Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression.

Adrenal adenomas/incidentalomas with mild autonomous cortisol secretion (MACS)/subclinical hypercortisolism (SH) are often associated with metabolic syndrome, glucocorticoid-induced osteoporosis, and fractures. In this background, the present systematic review and meta-analysis aimed to collate the available evidence and provide a summary of the effect of MACS/SH on bone health in terms of fractures, osteoporosis/osteopenia, microarchitecture, and bone turnover. PubMed/MEDLINE, Embase, and Web of Science databases were systematically searched for observational studies reporting prevalence of fractures, osteoporosis/osteopenia or data on bone microarchitecture/bone turnover markers (BTMs). Following literature search, 16 observational studies were included. Pooled prevalence of any fractures (vertebral and non-vertebral), vertebral fractures, and osteoporosis/osteopenia in MACS/SH were 43% [95% confidence intervals (CI): 23%, 62%], 45% (95% CI: 22%, 68%) and 50% (95% CI: 33%, 66%), respectively. On meta-regression, age, sex, 24-hour urinary free cortisol, and dehydroepiandrosterone-sulfate did not predict fracture risk. The likelihood of any fractures [odds ratio (OR) 1.61; 95% CI: 1.18, 2.20; P = 0.0026], vertebral fractures (OR 2.10; 95% CI: 1.28, 3.45; P = 0.0035), and osteoporosis/osteopenia (OR 1.46; 95% CI: 1.15, 1.85; P = 0.0018) was significantly higher in adrenal adenomas and MACS/SH than non-functional adrenal adenomas. Subjects with MACS/SH had significantly lower bone mineral density (BMD) at lumbar spine [mean difference (MD) -0.07 g/cm2; 95% CI: -0.11, -0.03; P = 0.0004) and femoral neck (MD -0.05 g/cm2; 95% CI: -0.08, -0.02; P = 0.0045) than their non-functional counterparts. Limited data showed no significant difference in BTMs. Publication bias was observed in the pooled prevalence of any fractures, vertebral fractures and pooled MD of femoral neck BMD. To conclude, people with adrenal adenomas/incidentalomas and MACS/SH are at a 1.5- to 2-fold higher likelihood of fractures and osteoporosis/osteopenia compared to non-functional adrenal adenomas and should routinely be screened for bone disease. Nevertheless, considering the modest sample size of studies and evidence of publication bias, larger and high-quality studies are required (CRD42023471045).

Mild autonomous cortisol secretion (MACS), often also referred to as subclinical hypercortisolism (SH), is usually associated with an underlying adrenal incidentaloma (AI), an adrenal mass incidentally found during abdomen imaging. Although signs of overt cortisol excess are lacking, subjects with MACS/SH often have features of metabolic syndrome, osteoporosis and fractures. The present systematic review and meta-analysis showed that the pooled prevalence of any fractures (vertebral and non­vertebral), vertebral fractures, and osteoporosis/osteopenia in MACS/SH were 43%, 45%, and 50%, respectively. People with adrenal adenomas/incidentalomas and MACS/SH are at a 1.5- to 2-fold higher likelihood of fractures and osteoporosis/osteopenia compared to non­functional adrenal adenomas. Besides, subjects with MACS/SH had significantly lower bone mineral density at lumbar spine and femoral neck than their non­functional counterparts. It is thus imperative to assess bone health in all subjects with MACS/SH.

Risk of Gallstone Disease in Primary Hyperparathyroidism: A Systematic Review and Meta-analysis.

OBJECTIVE: Apart from renal stones, primary hyperparathyroidism (PHPT) has been linked to the occurrence of gallstone disease (GSD). Nevertheless, the association is not consistent across all studies. The present systematic review and meta-analysis aims to collate the hitherto available evidence and provide a pooled estimate of the association between GSD and PHPT. METHODS: PubMed/MEDLINE, Embase, and Web of Science databases were systematically searched from inception till May 10, 2023 for observational studies reporting the prevalence of GSD (in terms of absolute numbers) in patients with PHPT. The pooled prevalence of GSD and odds ratio with 95% CI of the occurrence of GSD in patients with PHPT as compared to age- and sex-matched controls were calculated. Subgroup analysis was performed based on patient ethnicity (Indian/Caucasian). Statistical analysis was carried out using R version 4.2.2. Random-effects model with Hartung-Knapp adjustment was used for analyses. RESULTS: A total of 7 observational studies were included, pooling data from 15 949 patients with PHPT. The pooled prevalence of GSD in patients with PHPT was 16% (95% CI: 7%, 25%, I2 = 99%), being 13% (95% CI: 0%, 66%, I2 = 76%) in Indians, and 17% (95% CI: 4%, 31%, I2 = 99%) in Caucasians. Data consolidated from 3 studies showed that the pooled odds ratio of occurrence of GSD in patients with PHPT compared to controls was 1.77 (95% CI: 1.60, 1.97, P < .001, I2 = 0%). CONCLUSIONS: GSD is more prevalent in patients with PHPT than in the general population. Thus, PHPT may be considered an additional risk factor for GSD.

Do vitamin D levels or supplementation play A role in COVID-19 outcomes?-a narrative review.

