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Rachida Rafiq,1 Hendrik J Prins,2 Wim G Boersma,2 Johannes MA Daniels,3 Martin den Heijer,1 Paul Lips,1 Renate T de Jongh1 1Department of Internal Medicine and Endocrinology, VU University Medical Center, Amsterdam, 2Department of Pulmonary Diseases, Northwest Hospital group, Alkmaar, 3Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, the Netherlands Background: Although vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function. In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections. As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients. Objective: To assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients. Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life. Methods: We performed a randomized, double-blind, placebo-controlled pilot trial. Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months. Study visits were conducted at baseline, and at 3 and 6 months after randomization. During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed. In addition, participants kept a diary card in which they registered respiratory symptoms. Results: At baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group. Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P

Background: Peak expiratory flow rate (PEFR) predicts mortality and other negative health outcomes. However, little evidence exists on how PEFR changes with ageing and how trajectories of change differ among older people., Aims: To identify trajectories of PEFR in older men and women, and to study characteristics associated with these trajectories., Methods: Data from the Longitudinal Aging Study Amsterdam were used, an ongoing cohort study in a representative sample of Dutch older men and women. PEFR was assessed using the Mini-Wright peak flow meter across a 13-year follow-up in 991 men and 1107 women. Trajectories were analyzed using Latent Class Growth Analysis., Results: Mean age was 72.5 (SD 8.4) in men and 72.4 (SD 8.4) in women. In men, three declining trajectories were identified, i.e. high, intermediate and low, with prevalences of 30%, 46% and 24%, respectively. In women, two declining trajectories were identified, i.e. high and low, with prevalences of 62 and 38%. All trajectories showed linear decline and differed mostly with regard to their intercept. Significant differences between trajectories with regard to baseline demographic, health and lifestyle characteristics were observed, e.g., men and women in the low PEFR trajectory were older, had more chronic diseases, and were more often smoker., Discussion and Conclusions: Trajectories in both men and women differ mainly in baseline level of PEFR and not in rate of decline over time. Therefore, one PEFR measurement might be sufficient to give an indication of the trajectory that an older adult is likely to follow., (© 2024. The Author(s).)

Background: To improve effectiveness of vaccination against SARS-CoV-2, it is important to identify factors that influence the immune response induced by vaccination. Evidence for the role of vitamin D in immune response against SARS-CoV-2 is contradictory. It is therefore of interest whether 25-hydroxyvitamin D (25[OH]D) concentrations affect the humoral and/or cellular response following SARS-CoV-2 vaccination., Methods: In this prospective cohort study, blood samples were collected from 98 SARS-CoV-2 naive health care workers (HCW) receiving the first two doses of either BNT162b2 or mRNA-1273 in 2021. Wild-type spike (S) protein binding and neutralizing antibodies were determined approximately three weeks after the first dose and four to five weeks after the second dose. Antigen specific T-cells and functionality (proliferative response and interferon gamma [IFN-γ] release) were determined in 18 participants four weeks after the second dose of BNT162b2. We studied the association between 25(OH)D concentrations, which were determined prior to vaccination, and humoral and cellular immune responses following vaccination., Results: We found no association between 25(OH)D concentrations (median 55.9 nmol/L [IQR 40.5-69.8]) and binding or neutralizing antibody titers after complete vaccination (fold change of antibody titers per 10 nmol/L 25(OH)D increase: 0.98 [95% CI 0.93-1.04] and 1.03 [95% CI: 0.96-1.11], respectively), adjusted for age, sex and type of mRNA vaccine. Subsequently, continuous 25(OH)D concentrations were divided into commonly used clinical categories (<25 nmol/L [n = 6, 6%], 25-49 nmol/L [n = 33, 34%], 50-75 nmol/L [n = 37, 38%] and ≥75 nmol/L [n = 22, 22%]), but no association with the humoral immune response following vaccination was found. Also, 25(OH)D concentrations were not associated with the SARS-CoV-2 specific T cell response., Conclusion: No association was found between 25(OH)D concentrations and the humoral or cellular immune response following mRNA vaccination against SARS-CoV-2. Based on our findings there is no rationale to advise vitamin D optimization preceding SARS-CoV-2 vaccination in HCW with moderate vitamin D status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis., (© 2024. The Author(s).)

Purpose: This study aimed to illustrate the possibility of an unfavorable response to treatment with the anabolic agent romosozumab for patients with severe osteoporosis and to discuss explanations for treatment failure., Methods: Dual-energy x-ray absorptiometry (DXA) including vertebral fracture assessment (VFA) and X-rays of the thoracolumbar spine was used to assess bone mineral density (BMD) and the presence of vertebral fractures before and after treatment with romosozumab., Results: Our patient developed a decrease in the BMD of the hip, two incident new vertebral fractures, and worsening of one prevalent vertebral fracture during 1 year treatment with romosozumab. We have not detected non-adherence, there was no pretreatment with anti-resorptives, and we observed no signs of secondary osteoporosis and/or comorbidities., Conclusion: As the number of patients treated with romosozumab is rising, it becomes more likely that more patients will be found with new fractures and/or an unfavorable BMD response. Probably, the unfavorable response is a (bad) chance finding, but we think it is crucial for clinicians and patients to exclude nonadherence, new comorbidities and pretreatment with anti-resorptives as explanation in these patients., (© 2024. The Author(s).)

