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Studies suggest that melatonin may promote cardiovascular protection. Previous trials have primarily been performed on co-morbid patients. Little information exist on the effect in postmenopausal women with general good health. In a double-blinded placebo-controlled study, we randomized 41 postmenopausal women to either 10 mg melatonin per day or placebo for 3 months. Outcomes of the trial was changes in blood pressure, pulse wave velocity (PWV), and quality of sleep evaluated by Pittsburgh Sleep Quality Index (PSQI). Thirty-nine women completed the study. Mean age was 63 years (range 55–75 years). Over the 3 months of the trial, PWV did not differ between groups: Placebo 1.1% (IQR −2.1;9.9) vs. melatonin 0.0% (IQR-9.8;4.1), p = 0.43). The were no significant differences in blood pressure bewteen melatonin and placebo group. Both groups had a pour quality of sleep at baseline (placebo: PSQI 6.0 (IQR 3.3; 8.8) vs. melatonin PSQI 6.0 (IQR 3.0; 10.0), p = 0.94), which did not change in response to treatment. In healthy postmenopausal women, supplementation with 10 mg melatonin was well-tolerated, but we did not observe any significant improvements in pulse wave velocity, blood pressure or quality of sleep compared with placebo. •Randomized controlled trial on general healthy postmenopausal women.•Investigating the effect of melatonin on cardiovascular indices and quality of sleep.•Additional effect of melatonin on blood pressure and arterial stiffness was sparse in healthy women.

A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation. We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses. Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.

We wanted to investigate effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) on inflammatory cytokine expression in both activated and non-activated Mφ. Mononuclear cells, isolated from healthy donor buffy coats were cultured for a 6-day differentiation-period. Fully differentiated Mφ were pre-treated with either 25(OH)D3 or 1.25(OH)2D3 for (4, 12 or 24 hours) +/-LPS challenge for 4 hours. Gene expression analyses of VDR, Cyp27b1 and pro-inflammatory markers TNF-α, IL-6, NF-κB, MCP-1, was performed using RT-quantitative PCR. TNF-α protein levels from Mφ culture media were analysed by ELISA. Both 25(OH)D3 and 1.25(OH)2D3 significantly inhibited TNF-α expression in both LPS-stimulated and unstimulated Mφ. Also, NF-κB, and to a lesser extend IL-6 and MCP-1 were inhibited. LPS up-regulated Cyp27b1 gene expression which was partly reverted by 1.25(OH)2D3. These data show anti-inflammatory effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) in human macrophages, and support, that means for targeting high dose vitamin D3 to the immune system may have beneficial clinical effect in inflammatory conditions.

X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients. The management of X-linked hypophosphataemia has evolved owing to the availability of burosumab. In this Evidence-Based Guideline, the authors provide updated clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia with the aim of improving patient outcomes and quality of life.

Hypoparathyroidism (HypoPT) and pseudohypoparathyroidism (PHP) are diseases with abnormal calcium and phosphate homeostasis and low and high PTH levels, respectively. It has been hypothesized that this could dispose to vascular calcifications and thereby perhaps also cardiovascular morbidity. The aim of this study was to assess lower leg arterial calcifications (LLAC) in patients with HypoPT or PHP. Using a cross-sectional design, we measured the LLAC using a high-resolution peripheral quantitative computed tomography (HR-pQCT) scanner in 72 patients with HypoPT and 25 patients with PHP and compared them with findings in 61 controls. LLAC were found in only two (3%) of the controls. Compared to the controls, LLAC were significantly more prevalent in patients with HypoPT (N = 12, [17%], p < 0.01) and PHP (N = 4, [16%], p < 0.04). Compared to the patients without calcifications, patients with calcifications had higher plasma calcium levels and a lower eGFR, as well as they were older and more often males. Plasma phosphate levels and the calcium-phosphate product were not associated with LLAC. In conclusion, we found that HypoPT and PHP are associated with an increased prevalence of vascular calcifications.

Quantitative computed tomography (QCT), high-resolution peripheral QCT (HR-pQCT) and dual X-ray absorptiometry (DXA) scans are commonly used when assessing bone mass and structure in patients with osteoporosis. Depending on the imaging technique and measuring site, different information on bone quality is obtained. How well these techniques correlate when assessing central as well as distal skeletal sites has not been carefully assessed to date. One hundred and twenty-five post-menopausal women aged 56–82 (mean 63) years were studied using DXA scans (spine, hip, whole body and forearm), including trabecular bone score (TBS), QCT scans (spine and hip) and HR-pQCT scans (distal radius and tibia). Central site measurements of areal bone mineral density (aBMD) by DXA and volumetric BMD (vBMD) by QCT correlated significantly at the hip ( r  = 0.74, p  < 0.01). Distal site measurements of density at the radius as assessed by DXA and HR-pQCT were also associated ( r  = 0.74, p  < 0.01). Correlations between distal and central site measurements of the hip and of the tibia and radius showed weak to moderate correlation between vBMD by HR-pQCT and QCT ( r  = −0.27 to 0.54). TBS correlated with QCT at the lumbar spine ( r  = 0.35) and to trabecular indices of HR-pQCT at the radius and tibia ( r  = −0.16 to 0.31, p  < 0.01). There was moderate to strong agreement between measuring techniques when assessing the same skeletal site. However, when assessing correlations between central and distal sites, the associations were only weak to moderate. Our data suggest that the various techniques measure different characteristics of the bone, and may therefore be used in addition to rather than as a replacment for imaging in clinical practice.

