Is vitamin-D supplementation not useful in patients at risk of fractures and falls?

To evaluate numerous publications that question the bone and extraosseous benefits of vitamin D diet supplementation based on results, which often transcend to public opinion, but are not well interpreted. This may have negative consequences on compliance of patients under vitamin D supplementation. Critical appraisal of several articles on vitamin D supplementation and its relationship with fractures, falls, cardiovascular diseases, and cancer incidence. Such publications have certain limitations (i.e. patients excluded because of a diagnosis of osteoporosis, or at a higher risk for fractures and falls, or because they have a vitamin D deficiency, etc.), and conclusions and/or subsequent recommendations should be approached with caution. Our research shows that patients with osteoporosis, vitamin D deficiency, and at high risk of fractures and falls should not discontinue vitamin D supplementation (often associated with calcium). It is becoming increasingly evident that patients with hypovitaminosis D are those that gain a maximal benefit from vitamin D supplementation.

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial.

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

[Consensus statement: recommendations for the management of metabolic bone disease in human immunodeficiency virus patients]. / Documento de consenso: Recomendaciones para el manejo de la enfermedad ósea metabólica en pacientes con virus de la inmunodeficiencia humana.

OBJECTIVE: To provide practical recommendations for the evaluation and treatment of metabolic bone disease in human immunodeficiency virus (HIV) patients. PARTICIPANTS: Members of scientific societies related to bone metabolism and HIV: Grupo de Estudio de Sida (GeSIDA), Sociedad Española de Endocrinología y Nutrición (SEEN), Sociedad Española de Investigación Ósea y del Metabolismo Mineral (SEIOMM), and Sociedad Española de Fractura Osteoporótica (SEFRAOS). METHODS: A systematic search was carried out in PubMed, and papers in English and Spanish with a publication date before 28 May 2013 were included. Recommendations were formulated according to GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) setting both their strength and the quality of supporting evidence. Working groups were established for each major part, and the final resulting document was later discussed in a face-to-face meeting. All the authors reviewed the final written document and agreed with its content. CONCLUSIONS: The document provides evidence-based practical recommendations on the detection and treatment of bone disease in HIV-infected patients.

Use of Tirzepatide in Adults with Type 2 Diabetes Mellitus: Scientific Evidence and Practical Aspects.

Tirzepatide is a novel antidiabetic medication a single-molecule, agonist to the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors. It is approved in the USA and EU for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Due to the potential novelty represented by incorporating tirzepatide to clinical practice, we aim to review practical aspects of tirzepatide use in T2DM and the supporting scientific evidence. A group of ten endocrinologists involved as investigators in the phase 3 SURPASS clinical trial program followed a nominal group technique, a qualitative research methodology designed as a semi-structured group discussion to reach a consensus on the selection of a set of practical aspects. The scientific evidence for tirzepatide has been reviewed with respect to a number of patients' clinical profiles and care goals. Information of interest related to adverse events, special warnings and precautions, and other considerations for tirzepatide use has been included. Finally, information provided to the patients has been summarized. The practical aspects reported herein may be helpful in guiding physicians in the use of tirzepatide and contribute to optimizing the management of T2DM.

Comprehensive approach to people with type 2 diabetes. Diabetes Knowledge Area of the Spanish Society of Endocrinology and Nutrition.

OBJECTIVE: To provide practical recommendations for the comprehensive approach of people with type 2 diabetes according to evidence-based medicine. PARTICIPANTS: Members of the Diabetes Knowledge Area of the Spanish Society of Endocrinology and Nutrition. METHODS: The recommendations were formulated according to the degrees of evidence of the Standards of Medical Care in Diabetes-2022. After reviewing the available evidence and formulating recommendations by the authors of each section, several rounds of comments were developed incorporating the contributions and voting on controversial points. Finally, the final document was sent to the rest of the members of the area for review and incorporation of contributions, to finally carry out the same process with the members of the Spanish Society of Endocrinology and Nutrition Board of Directors. CONCLUSIONS: The document establishes practical recommendations based on the latest available evidence for the management of people with type 2 diabetes.

Psychometric properties of the Clarke questionnaire for hypoglycemia awareness in the Spanish population with type 2 diabetes.