Background: In addition to the role of vitamin D in bone mineralization, calcium and phosphate homeostasis, and skeletal health, evidence suggests an association between vitamin D deficiency and a wide range of chronic conditions. This is of clinical concern given the substantial global prevalence of vitamin D deficiency. Vitamin D deficiency has traditionally been treated with vitamin D 3 (cholecalciferol) or vitamin D 2 (ergocalciferol). Calcifediol (25-hydroxyvitamin D 3 ) has recently become available more widely., Methods: By means of targeted literature searches of PubMed, this narrative review overviews the physiological functions and metabolic pathways of vitamin D, examines the differences between calcifediol and vitamin D 3 , and highlights clinical trials conducted with calcifediol in patients with bone disease or other conditions., Results: For supplemental use in the healthy population, calcifediol can be used at doses of up to 10 µg per day for children ≥ 11 years and adults and up to 5 µg/day in children 3-10 years. For therapeutic use of calcifediol under medical supervision, the dose, frequency and duration of treatment is determined according to serum 25(OH)D concentrations, condition, type of patient and comorbidities. Calcifediol differs pharmacokinetically from vitamin D 3 in several ways. It is independent of hepatic 25-hydroxylation and thus is one step closer in the metabolic pathway to active vitamin D. At comparable doses to vitamin D 3 , calcifediol achieves target serum 25(OH)D concentrations more rapidly and in contrast to vitamin D 3 , it has a predictable and linear dose-response curve irrespective of baseline serum 25(OH)D concentrations. The intestinal absorption of calcifediol is relatively preserved in patients with fat malabsorption and it is more hydrophilic than vitamin D 3 and thus is less prone to sequestration in adipose tissue., Conclusion: Calcifediol is suitable for use in all patients with vitamin D deficiency and may be preferable to vitamin D 3 for patients with obesity, liver disease, malabsorption and those who require a rapid increase in 25(OH)D concentrations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

An increased fracture risk is a common chronic condition leading to a rising number of fractures, which are injurious to patients and costly to the health care system. Effective diagnostic and treatment options are available for primary and secondary prevention. In this article, we will answer specific practical questions with respect to increased fracture risk and fracture prevention. Topics discussed include definitions, risk factors, the diagnostic modalities and treatment options.

An estimated 1.5 million Dutch people take vitamin D supplements on prescription, not including those who take multivitamins or vitamin D over the counter. Yet, controversial health benefits of vitamin D supplementation in the general population continues, often explained with not adequately powered studies, combination therapy with calcium, high bolus doses of vitamin D and poor study designs. Recently, the VITAL study does not show an effect in fracture incidence after treatment with daily vitamin D (2000IU) compared to placebo. However, zooming into the results a positive trend is observed in patients with a fragility fracture and/or using anti-osteoporosis medication. Additionally this study does not rule out a positive effect of vitamin D supplementation in severe vitamin D deficiency and high fracture risk patients.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Objectives: The aim of this study was to develop an index to measure older adults' exposure to the COVID-19 pandemic and to study its association with various domains of functioning., Design: Cross-sectional study., Setting: The Longitudinal Aging Study Amsterdam (LASA), a cohort study in the Netherlands., Participants: Community-dwelling older adults aged 62-102 years (n=1089) who participated in the LASA COVID-19 study (June-September 2020), just after the first wave of the pandemic., Primary Outcome Measures: A 35-item COVID-19 exposure index with a score ranging between 0 and 1 was developed, including items that assess the extent to which the COVID-19 situation affected daily lives of older adults. Descriptive characteristics of the index were studied, stratified by several sociodemographic factors. Logistic regression analyses were performed to study associations between the exposure index and several indicators of functioning (functional limitations, anxiety, depression and loneliness)., Results: The mean COVID-19 exposure index score was 0.20 (SD 0.10). Scores were relatively high among women and in the southern region of the Netherlands. In models adjusted for sociodemographic factors and prepandemic functioning (2018-2019), those with scores in the highest tertile of the exposure index were more likely to report functional limitations (OR: 2.24; 95% CI: 1.48 to 3.38), anxiety symptoms (OR: 3.14; 95% CI: 1.82 to 5.44), depressive symptoms (OR: 2.49; 95% CI: 1.55 to 4.00) and loneliness (OR: 2.97; 95% CI: 2.08 to 4.26) than those in the lowest tertile., Conclusions: Among older adults in the Netherlands, higher exposure to the COVID-19 pandemic was associated with worse functioning in the physical, mental and social domain. The newly developed exposure index may be used to identify persons for whom targeted interventions are needed to maintain or improve functioning during the pandemic or postpandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ)., Methods: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety., Results: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity., Conclusion: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients., Objectives: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD., Methods: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life., Results: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes., Conclusions: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Vitamin D status varies across all continents and countries. Vitamin D status usually is adequate in Latin America and Australia, but in contrast it is very low in the Middle East and some countries in Asia. Trends in vitamin D status, whether it improves or declines over the years, carry important messages. Trends usually are small, but can be predictors and indicators of general health. Vitamin D status has improved in the older population in the United States, and improvement relates to dairy use and vitamin D supplements. To the contrary, vitamin D status has declined in the Inuit population of Canada due to a change from a traditional fish diet to a Western diet. A large improvement was seen in Finland after mandatory fortification of dairy products was introduced. Determinants of decline are less sun exposure, increased use of sunscreen, increase of body mass index (BMI), less physical activity, and poor socioeconomic status. Determinants of increase are food fortification with vitamin D and vitamin D supplements. Food fortification can lead to a population-wide increase in vitamin D status as shown by the Finnish example. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: PL reports a travel grant from Abiogen. RJ and NS do not have a conflict of interest., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings., Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia., Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021., Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values., Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated., Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia., Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Purpose: Delay of routine medical care during the COVID-19 pandemic may have serious consequences for the health and functioning of older adults. The aim of this study was to investigate whether older adults reported cancellation or avoidance of medical care during the first months of the COVID-19 pandemic, and to explore associations with health and socio-demographic characteristics., Methods: Cross-sectional data of 880 older adults aged ≥ 62 years (mean age 73.4 years, 50.3% female) were used from the COVID-19 questionnaire of the Longitudinal Aging Study Amsterdam, a cohort study among community-dwelling older adults in the Netherlands. Cancellation and avoidance of care were assessed by self-report, and covered questions on cancellation of primary care (general practitioner), cancellation of hospital outpatient care, and postponed help-seeking. Respondent characteristics included age, sex, educational level, loneliness, depression, anxiety, frailty, multimorbidity and information on quarantine., Results: 35% of the sample reported cancellations due to the COVID-19 situation, either initiated by the respondent (12%) or by healthcare professionals (29%). Postponed help-seeking was reported by 8% of the sample. Multimorbidity was associated with healthcare-initiated cancellations (primary care OR = 1.92, 95% CI = 1.09-3.50; hospital OR = 1.86, 95% CI = 1.28-2.74) and respondent-initiated hospital outpatient cancellations (OR = 2.02, 95% CI = 1.04-4.12). Depressive symptoms were associated with postponed help-seeking (OR = 1.15, 95% CI = 1.06-1.24)., Conclusion: About one third of the study sample reported cancellation or avoidance of medical care during the first months of the pandemic, and this was more common among those with multiple chronic conditions. How this impacts outcomes in the long term should be investigated in future research., (© 2021. The Author(s).)

