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Effect of Vitamin D3 Supplementation on Acute Fracture Healing: A Phase II Screening Randomized Double-Blind Controlled Trial.
Slobogean, GP, Bzovsky, S, O'Hara, NN, Marchand, LS, Hannan, ZD, Demyanovich, HK, Connelly, DW, Adachi, JD, Thabane, L, Sprague, S
JBMR plus. 2023;7(1):e10705
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Plain language summary
Almost half of all adult patients with fractures are vitamin D deficient. The aim of this double-blind, randomised, placebo-controlled trial was to evaluate the efficacy of different vitamin D regimens on the healing of acute tibia and femur fractures. 102 18-50-year-old patients were enrolled in the study and randomised to receive a) two high doses (150,000 IU) at time of injury and after 6 weeks, b) 4000 IU daily, c) 600 IU daily or d) placebo for 3 months. After 3 months, there were no statistically significant differences between the 3 intervention groups with respect to clinical or radiographic outcomes of fracture healing. The authors report a significantly better clinical, but not radiographic, outcome for 4000 IU per day versus placebo with a p-value of 0.15 (note: generally, to be considered statistically significant, p should be < 0.05). Similar results were observed after 12 months. There was no significant correlation between vitamin D levels and fracture healing. The authors concluded that high dose vitamin D may confer a modest benefit for fracture healing but that this requires confirmation from a larger clinical trial.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The evidence base for the use of vitamin D supplements in isolation to support fracture healing is weak.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- Low levels of vitamin D can have negative effects on bone metabolism and healing of fractures
- Almost half of all adult fracture patients are vitamin D deficient
- The aim of this study was to evaluate the effectiveness of supplementing vitamin D3 (VD3) to improve tibia and femur fracture healing.
Methods
- Four-arm, double-blind, randomised, phase II screening, placebo-controlled trial
- 102 adult patients (aged 18-50 years) with a non-osteoporotic tibial or femoral shaft fracture were randomised into 1 of 4 treatment groups
- Just over half (56%) of participants were vitamin D3 deficient at baseline
- Intervention groups: 1) 150,000 IU VD3 loading dose at injury and at 6 weeks (high loading) plus daily placebo; 2) placebo loading doses plus 4000 IU VD3 daily (high dose); 3) placebo loading doses plus 600 IU VD3 daily (low dose); 4) placebo loading dose plus placebo daily
- Duration: 3 months intervention, further 9 months follow-up. Vitamin D levels were assessed at 6 weeks and 3 months.
Primary outcome measures at 3 months:
- Clinical assessment using the Function IndeX for Trauma (FIX-IT)
- Radiographic assessment using the Radiographic Union Score for Tibial fractures (RUST).
Secondary outcomes: as above at 6, 9 and 12 months.
Results at 3 months:
- No statistically significant difference between high loading and high dose, high and low dose or low dose and placebo for either clinical or radiological assessment (all p-values ≥0.4)
- Post-hoc analysis of any dose vs placebo showed no significant difference with either clinical or radiological assessment (all p-values ≥0.25)
- Post-hoc analysis of high dose vs placebo showed no significant difference for radiological assessment (p=0.76) whilst it was reported as statistically significant for clinical assessment with p=0.16, with a benefit of VD3 supplementation.
- Similar results were seen at 12 months with reported benefit of high dose VD3 for fracture healing with p=0.18
- Vitamin D levels improved in all 3 VD3 groups from baseline to 6 weeks
- There was no statistically significant correlation between fracture healing and vitamin D level.
Conclusion
The authors conclude that VD3 supplementation may be of modest benefit for fracture healing, but further, larger trials are needed to confirm this.
Clinical practice applications:
- When working with clients who present with a fracture, it should be noted that the evidence for benefit of vitamin D supplementation alone for fracture healing is weak.
Considerations for future research:
- Larger studies to increase the statistical power to detect smaller benefits are required
- Larger studies may also identify differences in potential benefits between patient populations with different baseline levels of vitamin D.
