Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.
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Stefan Pilz, Armin Zittermann, Christian Trummer, Verena Theiler-Schwetz, Elisabeth Lerchbaum, Martin H Keppel, Martin R Grübler, Winfried März, and Marlene Pandis
Barbara J Boucher
Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860 and 1890, that both sunlight and cod liver oil (a well-known folk remedy) cured and prevented rickets. Vitamins D2/D3 were discovered exactly a hundred years ago, and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms affecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally. Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them.
Natércia Neves Marques de Queiroz, Franciane Trindade Cunha de Melo, Fabrício de Souza Resende, Luísa Corrêa Janaú, Norberto Jorge Kzan de Souza Neto, Manuela Nascimento de Lemos, Ana Carolina Lobato Virgolino, Maria Clara Neres Iunes de Oliveira, Angélica Leite de Alcântara, Lorena Vilhena de Moraes, Tiago Franco David, Wanderson Maia da Silva, Scarlatt Souza Reis, Márcia Costa dos Santos, Ana Carolina Contente Braga de Souza, Pedro Paulo Freire Piani, Neyla Arroyo Lara Mourão, Karem Mileo Felício, João Felício Abrahão Neto, and João Soares Felício
Investigate the prevalence of vitamin D deficiency in an equatorial population through a large-sample study.
Cross-sectional study with 30,224 healthy individuals from the North Region, in Brazil (Amazônia – state of Pará), who had 25-hydroxy-vitamin D (25(OH)D) and intact parathyroid hormone (PTH) serum levels measured by immunoassay method. Those with history of acute or chronic diseases were excluded. Abnormal levels of calcium, creatinine, glycemia and albumin were also exclusion criteria.
25(OH)D levels were 29.1 ± 8.2 ng/mL and values <12.7 ng/mL were equal to < −2 s.d. below average. Hypovitaminosis D was present in 10% of subjects according to the Institute of Medicine (values <20 ng/mL) and in 59%, in consonance with Endocrine Society (values 20–30 ng/mL as insufficiency and <20 ng/mL as deficiency) criteria. Individuals were divided according to four age brackets: children, adolescents, adults and elderly, and their 25(OH)D levels were: 33 ± 9; 28.5 ± 7.4; 28.3 ± 7.7; 29.3 ± 8.5 ng/mL, respectively. All groups differed in 25(OH)D, except adolescents vs adults. Regression model showed BMI, sex, living zone (urban or rural) and age as independent variables to 25(OH)D levels. Comparing subjects with vitamin D deficiency (<20 ng/mL) to those with vitamin D insufficiency (20–30 ng/mL), a difference between PTH levels in these two groups was observed (95.9 ± 24.7 pg/mL vs 44.2 ± 64.5 pg/mL; P < 0.01). Additionally, the most accurate predictive vitamin D level for subclinical hyperparathyroidism in ROC curve was 26 ng/mL.
Our equatorial population showed low prevalence of vitamin D hypovitaminosis ranging with age bracket. The insufficient category by Endocrine Society was corroborated by our PTH data.
Ranganathan R Rao, Harpal S Randeva, Sailesh Sankaranarayanan, Murthy Narashima, Matthias Möhlig, Hisham Mehanna, and Martin O Weickert
Vitamin D deficiency further increases circulating parathyroid hormone (PTH) levels in patients with primary hyperparathyroidism (pHPT), with potential detrimental effects on bone mass.
This was an observational clinical study in consecutive conservatively treated postmenopausal women (n=40) with pHPT and coexistent 25-hydroxyvitamin D deficiency (25OHD ≤50 nmol/l (≤20 ng/ml)). Patients who showed an increase in serum 25OHD above the threshold of vitamin D deficiency (>50 nmol/l; n=28) using treatment with various commonly prescribed vitamin D preparations were, for the purposes of statistical analyses, allocated to the treatment group. Patients who were retrospectively identified as having received no treatment with vitamin D and/or remained vitamin D deficient were considered as non-responders/controls (n=12). Adjusted calcium (adjCa), PTH and 25OHD concentrations were monitored in all subjects up to 54 months (mean observation period of 18±2 months).
Prolonged increased vitamin D intake, regardless of the source (serum 25OHD, increase from 32.2±1.7 nmol/l at baseline to 136.4±11.6 nmol/l, P<0.0001), significantly reduced serum PTH (13.3±1.1 vs 10.5±1.0 pmol/l, P=0.0001), with no adverse effects on adjCa levels (2.60±0.03 vs 2.60±0.02 mmol/l, P=0.77) and renal function tests (P>0.73). In contrast, serum PTH remained unchanged (15.8±2.6 vs 16.3±1.9 pmol/l, P=0.64) in patients who remained vitamin D deficient, with a significant difference between groups in changes of PTH (P=0.0003). Intrapartial correlation analyses showed an independent negative correlation of changes in 25OHD with PTH levels (r ic=−0.41, P=0.014).
Prolonged treatment with vitamin D in various commonly prescribed preparations appeared to be safe and significantly reduced PTH levels by 21%.