Osteoporosis is a common condition in older people. This condition leads to increased risk of fractures and is associated with morbidity and mortality. The number of patients with osteoporosis will increase significantly in the years to come due to the increasing numbers of older people and increasing life expectancy. This will be accompanied by increasing demand for care and clinical practice will be faced with questions about therapeutic options and the optimal treatment duration for patients with osteoporosis or increased risk of fractures. In this educational article, we are using practical questions to provide an overview of pathophysiology, diagnostics and treatment of osteoporosis and increased risk of fractures.

Parathyroid hormone (PTH) is the key hormone regulating calcium homeostasis and, as such, is an important diagnostic and prognostic marker. Although the measurement of PTH has greatly improved over the past few decades, oxidation status thereof is unaccounted for in currently used assays. PTH can be oxidized on methionine residues located at amino acid positions 8 and 18. This is a relevant post-translational modification as, due to refolding of the molecule, it results in the decreased ability to activate the PTH1 receptor. Although this loss of activity after oxidation was observed as early as 1934, only recently a method was developed to measure and distinguish non-oxidized PTH (n-oxPTH) from oxidized PTH. This method creates exciting possibilities for studying more specifically the role of n-oxPTH in physiology and pathology. Therefore, it can now be explored what the clinical implications of measuring n-oxPTH will be. Herein, we review the available evidence of the effect of oxidation on the biological activity of PTH. We also discuss studies examining the mechanism of PTH oxidation in vivo and efforts to stabilize synthetic PTH ex vivo for therapeutic applications. Lastly, the available studies regarding the clinical significance of n-oxPTH are evaluated and future directions discussed., Competing Interests: Declaration of Competing Interest Marc Vervloet reports grant support from Shire, Pfizer, Amgen and AbbVie; lecture fees from Baxter and Amgen and consultancy fees from FMC, Amgen Inc., Medice, AbbVie and Otsuka. The other authors declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C-reactive protein (CRP), leptin and adiponectin and the role of adiposity in this relationship., Methods: This is a cross-sectional analysis of The Netherlands Epidemiology of Obesity Study (NEO), a population-based cohort study in men and women aged 45 to 65 years. Main outcome measures were CRP, leptin and adiponectin. In the linear regression analyses we adjusted for age, sex, ethnicity, creatinine, education, alcohol use, smoking status, physical activity, number of chronic diseases, season, total body fat and waist circumference., Results: Of the 6287 participants, 21% were vitamin D deficient (serum 25(OH)D < 50 nmol/L). Mean (SD) age and BMI were 56 (6) years and 26.3 (4.4) kg/m 2 , respectively. Although after adjustment for most examined potential confounders, each 10 nmol/L increase in serum 25(OH)D was associated with 2.3% (95%CI: -4.0 to -0.5) lower CRP, 3.5% (-4.7 to -2.2) lower leptin, and 0.13 ng/mL (0.04-0.21) higher adiponectin, most of these associations seemed to largely stem from an additional potential confounder - adiposity - as they either disappeared (leptin and CRP) or were largely diminished (adiponectin) upon further adjustment for adiposity indices (total body fat and waist circumference)., Conclusion: We found that measures of adiposity largely explained the negative association of serum 25(OH)D with the pro-inflammatory CRP and leptin, and the positive association with the anti-inflammatory adiponectin. These results suggest that future studies should take the effect of adiposity into account., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Glucocorticoid use is the most common cause of osteoporosis in young individuals. In the current study, we investigated the effects of glucocorticoid treatment on circulating sclerostin concentrations and serum bone turnover markers in healthy young men. We performed additional measurements in two combined randomized, placebo-controlled, double-blind, dose-response intervention studies: 64 healthy men (age: 22 ± 2 years; BMI: 22.1 ± 1.7 kg/m 2 ) were allocated to receive placebo ( n = 16), prednisolone 7.5 mg once daily ( n = 24), or prednisolone 30 mg once daily ( n = 24) for 2 weeks using block randomization. Primary outcome variables were serum sclerostin and serum bone turnover markers (CTx and P1NP), before and after the intervention. Baseline characteristics and variables did not differ between intervention groups. Compared with placebo, prednisolone high-dose decreased serum sclerostin concentrations (-8.5 [-28.0 to 7.3] versus 1.5 [-6.5 to 20.0] pg/mL, p = 0.048), decreased P1NP concentrations (-28.0 [-39.3 to -18.3] versus -1.5 [-15.3 to 11.3] μg/L, p  < 0.001) and increased CTx concentrations (108.0 [55.0 to 177.0] versus 64.0 [-24.3 to 120.0] ng/L, p = 0.038). Compared with placebo, prednisolone low-dose did not alter sclerostin concentrations ( p = 0.5) or CTx concentrations ( p = 0.7), but tended to decrease P1NP concentrations (-9.0 [-24.0 to -1.3] versus -1.5 [-15.3 to 11.3] μg/L, p = 0.095). At baseline concentrations of sclerostin were positively correlated with concentrations of CTx (Spearman's rank correlation coefficient ρ = +0.409, p = 0.001), but not with P1NP. No significant correlations were observed between changes in outcome variables during the interventions. Short-term high-dose, but not low-dose, prednisolone treatment reduces serum sclerostin concentrations in healthy young men. Whether this reflects a counter regulatory mechanism to compensate glucocorticoid-induced negative effects through other mechanisms remains to be elucidated. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.)

