Search

The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.

Objectives: 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. Design, participants and intervention: In a double-blinded placebo-controlled study, we randomized 41 postmenopausal women to either 10 mg melatonin per day or placebo for 3 months. Outcome measures: Outcomes of the trial was changes in blood pressure, pulse wave velocity (PWV), and quality of sleep evaluated by Pittsburgh Sleep Quality Index (PSQI). Results: 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. Conclusion: 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.

Objective: Total thyroidectomy is associated with a high risk of postoperative hypoparathyroidism, mainly due to the unintended surgical damage to the parathyroid glands or their blood supply. It is possible that surgeons who also perform parathyroid surgery see lower rates of postoperative hypoparathyroidism. In a single institution, we investigated the effects of restricting total thyroidectomy oper ations for Graves’ disease to two surgeons who performed both thyroid and parathyroid surgeries. We aimed to evaluate the rates of postoperative hypoparathyroidism in a 10-year period with primary attention toward patients with Graves’ disease. Design: Retrospective cohort study from a single institution. Methods: We defined the rate of permanent hypoparathyroidism after total thyroidectomy as the need for active vitamin D 6 months postoperatively. Between 2012 and 2016, seven surgeons performed all thyroidectomies. From January 2017, only surgeons also performing parathyroid surgery carried out thyroidectomies for Graves’ disease. Results: We performed total thyroidectomy in 543 patients. The rate of permanent hypoparathyroidism decreased from 28% in 2012–2014 to 6% in 2020–2021. For patients with Graves’ disease, the rate of permanent hypoparathyroidism decreased from 36% (13 out of 36) in 2015–2016 to 2% (1 out of 56) in 2020–2021. In cancer patients, the rate of permanent hypoparathyroidism decreased from 30% (14 out of 46) in 2012–2014 to 10% (10 out of 51) in 2020–2021. Conclusion: Restricting thyroidectomy to surgeons who also performed parathyroid operations reduced postoperative hypoparathyroidism markedly. Accordingly, we recommend centralisation of the most difficult thyroid operations to centres and surgeons with extensive experience in parathyroid surgery. Significance statement: Thyroid surgery is performed by many different surgeons with marked differences in outcome. Indeed, the risk of postoper ative permanent hypoparathyroidism may be very high in low-volume centres. This serious condition affects the quality of life and increases long-term morbidity and the patients develop a life-long dependency of medical treatments. We encountered a high risk of hypoparathyroidism after the operation for Graves’ disease and restricted the number of surgeons to two for these operations. Further, these surgeons were experienced in both thyroid and parathyroid surgeries. We show a dramatic reduction in postoperative hypoparathyroidism after this change. Accordingly, we recommend centralisation of total thyroidectomy to surgeons with experience in both thyroid and parathyroid procedures.