OBJECTIVES: The Clarke questionnaire, validated in Spanish language, assesses hypoglycemia awareness in patients with type 1 diabetes. This study aimed to analyze its psychometric properties in patients with type 2 diabetes (T2DM). METHODS: This was a questionnaire validation study. Patients with T2DM and treated with insulin, sulfonylureas or glinides were consecutively recruited from six endocrinology consultations and six primary care centers. The internal structure of the 8-item Clarke questionnaire was analyzed by exploratory (training sample) and confirmatory (testing sample) factor analysis; the internal consistency using Omega's McDonald coefficient; and goodness of fit with comparative fit index (CFI, cutoff >0.9), Goodness of Fit Index (GFI, cutoff >0.9), and root mean-square error of approximation (RMSEA, cutoff <0.09), as well as unidimensionality indicators. RESULTS: The 265 participants (56.8% men) had a mean age of 67.8 years. Confirmatory factor analysis for one dimension obtained poor indicators: fit test (p < 0.001); CFI = 0.748; RMSEA = 0.122 and SRMR = 0.134. Exploratory factor analysis showed 2 or 3 dimensions with poor adjustment indicators. Omega's McDonald was 0.739. CONCLUSIONS: The Spanish version of the Clarke questionnaire was not valid or reliable for assessing hypoglycemia awareness in people with T2DM in Spanish population.

Guide of management of alterations in mineral and bone metabolism during gestation and lactation.

OBJECTIVE: To provide practical recommendations for the management of mineral and bone metabolism alterations in pregnancy and lactation. PARTICIPANTS: Members of the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition. METHODS: Recommendations were formulated according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. A systematic search was carried out in Medline of the available evidence for each pathology. Papers in English with publication date until 29 February 2020 were included. A methodologist resolved the differences that arose during the process of reviewing the literature and formulating recommendations. The recommendations were discussed and approved by all members of the Working Group. CONCLUSIONS: The document establishes practical recommendations based on evidence about the management of mineral and bone metabolism disorders in pregnancy and lactation.

Executive summary: Position document: Evaluation and management of hypoglycemia in the patient with diabetes mellitus 2020. Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition. / Resumen ejecutivo: Documento de posicionamiento: evaluación y manejo de la hipoglucemia en el paciente con diabetes mellitus 2020. Grupo de Trabajo de Diabetes Mellitus de la Sociedad Española de Endocrinología y Nutrición.

OBJECTIVE: To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). METHODS: The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 28 February 2020 were reviewed. This executive summary takes account of the evidence incorporated since 2013. CONCLUSIONS: The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

Executive summary: Position document: Evaluation and management of hypoglycemia in the patient with diabetes mellitus 2020. Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition.

OBJECTIVE: To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). METHODS: The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 30 November 2019 were reviewed. This executive summary takes account of the evidence incorporated since 2013. CONCLUSIONS: The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

Estimation of Long-Term Efficacy of Denosumab Treatment in Postmenopausal Women With Osteoporosis: A FRAX- and Virtual Twin-Based Post Hoc Analysis From the FREEDOM and FREEDOM Extension Trials.

The 3-year placebo-controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7-year open-label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long-term control group, thus limiting the ability to fully evaluate long-term efficacy. This analysis provides a quantitative estimate of the long-term antifracture efficacy of denosumab based on two approaches: comparison with FRAX®- (Fracture Risk Assessment Tool-) and virtual twin-estimated 10-year fracture rates. Subjects who were randomized to denosumab in the FREEDOM trial, continued into the Extension study, completed the 10-year visit, and missed ≤1 dose in the FREEDOM trial and ≤1 dose in the Extension (n = 1278) were included in the analysis. The 10-year observed cumulative incidence of major osteoporotic fracture (MOF) and hip fractures was compared with the 10-year fracture probability predicted at baseline by FRAX, a computer-based fracture risk algorithm, and with that estimated for a hypothetical cohort of 10-year placebo controls (virtual twins). The observed 10-year fracture incidence was lower than the 10-year probability predicted by FRAX for both MOF (10.75% [95% CI, 9.05 to 12.46] versus 15.63% [95% CI, 15.08 to 16.18], respectively), and hip fractures (1.17% [95% CI, 0.58 to 1.76] versus 5.62% [95% CI, 5.28 to 5.97], respectively). The observed fracture incidence was also lower than the fracture rate estimated in a hypothetical cohort of 10-year placebo controls for MOF (23.13% [95% CI, 17.76 to 28.87]; relative risk 0.49 [95% CI, 0.36 to 0.64]). These data support the long-term efficacy of denosumab in reducing MOF and hip fractures in postmenopausal women with osteoporosis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

New technologies in the evaluation of bone fragility and its application in Endocrinology. / Nuevas tecnologías en la evaluación de la fragilidad ósea y su aplicación en Endocrinología.