Concerns about bone health in transgender people using gender-affirming hormonal treatment (HT) exist, but the fracture risk is not known. In this nationwide cohort study, we aimed to compare the fracture incidence in transgender people using long-term HT with an age-matched reference population. All adult transgender people who started HT before 2016 at our gender-identity clinic were included and were linked to a random population-based sample of 5 age-matched reference men and 5 age-matched reference women per person. Fracture incidence was determined using diagnoses from visits to hospital emergency rooms nationwide between 2013 and 2015. A total of 1089 trans women aged <50 years (mean 38 ± 9 years) and 934 trans women aged ≥50 years (mean 60 ± 8 years) using HT for median 8 (interquartile range [IQR] 3-16) and 19 (IQR 11-29) years, respectively, were included. A total of 2.4% of the trans women aged <50 years had a fracture, whereas 3.0% of the age-matched reference men (odds ratio [OR] = 0.78, 95% confidence interval [CI] 0.51-1.19) and 1.6% of the age-matched reference women (OR = 1.49, 95% CI 0.96-2.32) experienced a fracture. In trans women aged ≥50 years, 4.4% experienced a fracture compared with 2.4% of the age-matched reference men (OR = 1.90, 95% CI 1.32-2.74) and 4.2% of the age-matched reference women (OR = 1.05, 95% CI 0.75-1.49). A total of 1036 trans men (40 ± 14 years) using HT for median 9 (IQR 2-22) years were included. Fractures occurred in 1.7% of the trans men, 3.0% of the age-matched reference men (OR = 0.57, 95% CI 0.35-0.94), and 2.2% of the age-matched reference women (OR = 0.79, 95% CI 0.48-1.30). In conclusion, fracture risk was higher in older trans women compared with age-matched reference men. In young trans women, fracture risk tended to be increased compared with age-matched reference women. Fracture risk was not increased in young trans men. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

Background & Aims: Obesity is a well-established risk factor of vitamin D deficiency. However, it is unclear which fat deposit is most strongly related to serum 25-hydroxyvitamin D (25(OH)D) concentrations. Our aim was to distinguish the specific contributions of total body fat (TBF), abdominal subcutaneous adipose tissue (aSAT), visceral adipose tissue (VAT) and hepatic fat on 25(OH)D concentrations., Methods: We performed a cross-sectional analysis of the Netherlands Epidemiology of Obesity study, a population-based cohort study. We used linear regression analyses to examine associations of TBF, aSAT, VAT (n = 2441) and hepatic fat (n = 1980) with 25(OH)D concentrations. Standardized values were used to compare the different fat deposits., Results: Mean (SD) age and 25(OH)D concentrations of the study population was 56 (6) years and 70.8 (24.2) nmol/L, respectively. TBF was inversely associated with 25(OH)D concentrations in women, but not in men. One percent higher TBF was associated with 0.40 nmol/L (95%CI: -0.67 to -0.13) lower 25(OH)D. aSAT was not associated with 25(OH)D concentrations. One cm 2 higher VAT was associated with 0.05 nmol/L (-0.09 to -0.02) lower 25(OH)D in men, and 0.06 nmol/L (-0.10 to -0.01) lower 25(OH)D in women. Hepatic fat was only associated with 25(OH)D in men. A tenfold increase in hepatic fat was associated with 6.21 nmol/L (-10.70 to -1.73) lower 25(OH)D. Regressions with standardized values showed VAT was most strongly related to 25(OH)D., Conclusions: In women, TBF and VAT were inversely related to 25(OH)D concentrations. In men, VAT and hepatic fat were inversely related to 25(OH)D concentrations. In both groups, VAT was most strongly associated with 25(OH)D concentrations., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Sex steroids play a key role in bone turnover and preserving BMD; hence, gender-affirming hormone treatment (HT) in transgender people affects bone metabolism. Most studies have looked into the effect of HT on changes in BMD; however, they do not provide insights into changes in bone metabolism caused by HT. This study investigated changes in bone turnover markers (BTMs) and sclerostin, as well as their correlations with change in BMD in transwomen and transmen during the first year of HT. Transwomen received estradiol and antiandrogens; transmen received testosterone. Sclerostin; P1NP; alkaline phosphatase (ALP); CTx; and BMD of the total hip, the femoral neck, and the lumbar spine were evaluated at baseline and after 1 year of HT. There were 121 transwomen (median age 30 years, interquartile range [IQR] 24 to 41 years) and 132 transmen (median age 24 years, IQR 21 to 33 years) included in the study. In transwomen, ALP decreased in 19% (95% CI, -21 to-16), CTx in 11% (95% CI, -18 to-4), and sclerostin in 8% (95%CI, -13 to-4) of study participants after 1 year of HT. In contrast, in transmen P1NP, ALP, and sclerostin increased in 33% (95% CI, 24 to 42), 16% (95% CI, 12 to 20), and 15% (95% CI, 10 to 20) of study participants, respectively, after 1 year of HT. No age differences were seen in transwomen, whereas in transmen aged ≥50 years a decrease in all BTMs was found in contrast with the other age groups. These transmen had low estrogen concentration at the start of HT based on their postmenopausal state before the start of HT; their estradiol concentrations increased during testosterone treatment. Changes in BTMs and BMD were weakly correlated (correlation coefficient all <0.30). To conclude, 1 year of HT resulted in decreased bone turnover in transwomen and older transmen, whereas it increased in younger transmen. The decrease in bone resorption in older transmen shows the importance of estrogen as a key regulator of bone turnover. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc., (© 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.)