ABSTRACT In hypoparathyroidism, lack of parathyroid hormone (PTH) leads to low calcium levels and decreased bone remodeling. Treatment with recombinant human PTH (rhPTH) may normalize bone turnover. This study aimed to investigate whether rhPTH(1–84) continued to activate intracortical bone remodeling after 30 months and promoted the transition from erosion to formation and whether this effect was transitory when rhPTH(1–84) was discontinued. Cortical histomorphometry was performed on 60 bone biopsies from patients (aged 31 to 78 years) with chronic hypoparathyroidism randomized to either 100 μg rhPTH(1–84) a day (n = 21) (PTH) or similar placebo (n = 21) (PLB) for 6 months as add‐on to conventional therapy. This was followed by an open‐label extension, where patients extended their rhPTH(1–84) (PTH) (n = 5), continued conventional treatment (CON) (n = 5), or withdrew from rhPTH(1–84) and resumed conventional therapy (PTHw) for an additional 24 months (n = 8). Bone biopsies were collected at months 6 (n = 42) and 30 (n = 18). After 6 and 30 months, the overall cortical microarchitecture (cortical porosity, thickness, pore density, and mean pore diameter) in the PTH group did not differ from that of the PLB/CON and PTHw groups. Still, the PTH group had a significantly and persistently higher percentage of pores undergoing remodeling than the PLB/CON groups. A significantly higher percentage of these pores was undergoing bone formation in the PTH compared with the PLB/CON groups, whereas the percentage of pores with erosion only was not different. This resulted in a shift in the ratio between formative and eroded pores, reflecting a faster transition from erosion to formation in the PTH‐treated patients. In the rhPTH(1–84) withdrawal group PTHw, the latter effects of PTH were completely reversed in comparison to those of the PLB/CON groups. In conclusion, rhPTH(1–84) replacement therapy in hypoparathyroidism patients promotes intracortical remodeling and its transition from erosion to formation without affecting the overall cortical microstructure. The effect persists for at least 30 months and is reversible when treatment is withdrawn. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Recombinant human parathyroid hormone (1‐84), rhPTH(1‐84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1‐84). This was a phase I, open‐label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1‐84) administered subcutaneously at 25 μg BID, 50 μg BID, and 100 μg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1‐84), both BID and QD, over the short‐term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline‐adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1‐84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1‐84) dosing. Future long‐term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background: Prior studies of the pharmacogenomics of osteonecrosis of the jaw (ONJ) have had various methodological limitations, including using candidate gene selection as their sole strategy, a small number of ONJ cases, or a study population based on an oncology setting. Objectives: The aim of our case-control study was to evaluate previously reported associations between genetic factors and ONJ, which were based on either genome-wide association studies (GWAS) or candidate gene approaches. Furthermore, we aimed to identify genetic risk factors for ONJ by using GWAS to determine single-nucleotide polymorphisms (SNPs) with statistically significant differences in frequency between ONJ patients and osteoporosis controls. Methods: Patients with medically confirmed ONJ and who were registered in the Scandinavian Cohort of ONJ patients were included. Controls from the general population were matched on age (±5 years), sex, and cumulative antiresorptive drug exposure. The ONJ diagnosis date for cases corresponded to the index date for matched controls. DNA isolation, genotyping, and data analyses were performed by Q2/EA Genomics using standard protocols and best practices. Blood or tissue samples for 55 ONJ cases and 125 controls were collected. Due to the low quality of the tissue samples, final analyses were based on blood samples of 40 ONJ cases and 124 controls. Results: We detected no significant genome-wide associations. Of the 43 SNPs with ONJ association in prior studies, none were replicated in our study. Conclusions: Even though our study sample is the largest to date, we had limited statistical power for GWAS but adequate power for replication analyses. Our study provides no evidence for any genetic predisposition to ONJ. Future studies could increase their statistical power by combining ONJ GWAS datasets and by performing a meta-analysis or pursuing a sequencing strategy in order to identify rare variants.

Abstract Background Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. Conclusion Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Abstract Background The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration EUPAS16927, NCT01922440

Objective. Reasons for the increased incidence of chronic kidney disease (CKD) in patients with chronic hypoparathyroidism are poorly understood. This study evaluated associations between levels of albumin-corrected serum calcium, serum phosphate, and calcium-phosphate product and the odds of CKD development in patients with chronic hypoparathyroidism. Design. A retrospective nested case-control study of adult patients with chronic hypoparathyroidism who had ≥1 prescription for calcitriol who developed CKD and matched controls who did not develop CKD were selected from the IBM® Explorys electronic medical record database. Patients. The study included a cohort of 300 patients for the albumin-corrected serum calcium analysis and 80 patients for the serum phosphate and calcium-phosphate product analyses. Measurements. We examined associations between albumin-corrected serum calcium, serum phosphate and calcium-phosphate product levels, and the risk of devloping CKD (defined as ≥2 outpatient estimated glomerular filtration values

