Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review.

This systematic review was performed to understand better the myriad presentations, various therapeutic options, response to therapy, and its clinical outcomes in hyperphosphatemic tumoral calcinosis (HTC). Full texts were selected according to strict inclusion criteria. All case reports of HTC wherein baseline phosphate was measured, treatment offered was mentioned, and information on follow-up and response to therapy that were available were included. A total of 43 of 188 eligible studies (N = 63 patients) met the inclusion criteria. A list of desired data was extracted and graded for methodological quality. A total of 63 individuals (Males = 33) were included from the 43 eligible case studies. The median age of the patients was 18 (IQR 8-32) years. The most frequently involved sites were the hip/gluteal region (34/63; 53.9%) followed by the elbow/forearm (26/63; 41.2%), and the shoulder (18/63; 28.5%). Three patients had conjunctival calcific deposits. The mean (SD) phosphate was 6.9 (1.1) mg/dL. Among the subjects, 36/63 (57.1%) underwent surgical excision with some form of medical therapy. Two patients underwent only surgical excision (2.1%). One patient was maintained on follow-up (1.6%) and 24/63 (38.1%) patients were treated with medical measures. The median (IQR) follow-up duration was 3 (1-9) years. Regression or reduction in lesion size was reported in 19/63 (30.2%) subjects; 20/63 (31.7%) showed progression, 24/63 (38.1%) had features of stable disease, and mortality was reported in 3 patients (4.7%). We report for the first time a detailed description of the clinical and therapeutic response of HTC. A combination of medical measures aimed at lowering serum phosphate appears to be the cornerstone of treatment, although clinical responses may vary.

Femoral Neck Osteoporosis Is Associated with a Higher Odds of Coronary Artery Disease in Indian Postmenopausal Women: A Cross-sectional Study from a Teaching Hospital in Southern India.

Purpose: Epidemiological studies have shown an association between coronary artery disease (CAD) and osteoporosis. We studied the prevalence of CAD among postmenopausal women with osteoporosis. Factors that were significantly associated with CAD were also assessed. Methods: This was a cross-sectional study conducted over a period of 2 years. Consecutive postmenopausal women aged ≥50 years were recruited. The details of an underlying CAD were obtained. Bone biochemical parameters, bone mineral density and body composition were assessed. Results: A total of 370 postmenopausal women with mean (standard deviation [SD]) ages of 61.6 (6.2) and 60.1 (6.0) years and a body mass index of 25.3 (14.1) kg/m2 were recruited. Among them, 110 of 370 patients (29.7%) had an underlying CAD and 222 of 370 (60%) had osteoporosis at either the femoral neck or lumbar spine (LS). The odds of CAD among those with osteoporosis were 3.5 (95% confidence interval [CI]: 2.1-5.9). An LS T-score of ≤-2.2 had a sensitivity of 80% and a specificity of 45% in predicting CAD (area under the curve, AUC: 0.736; 95% CI: 0.677-0.795; p<0.001). A femoral neck T-score of ≤-1.9 had a sensitivity of 80% and a specificity of 60% in predicting CAD (AUC: 0.748; 95% CI: 0.696-0.800; p<0.001). On a logistic regression analysis after adjusting for various clinical parameters, femoral neck osteoporosis had the highest odds of CAD. Conclusion: The prevalence of CAD was higher among postmenopausal women with osteoporosis. Femoral neck osteoporosis conferred the highest odds of CAD after adjustment for other clinical factors.

Diabetic foot ulcers, their characteristics, and trends in survival: Real world outcomes at a tertiary care facility in India.