Background: Gender-affirming hormonal treatment (HT) in adult transgender people influences bone mineral density (BMD). Besides BMD, bone geometry and trabecular bone score are associated with fracture risk. However, it is not known whether bone geometry and TBS changes during HT., Purpose: To investigate the bone geometry and TBS in adult transgender people at different time points, up to 25 years, of HT., Methods: A total of 535 trans women and 473 trans men were included, who were divided into three groups at time of their DXA: 20-29 years, 30-39 years, and 40-59 years. Subsequently, each group was divided into different HT durations: baseline, or after 5, 15, or 25 years of HT. Hip structure analysis was performed to measure subperiosteal width, endocortical diameter, average cortical thickness, and section modulus. TBS was calculated based on lumbar spine DXA images., Results: In trans women in all age groups and in young trans men, no differences were observed in periosteal width, endocortical diameter, average cortical thickness, and section modulus for different durations of HT. In trans men aged 40-59 years, subperiosteal width, endocortical diameter, and section modulus were slightly higher in the groups who were using HT compared to the (peri- or postmenopausal) baseline group. In younger trans women, TBS tended to be higher in those using HT compared to the baseline groups, and in older trans women TBS was higher in those using HT for 25 years versus baseline (+0.04, 95%CI +0.00; +0.08). In younger trans men, TBS tended to be lower in those who used HT compared to the baseline groups, and in older trans men TBS was lower in those using 5 years HT versus baseline (-0.05, 95%CI -0.08; -0.01)., Conclusion: No differences in cortical bone geometry parameters were found during different HT-durations. TBS increased in trans women and decreased in trans men, indicating that estrogens have positive effects on TBS. These data may be helpful in determining what sex reference values for calculating T-scores and Z-scores in adult transgender people should be used., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Total 25-hydroxyvitamin D [25(OH)D] is mainly bound to vitamin d-binding protein (DBP). Bioavailable 25(OH)D consists of albumin-bound and free 25(OH)D and is available for metabolic processes. As sex steroids influence DBP, hormonal treatment (HT) in transgender people might affect DBP and consequently the available 25(OH)D. Total 25(OH)D might therefore not well represent bioavailable and free 25(OH)D., Objective: To investigate the effects of HT on DBP, and total, bioavailable, and free 25(OH)D, and to assess whether total 25(OH)D well represents bioavailable and free 25(OH)D., Design: A prospective study., Setting: A university hospital., Participants: Twenty-nine transwomen and 30 transmen., Intervention: Estradiol and cyproterone acetate in transwomen, and testosterone in transmen., Main Outcome Measures: DBP, total 25(OH)D, free 25(OH)D, and albumin were measured at baseline and after 3 months of HT, and deseasonalized total 25(OH)D and bioavailable 25(OH)D were calculated., Results: DBP changed with +5% (95% CI, -0% to 10%; P = 0.06) in transwomen and with -3% (95% CI: -9% to 3%; P = 0.34) in transmen. No significant changes were found in total 25(OH)D, free, and bioavailable 25(OH)D concentrations. Total 25(OH)D was well correlated with bioavailable (R2, 0.75) and free (R2, 0.76) 25(OH)D., Conclusions: DBP tended to increase in transwomen, but did not change in transmen. HT did not influence free 25(OH)D, total 25(OH)D, and bioavailable 25(OH)D concentrations in transwomen and transmen. As total 25(OH)D represents bioavailable and free 25(OH)D well, HT in transgender people does not interfere with the assessment of vitamin D status., (Copyright © 2019 Endocrine Society.)

Background: Randomised controlled trials (RCTs) of vitamin D to prevent COPD exacerbations have yielded conflicting results.Individual participant data meta-analysis could identify factors that explain this variation., Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial., Results: Four eligible RCTs (total 560 participants) were identified; individual participant data were obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels <25 nmol/L (aIRR 0.55, 95% CI 0.36 to 0.84) but not in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (aIRR 1.04, 95% CI 0.85 to 1.27; p for interaction=0.015). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted OR 1.16, 95% CI 0.76 to 1.75)., Conclusions: Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels <25 nmol/L but not in those with higher levels., Trial Registration Number: CRD42014013953., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

A randomised, double-blind, placebo-controlled trial assessing the effect of zoledronic acid on osteopenia in 2000 women aged 65 years and older over a 6-year treatment period has revealed a statistically significant reduction of fracture incidence. Although the treatment effect seen in this study may have been somewhat overestimated due to selection, the implications for clinical practice could be considerable, as half of all women aged over 65 years are osteopenic and most fractures in the general population occur in this group. However, treatment with zoledronic acid is relatively expensive and the impact on health care costs of treating all older women with osteopenia would be dramatic. Additionally, the decision to treat should be based primarily on fracture risk, which is not only dependent on bone density, but also on other factors such as genetic susceptibility, risk of falling and previous fracture. Zoledronic acid should be reserved for osteopenic women who have an evidently high fracture risk due to these other factors.