Multiple endocrine neoplasia 1 (MEN1) is a rare genetic syndrome characterized by the manifestation of tumors in endocrine glands most often in the parathyroid gland (PG). Treatment may involve several parathyroidectomies (PTX), especially in young patients, which increases the risk of postoperative complications. We present a 16-year-old patient with a family history of MEN1 syndrome. The patient started to show biochemical signs of hyperparathyroidism (HPT) and hypercalcemia at the age of 10. One and a half years later a PTX was successfully performed with removal of the two left PGs. However, a rise in plasma parathyroid hormone and ionized calcium was observed 4 years later. Preoperative noninvasive imaging with 99mTc-sestamibi scintigraphy showed no definitive parathyroid adenoma. A 11C-methionine position emission tomography combined with MRI (MET-PET/MRI) was then performed and detected a focus posterior to the lower part of the right thyroid lobe. Intraoperative angiography with fluorescence and indocyanine green dye was used to assess the vascularization of the remaining PGs. The lower right PG was removed. The patient was discharged with normalized biochemical values and without postoperative complications. Recurrence of primary HPT is frequent in MEN1 patients which often necessitates repeated operations. Our case report showed that the use of advanced noninvasive preoperative imaging techniques and intraoperative fluorescent imaging are valuable tools and should be taken into consideration in selected cases to avoid postoperative complications. To our knowledge, this is the first case where MET-PET/MRI has been used to detect parathyroid pathology.

Abstract 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 (pboth

Abstract Introduction In our clinical experience, need for doses of active vitamin D and calcium supplements changes during the period following a diagnosis of postsurgical hypoparathyroidism (HypoPT), but only sparse data are available. In the present study, we aimed to investigate the magnitude of changes in need for activated vitamin D (alfacalcidol) and calcium supplements during initiation of therapy as well as time to be expected until a stable phase was achieved. Furthermore, we determined the frequency of (unexpected) episodes of hypo‐ and hypercalcaemia after reaching a steady state for alfacalcidol and calcium. Methods Retrospective study of twenty‐four patients with chronic postsurgical HypoPT (>6 months) diagnosed from 2016 to 2018. Data were extracted from medical records on doses of alfacalcidol and calcium as well as ionized plasma calcium levels (P‐Ca2+) from time of diagnosis and until 86 weeks after surgery. Results Patients were treated with alfacalcidol and calcium in order to maintain a stable concentration of P‐Ca2+. Our data demonstrated a great variation in treatment needs until 11 weeks after surgery, where the mean doses of alfacalcidol stabilize, while calcium doses stabilized a bit earlier. After the stable phase had emerged, 21 out of 24 patients continued to have one or more episodes of spontaneous hypo‐ or hypercalcaemia. Conclusions Patients with chronic HypoPT attain a steady state for alfacalcidol 11 weeks after the diagnosis. Continuous monitoring of P‐Ca2+ is of continued importance after reaching steady state due to a high frequency of spontaneous hypo‐ or hypercalcaemia.

A way to maintain an adequate vitamin D status is through supplementation. Demonstration of blood-metabolome rhythmicity of vitamin D3 post-dosing effects is lacking in the pharmaco-metabonomics area. Thus, the overall aim of this study was to investigate the diurnal changes in the blood metabolome and how these are affected by vitamin D3 supplementation. The study was conducted as a crossover study, and the treatment included 200 µg (8000 IU) of vitamin D3 as compared with placebo with a washout period of at least 10 days. The participants were postmenopausal women aged 60–80 years (N = 29) with vitamin D insufficiency (serum 25-hydroxyvitamin D < 50 nmol/L) but otherwise healthy. During the intervention day, blood samples were taken at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h, and plasma was analysed by proton nuclear magnetic resonance (NMR) spectroscopy as a metabolomics approach. In general, diurnal effects were identified for the majority of the 20 quantified metabolites, and hierarchical cluster analysis revealed a change in the overall plasma metabolome around 12 AM (6 h after intervention), suggesting that the diurnal rhythm is reflected in two diurnal plasma metabolomes; a morning metabolome (8–12 AM) and an afternoon/evening metabolome (2–8 PM). Overall, the effect of vitamin D supplementation on the blood metabolome was minor, with no effect on the diurnal rhythm. However, a significant effect of the vitamin D supplementation on plasma acetone levels was identified. Collectively, our findings reveal an influence of diurnal rhythm on the plasma metabolome, while vitamin D supplementation appears to have minor influence on fluctuations in the plasma metabolome.

