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Celli A, Aloisi P, Manelli M, Celli LE, Celli L. Vitamin D status in healing of distal humeral fractures: Clinical observations. Injury 2024; 55 Suppl 4:111671. [PMID: 39542583 DOI: 10.1016/j.injury.2024.111671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/28/2024] [Accepted: 06/09/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Fracture healing is a complex biological process that begins soon after a fracture has occurred. Whereas the role of vitamin D status on the maintenance of bone health is well established, the clinical effects of vitamin D deficiency in the healing of distal humeral fractures are less well explored. This study examines the role of vitamin D serum levels in distal humeral fractures (C2, C3) managed with open reduction and double plate fixation, by comparing its concentration in patients with or without radiographic signs of fracture healing and in control subjects. Our hypothesis is that 6 months from treatment vitamin D levels will be different between the groups of patients. MATERIAL AND METHODS We measured the vitamin D serum level in a cohort of consecutive adult patients aged 30 to 60 years. They included a group of subjects without fractures who were admitted to our clinic in the 6 months preceding the study (controls) and two groups of patients with humeral fractures who at 6-month follow-up showed or failed to show radiological signs of fracture healing. RESULTS The mean vitamin D concentration was 23.03 μg/L (±5.8) in the group with radiographic signs of fracture healing, 9.30 μg/L (±2.60) in the group with radiographic signs of delayed union and 26.15 μg/L (±11.76 μg/L) in the control group. Significantly different (p < 0.05) concentrations were measured between the fracture groups, between the group with radiographic signs of fracture healing and the control group and between the group with radiographic signs of delayed union and the control group. DISCUSSION Vitamin D is primarily involved in the stages of hard callus formation and remodelling. It also has several functions that affect the early stages of fracture healing. Vitamin D influences the cellular process of bone healing, although the underlying mechanism is still partly unclear. It would be useful to determine the vitamin D status of fracture patients at admission and to start supplementation, with periodic checks, to foster the consolidation phase. Although vitamin D is clearly not the only factor influencing the consolidation of a surgically treated distal humerus fracture, its concentration can easily be determined and managed. Our data suggest that vitamin D levels should be determined at admission and that fracture patients with low concentrations should be started on vitamin D supplementation.
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Affiliation(s)
- Andrea Celli
- Shoulder and Elbow Unit, Department of Orthopaedic Surgery, Hesperia Hospital, Modena, Italy.
| | - Piero Aloisi
- Department of Biochemistry and Microbiology, Hesperia Hospital, Modena, Italy
| | - Mattia Manelli
- Department of Biochemistry and Microbiology, Hesperia Hospital, Modena, Italy
| | - Ludovica Elena Celli
- Shoulder and Elbow Unit, Department of Orthopaedic Surgery, Hesperia Hospital, Modena, Italy
| | - Luigi Celli
- Shoulder and Elbow Unit, Department of Orthopaedic Surgery, Hesperia Hospital, Modena, Italy
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Vaculik J, Wenchich L, Bobelyak M, Pavelka K, Stepan JJ. A decrease in serum 1,25(OH) 2D after elective hip replacement and during bone healing is associated with changes in serum iron and plasma FGF23. J Endocrinol Invest 2022; 45:1039-1044. [PMID: 35079976 DOI: 10.1007/s40618-022-01746-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/13/2022] [Indexed: 10/19/2022]
Abstract
OBJECTIVE Although calcitriol is essential for bone healing, its serum concentrations are low after hip surgery, and they continue to decline during bone healing. This study aimed to test the hypothesis of an association of changes in calcitriol production with the status of fibroblast growth factor 23 (FGF23) and iron deficiency after elective hip replacement for coxarthrosis. METHODS In this prospective study, we measured the biomarkers of 17 patients undergoing elective hip replacement on admission, on the first day after surgery, and at the regular check-up after 48 ± 8 days. The serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, transferrin, ferritin, parathyroid hormone, intact plasma FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) were determined. RESULTS In our patients who underwent elective hip replacement, significant correlations existed between the percent change in the conversion rate of 25(OH)D to 1,25(OH)2D, plasma intact to C-terminal FGF23 ratio, and serum iron. CONCLUSIONS The production of calcitriol is compromised after elective hip replacement surgery, leading to reduced levels of active vitamin D in the serum. Significant correlations between the percent change in the conversion rate of 25(OH)D to 1,25(OH)2D, plasma intact to C-terminal FGF23 ratio, and serum iron on the first day as well as 7 weeks after surgery could inspire future studies to determine whether and how calcitriol deficiency should be corrected, especially in fracture cases.
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Affiliation(s)
- J Vaculik
- Orthopedic Department, Bulovka Hospital, Prague, Czech Republic
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Orthopedic Department, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - L Wenchich
- Institute of Rheumatology, Prague, Czech Republic
| | - M Bobelyak
- Orthopedic Department, Bulovka Hospital, Prague, Czech Republic
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - K Pavelka
- Institute of Rheumatology, Prague, Czech Republic
- Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - J J Stepan
- Institute of Rheumatology, Prague, Czech Republic.
- Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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Vaculik J, Wenchich L, Bobelyak M, Pavelka K, Stepan JJ. Decrease in serum calcitriol (but not free 25-hydroxyvitamin D) concentration in hip fracture healing. J Endocrinol Invest 2021; 44:1847-1855. [PMID: 33492601 DOI: 10.1007/s40618-020-01489-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/18/2020] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To assess the decrease in serum calcitriol concentrations after hip fracture. METHODS Serum concentrations of calcitriol, 25(OH)D, parathyroid hormone (PTH), directly measured free 25(OH)D, and indices of bone formation were measured in elderly patients with hip fracture (HF) and patients with elective hip replacement (EHR) at admission and after 7 weeks. RESULTS A total of 45 patients with HF and 17 patients with EHR completed this prospective study. Baseline serum calcitriol levels were ≤ 60 pmol/l in 26% of the HF patients. After 7 weeks, they significantly decreased (p < 0.001). In patients with EHR, serum calcitriol was within the reference range in all but one patient and did not change during the 7-week recovery phase. Seven weeks after HF, a significant positive relationship was observed between the change in calcitriol and serum 25(OH)D concentration (r = 0.385, p = 0.009) and free 25(OH)D (r = 0.296, p = 0.048), and a decrease in calcitriol during recovery was associated with a decrease in serum PTH (p = 0.038). Seven weeks after HF, changes in both serum PTH and serum 25(OH)D concentrations contributed to the prediction of changes in serum calcitriol (R2 = 0.190, p = 0.012). CONCLUSIONS Unlike patients with EHR, subjects with HF had low serum 25(OH)D and low free 25(OH)D concentrations at admission, while their serum 1,25D levels were relatively elevated. Decreases in circulating calcitriol levels in the 7 weeks following hip surgery were associated with a resolution of secondary hyperparathyroidism and low availability of free 25(OH)D.
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Affiliation(s)
- J Vaculik
- Orthopedic Department, Bulovka Hospital, Prague, Czech Republic
- Faculty of Medicine 1, Charles University, Prague, Czech Republic
- Faculty of Medicine 3, Charles University, Prague, Czech Republic
| | - L Wenchich
- Institute of Rheumatology, Prague, Czech Republic
| | - M Bobelyak
- Orthopedic Department, Bulovka Hospital, Prague, Czech Republic
- Faculty of Medicine 3, Charles University, Prague, Czech Republic
| | - K Pavelka
- Faculty of Medicine 1, Charles University, Prague, Czech Republic
- Institute of Rheumatology, Prague, Czech Republic
| | - J J Stepan
- Faculty of Medicine 1, Charles University, Prague, Czech Republic.
- Institute of Rheumatology, Prague, Czech Republic.
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Abstract
The COVID-19 pandemic has generated high interest in factors modulating risk of infection, disease severity and recovery. Vitamin D has received interest since it is known to modulate immune function and vitamin D deficiency is associated with increased risk of respiratory infections and adverse health outcomes in severely ill patients. There are no population representative data on the direct relationship between vitamin D status and SARS-CoV-2 infection risk and severity of COVID-19. Data from intervention studies are limited to 4 studies. Here we summarise findings regarding vitamin D status and metabolism and their alterations during severe illness, relevant to COVID-19 patients. Further, we summarise vitamin D intervention studies with respiratory disease outcomes and in critically ill patients and provide an overview of relevant patient and population guidelines. Vitamin D deficiency is highly prevalent in hospitalised patients, particularly when critically ill including those with COVID-19. Acute and critical illness leads to pronounced changes in vitamin D metabolism and status, suggestive of increased requirements. This needs to be considered in the interpretation of potential links between vitamin D status and disease risk and severity and for patient management. There is some evidence that vitamin D supplementation decreases the risk of respiratory tract infections, while supplementation of ICU patients has shown little effect on disease severity or length of treatment. Considering the high prevalence of deficiency and low risks associated with supplementation, pro-actively applying current population and patient management guidelines to prevent, monitor and correct vitamin D deficiency is appropriate.