Mirjam M Oosterwerff, Rosa Meijnen, Natasja M Van Schoor, Dirk L Knol, Mark H H Kramer, Mireille N M Van Poppel, Paul Lips, and E Marelise W Eekhoff
Vitamin D deficiency is highly prevalent among non-western immigrants in The Netherlands and associated with poor physical performance. The aim of this study was to assess the effect of vitamin D supplementation on physical performance, exercise capacity, and daily physical activity in vitamin D-deficient, overweight non-western immigrants. A randomized double-blind, placebo-controlled trial was conducted to assess the effect of vitamin D on physical performance. A total of 130 participants were included. Eligibility criteria included overweight (BMI >27 kg/m2), 25-hydroxy vitamin D (25(OH)D) ≤50 nmol/l, and an age range of 20–65 years. The intervention group received 1200 IU vitamin D3 daily for 4 months; the control group received placebo. Both groups received 500 mg calcium daily. Outcome measures included physical performance (physical performance score), exercise capacity (a 6-min walk test (6-MWT)), and daily physical activity (questionnaire and accelerometer). There was no significant effect on physical performance, exercise capacity, or physical activity in the intention to treat analysis. In an explorative post hoc analysis restricted to participants reaching a serum 25(OH)D concentration of >60 nmol/l after intervention, there was an improvement of 19 m in the 6-MWT compared with the control group (P=0.053). Moderate dose vitamin D supplementation did not significantly improve physical performance, exercise capacity, or physical activity. However, when 25(OH)D concentrations reached >60 nmol/l after intervention, there was a borderline significant improvement in exercise capacity. Although the clinical relevance is not clear, this is a promising result, as all participants were overweight and did not improve their overall activity levels.
Sharon A Huish, Carl Jenkinson, Janet A Dunn, David J Meredith, Rosemary Bland, and Martin Hewison
Low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) in end-stage renal disease (ESRD) is considered a consequence of elevated fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (CYP27B1). Current ESRD treatment strategies to increase serum calcium and suppress secondary hyperparathyroidism involve supplementation with vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of 25-hydroxyvitamin D (25(OH)D) deficiency as a contributor to low serum 1,25(OH)2D. We investigated the effects of vitamin D (cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum vitamin D metabolites (25(OH)D, 1,25(OH)2D3 and 24,25(OH)2D3) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active vitamin D analogues as part of routine ESRD care. 1,25(OH)2D3 levels were low at baseline (normal range: 60–120 pmol/L). Cholecalciferol supplementation normalised both serum 25(OH)D and 1,25(OH)2D3. Median serum 25(OH)D increased from 35.1 nmol/L (IQR: 23.0–47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5–143.3 nmol/L) (P < 0.001). Median serum 1,25(OH)2D3 and 24,25(OH)2D3 increased from 48.3 pmol/L (IQR: 35.9–57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3–6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1–130.6 pmol/L) and 12.3 nmol/L (IQR: 9–16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise 1,25(OH)2D3 in ESRD is maintained but is substrate dependent, and serum 25(OH)D was a limiting factor at baseline. Therefore, 1,25(OH)2D3 deficiency in ESRD is partly a consequence of 25(OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.
Stan Ursem, Vito Francic, Martin Keppel, Verena Schwetz, Christian Trummer, Marlene Pandis, Felix Aberer, Martin R Grübler, Nicolas D Verheyen, Winfried März, Andreas Tomaschitz, Stefan Pilz, Barbara Obermayer-Pietsch, and Annemieke C Heijboer
PTH can be oxidised in vivo, rendering it biologically inactive. Non-oxidised PTH (n-oxPTH) may therefore give a better image of the hormonal status of the patient. While vitamin D supplementation decreases total PTH (tPTH) concentration, the effect on n-oxPTH concentration is unexplored. We investigated the effect of vitamin D on n-oxPTH concentration in comparison to tPTH and compared the correlations between parameters of calcium, bone and lipid metabolism with n-oxPTH and tPTH.
N-oxPTH was measured in 108 vitamin D-insufficient (25(OH)D <75 nmol/L) hypertensive patients, treated with vitamin D (2800 IE daily) or placebo for 8 weeks in the Styrian Vitamin D Hypertension Trial (NCT02136771). We calculated the treatment effect and performed correlation analyses of n-oxPTH and tPTH with parameters of calcium, bone and lipid metabolism and oxidative stress.
After treatment, compared to placebo, 25(OH)D concentrations increased, tPTH decreased by 9% (P < 0.001), n-oxPTH by 7% (P = 0.025) and the ratio of n-oxPTH/tPTH increased (P = 0.027). Changes in phosphate and HDL concentration correlated with changes in n-oxPTH, but not tPTH.
tPTH and n-oxPTH decrease upon vitamin D supplementation. Our study suggests that vitamin D supplementation reduces the oxidation of PTH, as we observed a small but significant increase in the non-oxidised proportion of PTH upon treatment. In addition, we found that changes in phosphate and HDL concentration showed a relationship with changes in n-oxPTH, but not tPTH. This may be explained by the biological activity of n-oxPTH. Further research should be carried out to establish the clinical relevance of n-oxPTH.