OBJECTIVES: The aim of this study was to examine blood concentrations of 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) among indoor, outdoor, permanent and rotating night workers and the association with hours spent outdoors on and off work days. METHODS: Blood samples were collected from 425 workers (162 indoor, 112 outdoor, 118 rotating night and 33 permanent night workers) throughout all seasons. Serum concentrations of 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were analyzed by isotope dilution liquid chromatography-tandem mass spectrometry (LC MS/MS) and an automated immune analyzer, respectively. Personal light exposure levels were continuously recorded and used to estimate hours spent outdoors (all workers). RESULTS: Permanent night workers had 25.3% (95% CI 11.9–36.6) lower 25OHD concentration, 4.55 (95% CI 1.39–14.94) higher odds of vitamin D insufficiency (

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.

BackgroundDystocia 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.MethodWe 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.ResultsThe 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.ConclusionsIn a Danish group of women having a cesarean section due to dystocia, we found decreased vitamin D levels.

Introduction: Low levels of sex hormones are common in patients with chronic kidney disease (CKD) and may be a contributing factor to bone fragility. We investigated associations between levels of sex hormones and bone mineral density (BMD) in adult kidney transplantation candidates. Methods: Volumetric BMD of spine and hip were measured by computed tomography. Parathyroid hormone (PTH), testosterone (T), estradiol (E), and sex hormone–binding globulin were measured from fasting morning blood samples. Bioavailable (Bio) T and E were calculated based on constants for protein binding. Results: A total of 146 patients (102 men and 44 women) were included in the analyses. The median age was 54 years (range, 32−72 years); 32% were diabetic; and 36% received maintenance dialysis therapy. In men, Bio T was positively associated with BMD at the lumbar spine (β = 5.02, P = 0.002), total hip (β = 6.35, P = 0.001), and femoral neck (β = 13.9, P = 0.002), independently of age, body mass index, dialysis, diabetes type 1 and 2, parathyroid hormone, and steroid exposure. Bio E was positively associated with BMD at the lumbar spine (β = 0.23, P = 0.03) and femoral neck (β = 0.61, P = 0.04) using the same fully adjusted model. In postmenopausal women, Bio T was positively correlated with lumbar spine BMD (r = 0.46, P = 0.02). Conclusion: High endogenous levels of sex hormones are associated with greater BMD in male kidney transplantation candidates. Disturbances in the gonadal axis may contribute to skeletal fragility in men with late-stage CKD. Keywords: bone density, chronic kidney disease, gonadal sex steroids, hypogonadism, osteoporosis

Abstract Background Fracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates. Methods Volumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures. Results The fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z-score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z-score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z-score. Conclusions Bone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation. Trial registration This study was registered at ClinicalTrials.gov with identifier NCT01344434 .

PurposeWe 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.Materials and methodsMononuclear 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.ResultsBoth 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.ConclusionThese 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.

Hypoparathyroidism (HypoPT) is characterized by low serum calcium levels caused by an insufficient secretion of parathyroid hormone (PTH). Despite normalization of serum calcium levels by treatment with activated vitamin D analogues and calcium supplementation, patients are suffering from impaired quality of life (QoL) and are at increased risk of a number of comorbidities. Thus, despite normalization of calcium levels in response to conventional therapy, this should only be considered as an apparent normalization, as patients are suffering from a number of complications and calcium-phosphate homeostasis is not normalized in a physiological manner. In a number of recent studies, replacement therapy with recombinant human PTH (rhPTH(1-84)) as well as therapy with the N-terminal PTH fragment (rhPTH(1-34)) have been investigated. Both drugs have been shown to normalize serum calcium while reducing needs for activated vitamin D and calcium supplements. However, once a day injections cause large fluctuations in serum calcium. Twice a day injections diminish fluctuations, but don't restore the normal physiology of calcium homeostasis. Recent studies using pump-delivery have shown promising results on maintaining normocalcemia with minimal fluctuations in calcium levels. Further studies are needed to determine whether this may improve QoL and lower risk of complications. Such data are needed before replacement with the missing hormone can be recommended as standard therapy.