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Yang G, Lee WYW, Hung ALH, Tang MF, Li X, Kong APS, Leung TF, Yung PSH, To KKW, Cheng JCY, Lam TP. Association of serum 25(OH)Vit-D levels with risk of pediatric fractures: a systematic review and meta-analysis. Osteoporos Int 2021; 32:1287-1300. [PMID: 33704541 DOI: 10.1007/s00198-020-05814-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 12/30/2020] [Indexed: 12/22/2022]
Abstract
UNLABELLED The association between the risk of fractures and suboptimal vitamin D (Vit-D) status remains controversial in children. This meta-analysis suggested that serum 25(OH)Vit-D levels were lower in pediatric cases with fractures. 25-hydroxyvitamin D (25(OH)Vit-D) levels less than 50 nmol/L were associated with increased fracture risk in children. INTRODUCTION This study aimed to assess the association between serum 25(OH)Vit-D and the risk of fractures in children, and to explore the sources of heterogeneity and investigate their impact on results. METHODS Systematic review and meta-analysis were conducted for observational studies comparing serum 25(OH)Vit-D levels between fracture and non-fracture pediatric cases. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS Analysis on 17 case-control and 6 cross-sectional studies (2929 fracture cases and 5000 controls) suggested that 25(OH)Vit-D was lower in fracture cases than in controls (pooled mean difference (MD) = - 3.51 nmol/L; 95% confidence interval (CI): - 5.60 to - 1.42) with a heterogeneity (I2) of 73.9%. The sensitivity analysis which merged the case-control studies that had a NOS score ≥ 4 showed a pooled MD of - 4.35 nmol/L (95% CI: - 6.64 to - 2.06) with a heterogeneity (I2) of 35.9%. Pooled odds ratio of fracture in subjects with 25(OH)Vit-D ≤ 50 nmol/L compared to subjects with 25(OH)Vit-D > 50 nmol/L was 1.29 (95% CI: 1.10 to 1.53; I2 < 1%). CONCLUSION This study indicated that serum 25(OH)Vit-D levels were lower in pediatric patients with fractures. 25(OH)Vit-D ≤ 50 nmol/L was associated with increased fracture risk in children.
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Affiliation(s)
- G Yang
- SH Ho Scoliosis Research Lab, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - W Y W Lee
- SH Ho Scoliosis Research Lab, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - A L H Hung
- SH Ho Scoliosis Research Lab, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - M F Tang
- Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - X Li
- JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - A P S Kong
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - T F Leung
- Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - P S H Yung
- JC Sports Medicine and Health Sciences Centre, Lui Che Woo Institute of Innovative Medicine, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - K K W To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, China
- Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between Shanghai Institute of Materia Medica, Chinese Academy of Sciences and The Chinese University of Hong Kong, Hong Kong SAR, China
| | - J C Y Cheng
- SH Ho Scoliosis Research Lab, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - T P Lam
- SH Ho Scoliosis Research Lab, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Proteomics of regenerated tissue in response to a titanium implant with a bioactive surface in a rat tibial defect model. Sci Rep 2020; 10:18493. [PMID: 33116264 PMCID: PMC7595204 DOI: 10.1038/s41598-020-75527-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 10/07/2020] [Indexed: 12/21/2022] Open
Abstract
Due to their excellent mechanical and biocompatibility properties, titanium-based implants are successfully used as biomedical devices. However, when new bone formation fails for different reasons, impaired fracture healing becomes a clinical problem and affects the patient's quality of life. We aimed to design a new bioactive surface of titanium implants with a synergetic PEG biopolymer-based composition for gradual delivery of growth factors (FGF2, VEGF, and BMP4) during bone healing. The optimal architecture of non-cytotoxic polymeric coatings deposited by dip coating under controlled parameters was assessed both in cultured cells and in a rat tibial defect model (100% viability). Notably, the titanium adsorbed polymer matrix induced an improved healing process when compared with the individual action of each biomolecules. High-performance mass spectrometry analysis demonstrated that recovery after a traumatic event is governed by specific differentially regulated proteins, acting in a coordinated response to the external stimulus. Predicted protein interactions shown by STRING analysis were well organized in hub-based networks related with response to chemical, wound healing and response to stress pathways. The proposed functional polymer coatings of the titanium implants demonstrated the significant improvement of bone healing process after injury.