Concerns about the effects of gender-affirming hormonal treatment (HT) on bone mineral density (BMD) in transgender people exist, particularly regarding the decrease in estrogen concentrations in transmen. Although it is known that HT is safe for BMD in the short term, long-term follow-up studies are lacking. Therefore this study aimed to investigate the change in BMD during the first 10 years of HT, to determine whether HT is safe and if assessing BMD during HT is necessary. A follow-up study was performed in adult transgender people receiving HT at the VU University Medical Center Amsterdam between 1998 and 2016. People were included if they were HT naive and had a dual-energy X-ray absorptiometry (DXA) scan at the start of HT. Follow-up DXA scans performed after 2, 5, and/or 10 years of HT were used for analyses. The course of BMD of the lumbar spine during the first 10 years of HT was analyzed using multilevel analyses. A total of 711 transwomen (median age 35 years; IQR, 26 to 46 years) and 543 transmen (median age 25 years; IQR, 21 to 34 years) were included. Prior to the start of HT, 21.9% of transwomen and 4.3% of transmen had low BMD for age (Z-score < -2.0). In transwomen lumbar spine BMD did not change (+0.006; 95% CI, -0.005 to +0.017), but lumbar spine Z-score increased by +0.22 (95% CI, +0.12 to +0.32) after 10 years of HT. Also in transmen lumbar spine BMD did not change (+0.008; 95% CI, -0.004 to +0.019), but lumbar spine Z-score increased by +0.34 (95% CI, +0.23 to +0.45) after 10 years of HT. This study showed that HT does not have negative effects on BMD, indicating that regularly assessing BMD during HT is not necessary. However, a high percentage of low BMD was found prior to HT, especially in transwomen. Therefore, evaluation of BMD before start of HT may be considered. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc., (© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.)

Measurements of bone markers (BMs) in peripheral blood or urine are a pivotal part of bone research within modern clinical medicine. In recent years the use of BMs increased substantially as they can be useful either to diagnose bone (related) disease and to follow its natural history, but also to monitor the effects of interventions. However, the use of BMs is still complicated mainly due to (pre)analytical variability of these substances, limited accessibility of assays, variable cut-off values in different countries and laboratories and heterogeneous results with regard to clinical implications of measuring BMs in several studies. This review will provide the clinician with a practical guide, based on current evidence, in which circumstances to test which bone markers for optimal diagnostic purposes, in order to improve patient care in different areas of bone diseases including Paget's disease, primary osteoporosis, tumor induced osteomalacia, hypophosphatemic rickets, van Buchem disease, chronic kidney disease, rheumatoid arthritis, neoplasma/multiple myeloma, type 2 diabetes mellitus and primary hyperparathyroidism. The clinician should consider fasting state, recent fractures, aging, menopausal status, concomitant liver and kidney disease when ordering and interpreting BM measurements as these factors might result in misleading BM concentrations. We found that BMs are clearly useful in the current diagnosis of tumor induced osteomalacia, van Buchem disease, Paget's disease and hypophosphatemic rickets. In addition, BMs are useful to monitor disease activity in chronic kidney disease, Paget's disease and are useful to monitor treatment adherence in osteoporosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Early renal dysfunction is associated with a 38% increased fracture risk in individuals aged 65 years and older. In men but not women, early renal dysfunction is associated with decreased femoral neck bone mineral density (BMD) which can be partially explained by increased parathyroid hormone (PTH) concentrations., Introduction: It is uncertain whether early renal dysfunction is associated with osteoporosis and increased fracture risk. The aim of this study was to determine the relationship of decreased renal function with BMD and fracture risk and the role of PTH therein., Methods: We analyzed data of participants aged 65 years and older from the Longitudinal Aging Study Amsterdam. A 6-year fracture follow-up was obtained in 1477 participants. BMD was measured by dual-energy x-ray absorptiometry (n = 535) and vertebral fractures by lateral spinal radiograph (n = 527) in a subsample at baseline. Glomerular filtration rate (eGFR) was estimated according to the modification of diet in renal disease equation and assessed by the five stages of chronic kidney disease (CKD)., Results: In men and women, eGFR < 57 ml/min/1.73 m 2 (lowest quartile) compared to eGFR > 74 ml/min/1.73 m 2 (highest quartile) was associated with a 38% increase in fracture risk after adjustment for relevant confounders [hazard ratio (95%CI): 1.38 (1.17 to 1.61)]. Also, CKD stages 3a and 3b were associated to a 28 and 46% increase in fracture risk, respectively, as compared to CKD stages 1 and 2 together (eGFR > 60 ml/min/1.73 m 2 ) after adjustment for confounders. Renal function was not associated with prevalent vertebral fractures. In men, but not women, lowest quartile of eGFR was related to lower femoral neck BMD as compared to the highest quartile eGFR [unstandardized B (95%CI) - 0.052 g/cm 2 (- 0.098 to - 0.006)], after adjustment for relevant confounders. Further adjustment for PTH attenuated this relationship by 27%., Conclusions: In men and women, early decreased renal function (eGFR < 60 ml/min/1.73 m 2 ) was related to increased incident any fracture risk but not with increased prevalence of vertebral fractures. In men, but not women, early renal dysfunction was related to lower femoral neck BMD which could statistically be partially explained by increased PTH concentrations.