AIMS: Characteristics of diabetes-related foot ulcers (DFU), association with recurrence and amputation are poorly described in the Asian Indian population. METHODS: A prospectively maintained database was reviewed to characterize DFU and its association with amputation and recurrence. RESULTS: Of 200 patients, 63.5 % were male, the median age was 62 years (Min-Max:40-86), and median BMI was 27.90 kg/m2 (Min-Max:18.5-42.7). Median duration of Diabetes mellitus was 15 years (Min-Max:2-43). Complete healing occurred at a median of three months (Min-Max:0.23-37.62). Amputation for the current ulcer was required in 43.4 % of individuals. Ulcer recurrence was documented in 42.4 % instances, 66.1 % evolving on the ipsilateral side. Previous amputation was associated with the risk of subsequent amputation (Adjusted OR-3.08,p-0.047). Median time to ulcer recurrence was 4.23 years among those with amputation, in contrast to 9.61 years in those with healing. Cardiovascular death was the commonest cause of mortality, followed by sepsis. At a median follow up of 6.08 years, mortality at 1,3,5 and 10 years was 2.5 %,2.5 %,8.2 % and 30.9 % respectively among those who underwent amputation versus 0 %,0 %,10.1 % and 24.5 % respectively for those who achieved healing. CONCLUSIONS: Patients with DFU in India incur amputations at rates higher than conventionally described. With previous amputation, subsequent amputation risk triples. Ten-year mortality is 25%-30 %. Underestimates of the burden of recurrence and mortality are consequential of limited follow-up.

Inherited fibroblast growth factor 23 excess.

Syndromes of inherited fibroblast growth factor 23 (FGF-23) excess encompass a wide spectrum that includes X-linked hypophosphataemia (XLH), autosomal dominant and recessive forms of rickets as well as various syndromic conditions namely fibrous dysplasia/McCune Albright syndrome, osteoglophonic dysplasia, Jansen's chondrodysplasia and cutaneous skeletal hypophosphataemia syndrome. A careful attention to patient symptomatology, family history and clinical features, supported by appropriate laboratory tests will help in making a diagnosis. A genetic screen may be done to confirm the diagnosis. While phosphate supplements and calcitriol continue to be the cornerstone of treatment, in recent times burosumab, the monoclonal antibody against FGF-23 has been approved for the treatment of children and adults with XLH. While health-related outcomes may be improved by ensuring adherence and compliance to prescribed treatment with a smooth transition to adult care, bony deformities may persist in some, and this would warrant surgical correction.

Do Bone Mineral Density, Trabecular Bone Score, and Hip Structural Analysis Differ in Indian Men with Parkinson's Disease? A Case-Control Pilot Study from a Tertiary Center in Southern India.

Objective: Parkinson's disease (PD) is a neurodegenerative condition that is characterized by bradykinesia, rigidity, and gait instability. Inherent to this condition is an increased predisposition to falls and fractures. Bone health in Parkinson's disease in India has not been studied thus far. This study aimed to assess the bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA) in Indian men with PD and compare them with matched controls. Methodology: A case-control study done at a tertiary care center from southern India. Bone biochemistry, BMD, TBS, and HSA were assessed. Results: Among 40 cases and 40 age, gender, and body mass index (BMI)-matched controls, there was no significant difference in BMD between both groups. The mean (SD) TBS at the lumbar spine [1.349 (0.090)] was significantly (P = 0.019) lower in men with PD as compared to matched controls [1.401 (0.089)]. Among the parameters of HSA, the buckling ratios were significantly higher at the femoral neck [11.8 (2.2) vs 9.4 (2.2); P = 0.001] and inter-trochanteric region [9.4 (2.1) vs 7.8 (1.4); P = 0.002] among cases as compared to matched controls. Vitamin D deficiency was significantly higher in this cohort of patients as was bone turnover marker indicating bone loss and a high bone turnover state. Conclusion: A comprehensive bone health assessment comprising BMD, TBS, and HSA may be required to capture all aspects of bone strength in Indian men with PD as BMD assessment as a stand-alone tool may not suffice to obtain all information pertaining to fracture risk in these individuals.

Bone Mineral Density and Serum Bone Turnover Markers among Post-Menarchal Girls from Rural South India.