Bone mineral density using dual-energy X-ray absorptiometry is the gold standard for the assessment of bone and an important predictor of fracture risk. However, most fragility fractures occur in people without densitometric osteoporosis, especially in endocrinological diseases. Fracture risk estimation tools such as FRAX have improved diagnostic sensitivity but do not include additional skeletal features. Bone microarchitecture research represents an improvement in the treatment of these patients. In this document members of the Mineral and Bone Metabolism Working Group of the Spanish Society of Endocrinology and Nutrition review new advances in dual-energy X-ray absorptiometry and other complex techniques for the study of bone microarchitecture as well as the available data on type 2 diabetes and parathyroid pathology.

Phosphate disorders and clinical management of hypophosphatemia and hyperphosphatemia. / Trastornos del fosfato y actitud clínica ante situaciones de hipofosfatemia e hiperfosfatemia.

Serum phosphorus levels range from 2.5 and 4.5mg/dL (0.81-1.45 mmol/L) in adults, with higher levels in childhood, adolescence, and pregnancy. Intracellular phosphate is involved in intermediary metabolism and other essential cell functions, while extracellular phosphate is essential for bone matrix mineralization. Plasma phosphorus levels are maintained within a narrow range by regulation of intestinal absorption, redistribution, and renal tubular absorption of the mineral. Hypophosphatemia and hyperphosphatemia are common clinical situations, although changes are most often mild and oligosymptomatic. However, acute and severe conditions that require specific treatment may occur. In this document, members of the Mineral and Bone Metabolism Working Group of the Spanish Society of Endocrinology and Nutrition review phosphate disorders and provide algorithms for adequate clinical management of hypophosphatemia and hyperphosphatemia.

Document on a comprehensive approach to type 2 diabetes mellitus. / Documento de abordaje integral de la diabetes tipo 2.

OBJECTIVE: Treatment of type 2 diabetes mellitus (T2DM) is complex and is intended to decrease morbidity and mortality. Management should therefore include adequate diabetes education, lifestyle changes, drug treatment to achieve early blood glucose control and reduction of cardiovascular (CV) risk factors, early detection and treatment of complications, and assessment of associated comorbidities. The objective was to prepare a document including all aspects required for a comprehensive approach to T2DM. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology. METHODS: The available evidence regarding each aspect of diabetes management (blood glucose control goals, diet and exercise, drug treatment, risk factor management and control, detection of complications, and management of frail patients) was reviewed. Recommendations were formulated based on the grades of evidence stated in the 2018 Standards of Medical Care in Diabetes. Recommendations were discussed and agreed by the working group members. CONCLUSIONS: This document is intended to provide evidence-based practical recommendations for comprehensive management of T2DM by clinical endocrinologists.

Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide.

CONTEXT: Semaglutide, a once-weekly glucagon-like peptide-1 analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 1-3 clinical trials. OBJECTIVE: To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials. DESIGN: Post hoc analysis of the SUSTAIN 1-3 trials. SETTING: Three hundred and eleven sites in 30 countries. PATIENTS OR OTHER PARTICIPANTS: 2432 subjects with T2D. INTERVENTIONS: Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg). MAIN OUTCOME MEASURE: To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW. RESULTS: Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7 kg to 4.3 kg; P < 0.0001) and semaglutide 1.0 mg (4.5 kg to 6.1 kg; P < 0.0001) vs comparators (1.0 kg to 1.9 kg). There were greater reductions in IR with semaglutide 0.5 mg (27% to 36%) and semaglutide 1.0 mg (32% to 46%) vs comparators (17% to 28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70% to 80% and 34% to 94%, for semaglutide 0.5 mg and 1.0 mg, respectively, vs comparator). CONCLUSIONS: Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1-3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.

Recommendations on the effect of antidiabetic drugs in bone. / Recomendaciones sobre el efecto de los fármacos antidiabéticos en el hueso.

OBJECTIVE: To provide recommendations on the effect of antidiabetic drugs on bone fragility to help select the most adequate antidiabetic treatment, especially in diabetic patients with high risk of fracture. PARTICIPANTS: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. METHODS: The GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) was used to establish both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each antidiabetic drug: AND "osteoporosis", "fractures", "bone mineral density", "bone markers", "calciotropic hormones". Papers in English with publication date before 30 April 2016 were reviewed. Recommendations were jointly discussed by the Working Group. CONCLUSIONS: The document summaries the data on the potential effects of antidiabetic drugs on bone metabolism and fracture risk.