Haojie Zhang, Yuke Cui, Ruihua Dong, Wen Zhang, Shihan Chen, Heng Wan, Chi Chen, Yi Chen, Yuying Wang, Chunfang Zhu, Bo Chen, Ningjian Wang, and Yingli Lu
Bone is thought to be the reservoir of the human lead burden, and vitamin D is associated with bone turnover. We aimed to explore whether exposure to lower 25-hydroxy vitamin D (25(OH)D) levels was associated with higher blood lead levels (BLLs) by increasing the bone turnover rate in individuals with type 2 diabetes.
A total of 4103 type 2 diabetic men and postmenopausal women in Shanghai, China, were enrolled in 2018. Their 25(OH)D, β-C-terminal telopeptide (β-CTX), N-MID osteocalcin and procollagen type 1 N-peptide (P1NP) levels were detected. Their BLLs were determined by atomic absorption spectrometry. Mediation analyses were performed to identify the possible role that bone turnover played in the underlying mechanisms.
In both the men and postmenopausal women, all three bone turnover markers were inversely associated with 25(OH)D and positively associated with the BLL (all P < 0.01) after adjusting for age, current smoking habits, metabolic parameters, duration of diabetes, vitamin D intake, and use of anti-osteoporosis medication. In the mediation analyses, none of the direct associations between 25(OH)D and BLL was significant for the three bone turnover markers, but all three bone turnover markers were found to be significant mediators of the indirect associations between 25(OH)D and BLL.
The association between vitamin D and BLL was fully mediated by bone turnover markers in type 2 diabetic patients (mediation effect). This finding suggested that vitamin D may protect against blood lead exposure from the bone reservoir by decreasing bone turnover in individuals with type 2 diabetes.
Melissa Braga, Zena Simmons, Keith C Norris, Monica G Ferrini, and Jorge N Artaza
Skeletal muscle wasting is a serious disorder associated with health conditions such as aging, chronic kidney disease and AIDS. Vitamin D is most widely recognized for its regulation of calcium and phosphate homeostasis in relation to bone development and maintenance. Recently, vitamin D supplementation has been shown to improve muscle performance and reduce the risk of falls in vitamin D deficient older adults. However, little is known of the underlying molecular mechanism(s) or the role it plays in myogenic differentiation. We examined the effect of 1,25-D3 on myogenic cell differentiation in skeletal muscle derived stem cells. Primary cultures of skeletal muscle satellite cells were isolated from the tibialis anterior, soleus and gastrocnemius muscles of 8-week-old C57/BL6 male mice and then treated with 1,25-D3. The efficiency of satellite cells isolation determined by PAX7+ cells was 81%, and they expressed VDR. Incubation of satellite cells with 1,25-D3 induces increased expression of: (i) MYOD, (ii) MYOG, (iii) MYC2, (iv) skeletal muscle fast troponin I and T, (v) MYH1, (vi) IGF1 and 2, (vii) FGF1 and 2, (viii) BMP4, (ix) MMP9 and (x) FST. It also promotes myotube formation and decreases the expression of MSTN. In conclusion, 1,25-D3 promoted a robust myogenic effect on satellite cells responsible for the regeneration of muscle after injury or muscle waste. This study provides a mechanistic justification for vitamin D supplementation in conditions characterized by loss of muscle mass and also in vitamin D deficient older adults with reduced muscle mass and strength, and increased risk of falls.
Laura P B Elbers, Marije Wijnberge, Joost C M Meijers, Dennis C W Poland, Dees P M Brandjes, Eric Fliers, and Victor E A Gerdes
Abnormal coagulation tests have been observed in patients with primary hyperparathyroidism (HPT) suggesting a prothrombotic effect of parathyroid hormone (PTH). Vitamin D deficiency (VIDD) is the most frequent cause of secondary HPT. Aim of our study was to investigate the influence of HPT secondary to moderate-to-severe VIDD and vitamin D replacement on the coagulation and fibrinolysis system.
Subjects and methods
Prospective cohort study of patients with vitamin D <25 nmol/L with and without HPT, and a control group of patients on vitamin D suppletion. At baseline and after 2 months of vitamin D suppletion (900,000 IU in 2 months), endocrine and coagulation markers were measured.
59 patients with VIDD of which 34 had secondary HPT and 36 controls were included. After 2 months of suppletion, vitamin D increased by 399% (VIDD with HPT), 442% (all patients with VIDD) and 6% (controls). PTH decreased by 34% (VIDD with HPT, P < 0.01 for decrease), 32% (all VIDD, P < 0.01) and increased by 8% in the controls (P-values: <0.01 for relative changes between VIDD with HPT or all VIDD patients vs controls). Relative changes in PT, aPTT, fibrinogen, Von Willebrand factor, factors VII, VIII and X, thrombin generation, TAFI, clot-lysis time and d-dimer were not different between patients with VIDD with HPT or all VIDD vs controls.
Secondary HPT due to VIDD does not have a prothrombotic effect. In contrast with previous reports, PTH does not seem to influence coagulation or fibrinolysis, which is relevant because of the high prevalence of VIDD.