Background: The data on the bone mineral density (BMD) and bone turnover markers (BTMs) in Indian adolescents are limited. Objectives: To assess BMD at lumbar spine (LS, L1-L4) and femoral neck (FN) in South Indian post-menarchal girls and correlate it with dietary calcium intake (mg/day), physical activity score and post-menarchal years. The study also assessed serum BTMs and their correlation with chronological age in the study population. Methods: This cross-sectional study included apparently healthy post-menarchal adolescent girls aged 12-16 years randomly selected from the community. Participants with vitamin D deficiency were excluded. The data on calcium intake and physical activity were obtained using validated questionnaires. All participants were evaluated with serum calcium, 25-hydroxy vitamin D, parathyroid hormone, N-terminal propeptide of type 1 collagen (P1NP) and Beta-CrossLaps (CTx) and BMD at LS and FN using dual X-ray absorptiometry (DXA). Statistical Analysis: EpiData version 3.1 was used for the data entry. The data analysis was done using Statistical Package for Social Sciences (SPSS) version 21. Continuous variables were expressed as mean ± SD. Pearson's correlation coefficient (r) was calculated, and two-tailed Kendall's tau-b test was used for assessing correlation of all nonparametric measures. Results: A total of 103 participants were screened, and data from 77 were analysed. There was a significant positive correlation of BMD at LS with chronological age (r: +0.235, P = 0.036), but not at FN. Positive correlation of BMD with increase in post-menarchal years was also noted at LS (r: +0.276, P = 0.015). There was no significant association of BMD with calcium intake and physical activity scores at both sites. There was a significant negative correlation of serum BTMs with age CTx (r: -0.596, P = 0.0001) and P1NP (r: -0.505, P = 0.0001). Conclusion: This study provides insight into the reference BMD range at LS spine and FN in South Indian rural post-menarchal adolescent girls. BMD positively correlated, whereas BTMs negatively correlated with age. The study also provides the first Indian reference range for serum BTMs in this age group.

Predictors of Delayed Hyponatraemia After Surgery for Pituitary Tumour.

Delayed hyponatraemia(DH) is a common complication following trans-sphenoidal surgery(TSS) for pituitary tumour. We evaluated the prevalence of DH following TSS, and assessed the factors associated with DH, including early post-operative diabetes insipidus(EPDI). This retrospective study included 100 TSS for pituitary tumours in 98 patients, over a period of 26 months. Subjects were divided into two groups: those who developed hyponatraemia and those who did not develop hyponatraemia, during post-operative days 4 to 14. The clinical characteristics and peri-operative parameters were compared between the two groups, to identify factors predicting DH. The mean age of the patients was 42.0±13.6 years, 58 (59%) were females and 61 (61%) had functional tumours. Thirty-six patients(36%) developed DH following TSS of whom majority(58%) were diagnosed on post-operative days 7 and 8; only 8/36 (22%) were symptomatic. Syndrome of inappropriate antidiuretic hormone secretion(SIADH) was found to be the most common aetiology of DH. On logistic regression analysis, intra-operative cerebrospinal fluid(CSF) leak (OR 5.0; 95% CI 1.9-13.8; p=0.002), EPDI (OR 3.4; 95% CI 1.3-9.2; p=0.015) and peri-operative steroid use (OR 3.6; 95% CI 1.3-9.8; p=0.014) were found to be significantly associated with DH. In conclusion, EPDI, intra-operative CSF leak and peri-operative steroid use were significant predictors of DH. EPDI predicts moderate to severe hyponatraemia with 80% specificity but has low sensitivity(47%). As most patients have asymptomatic hyponatraemia, serum sodium measurement on POD 7 to 10 would be helpful to identify DH in patients at increased risk.

Tenofovir-induced hypophosphatemic osteomalacia: how do bone mineral density, trabecular bone score and proximal hip geometry change with treatment?