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Martineau C, Kaufmann M, Arabian A, Jones G, St-Arnaud R. Preclinical safety and efficacy of 24R,25-dihydroxyvitamin D 3 or lactosylceramide treatment to enhance fracture repair. J Orthop Translat 2020; 23:77-88. [PMID: 32518749 PMCID: PMC7270532 DOI: 10.1016/j.jot.2020.03.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 02/05/2020] [Accepted: 03/25/2020] [Indexed: 01/22/2023] Open
Abstract
Background/Objective Cyp24a1-null mice deficient in 24,25(OH)2D3 display impaired callus formation during the endochondral phase of bone fracture repair. The 24,25(OH)2D3 metabolite acted by binding to the TLC domain containing 3B isoform 2 (TLCD3B2, previously named FAM57B2) effector protein, which then synthesizes lactosylceramide (LacCer). Treatment with 24,25(OH)2D3 or LacCer restored callus size and mechanical properties in Cyp24a1-null mice. Methods To assess the safety of these molecules and test their efficacy for bone healing in wild-type, non-genetically modified mice, we treated 12-week-old, osteotomized C57BL/6 female mice with each compound for up to 21 days post-osteotomy. Control cohorts were injected with vehicle. Results Neither compound was found to exhibit any nephro- nor hepato-toxicity. Calcemia remained stable throughout the experiment and was unaffected by either treatment. Supplementation with 24,25(OH)2D3 increased circulating levels of this metabolite about 8-fold, decreased 1,25(OH)2D3 levels, and significantly increased circulating 1,24,25(OH)3D3 levels, suggesting 1?-hydroxylation of 24,25(OH)2D3. TLCD3B2 was found to be expressed in fracture callus at the surface of unmineralized or pre-mineralized cartilage on day 10 and day 12 post-osteotomy and to progressively recede to become undetectable by day 18. Treatment with 24,25(OH)2D3 or LacCer reduced the number of TLCD3B2-positive cells. Both treatments also significantly increased stiffness and elastic modulus of the healing bone callus. Conclusion Exogenous administration of 24,25(OH)2D3 or LacCer improved the biomechanical properties of repaired bones in wild-type animals without affecting circulating calcium levels or other blood parameters, demonstrating preclinical safety and efficacy. Translational potential Our data suggest the use of 24R,25-dihydroxyvitamin D3 or lactosylceramide for ameliorating fracture healing in clinical practice.
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Affiliation(s)
- Corine Martineau
- Research Centre, Shriners Hospitals for Children – Canada, Montreal, Quebec, H4A 0A9, Canada
| | - Martin Kaufmann
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
- Department of Surgery, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Alice Arabian
- Research Centre, Shriners Hospitals for Children – Canada, Montreal, Quebec, H4A 0A9, Canada
| | - Glenville Jones
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - René St-Arnaud
- Research Centre, Shriners Hospitals for Children – Canada, Montreal, Quebec, H4A 0A9, Canada
- Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1A1, Canada
- Department of Surgery, McGill University, Montreal, Quebec, H3A 1A1, Canada
- Department of Medicine, McGill University, Montreal, Quebec, H3A 1A1, Canada
- Research Institute of the McGill University Health Centre, Montreal, Quebec, H3H 2R9, Canada
- Corresponding author. Research Centre, Shriners Hospitals for Children – Canada, 1003 Decarie Boulevard, Montreal, Quebec, H4A 0A9, Canada.
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Martineau C, Naja RP, Husseini A, Hamade B, Kaufmann M, Akhouayri O, Arabian A, Jones G, St-Arnaud R. Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2. J Clin Invest 2018; 128:3546-3557. [PMID: 30010626 DOI: 10.1172/jci98093] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 05/08/2018] [Indexed: 12/18/2022] Open
Abstract
The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1-/- mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing.
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Affiliation(s)
- Corine Martineau
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada
| | - Roy Pascal Naja
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Human Genetics, and
| | - Abdallah Husseini
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Surgery, McGill University, Montreal, Quebec, Canada
| | - Bachar Hamade
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Surgery, McGill University, Montreal, Quebec, Canada
| | - Martin Kaufmann
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Omar Akhouayri
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada
| | - Alice Arabian
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada
| | - Glenville Jones
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - René St-Arnaud
- Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.,Department of Human Genetics, and.,Department of Surgery, McGill University, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada.,Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
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Tsuprykov O, Chen X, Hocher CF, Skoblo R, Hocher B. Why should we measure free 25(OH) vitamin D? J Steroid Biochem Mol Biol 2018; 180:87-104. [PMID: 29217467 DOI: 10.1016/j.jsbmb.2017.11.014] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 11/30/2017] [Accepted: 11/30/2017] [Indexed: 11/21/2022]
Abstract
Vitamin D, either in its D2 or D3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some autoimmune diseases. Given this huge impact of vitamin D on human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D - like other steroid hormones - is bound tightly to a special carrier - vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins - albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D - DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to non-pregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D.
