title: No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene.
abstract: Uncertainty remains over whether or not high intakes of retinol or vitamin A consumed through food or supplements may increase fracture risk. This intervention study found no increase in fracture risk among 2,322 adults who took a controlled, high-dose retinol supplement (25,000 IU retinyl palmitate/day) for as long as 16 years. There was some evidence that beta-carotene supplementation decreased fracture risk in men.
  
  
  BACKGROUND
  There is conflicting epidemiological evidence regarding high intakes of dietary or supplemental retinol and an increased risk for bone fracture. We examined fracture risk in a study administering high doses of retinol and beta-carotene (BC) between 1990 and 2007.
  
  
  METHODS
  The Vitamin A Program was designed to test the efficacy of retinol and BC supplements in preventing malignancies in persons previously exposed to blue asbestos. Participants were initially randomised to 7.5 mg retinol equivalents (RE)/day as retinyl palmitate, 30 mg/day BC or 0.75 mg/day BC from 1990 to 1996; after which, all participants received 7.5 mg RE/day. Fractures were identified by questionnaire and hospital admission data up until 2006. Risk of any fracture or osteoporotic fracture according to cumulative dose of retinol and BC supplementation was examined using conditional logistic regression models adjusting for age, sex, smoking, body mass index, medication use and previous fracture.
  
  
  RESULTS
  Supplementation periods ranged from 1 to 16 years. Of the 2,322 (664 females and 1,658 males) participants, 187 experienced 237 fractures. No associations were observed between cumulative dose of retinol and risk for any fracture (OR per 10 g RE=0.83; 95% CI, 0.63-1.08) or osteoporotic fracture (OR per 10 g RE=0.95; 95% CI 0.64-1.40). Among men, cumulative dose of BC was associated with a slightly reduced risk of any fracture (OR per 10 g=0.89; 95% CI 0.81-0.98) and osteoporotic fracture (OR per 10 g=0.84; 95% CI 0.72-0.97).
  
  
  CONCLUSIONS
  This study observed no increases in fracture risk after long-term supplementation with high doses of retinol and/or beta-carotene.
authors.affiliation: School of Population Health, The University of Western Australia, Perth, WA, Australia.
authors.forename: G L
authors.initials: GL
authors.lastname: Ambrosini
authors.forename: A P
authors.initials: AP
authors.lastname: Bremner
authors.forename: A
authors.initials: A
authors.lastname: Reid
authors.forename: D
authors.initials: D
authors.lastname: Mackerras
authors.forename: H
authors.initials: H
authors.lastname: Alfonso
authors.forename: N J
authors.initials: NJ
authors.lastname: Olsen
authors.forename: A W
authors.initials: AW
authors.lastname: Musk
authors.forename: N H
authors.initials: NH
authors.lastname: de Klerk
mesh_terms: D000328:Adult; D000368:Aged; D019587:Dietary Supplements / Q000009:adverse effects*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000517:prevention & control; D008297:Male; D008654:Mesothelioma / Q000517:prevention & control; D008875:Middle Aged; D009784:Occupational Diseases / Q000517:prevention & control; D058866:Osteoporotic Fractures / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control; D000084562:Retinyl Esters; D018570:Risk Assessment / Q000379:methods; D014801:Vitamin A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014904:Western Australia / Q000453:epidemiology; D019207:beta Carotene / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D004224:Diterpenes; D000084562:Retinyl Esters; D019207:beta Carotene; D014801:Vitamin A; C014794:retinol palmitate