Summary: Tenofovir-induced osteomalacia secondary to proximal renal tubular dysfunction is not an uncommon complication known to occur. A 46-year-old woman was referred for the evaluation of osteoporosis which was diagnosed elsewhere. She had polyarthralgia, bony pains and proximal muscle weakness of 1 year duration. She was diagnosed to have HIV infection and was on antiretroviral therapy that consisted of tenofovir, lamivudine and efavirenz for the past 12 years. She had attained menopause 5 years back. On examination, she had bone tenderness, proximal myopathy and painful restriction of movement of her lower limbs. Investigations showed features of renal tubular acidosis, hypophosphatemia and raised alkaline phosphatase that were suggestive of osteomalacia. X-ray of the pelvis showed diffuse osteopenia and an MRI of the pelvis done showed multiple insufficiency fractures involving the head of femur on both sides. Following this, her tenofovir-based regimen was changed to abacavir, efavirenz and lamivudine with addition of neutral phosphate supplements and calcitriol. On follow-up after 6 months, she had significant improvement in her symptoms as well as in the bone mineral density at the lumbar spine (33.2%), femoral neck (27.6%), trabecular bone score (13.2%) and reduction in the buckling ratio at the narrow neck (6.3%), inter-trochanteric region (34%) and femoral shaft (28.8%). Tenofovir-induced osteomalacia is encountered in individuals on prolonged treatment with tenofovir. Treatment consists of changing to a non-tenofovir-based regimen, as well as supplementation of phosphate and calcitriol. Treatment results in remarkable improvement in symptoms and most densitometric indices. Learning points: Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections. Tenofovir-related hypophosphatemic osteomalacia is related to proximal tubulopathy and is not an uncommon occurrence. Treatment mandates changing to a non-tenofovir-based regimen with supplementation of neutral phosphate and calcitriol. Treatment results in a significant improvement in bone mineral density, trabecular bone score and hip geometric parameters.

Chronic Alcohol Consumption and its Impact on Bone and Metabolic Health - A Narrative Review.

Chronic consumption of a large quantity of alcohol often results in the disruption of the communication between the nervous, endocrine and immune systems leading to profound and serious consequences at the physiological and behavioral levels. The overall impact of excessive alcohol consumption on bone health, metabolic profile and body composition, especially at moderate levels, is not well understood. Chronic excessive alcohol consumption adversely affects bone health through multiple mechanisms leading to low bone mass. It may also be significantly associated with various components on the metabolic syndrome. This review summarizes the findings from published studies that provide consistent evidence on the various effects of alcohol abuse on the bone health and metabolism.

A Pilot Study of Electrocardiographic Features in Patients with Obesity from a Tertiary Care Centre in Southern India (Electron).

Background: Obesity is associated with increased all-cause mortality and cardiovascular disease (CVD). An electrocardiogram (ECG) may be used to screen for subtle signs of CVD or altered cardiac morphology in the obese. Methodology: This observational cross-sectional analysed ECG changes in patients with obesity at a tertiary care centre in southern India. Results: One hundred and fifty adult patients with a mean (SD) BMI of 39.9 (6.7) kg/m2 were recruited in the study after excluding those with comorbidities (diabetes mellitus, systemic hypertension) or on chronic medications (ACE inhibitors). The cohort showed a female predominance (69.3%), with a mean (SD) age of 45.4 (11.2) years. Most patients exhibited a sinus rhythm (78%), with one patient showing features of first-degree conduction block. Sinus tachycardia was seen in 32 (21.3%) patients. We observed left and right ventricular hypertrophy in five (3.3%) and three (2%) patients, respectively. Observed ECG patterns included a prolonged QTc in 16 (10.7%) patients, inverted T-waves (mostly in the inferior leads) in 39 (26%) patients and ST-segment depression (predominantly in the lateral leads) in 14 (9.3%) patients. A greater prevalence was noted for morbid obesity. No deaths were reported in our cohort. Conclusions: The predominant ECG variations in this cohort included tachycardia, atrial enlargement, ventricular hypertrophy, conduction defects, LAD, features of ischemia or old infarction and repolarization abnormalities, with a greater prevalence in morbid obesity. Further studies are needed to assess the impact of weight reducing measures on reversibility of these changes and determine the association with outcomes in obese patients.

OSTA as a screening tool to predict osteoporosis in Indian postmenopausal women - a nationwide study.