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Affiliation(s)
- Oleg Tsuprykov
- IFLB, Institute for Laboratory Medicine, Berlin, Berlin, Germany; Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany
| | - Xin Chen
- Departments of Embryology and Nephrology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Carl-Friedrich Hocher
- Departments of Embryology and Nephrology, The First Affiliated Hospital, Jinan University, Guangzhou, China; First Medical Faculty, Charles University of Prague, Prague, Czech Republic
| | - Roman Skoblo
- IFLB, Institute for Laboratory Medicine, Berlin, Berlin, Germany
| | - Berthold Hocher
- Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Departments of Embryology and Nephrology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
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Sadat-Ali M, Al Essa ON, Alani FM, Al Omar HK, Ebrahim WY. Correlation of symptoms to serum vitamin D levels? Clin Nutr ESPEN 2018; 24:31-34. [DOI: 10.1016/j.clnesp.2018.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 02/13/2018] [Indexed: 02/08/2023]
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Bikle D, Bouillon R, Thadhani R, Schoenmakers I. Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status? J Steroid Biochem Mol Biol 2017; 173:105-116. [PMID: 28093353 PMCID: PMC9005158 DOI: 10.1016/j.jsbmb.2017.01.007] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 12/31/2016] [Accepted: 01/10/2017] [Indexed: 01/03/2023]
Abstract
There is general consensus that serum 25(OH)D is the best biochemical marker for nutritional vitamin D status. Whether free 25(OH)D would be a better marker than total 25(OH)D is so far unclear. Free 25(OH)D can either be calculated based on the measurement of the serum concentrations of total 25(OH)D, vitamin D-binding protein (DBP), albumin, and the affinity between 25(OH)D and its binding proteins in physiological situations. Free 25(OH)D can also be measured directly by equilibrium dialysis, ultrafitration or immunoassays. During the vitamin D workshop held in Boston in March 2016, a debate was organized about the measurements and clinical value of free 25(OH)D, and this debate is summarized in the present manuscript. Overall there is consensus that most cells apart from the renal tubular cells are exposed to free rather than to total 25(OH)D. Therefore free 25(OH)D may be highly relevant for the local production and action of 1,25(OH)2D. During the debate it became clear that there is a need for standardization of measurements of serum DBP and of direct measurements of free 25(OH)D. There seems to be very limited genetic or racial differences in DBP concentrations or (probably) in the affinity of DBP for its major ligands. Therefore, free 25(OH)D is strongly correlated to total 25(OH)D in most normal populations. Appropriate studies are needed to define the clinical implications of free rather than total 25(OH)D in normal subjects and in disease states. Special attention is needed for such studies in cases of abnormal DBP concentrations or when one could expect changes in its affinity for its ligands.
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Affiliation(s)
- Daniel Bikle
- VA Medical Center and University of California San Francisco, San Francisco, CA 94158, USA.
| | - Roger Bouillon
- Clinical & Experimental Endocrinology, KULeuven, Herestraat 49 ON1 Box 902, 3000 Leuven, Belgium.
| | - Ravi Thadhani
- Division of Nephrology, Massachusetts General Hospital, Boston, USA.
| | - Inez Schoenmakers
- Medical Research Council (MRC), Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, CB1 9NL Cambridge, UK; Department of Medicine, Faculty of Medicine and Health Sciences, University of East Anglia, NR4 7TJ Norwich, UK.
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Fentaw Y, Woldie H, Mekonnen S, Tsegaye AT. Change in serum level of vitamin D and associated factors at early phase of bone healing among fractured adult patients at University of Gondar teaching hospital, Northwest Ethiopia: a prospective follow up study. Nutr J 2017; 16:54. [PMID: 28870252 PMCID: PMC5583753 DOI: 10.1186/s12937-017-0277-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 08/28/2017] [Indexed: 11/30/2022] Open
Abstract
Introduction Currently, Vitamin D deficiency is a major public health problem and it affects more than one billion people worldwide. Vitamin D is crucial for bone mineralization and ossification. Patients with fractures need Vitamin D for the healing of their fractured bone. The current study was carried out to determine if there is change in the serum level of Vitamin–D associated with factors at early phase of fractured bone healing (ossification) process among adult fractured patients at University of Gondar teaching hospital, Northwest Ethiopia. Methods This facility-based prospective follow up study was conducted from March to June 2016. Data was collected by an interviewer, and pretested and structured questionnaires were used. Biological samples were collected to determine the serum level of vitamin–D in all subjects. In addition, X–Ray findings were used to determine the early phase of bone healing process. Data was entered into EPI INFO version 3.5.3 and analyzed using the Statistical Package for Social Sciences (SPSS) version 20. Both bivariate and multivariate logistic regression analysis was done to screen for factors associated with decreased serum levels of Vitamin–D. In the Multivariate regression analysis, those variables which had a P–value of <0.05 were considered as independently associated with change in serum level of Vitamin–D. Results A total of 118 adult patients with fractures participated in this study. The prevalence of patients’ with decreased serum levels of vitamin–D at post-test was 63.6% [95% CI; (0.551–0.720)]. Inadequate intake of milk and milk products in the 1st week of fracture [AOR = 95%CI: 0.20 (0.05–0.90)], Poor Dietary Diversity Score [AOR = 95% CI: 29.1 (2.27–371.65)], and ossified bone [AOR =95% CI: 4.10 (1.12–14.95)] showed statistically significant association with decreased serum level of Vitamin–D. Conclusion and recommendations Decreased serum level of Vitamin–D at early phase of fractured bone healing process was found in the majority of patients (>63%) raising concern for Vitamin D deficiency to be a significant public health problem in the study population. It was statistically associated with: poor dietary diversity score, in adequate intake of milk and milk products in the 1stone week of fracture and ossified (healed) bone. Introducing hospital based Vitamin–D supplementation and integrated with health and nutritional education is a vital intervention needed to improve serum levels of Vitamin–D.
