title: The role of vitamin D in human fracture healing: a systematic review of the literature.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery and Traumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: e.a.gorter@lumc.nl.
authors.forename: Erwin A
authors.initials: EA
authors.lastname: Gorter
authors.affiliation: Department of Endocrinology and Metabolic Diseases, and Centre for Bone Quality, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: n.a.t.hamdy@lumc.nl.
authors.forename: Neveen A T
authors.initials: NA
authors.lastname: Hamdy
authors.affiliation: Department of Endocrinology and Metabolic Diseases, and Centre for Bone Quality, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: n.m.appelman-dijkstra@lumc.nl.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Appelman-Dijkstra
authors.affiliation: Department of Surgery and Traumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: i.b.schipper@lumc.nl.
authors.forename: Inger B
authors.initials: IB
authors.lastname: Schipper
mesh_terms: D017102:Fracture Healing / Q000502:physiology*; D006801:Humans; D014807:Vitamin D / Q000502:physiology*
chemical_list: D014807:Vitamin D
keywords: Bone; Calcidiol; Fracture; Fracture healing; Vitamin D; Vitamin D deficiency