Recently, we demonstrated negative effects of vitamin D supplementation on muscle strength and physical performance in women with vitamin D insufficiency. The underlying mechanism behind these findings remains unknown. In a secondary analysis of the randomized placebo-controlled trial designed to investigate cardiovascular and musculoskeletal health, we employed NMR-based metabolomics to assess the effect of a daily supplement of vitamin D3 (70 µg) or an identically administered placebo, during wintertime. We assessed the serum metabolome of 76 postmenopausal, otherwise healthy, women with vitamin D (25(OH)D) insufficiency (25(OH)D < 50 nmol/L), with mean levels of 25(OH)D of 33 ± 9 nmol/L. Compared to the placebo, vitamin D3 treatment significantly increased the levels of 25(OH)D (−5 vs. 59 nmol/L, respectively, p < 0.00001) and 1,25(OH)2D (−10 vs. 59 pmol/L, respectively, p < 0.00001), whereas parathyroid hormone (PTH) levels were reduced (0.3 vs. −0.7 pmol/L, respectively, p < 0.00001). Analysis of the serum metabolome revealed a significant increase of carnitine, choline, and urea and a tendency to increase for trimethylamine-N-oxide (TMAO) and urinary excretion of creatinine, without any effect on renal function. The increase in carnitine, choline, creatinine, and urea negatively correlated with muscle health and physical performance. Combined with previous clinical findings reporting negative effects of vitamin D on muscle strength and physical performance, this secondary analysis suggests a direct detrimental effect on skeletal muscle of moderately high daily doses of vitamin D supplements.

Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10–≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 μg (400–800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations

Background: Dental aberrations have been mentioned in relation to non-surgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP). However, a systematic review of dental characteristics have not been performed. The present systematic review describes the dental findings in patients with Ns-HypoPT and PHP.Methods: Studies on Ns-HypoPT and PHP reporting dental features were eligible. A systematic literature search was conducted using four bibliographic databases (Web of Science, Scopus, Pubmed, and Embase) and was limited to studies written in English. Reviews, meta-analyses and letters were excluded. Both the research and reporting of results were based on PRISMA (preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines.Results: Of 88 studies included, nine were cross-sectional, one was a prospective cohort study, 26 were case series, and 52 were case reports. The most frequently reported findings in patients with Ns-HypoPT were enamel opacities, enamel hypoplasia, hypodontia, and eruption disturbances. In patients with PHP, enamel hypoplasia, eruption disturbance, and deviation of the root morphology were the most frequently reported findings.Conclusion: An association between enamel hypoplasia and Ns-HypoPT and PHP is likely. The results should, however, be interpreted cautiously due to the limited number of high-quality studies. The present review confirms the need of further well-designed studies, such as large-scale studies, e.g., multicenter studies, to conclude on the reported associations between Ns-HypoPT/PHP and enamel hypoplasia.

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.

BACKGROUND:Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS:In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS:We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and

The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

Use of hormonal contraceptives (HC) may influence total plasma concentrations of vitamin D metabolites. A likely cause is an increased synthesis of vitamin D binding protein (VDBP). Discrepant results are reported on whether the use of HC affects free concentrations of vitamin D metabolites. Aim: In a cross-sectional study, plasma concentrations of vitamin D metabolites, VDBP, and the calculated free vitamin D index in users and non-users of HC were compared and markers of calcium and bone metabolism investigated. Results: 75 Caucasian women aged 25–35 years were included during winter season. Compared with non-users (n = 23), users of HC (n = 52) had significantly higher plasma concentrations of 25-hydroxyvitamin D (25OHD) (median 84 interquartile range: [67–111] vs. 70 [47–83] nmol/L, p = 0.01), 1,25-dihydroxyvitamin D (1,25(OH)2D) (198 [163–241] vs. 158 [123–183] pmol/L, p = 0.01) and VDBP (358 [260–432] vs. 271 [179–302] µg/mL, p < 0.001). However, the calculated free indices (FI-25OHD and FI-1,25(OH)2D) were not significantly different between groups (p > 0.10). There were no significant differences in indices of calcium homeostasis (plasma concentrations of calcium, parathyroid hormone, and calcitonin, p > 0.21) or bone metabolism (plasma bone specific alkaline phosphatase, osteocalcin, and urinary NTX/creatinine ratio) between groups. In conclusion: Use of HC is associated with 13%–25% higher concentrations of total vitamin D metabolites and VDBP. This however is not reflected in indices of calcium or bone metabolism. Use of HC should be considered in the interpretation of plasma concentrations vitamin D metabolites.