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Affiliation(s)
- Yalelet Fentaw
- Department of Nutrition, University of Gondar Teaching Hospital, Gondar, Ethiopia.
| | - Haile Woldie
- Department of Human Nutrition, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Solomon Mekonnen
- Department of Human Nutrition, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Adino Tesfahun Tsegaye
- Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Abstract
BACKGROUND Adequate vitamin D availability is required for normal bone metabolism. Hypovitaminosis D is highly prevalent in latitudes above 30 degrees. The goal of this prospective study was to determine the prevalence of hypovitaminosis D in an unselected population of patients undergoing major ankle or hindfoot arthrodesis in Burlington, Vermont (latitude 44.5° N). METHODS One hundred eighteen patients undergoing a major ankle, hindfoot, or midfoot arthrodesis between May 2012 and February 2014 were eligible for the study, of which 81 participated. All clinical data, including comorbidities, demographics, and lab values, were obtained from the comprehensive electronic medical record system that encompassed all inpatient and outpatient care. Based on the recommendations published by the Vitamin D Task Force Committee of the Endocrine Society, vitamin D levels above 30 ng/mL were considered normal. Statistical analyses were performed using a significance level of P <.05. RESULTS Of 81 patients tested, 54 (67%) had low serum vitamin D. Older patients had lower risk for hypovitaminosis D (RR = 0.953, CI = 0.908, 0.999, P = .046), whereas a Charlson Index ≥3 had increased risk (RR = 16.8, CI = 1.5, 192.3, P = .023). Of the 16 patients retested after vitamin supplementation, only 9 (56%) corrected to normal. CONCLUSIONS In an unselected population in Vermont undergoing hindfoot and ankle arthrodesis, there was a high prevalence of hypovitaminosis D, even in patients without predisposing risk factors. Consequently, routine testing or presumptive high-dose vitamin D replenishment therapy should be considered for all patients scheduled for such surgery, primarily to promote adequate skeletal calcium metabolism. LEVEL OF EVIDENCE Level II, prospective study.
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Affiliation(s)
- James D Michelson
- Department of Orthopaedics and Rehabilitation, University of Vermont College of Medicine, Burlington, VT, USA
| | - Mark D Charlson
- Department of Orthopaedics and Rehabilitation, University of Vermont College of Medicine, Burlington, VT, USA
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Glendenning P, Inderjeeth CA. Controversy and consensus regarding vitamin D: Recent methodological changes and the risks and benefits of vitamin D supplementation. Crit Rev Clin Lab Sci 2015; 53:13-28. [DOI: 10.3109/10408363.2015.1074157] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Vitamin D deficiency in adult fracture patients: prevalence and risk factors. Eur J Trauma Emerg Surg 2015; 42:369-78. [PMID: 26194498 PMCID: PMC4886150 DOI: 10.1007/s00068-015-0550-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 06/26/2015] [Indexed: 12/20/2022]
Abstract
PURPOSE Although vitamin D levels are not routinely monitored in outpatient fracture patients, identification of fracture patients with a deficient vitamin D status may be clinically relevant because of the potential role of vitamin D in fracture healing. This study aimed to determine the prevalence of and risk factors for vitamin D deficiency in non-operatively treated adult fracture patients. PATIENTS AND METHODS Vitamin D levels were determined in a cross-sectional study of adult patients, who were treated non-operatively for a fracture of the upper or lower extremity in the outpatient clinic of a level 1 trauma center, during one calendar year. Potential risk factors for (severe) vitamin D deficiency were analyzed using multivariable logistic regression analysis. RESULTS A total of 208 men and 319 women with a mean age of 49.7 years (SD 19.9) were included. In this population, 71 % had a serum calcidiol <75 nmol/L, 40 % were vitamin D deficient (serum calcidiol <50 nmol/L) and 11 % were severely vitamin D deficient (serum calcidiol <25 nmol/L). Smoking and season (winter and spring) were independent risk factors for vitamin D deficiency. An increasing age, a non-Caucasian skin type, winter and smoking were identified as independent risk factors for severe vitamin D deficiency. The use of vitamin D, alcohol consumption and higher average daily sun exposure were independent protective factors against (severe) vitamin D deficiency. CONCLUSION Given the potential role of vitamin D in fracture healing, clinicians treating adult fracture patients should be aware of the frequent presence of vitamin D deficiency during the winter, especially in smoking and non-Caucasian patients. Research on the effect of vitamin D deficiency or supplementation on fracture healing is needed, before suggesting routine monitoring or supplementation.
