few months. The clinical presentation was suggestive of central precocious puberty (CPP). However, the rapid progression of pubertal changes and occurrence of menarche at breast Tanner stage 2 indicated peripheral precocious puberty (PPP). Due to uncertainty of clinical diagnosis, investigations were conducted for CPP as well as PPP. The basal and peak stimulated LH concentrations were < 0.3 IU/l and < 2 IU/l, respectively, indicating PPP. However, the peak LH : FSH ratio was > 1, which is consistent with CPP. Abdominal imaging revealed an ovarian mass, which was laparoscopically excised, but the true nature of the mass could not be ascertained because the excised specimen showed only haemorrhage and features of ovarian torsion on histopathological examination. Regression of pubertal development occurred over a three-month period postoperatively.

A CURIOUS CASE OF "DOUBLE CUSHING SYNDROME".

OBJECTIVE: Chronic exogenous steroid therapy can lead to iatrogenic Cushing syndrome (CS). However, concomitant presence of endogenous CS in a patient on exogenous steroids has not been previously reported. We report a case of a 23-year-old who had manifestations of both exogenous as well as endogenous CS. METHODS: We present a case report and literature review. RESULTS: A 23-year-old woman presented to us with severely deforming polyarthritis of both small and large joints since childhood, associated with recurrent bouts of uveitis. She was on triamcinolone therapy for the last 16 years, with cushingoid features and severely reduced bone mineral density, presumably due to exogenous CS. Anthropometry revealed severely retarded height for age and weight for age. She underwent hormonal profile assessment for evaluation of her hypothalamic-pituitary-adrenal axis status, which revealed the concurrent presence of adrenocorticotropic hormone-independent endogenous hypercortisolemia. Abdominal imaging showed bulky and nodular adrenal glands. A diagnosis of primary pigmented nodular adrenal disease in the background of juvenile idiopathic arthritis was considered, as was therapy with chronic glucocorticoid treatment. She was started on methotrexate and analgesics. Surgery was also recommended, however she refused bilateral adrenalectomy. CONCLUSION: This case highlights that both exogenous and endogenous CS can coexist in an individual. Furthermore, diagnosis of endogenous CS in a patient on chronic steroid therapy requires a high degree of clinical suspicion.