Background. Studies on bone effects of long-term substitution therapy with levothyroxine (LT4) have shown discrepant results. Previous studies have, however, not evaluated volumetric bone mineral densities (vBMD), bone structure, and strength using high resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA). Using a cross-sectional design, we aimed to determine whether BMD, structure, and strength are affected in hypothyroid patients on LT4 substitution therapy. Methods. We compared 49 patients with well-substituted hypothyroidism with 49 age- and gender-matched population based controls. Areal BMD was assessed by DXA, vBMD and bone geometry by HR-pQCT, and bone strength by FEA. Results. Patients had been thyroidectomized due to thyroid cancer (10%) and nontoxic (33%) or toxic goiter (57%). 82% were women. TSH levels did not differ between groups, but patients had significantly higher levels of T4 (p

Hypoparathyroidism (HypoPT) is a state of hypocalcemia due to inappropriate low levels of parathyroid hormone (PTH). HypoPT is normally treated by calcium supplements and activated vitamin D analogues. Although plasma calcium is normalized in response to conventional therapy, quality of life (QoL) seems impaired and patients are at increased risk of renal complications. A number of studies have suggested subcutaneous injections with PTH as an alternative therapy. By replacement with the missing hormone, urinary calcium may be lowered and QoL may improve. PTH replacement therapy (PTH-RT) possesses, nevertheless, a number of challenges. If PTH is injected only once a day, fluctuations in calcium levels may occur resulting in hypercalcemia in the hours following an injection. Twice-a-day injections seem to cause less fluctuation in plasma calcium but do stimulate bone turnover to above normal. Most recently, continuous delivery of PTH by pump has appeared as a feasible alternative to injections. Plasma calcium levels do not fluctuate, urinary calcium is lowered, and bone turnover is only stimulated modestly (into the normal range). Further studies are needed to assess the long-term effects. If beneficial, it seems likely that standard treatment of HypoPT in the future will change into replacement therapy with the missing hormone.

Hypophosphatemic rickets (HR) is a rare inherited disorder characterized by a classic rickets phenotype with low plasma phosphate levels and resistance to treatment with vitamin D. Development of secondary hyperparathyroidism (SHPT) as a direct consequence of treatment is a frequent complication and a major clinical challenge, as this may increase risk of further comorbidity. Cinacalcet, a calcimimetic agent that reduces the secretion of PTH from the parathyroid glands, has been suggested as adjuvant treatment to SHPT in patients with HR. However, only two papers have previously been published and no data are available on effects of treatment for more than six months. We now report a case of 3-year treatment with cinacalcet in a patient with HR complicated by SHPT. A 53-year-old woman with genetically confirmed X-linked dominant hypophosphatemic rickets developed SHPT after 25 years of conventional treatment with alfacalcidol and phosphate supplements. Cinacalcet was added to her treatment, causing a sustained normalization of PTH. Ionized calcium decreased, requiring reduction of cinacalcet, though asymptomatical. Level of phosphate was unchanged, but alkaline phosphatase increased in response to treatment. Cinacalcet appeared to be efficient, safe, and well tolerated. We recommend close control of plasma calcium to avoid hypocalcemia.

Objectives. Statin drugs act as inhibitors of the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase enzyme early in the mevalonate pathway, thereby reducing the endogenous cholesterol synthesis. In recent studies, it has been suggested from epidemiological data that statins also may improve vitamin D status, as measured by increased plasma 25-hydroxyvitamin D (25OHD) levels. We now report the results from a randomised controlled trial on effects of simvastatin on plasma 25OHD levels. Design and Methods. We randomised 82 healthy postmenopausal women to one year of treatment with either simvastatin 40 mg/d or placebo and performed measurement at baseline and after 26 and 52 weeks of treatment. The study was completed by 77 subjects. Results. Compared with placebo, plasma levels of cholesterol and low-density lipoproteins decreased in response to treatment with simvastatin, but our study showed no effect of simvastatin on vitamin D status. However, plasma levels of triglycerides were inversely associated with tertiles of plasma 25OHD levels and changes in plasma triglycerides levels correlated inversely with seasonal changes in vitamin D status. Conclusion. Our data do not support a pharmacological effect of statins on vitamin D status, but do suggest that vitamin D may influence plasma lipid profile and thus be of importance to cardiovascular health.