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Cherian VM, Gouse M, Albert S, Jayasankar V. Prevalence of Vitamin D Deficiency in Patients Presenting with an Orthopaedic Trauma at a Tertiary Centre in South India - Implications and Protocols for Replacement Therapy. Malays Orthop J 2015; 9:21-25. [PMID: 28435605 PMCID: PMC5333661 DOI: 10.5704/moj.1507.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- V M Cherian
- Department of Orthopaedics, Christian Medical College, Vellore, India
| | - M Gouse
- Department of Orthopaedics, Christian Medical College, Vellore, India
| | - S Albert
- Department of Orthopaedics, Christian Medical College, Vellore, India
| | - V Jayasankar
- Department of Orthopaedics, Christian Medical College, Vellore, India
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Sebestyén A, Mester S, Vokó Z, Gajdácsi J, Cserháti P, Speer G, Patczai B, Warta V, Bódis J, Horváth C, Boncz I. Wintertime surgery increases the risk of conversion to hip arthroplasty after internal fixation of femoral neck fracture. Osteoporos Int 2015; 26:1109-17. [PMID: 25472855 DOI: 10.1007/s00198-014-2966-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 11/05/2014] [Indexed: 11/24/2022]
Abstract
UNLABELLED The study demonstrates that wintertime surgeries are associated with impaired fracture healing and increases the risk of conversion to hip arthroplasty after osteosynthesis of femoral neck fracture. Furthermore, the results raise the possibility of association between seasonal changes in vitamin D levels and impaired fracture healing of femoral neck fracture. INTRODUCTION Although the changes of vitamin D level and calcitropic hormones influencing bone metabolism are seasonal, the effect of seasons on hip fracture healing is unknown. We assessed the effects of seasonal periodicity on conversion to hip arthroplasty after primary osteosynthesis of femoral neck fracture. METHODS This nationwide retrospective observational cohort study involved 2779 patients aged ≥ 60 years who underwent internal screw fixation for primary femoral neck fracture and were discharged in 2000. Cases requiring conversion to arthroplasty during the 8-year follow-up derived from the Hungarian health insurance database were registered. Risk factors assessed included sex, age, fracture type, season of primary surgery and surgical delay. Competing-risks regression analysis was used for data analyses. RESULTS During the observation period, 190 conversions to hip arthroplasty (6.8%) were identified, yielding an overall incidence of 19.5 per 1000 person-years. The crude incidence rates of conversions after osteosynthesis in winter, spring, summer and fall were 28.6, 17.8, 16.9 and 14.7 per 1000 person-years, respectively. Besides younger age, female sex and intracapsular fracture displacement, wintertime primary osteosynthesis significantly increased the risk of conversion (fall vs. winter, hazard ratio (HR): 0.50, 95% confidence interval [95% CI 0.33-0.76]; spring vs. winter, HR: 0.63, [95% CI 0.44-0.92]; summer vs. winter, HR: 0.62, [95% CI 0.42-0.91]). CONCLUSIONS Our study demonstrate that wintertime primary osteosynthesis increases the risk of conversion surgeries. The results may help improving the outcome of primary fixation of femoral neck fractures.
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Affiliation(s)
- A Sebestyén
- South-Transdanubian Regional Office, National Health Insurance Fund Administration, Pécs, Nagy Lajos király út 3, H-7623, Hungary,
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Ray M. Vitamin D and bone fracture healing. World J Pharmacol 2014; 3:199-208. [DOI: 10.5497/wjp.v3.i4.199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/08/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine whether vitamin D is of potential relevance in the healing process of fractures.
METHODS: The present narrative review examined the bulk of the evidence based literature on the topic of vitamin D and bone healing in key electronic data bases from 1980 onwards using the terms vitamin D and bone healing, callus, fracture healing. All data were examined carefully and categorized according to type of study. A summary of the diverse terms and approaches employed in the research, as well as the rationale for hypothesizing vitamin D has a role in fracture healing was detailed.
RESULTS: The results show very few human studies have been conducted to examine if vitamin D is effective at promoting post fracture healing, and the different animal models that have been studied provide no consensus on this topic. The terms used in the related literature, as well as the methods used to arrive at conclusions on this clinical issue are highly diverse, there is no standardization of either of these important terms and methodologies, hence no conclusive statements or clinical guidelines can be forthcoming. There is a strong rational for continuing to examine if vitamin D supplements should be administered post-fracture, and ample evidence vitamin D is an essential hormone for functioning in general, as well as bone health and muscle as this relates to bone density.
CONCLUSION: Whether those with low vitamin D levels can benefit from supplements if their nutritional practices do not cover recommended daily amounts, remains in question.