Hypothesis: Glucocorticoids (GCs) induce osteoporosis predominantly by inhibiting osteoblast activity. We hypothesised that osteoblastic factors could also be linked to GC-induced adverse metabolic effects., Methods: We performed a post-hoc analysis of a randomised, placebo-controlled, double blind, dose-response intervention study involving 32 healthy males (age: 22 ± 3 years; BMI 22.4 ± 1.7 kg/m 2 ) who were allocated to prednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for two weeks using block randomisation. Mean outcomes measures included osteocalcin, N-terminal propeptide of type 1 procollagen (P1NP) and their relation to glucose and lipid metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp., Results: Osteocalcin and P1NP concentrations were dose-dependently decreased by PRED treatment (p < 0.001 both). PRED dosages dose-dependently reduced sensitivity of the liver and skeletal muscle for insulin (p < 0.001 both) and impaired suppression of lipolysis mediated by insulin (p < 0.01). In multivariate analyses, GC-induced changes in osteocalcin concentrations related to reduces hepatic insulin sensitivity (β = -0.315; p = 0.044). In addition, GC-induced changes in P1NP were negatively related to changes in insulin-mediated suppression of hepatic glucose production (r = -0.582; p = 0.001), and were positively related to insulin-stimulated glucose uptake (r = 0.638; p < 0.001). Finally, changes in PN1P were negatively related to changes in fasting hypertriglyceridemia (r = -0.499; p = 0.004) and insulin-induced suppression of lipolysis rates (r = -0.494; p = 0.006)., Conclusion: GC treatment alters osteoblastic function which is associated with several adverse metabolic effects of GC treatment. Future causal studies are needed to assess the specific mediator(s) by which the osteoblast alters intermediary metabolism., Clinical Trial Registration Number: ISRCTN83991850., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vitamin D deficiency and rickets are more common in non-western immigrants and refugees than in the native population. Severe vitamin D deficiency (serum 25-hydroxyvitamin D <25 nmol/l) may occur in up to 50% of children and adults of non-western origin. They are not used to sunshine exposure due to the often excessive sunshine in the country of origin. They usually have a more pigmented skin. Non-western immigrants and refugees often wear skin-covering clothes due to religious or cultural tradition. The food contains little vitamin D with the exception of fatty fish. In addition, many immigrants have a low calcium intake. Complaints may include fatigue, pain in shoulders, ribs, lower back and thighs. Neonates and young children may have spasms and convulsions due to hypocalcemia. Older children and adolescents may have bone pain, muscle weakness and skeletal deformities. Widening of the wrist, chest deformities and bowing of the legs may occur, and longitudinal growth is delayed. In adults, muscle weakness and bone pain are predominant. Laboratory examination may show hypocalcemia and hypophosphatemia and elevated alkaline phosphatase. The serum 25(OH)D is below 25 nmol/l in case of severe vitamin D deficiency with symptoms. Impaired 25-hydroxylation or 1α-hydroxylation may occur in case of severe liver or renal disease or by genetic causes. Radiographs of wrists or knees may show widening of the growth plates and cupping of radius and ulna may confirm the diagnosis. In adolescents and adults, radiographs of painful bones may show pseudofractures or Looser zones. Rickets and osteomalacia are treated by vitamin D3 2000 IU/d in infants, 3000-6000 IU/d in older children in combination with calcium 500 mg /d. In osteomalacia, the adult vitamin D3 dose is 2000-3000 IU/d, combined with calcium 1000-2000 mg/d. Prevention of vitamin D deficiency can be done with vitamin D3 400-800 IU/d, depending on age. Nutritional measures include fortification of milk or other foods.

We now have the ability to measure a number of different vitamin D metabolites with very accurate methods. The most abundant vitamin D metabolite, 25-hydroxyvitamin D, is currently the best marker for overall vitamin D status and is therefore most commonly measured in clinical medicine. The added value of measuring metabolites beyond 25-hydroxyvitamin D, like 1,25-, and 24,25-dihydroxyvitamin D is not broadly appreciated. Yet, in some more complicated cases, these metabolites may provide just the information needed for a legitimate diagnosis. The problem at present, is knowing when to measure, what to measure and how to measure. For 25-hydroxyvitamin D, the most frequently used automated immunoassays do not meet the requirements of today's standards for certain patient groups and liquid chromatography-tandem mass spectrometry is the desired method of choice in these individuals. The less frequently measured 1,25-dihydroxyvitamin D metabolite enables us to identify a number of conditions, including 1α-hydroxylase deficiency, hereditary vitamin D-resistant rickets and a number of granulomatous diseases or lymphoproliferative diseases accompanied by hypercalcaemia. Furthermore, it discriminates between the FGF23-mediated and non-FGF23-mediated hypophosphatemic syndromes. The 24,25-dihydroxyvitamin D metabolite has proven its value in the diagnosis of idiopathic infantile hypercalcaemia and has the potential of having value in identifying other diseases. For both metabolites, the understanding of the origin of differences between assays is limited and requires further attention. Nonetheless, in every way, appropriate measurement of vitamin D metabolism in the clinical laboratory hinges eminently on the comprehension of the value of the different metabolites, and the importance of the choice of method., Competing Interests: The authors declare no conflict of interest.