This cross-sectional study done on 5356 postmenopausal women showed that OSTA may be used as a reliable screening tool for osteoporosis across different regions of India, a country known for its ethno-linguistic, cultural, and genetic diversity. BACKGROUND: The gold standard for diagnosing osteoporosis is DXA (dual-energy X-ray absorptiometry) scan, and this is not widely available across India. OSTA (Osteoporosis Self-Assessment Tool for Asians) score predicts risk of osteoporosis and can be used as reference tool for DXA. At a cutoff of ≤ + 1, OSTA predicted femoral neck osteoporosis with a sensitivity of 88% in a previous study among south Indian postmenopausal women. This study was done to validate the OSTA score in postmenopausal women across India. METHODOLOGY: A cross-sectional study in 5356 postmenopausal women from four regions of India namely south, east, north, and west. Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by DXA. The performance of OSTA in predicting BMD and TBS was assessed using ROC curve. RESULTS: The mean (SD) age was 61.6 (7.6) years. The performance of OSTA in predicting osteoporosis was fair (P < 0.001) with an AUC of 0.727 (95% CI 0.705-0.749) in the south, 0.693 (95% CI 0.664-0.723) in east India, 0.730 (95% CI 0.700-0.759) in the north, and 0.703 (95% CI 0.672-0.735) in the western region. At a cut-off below + 1.0, sensitivity was 76-84% and specificity was 45-53% in diagnosing osteoporosis at any site. In predicting degraded microarchitecture, the AUC was 0.500-0.600. CONCLUSION: OSTA may be reliably used as a screening tool for women at high risk of osteoporosis across India and may circumvent the limited availability of DXA scanners across the country.

Impact of teriparatide therapy in Indian postmenopausal women with osteoporosis with regard to DXA-derived parameters.

Background: There is paucity of literature on the impact of teriparatide on hip geometry and bone microarchitecture globally and none from the Indian subcontinent. This study examined the outcome of teriparatide therapy on vertebral fractures, bone mineral density (BMD), hip structural analysis (HSA), and trabecular bone score (TBS) in Indian postmenopausal women with severe osteoporosis. Methodology: Ambulatory postmenopausal women above the age of 50 years with either severe osteoporosis or vertebral fractures, or both, were recruited. All patients received cholecalciferol (2000 IU/day), calcium carbonate (elemental calcium 1 g/day), and teriparatide (20 mcg subcutaneously/day) for 24 months. Baseline bone biochemistry, BMD, TBS, and HSA were assessed and repeated after 24 months of therapy. Incident vertebral and nonvertebral fractures were also studied. Results: A total of 51 postmenopausal women with mean (SD) age of 65.7(8.6) years, and mean (SD) body mass index of 22.7 (3.5) kg/m2 were recruited in this study. Vertebral fractures were present in 74.5% (38/51) at baseline. Following teriparatide therapy, significant improvement was observed in the BMD (g/cm2) at both the lumbar spine (0.706-0.758: p < 0.001) and femoral neck (0.551-0.579: p = 0.047) as well as the TBS (1.160-1.271: p < 0.001). Most indices of proximal hip geometry also showed significant improvement following teriparatide therapy at 24 months. Incident vertebral fractures were noted in only 7.8% (4/51) of participants, while 92% (47/51) of participants did not develop any new vertebral fractures on follow-up. Conclusion: In South Indian postmenopausal women with either severe osteoporosis or vertebral fractures, or both, teriparatide was effective in improving the bone mineral parameters and bone quality.

Bisphosphonate-induced atypical femoral fracture in tandem: long-term follow-up is warranted.

Summary: Although bisphosphonates (BPs) are mainly used for the treatment of osteoporosis and are generally safe, long-term use and more dosage as utilised in malignant conditions may be associated with the rare adverse event of an atypical femoral fracture (AFF). Occasionally, the risk of developing an AFF persists long after BPs are withdrawn. A 39-year-old woman who underwent chemotherapy and an autologous stem cell transplantation for multiple myeloma presented to us with history of pain in the left thigh. She had received multiple doses of oral and parenteral BPs for about 10 years in view of the underlying myeloma with osteoporosis. Her investigations showed a suppressed CTX of 192 pg/mL, and radiograph of pelvis displayed thickened cortices with beaking of the left femoral shaft, which was suggestive of an AFF. Following discontinuation of BPs, she underwent prophylactic intra-medullary nailing with which her symptoms improved. Five years later, she presented with similar complaints on the right side. Investigations showed that her bone turnover continued to be suppressed with Cross linked C- Telopeptide of type 1 collagen (CTX) of 165 pg/mL and an X-ray done showed AFF on the right side despite being off BPs. A second intra-medullary nailing was done and on follow-up, she has been symptom-free and independent in her daily activities. Discontinuation of BPs may not prevent the incident second AFF and, therefore, thus warranting long-term follow-up. Learning points: Regular screening and follow-up of patients who receive long-term bisphosphonate (BP) therapy should be done. Discontinuation of BPs does not preclude the possibility of repeated occurrence of a second AFF. Long-term BP therapy warrants regular monitoring and follow-up should an AFF occur.