Purpose Previous studies have shown that low levels of 25-hydroxyvitamin D (25(OH)D) are associated with a poorer breast cancer survival. The relationship between vitamin D status and breast cancer outcomes is however still debated. The aim of the present study was to investigate the association between 25(OH)D blood levels measured at time of diagnosis and event-free survival (EFS) and overall survival (OS) in a large cohort of patients with early-stage primary invasive breast cancer. Methods From April 2008 to April 2013, 25(OH)D status was measured at time of diagnosis in all women operated for early stage primary invasive breast cancer at Rigshospitalet, Copenhagen, Denmark. Associations between 25(OH)D and EFS and OS were investigated using a Cox Proportional hazards model, adjusting for age, disease characteristics, time period, and BMI. Differences in survival were evaluated by hazard ratios (HR). Results In the present study, 2510 women with primary invasive breast cancer were included. Women with the lowest 25(OH)D levels (≤ 52 nmol/L) had an inferior EFS with a HR of 1.63 (95% CI 1.21–2.19) compared to women in the third quartile (76–99 nmol/L). Women with the highest 25(OH)D levels (≥ 99 nmol/L) also had an inferior EFS with a HR of 1.37 (95% CI 1.02–1.83). Plotting 25(OH)D status against EFS, the association was inversely J-shaped. For OS, a similar association with 25(OH)D status was observed. Conclusion We confirmed previous findings suggesting that a low 25(OH)D status is associated with an inferior breast cancer survival, but unlike previous findings, we found an indication of poorer breast cancer survival also among women with high 25(OH)D levels.

Our preliminary findings have lead us to propose bone marrow adipocyte secretions as new contributors to bone loss. Indeed, using a coculture model based on human bone marrow stromal cells, we previously showed that soluble factors secreted by adipocytes induced the conversion of osteoblasts towards an adipocyte-like phenotype. In this study, microarray gene expression profiling showed profound transcriptomic changes in osteoblasts following coculture and confirmed the enrichment of the adipocyte gene signature. Double immunofluorescence microscopic analyses demonstrated the coexpression of adipogenic and osteoblastic specific markers in individual cells, providing evidence for a transdifferentiation event. At the molecular level, this conversion was associated with upregulated expression levels of reprogramming genes and a decrease in the DNA methylation level. In line with these in vitro results, preliminary immunohistochemical analysis of bone sections revealed adipogenic marker expression in osteoblasts from elderly subjects. Altogether, these data suggest that osteoblast transdifferentiation could contribute to decreased bone mass upon ageing.

Dystocia is one of the most common causes of cesarean section in nulliparous women. Studies have described the presence of vitamin D receptors in the myometrium, but it is still unclear whether vitamin D affects the contractility of the smooth muscles. We therefore aimed to determine the association between the vitamin D serum level at labor and the risk of dystocia. We conducted a case-control study between January 2012 and June 2017. Cases were primiparous women, with spontaneous onset of labor, who gave birth by cesarean section due to dystocia. Controls were primiparous women with a spontaneous vaginal delivery. We included 60 women (30 cases and 30 controls) in the analysis. The differences between cases and controls were assessed using chi-squared test for categorical variables and two-sample t-test or unequal t-test for continuous variables, as appropriate, after evaluation of whether they followed the normal distributions. The mean serum 25-hydroxyvitamin D concentrations were 53.1nmol/l (95%CI; 45.2 to 60.9) among cases and 69.9nmol/l (95%CI; 57.5 to 82.4) among controls (P = 0.02). The mean plasma parathyroid hormone levels were 2.25 pmol/l and 2.38, respectively (P = 0.57). Even though 78% of all women reported taking a minimum of 10μg/day of vitamin D throughout pregnancy, 43% had vitamin D insufficiency, defined as serum 25-hydroxyvitamin D levels below 50nmol/l. In a Danish group of women having a cesarean section due to dystocia, we found decreased vitamin D levels.

Background Pseudohypoparathyroidism (PHP) is a rare and inherited disease caused by mutations in the GNAS -gene or upstream of the GNAS complex locus. It is characterized by end-organ resistance to PTH, resulting in hypocalcemia and hyperphosphatemia. We aimed to investigate the dental anomalies according to tooth types and the orthodontic characteristics of patients with PHP. Methods Using a cross-sectional design, 29 patients (23 females) with PHP, living in Denmark, were included, and their clinical intraoral photos and radiographs were examined. Results Pulp calcification was found in 76% of the patients. Blunting of root apex was present in 55% and shortening of root in 48% of the examined patients. Blunting and shortening of roots were seen more often in premolars than in other tooth types (p both  < 0.01). Crowding of lower anterior teeth was frequently observed (36%) as well as diastema in the upper arch (25%), midline diastema (18%), and Class III malocclusion (11%). Conclusion In the present study population, the teeth were frequently affected by pulp calcification and/or deviation of the root morphology. Blunting and shortening of root(s) were more often seen in premolars than in other tooth types. Class III malocclusion was relatively prevalent. It is important to pay attention to dental anomalies and occlusion in order to provide adequate care for patients with PHP.