Abstract
Nearly half of adult fracture patients are vitamin D deficient (serum 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Many surgeons advocate prescribing vitamin D supplements to improve fracture healing outcomes; however, data supporting the effectiveness of vitamin D3 supplements to improve acute fracture healing are lacking. We tested the effectiveness of vitamin D3 supplementation for improving tibia and femur fracture healing. We conducted a single-center, double-blinded phase II screening randomized controlled trial with a 12-month follow-up. Patients aged 18-50 years receiving an intramedullary nail for a tibia or femoral shaft fracture were randomized 1:1:1:1 to receive (i) 150,000 IU loading dose vitamin D3 at injury and 6 weeks (n = 27); (ii) 4000 IU vitamin D3 daily (n = 24); (iii) 600 IU vitamin D3 daily (n = 24); or (iv) placebo (n = 27). Primary outcomes were clinical fracture healing (Function IndeX for Trauma [FIX-IT]) and radiographic fracture healing (Radiographic Union Score for Tibial fractures [RUST]) at 3 months. One hundred two patients with a mean age of 29 years (standard deviation 8) were randomized. The majority were male (69%), and 56% were vitamin D3 deficient at baseline. Ninety-nine patients completed the 3-month follow-up. In our prespecified comparisons, no clinically important or statistically significant differences were detected in RUST or FIX-IT scores between groups when measured at 3 months and over 12 months. However, in a post hoc comparison, high doses of vitamin D3 were associated with improved clinical fracture healing relative to placebo at 3 months (mean difference [MD] 0.90, 80% confidence interval [CI], 0.08 to 1.79; p = 0.16) and within 12 months (MD 0.89, 80% CI, 0.05 to 1.74; p = 0.18). The study was designed to identify potential evidence to support the effectiveness of vitamin D3 supplementation in improving acute fracture healing. Vitamin D3 supplementation, particularly high doses, might modestly improve acute tibia or femoral shaft fracture healing in healthy adults, but confirmatory studies are required. The Vita-Shock trial was awarded the Orthopaedic Trauma Association's (OTA) Bovill Award in 2020. This award is presented annually to the authors of the most outstanding OTA Annual Meeting scientific paper. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Paroxysmal slow wave events are associated with cognitive impairment in patients with obstructive sleep apnea.
Li, M, Sun, Z, Sun, H, Zhao, G, Leng, B, Shen, T, Xue, S, Hou, H, Li, Z, Zhang, J
Alzheimer's research & therapy. 2022;14(1):200
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Obstructive sleep apnoea (OSA) is a disorder which results in an individual’s breathing being cut off momentarily whilst asleep. OSA has been associated with the development of cognitive impairment, which is characterised by declining memory. The reason for the link is thought to involve a dysfunction in the blood brain barrier, which can be measured by paroxysmal slow wave events (PSWEs). This study of 339 individuals with complaints of snoring aimed to determine the correlation between PSWEs and cognitive impairment. The results showed that cognitive impairment in individuals with OSA due to a lack of oxygen could be due to a dysfunction in the blood brain barrier and that PSWEs are a reliable measure of this. It was concluded that PSWEs can be used as a measure of cognitive impairment in patients with OSA and that brain barrier dysfunction may be involved in its development in this subset of individuals. This study could be used by healthcare professionals to understand that sleep apnoea is more than just snoring, it can be involved in the development of certain chronic diseases.
Abstract
BACKGROUND Increasing evidence has supported a link between obstructive sleep apnea (OSA) and cognition, and blood-brain barrier (BBB) dysfunction which can be reflected by paroxysmal slow wave events (PSWEs) may be a potential mechanism. The purpose of our study was to investigate the correlation between the PSWEs and cognitive impairment in patients with OSA, with a focus on the possible mechanism. METHODS In total, 339 subjects with subjective snoring complaints from the Sleep Medicine Center underwent magnetic resonance imaging and whole-night polysomnography. OSA was defined as apnea-hypopnea index (AHI) ≥ 5 events/h. MCI was defined as the MoCA < 26 and met the criteria: (1) subjective cognitive impairment; (2) objective impairment in one or more cognitive domains; (3) slightly impaired complex instrumental daily abilities, but independent daily living abilities; and (4) no dementia. The PSWEs calculated by self-developed Python scripts were defined for EEG recordings as a median power frequency of < 6 Hz for more than five consecutive seconds. Serum cyclophilin A (CyPA) and matrix metalloproteinase-9 (MMP-9) levels and amyloid-β 42 levels in neuron-derived exosomes were determined. The participants who received continuous positive airway pressure (CPAP) were followed up and their PSWEs were recalculated after 1 year of treatment. RESULTS A total of 339 participants were divided into the OSA+MCI group (n = 157), OSA-MCI group (n = 118), and controls (normal cognitive state without OSA) (n = 64). The total PSWEs and the occurrence per minute of PSWEs at stage REM in the OSA+MCI group were higher than those in the OSA-MCI and control groups. The duration ratio of PSWEs at stage REM in the OSA+MCI group significantly increased. The total PSWEs and PSWEs at the F4-M1, O1-M2, and O2-M1 channels in stage REM were independently associated with cognitive impairment in OSA patients. There were positive correlations between the PSWEs and serum CyPA and MMP-9 levels in patients with OSA. The mediation analysis showed that the relationship between mean SaO2 and percentage of sleep time spent with oxygen saturation <90% with MoCA scores was mediated by the total PSWEs (proportion of mediation 77.89% and 82.89%). The PSWEs were negatively correlated with global cognitive performance and cognitive subdomains. After 1 year of CPAP treatment, the total PSWEs, PSWEs in stage REM, and serum CyPA and MMP-9 levels decreased significantly, and MoCA scores were improved compared with baseline. CONCLUSIONS The PSWEs were implicated in cognitive impairment in patients with OSA, and the mechanisms of cognitive impairment due to hypoxia in OSA patients could be BBB dysfunction. The PSWEs can be used as a marker of cognitive impairment in patients with OSA. TRIAL REGISTRATION This trial is registered on the Chinese Clinical Trial Registry, number ChiCTR1900021544. The trial was registered on February 27, 2019.