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Gorter EA, Hamdy NAT, Appelman-Dijkstra NM, Schipper IB. The role of vitamin D in human fracture healing: a systematic review of the literature. Bone 2014; 64:288-97. [PMID: 24792958 DOI: 10.1016/j.bone.2014.04.026] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/10/2014] [Accepted: 04/23/2014] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality. Mineralization is part of hard callus formation and bone remodelling, processes, which are part of fracture healing. We provide a comprehensive review of the literature to summarize and clarify if possible, the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human. MATERIAL AND METHODS We conducted a literature search in PubMed, Embase (OVID version), and Web of Science. RESULTS A total of 75 in vitro and 30 in vivo studies were found with inconsistent results about the cellular effect of vitamin D on fracture involved inflammatory cells, cytokines, growth factors, osteoblasts, osteoclasts and on the process of mineralization. With only five in vitro studies performed on material derived from a fracture site and one in vivo study in fracture patients, the exact cellular role remains unclear. Seven studies investigated the circulating vitamin D metabolites in fracture healing. Although it appears that 25(OH)D and 24,25(OH)2D3 are not affected by the occurrence of a fracture, this might not be the case with serum concentrations of 1,25(OH)2D3. The potential clinical effect of vitamin D deficiency is only described in one case series and three case controlled studies, where the results tend to show no effect of a vitamin D deficiency. No clinical studies were found investigating solely vitamin D supplementation. Two clinical studies found a positive effect of vitamin D supplementation and calcium, of increased bone mineral density or respectively increased fracture callus area at the fracture site. One study found indirect evidence that vitamin D and calcium promoted fracture healing. CONCLUSION Despite these results, and the presumed beneficial effect of vitamin D supplementation in deficient patients, clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive. We conclude that vitamin D has a role in fracture healing, but the available data are too inconsistent to elucidate how and in what manner.
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Affiliation(s)
- Erwin A Gorter
- Department of Surgery and Traumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Neveen A T Hamdy
- Department of Endocrinology and Metabolic Diseases, and Centre for Bone Quality, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Natasha M Appelman-Dijkstra
- Department of Endocrinology and Metabolic Diseases, and Centre for Bone Quality, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Inger B Schipper
- Department of Surgery and Traumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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Curtis KM, Aenlle KK, Roos BA, Howard GA. 24R,25-dihydroxyvitamin D3 promotes the osteoblastic differentiation of human mesenchymal stem cells. Mol Endocrinol 2014; 28:644-58. [PMID: 24597546 DOI: 10.1210/me.2013-1241] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Although 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is considered the most biologically active vitamin D3 metabolite, the vitamin D3 prohormone, 25-hydroxyvitamin D3 [25(OH)D3], is metabolized into other forms, including 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3]. Herein we show that 24R,25(OH)2D3 is fundamental for osteoblastic differentiation of human mesenchymal stem cells (hMSCs). Our approach involved analyses of cell proliferation, alkaline phosphatase activity, and pro-osteogenic genes (collagen 1A1, osteocalcin, vitamin D receptor [VDR], vitamin D3-hydroxylating enzymes [cytochrome P450 hydroxylases: CYP2R1, CYP27A1, CYP27B1 and CYP24A1]) and assessment of Ca(2+) mineralization of extracellular matrix. 24R,25(OH)2D3 inhibited hMSC proliferation, decreased 1α-hydroxylase (CYP27B) expression, thereby reducing the ability of hMSCs to convert 25(OH)D3 to 1α,25(OH)2D3, and promoted osteoblastic differentiation through increased alkaline phosphatase activity and Ca(2+) mineralization. 24R,25(OH)2D3 decreased expression of the 1α,25(OH)2D3 receptor, VDR. 24R,25(OH)2D3 but not 1α,25(OH)2D3 induced Ca(2+) mineralization dependent on the absence of the glucocorticoid analog, dexamethasone. To elucidate the mechanism(s) for dexamethasone-independent 1α,25(OH)2D3 inhibition/24R,25(OH)2D3 induction of Ca(2+) mineralization, we demonstrated that 1α,25(OH)2D3 increased whereas 24R,25(OH)2D3 decreased reactive oxygen species (ROS) production. 25(OH)D3 also decreased ROS production, potentially by conversion to 24R,25(OH)2D3. Upon inhibition of the vitamin D3-metabolizing enzymes (cytochrome P450s), 25(OH)D3 increased ROS production, potentially due to its known (low) affinity for VDR. We hypothesize that vitamin D3 actions on osteoblastic differentiation involve a regulatory relationship between 24R,25(OH)2D3 and 1α,25(OH)2D3. These results implicate 24R,25(OH)2D3 as a key player during hMSC maturation and bone development and support the concept that 24R,25(OH)2D3 has a bioactive role in the vitamin D3 endocrine system.
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Affiliation(s)
- Kevin M Curtis
- Geriatric Research, Education, and Clinical Center and Research Service (K.M.C., K.K.A., B.A.R., G.A.H.), Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida 33125; and Departments of Biochemistry and Molecular Biology (K.M.C., G.A.H.), Medicine (B.A.R., G.A.H.), and Neurology (B.A.R.), University of Miami Miller School of Medicine, Miami, Florida 33101
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