Disrupted Sleep Architecture Is Associated With Incident Bone Loss in Indian Postmenopausal Women: A Prospective Study.

Inadequate sleep has been shown to be detrimental to several body systems, including the bone. We proposed to study the impact of insomnia on bone health in Indian postmenopausal women. In a 2-year prospective study, ambulant community-dwelling postmenopausal women aged >50 years were recruited through simple random sampling. Sleep duration was recorded based on self-reported sleep duration and sleep quality using the Women's Health Initiative Insomnia Rating Scale (WHIIRS). Anthropometry, bone biochemistry including bone turnover markers (C-terminal telopeptide of type 1 collagen [CTX], N-terminal telopeptide of type 1 pro-collagen [P1NP]), bone mineral density (BMD), and trabecular bone score (TBS) were assessed at baseline and at the end of 2 years. Among 190 postmenopausal women with mean (SD) age of 58.2 (6.9) years, 65/190 (34.2%) had insomnia (WHIIRS ≥ 9) and 20/190 (10.5%) developed osteoporosis at any site on follow-up. The percentage decline over 2 years in BMD in women with insomnia was significantly (p < 0.001) higher at femoral neck (2.9 [1.6] versus 1.2 [1.2]%) and lumbar spine (4.5 [2.0] versus 1.6 [1.1]%). The decrement in TBS was also significantly higher (p < 0.001) in women with suboptimal sleep (1.5 [2.1] versus 0.5 [1.0] %) when compared with those with adequate sleep. The increment in CTX (46.4 [32.2] versus 18.9 [26.4]) and decrement in P1NP (35.4 [9.1] versus 16.7 [18.9]), respectively, were also greater (p < 0.001) in women with insomnia compared with those without. On multivariate analysis, insomnia was the sole factor that was predictive (adjusted odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.9-29.6; p < 0.001) of incident osteoporosis. In conclusion, poor sleep quality was associated with incident osteoporosis in Indian postmenopausal women. Optimal sleep may help to retard ongoing bone loss that results from sleep deprivation and requires further research. © 2022 American Society for Bone and Mineral Research (ASBMR).

Cathepsin K Mutation-A Subtle Clinical Presentation.

Context: Pyknodysostosis is an uncommon inherited disorder associated with consanguinity, often presenting with sclerotic bone disease, short stature, dysmorphic features, and recurrent fragility fractures at an early age. Case: A 34-year-old woman was evaluated for the cause of recurrent fragility fractures. She was born of a third-degree consanguineous marriage and had a twin brother who was of short stature. The index patient had a height of 141 cm, dysmorphic features including frontoparietal bossing, blue sclera with short stubby fingers and toes. Radiological evaluation revealed diffuse osteosclerosis with acro-osteolysis exclusively in the toes, apart from mid-facial hypoplasia, lack of pneumatization of the paranasal sinuses, dental abnormalities, and scoliosis. Dual-energy x-ray absorptiometry revealed increased bone mineral density. Based on the clinical features, the patient was tested for cathepsin K gene variants using next-generation sequencing and was found to be positive for a novel homozygous c.224T>C, p.Met75Thr likely pathogenic missense variant. Discussion: This patient presented at a later age than expected with recurrent fragility fractures and the diagnosis was not suspected till adulthood, owing to the subtle clinical features. Confirmation with genetic testing helped in establishing the diagnosis. Conclusion: Pyknodysostosis, although uncommon, is one of the differential diagnoses for diffuse osteosclerosis presenting with recurrent fragility fractures. Next-generation sequencing in an appropriate setting may confirm the diagnosis.