BACKGROUND AND OBJECTIVE: Hypovitaminosis D has been proposed as a risk factor for increased susceptibility to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and severe outcomes in coronavirus disease 2019 (COVID-19). Likewise, vitamin D supplementation has been proposed as an effective means for preventing and improving clinical outcomes in COVID-19. Nevertheless, available data are markedly inconsistent and contradictory. Considering the heterogeneity in the available clinical evidence, we planned to undertake a narrative review and provide a precise summary of the role of vitamin D in COVID-19. METHODS: PubMed/MEDLINE database was searched from inception till September 30, 2023 using appropriate MeSH terms. The initial search revealed 900 results. Thereafter, titles and abstracts were scanned and commentaries, letters, and editorials were excluded. Relevant observational studies and clinical trials/randomized controlled trials (RCTs) were full-text assessed and pertinent data were extracted for this narrative review. KEY CONTENT AND FINDINGS: Data from observational and ecological studies suggest that hypovitaminosis D is associated with a higher risk of acquiring COVID-19. Similarly, evidence support a negative association between 25-hydroxyvitamin D levels and COVID-19 severity, nevertheless, causality remains to be established. With regard to vitamin D supplementation and COVID-19-related health outcomes, data from observational studies and RCTs are contradictory. Even in moderate-to-severe/severe COVID-19, vitamin D supplementation has not been shown to be beneficial. Besides, data suggest that vitamin D levels might alter COVID-19 vaccine efficacy and be associated with long COVID. CONCLUSIONS: Vitamin D deficiency is linked to an increased risk of acquiring SARS-CoV-2 infection and poor COVID-19 prognosis, however, available evidence with regard to improved clinical outcomes with vitamin D supplementation is inconsistent.

Osteoporosis and Obesity.

Introduction: This article concisely overviews the complex relationship between obesity and bone health. Obesity, characterized by excessive fat accumulation, has been traditionally associated with higher bone mineral density. Also, recent data suggest a favorable bone microarchitecture profile in these patients. However, the increase in bone mineral density does not necessarily confer protection against fractures, and the risk of fractures may vary depending on the skeletal sites. Factors affecting bone health: Various factors, including mechanical factors, hormones, cytokines, inflammation, and bone marrow adiposity, contribute to the adverse effect of obesity on bone. The article explores these factors alongside non-invasive techniques and tools like the Fracture Risk Assessment (FRAX) to evaluate fracture risk. Bone and Adipose tissue: This article also highlights the essential roles of hormones such as vitamin D, Parathormone (PTH), FGF-23 (Fibroblast Growth Factor 23), which affect bone health, and some of the hormones secreted from the adipose tissues such as adiponectin and leptin. Obesity Paradox and Sarcopenic Obesity: The article delves into the intriguing obesity paradox, where an increased BMI correlates with higher bone mineral density but not necessarily reduced fracture risk. Sarcopenic obesity, a combination of excessive fat accumulation and reduced muscle mass, further complicates the relationship between obesity and bone health. Conclusions: Physicians should keep a comprehensive approach to treating obese patients with osteoporosis, including lifestyle modifications, weight management, fall prevention strategies, and pharmacological interventions. Further research is needed to better understand the relationship between obesity and bone health.

Diabetes and Osteoporosis.

Bone fragility is an emerging complication of diabetes. People with diabetes are at a significantly higher risk of fractures compared to the general population. Bone fragility occurs in diabetes as a result of complex and poorly understood mechanisms occurring at the cellular level contributed by vascular, inflammatory and mechanical derangements. Bone mineral density (BMD) as assessed by DEXA is low in type 1 diabetes. Type 2 diabetes has a high risk of fracture despite a normal to raised BMD. DEXA thus underestimates the fracture risk in diabetes. Data are scare regarding the efficacy of the available therapies in this low bone turnover state.

Efficacy of zoledronate, denosumab or teriparatide in postmenopausal women with type 2 diabetes mellitus at high risk of fragility fractures: protocol of an open, blinded endpoint randomized controlled pilot trial.

Background: People with type 2 diabetes (T2D) are at high risk of fragility fractures; however, there are no randomized controlled trials evaluating the efficacy of anti-osteoporosis drugs as a primary pre-specified endpoint in T2D. Objectives: To compare the efficacy of anti-osteoporotic drugs in postmenopausal women with T2D. Design: Prospective, randomized, open, blinded endpoint clinical pilot trial. Methods: Postmenopausal women (⩾50 years) with T2D (duration ⩾5 years), HbA1c 7-10%, eGFR ⩾45 mL/min/1.73 m2 and prior vertebral (clinical/morphometric), hip, radius, humeral fragility fracture or bone mineral density (BMD) T-score (adjusted for diabetes) at lumbar spine/femoral neck ⩽-2.5 and high FRAX score will be eligible for inclusion. Subjects with secondary causes of osteoporosis, prior exposure to bone-active therapies or history of use of glucocorticoids/pioglitazone/thiazides/canagliflozin will be excluded. Finally, eligible subjects will undergo estimation of serum calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and bone turnover markers (BTMs) (total procollagen type I N-propeptide, ß-CTX) along with trabecular bone score (TBS) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of non-dominant hand and leg. After a 2-week run in phase, they will be randomized in a 1:1:1:1 ratio to receive yearly zoledronate, or biannually denosumab or daily teriparatide (in addition to standard of care, i.e., calcium 1000 mg/day and cholecalciferol 1000 IU/day) or only standard of care (control). The primary endpoints will be change in areal BMD and frequency of incident fractures at 18 months. The secondary endpoints will be change in HR-pQCT parameters, TBS and BTMs at 18 months. Adverse events will be recorded for all randomized participants. Ethics: The study has been approved by the Institute Ethics Committee. Written informed consent will be obtained from each participant. Discussion: The trial is expected to provide information regarding optimal anti-osteoporotic therapy in people with T2D and bone fragility. Registration: Prospectively registered in Clinical Trial Registry of India (CTRI/2022/02/039978).