Background: Over the past decade, the number of people referred to gender identity clinics has rapidly increased. This raises several questions, especially concerning the frequency of performing gender-affirming treatments with irreversible effects and regret from such interventions., Aim: To study the current prevalence of gender dysphoria, how frequently gender-affirming treatments are performed, and the number of people experiencing regret of this treatment., Methods: The medical files of all people who attended our gender identity clinic from 1972 to 2015 were reviewed retrospectively., Outcomes: The number of (and change in) people who applied for transgender health care, the percentage of people starting with gender-affirming hormonal treatment (HT), the estimated prevalence of transgender people receiving gender-affirming treatment, the percentage of people who underwent gonadectomy, and the percentage of people who regretted gonadectomy, specified separately for each year., Results: 6,793 people (4,432 birth-assigned male, 2,361 birth-assigned female) visited our gender identity clinic from 1972 through 2015. The number of people assessed per year increased 20-fold from 34 in 1980 to 686 in 2015. The estimated prevalence in the Netherlands in 2015 was 1:3,800 for men (transwomen) and 1:5,200 for women (transmen). The percentage of people who started HT within 5 years after the 1st visit decreased over time, with almost 90% in 1980 to 65% in 2010. The percentage of people who underwent gonadectomy within 5 years after starting HT remained stable over time (74.7% of transwomen and 83.8% of transmen). Only 0.6% of transwomen and 0.3% of transmen who underwent gonadectomy were identified as experiencing regret., Clinical Implications: Because the transgender population is growing, a larger availability of transgender health care is needed. Other health care providers should familiarize themselves with transgender health care, because HT can influence diseases and interact with medication. Because not all people apply for the classic treatment approach, special attention should be given to those who choose less common forms of treatment., Strengths and Limitations: This study was performed in the largest Dutch gender identity clinic, which treats more than 95% of the transgender population in the Netherlands. Because of the retrospective design, some data could be missing., Conclusion: The number of people with gender identity issues seeking professional help increased dramatically in recent decades. The percentage of people who regretted gonadectomy remained small and did not show a tendency to increase. Wiepjes CM, Nota NM, de Blok CJM, et al. The Amsterdam Cohort of Gender Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets. J Sex Med 2018;15:582-590., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Previous studies indicate that human immunodeficiency virus (HIV)-infection and combination antiretroviral therapy (cART) can affect bone turnover. Furthermore, HIV-infected patients have lower bone mineral density (BMD) compared to a healthy reference population., Objective: To evaluate the longitudinal effect of HIV-infection and cART on bone turnover markers (BTMs) and BMD in men with primary HIV-infection (PHI)., Design, Methods: Thirty-five PHI-men were divided into two groups, those that received cART for the first time (n = 26) versus no-cART (n = 9). Dual-energy X-ray absorptiometry (DXA) was performed on femoral neck (FN), total hip (TH) and lumbar spine (LS) and BTMs (P1NP, alkaline phosphatase, osteocalcin, ICTP and CTX) were measured at baseline and follow-up., Results: At baseline, the median CD4+ T-cell count was 455 cells/mm3 (IQR 320-620) and plasma viral load 5.4 log10 copies/mL (IQR 4.7-6.0) in the cART treated group, compared to 630 (IQR 590-910) and 4.8 (IQR 4.2-5.1) in the untreated group. The median follow-up time was 60.7 weeks (IQR 24.7-96.0). All BTMs, except ICTP, showed a significant increase during cART versus no changes of BTMs in the untreated group. FN and TH BMD showed a significant decrease in both groups. LS BMD did not change in both groups., Conclusion: Bone turnover increased in PHI-men treated with cART which was accompanied by a decrease in FN and TH BMD. No increase of bone turnover was seen in untreated PHI-men. Our study suggests that cART results in increased bone turnover and decreased BMD of the hip in PHI-men.

Background: Posttranslational oxidation of parathyroid hormone (PTH) modifies its biological activity. Measurement of non-oxidized PTH (n-oxPTH) could be an improvement in assessing PTH status, as intact PTH may rather reflect oxidative stress. However, it is debated whether oxidation of PTH occurs in vivo, or whether it is mainly an in vitro artifact. The aim of this study was to investigate the influence of different preanalytical conditions on the oxidation of PTH within a wide range of plasma PTH concentrations and oxidation propensity., Methods: n-oxPTH was separated from its oxidized form using an affinity column capturing the oxidized PTH. n-oxPTH was measured in eluate using commercially available PTH assays. The study included ethylenediaminetetraacetic acid plasma samples from 17 patients undergoing hemodialysis and 32 healthy subjects. We determined effects of storage temperature, time until centrifugation and freeze-thaw cycles. PTH and n-oxPTH concentrations were measured in each sample using six different immunoassays., Results: n-oxPTH concentrations remained unchanged up to 180 min until centrifugation, two freeze-thaw cycles or after storage at -20°C or -80°C up to 79 days. Various methods for n-oxPTH and PTH measurements yielded highly comparable results, apart from standardization differences between various PTH and n-oxPTH assays., Conclusions: n-oxPTH concentrations were stable under our study conditions, indicating negligible ex vivo oxidation of PTH. In addition, PTH immunoassays have a different sensitivity for n-oxPTH than for total PTH. For this reason, the n-oxPTH/total PTH ratio cannot be used in absence of a n-oxPTH standard. Clinical implications of determining n-oxPTH require additional study.

Vitamin D is hypothesized to have a beneficial effect on lung function and respiratory infections. The aim of this study was to assess the relationship of serum 25-hydroxyvitamin D (25(OH)D) concentrations with lung function, airway inflammation and common colds. We performed a cross-sectional analysis in the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort study. We included participants with measurements of serum 25(OH)D, Forced Expiratory Volume in 1 s (FEV₁), Forced Vital Capacity (FVC), Fractional Exhaled Nitric Oxide (Fe NO ), and data on self-reported common colds ( n = 6138). In crude associations, serum 25(OH)D was positively associated with FEV₁ and FVC, and negatively with Fe NO and the occurrence of a common cold. After adjustment for confounders, however, these associations disappeared. Stratified analyses showed that Body Mass Index (BMI) was an effect modifier in the relationship between serum 25(OH)D and FEV₁, FVC and Fe NO . In obese participants (BMI ≥ 30 kg/m²), 10 nmol/L higher 25(OH)D was associated with 0.46% predicted higher FEV₁ (95% Confidence Interval: 0.17 to 0.75), 0.46% predicted higher FVC (0.18 to 0.74), and 0.24 ppb lower Fe NO (-0.43 to -0.04). Thus, in the total study population, 25(OH)D concentrations were not associated with lung function, airway inflammation and common colds. In obese participants, however, higher 25(OH)D concentrations were associated with a better lung function and lower airway inflammation., Competing Interests: The authors declare no conflict of interest.