Recommended vitamin D levels in the general population. / Recomendaciones de vitamina D para la población general.

OBJECTIVE: To provide recommendations based on evidence on the management of vitaminD deficiency in the general population. PARTICIPANTS: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. METHODS: Recommendations were formulated using the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the term VitaminD and the name of each issue. Papers in English and Spanish with publication date before 17 March 2016 were included. Recommendations were jointly discussed by the Working Group. CONCLUSIONS: This document summarizes the data about vitaminD deficiency in terms of prevalence, etiology, screening indications, adequate levels and effects of supplementation on bone and non-skeletal health outcomes.

[Update of recommendations for evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions. Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology]. / Actualización de las recomendaciones para la evaluación y tratamiento de la osteoporosis asociada a enfermedades endocrinas y nutricionales. Grupo de trabajo de osteoporosis y metabolismo mineral de la SEEN.

OBJECTIVE: To update previous recommendations developed by the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition for the evaluation and treatment of osteoporosis associated to different endocrine and nutritional diseases. PARTICIPANTS: Members of the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition. METHODS: Recommendations were formulated according to the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each condition: AND "osteoporosis", "fractures", "bone mineral density", and "treatment". Papers in English with publication date between 18 October 2011 and 30 October 2014 were included. The recommendations were discussed and approved by all members of the Working Group. CONCLUSIONS: This update summarizes the new data regarding evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions.

Prevalence of osteoporosis, vertebral fractures and hypovitaminosis D in postmenopausal women living in a rural environment.

OBJECTIVES: First, to study the difference between two groups of postmenopausal women living in different population centres (rural vs urban) in the prevalence of osteoporosis, fragility fractures and factors which may influence them: hypovitaminosis D, bone mineral density, coexistence of other diseases which predispose to their appearance; secondly, to observe the influence of low socioeconomic status, categorised as poverty. STUDY DESIGN: 1229 postmenopausal women were studied, of whom 390 (31.7%), were living in rural areas and 839 (68.3%), in urban areas. Data regarding risk factors related to osteoporosis were obtained, and, among other biochemical measures, 25 hydroxyvitamin D and parathyroid hormone were determined. Bone densitometry was carried out in the lumbar spine and proximal femur, as well as lateral X-rays of the dorsal and lumbar spine. RESULTS: The women who lived in rural areas were older, shorter, heavier and had a higher body mass index than those from urban areas. Among the women from rural areas there was a higher prevalence of poverty, and higher levels of obesity, arterial hypertension and diabetes mellitus were observed, as well as a higher prevalence of densitometric osteoporosis. The rural women had lower values of bone mineral density in the lumbar spine and a higher prevalence of vertebral fractures and hypovitaminosis D. The variables which were associated independently with living in rural areas were poverty, obesity, vertebral fractures, BMD in the lumbar spine and levels of 25 hydroxyvitamin D. CONCLUSIONS: In our study, postmenopausal women who live in rural populations have more poverty, lower values of vitamin D, lower BMD in the lumbar spine and a higher prevalence of vertebral fractures and of osteoporosis. The higher prevalence of obesity, arterial hypertension and diabetes mellitus observed in these women may be adjuvant factors, all fostered by their socioeconomic state of poverty.

[Vitamin D hormone system and diabetes mellitus: lessons from selective activators of vitamin D receptor and diabetes mellitus]. / Sistema hormonal D y diabetes mellitus: lecciones de los activadores selectivos del receptor de vitamina D.

The vitamin D hormone system has significant skeletal and extra-skeletal effects. Vitamin D receptor occurs in different tissues, and several cells other than renal cells are able to locally produce active vitamin D, which is responsible for transcriptional control of hundreds of genes related to its pleiotropic effects. There is increasing evidence relating vitamin D to development and course of type 1 and 2 diabetes mellitus. Specifically, influence of vitamin D on the renin-angiotensin-aldosterone system, inflammatory response, and urinary albumin excretion could explain the relevant impact of vitamin D status on diabetic nephropathy. Selective vitamin D receptor activators are molecules able to reproduce agonistic or antagonistic effects of active vitamin D depending on the tissue or even on the cell type. Specifically, paricalcitol has a beneficial profile because of its potency to reduce parathyroid hormone, with lower effects on serum calcium or phosphate levels. Moreover, in patients with diabetes and renal disease, paricalcitol decreases microalbuminuria, hospitalization rates, and cardiovascular mortality. Therefore, these molecules represent an attractive new option to improve prognosis of renal disease in patients with diabetes.