No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene

Our plain-English summary of No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene, by G.L. Ambrosini, A.P. Bremner, A. Reid, et al (Osteoporosis International, 2013).

The study

• Authors: G.L. Ambrosini, A.P. Bremner, A. Reid, D. Mackerras, H. Alfonso, N.J. Olsen, A.W. Musk, N.H. de Klerk
• Journal: Osteoporosis International
• Published: 2013;24(4):1285-93
• Type of article: Randomized trial
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Unlabelled: 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.

Introduction: 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.

In plain English

This study analysed the Vitamin A Program in Western Australia. Between 1990 and 2007 it gave high-dose retinol and beta-carotene supplements to former workers and residents of Wittenoom, where crocidolite (blue asbestos) was mined. It aimed to test whether the supplements reduced mesothelioma and lung cancer; fracture risk was an exploratory secondary question. From 1990 to 1996 former workers were randomised to retinol (7.5 mg retinol equivalents daily) or beta-carotene (30 mg daily), and former residents to 30 or 0.75 mg beta-carotene daily. From 1997 all received retinol. Of 2,322 participants (664 females, 1,658 males), 187 had at least one fracture. After adjustment, cumulative retinol dose was not associated with any fracture (odds ratio 0.83 per 10 g retinol equivalents, 95% CI 0.63 to 1.08) or osteoporotic-site fracture (0.95, 0.64 to 1.40). In men, higher cumulative beta-carotene dose was associated with slightly lower fracture risk, but not in women. The authors concluded the study does not support earlier reports of raised fracture risk with higher dietary retinol intake. They noted confounding cannot be ruled out after randomisation ended.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Exploratory secondary analysis of fracture risk within an intervention (supplement) study whose primary outcomes were mesothelioma and lung cancer. Participants were randomised in phase 1 (1990 to 1996) and single-blinded. There was no placebo. Analysis used conditional logistic regression by cumulative supplement dose.
• Who was studied: 2,322 of 2,346 former workers and residents of Wittenoom, Western Australia, who took part in the Vitamin A Program in Perth between 1990 and 2007 and had a known fracture outcome. Of these, 664 were female and 1,658 male. Mean age at entry was 55 years. Follow-up ranged from 1 to 16 years (median 7).
• Exposure: Daily supplements, given to people previously exposed to crocidolite (blue asbestos) at work or as residents. In phase 1 (1990 to 1996), former workers were randomised to 30 mg/day beta-carotene or 7.5 mg retinol equivalents/day as retinyl palmitate (25,000 IU). Former residents were randomised to 30 or 0.75 mg/day beta-carotene. From July 1997 all participants received 7.5 mg RE/day retinol. Some participants (women of childbearing age, abnormal liver function) received 1.5 mg RE/day instead. Doses were analysed as cumulative totals.
• Main results:
  • 187 of the 2,322 participants had at least one fracture during follow-up.
  • There were 237 fractures in total. Of these, 95 (40%) were at osteoporotic sites.
  • In the adjusted model (1,743 subjects), cumulative retinol dose was not associated with fracture risk in males and females. Per 10 g RE: any fracture OR 0.83 (95% CI 0.63 to 1.08, p = 0.17); osteoporotic fracture OR 0.95 (95% CI 0.64 to 1.40, p = 0.79).
  • In males, a higher cumulative beta-carotene dose was associated with reduced fracture risk. Per 10 g: any fracture OR 0.89 (95% CI 0.81 to 0.98, p = 0.014); osteoporotic fracture OR 0.84 (95% CI 0.72 to 0.97, p = 0.022).
  • In females, no relationship was observed between cumulative beta-carotene dose and fracture risk. Table 3, per 10 g: any fracture OR 1.09, 95% CI 0.99 to 1.19; osteoporotic fracture OR 1.08, 95% CI 0.94 to 1.23.
  • In the adjusted model, each previous fracture was associated with greater risk of any fracture (OR 1.27, 95% CI 1.14 to 1.42). So was use of medications for bone health (OR 1.81, 95% CI 1.16 to 2.82).
• The authors' conclusion: The authors concluded that the study observed no increases in fracture risk after supplementation with beta-carotene or retinol for as long as 16 years. In their view, it does not support previous reports of increased fracture risk with higher dietary retinol intake.
• Limitations the authors state:
  • Randomisation was not possible beyond phase 1, and there was no placebo, so confounding cannot be ruled out.
  • Compliance, and therefore cumulative dose, relied on self-report and may be subject to error or reporter bias.
  • Whether fractures were traumatic or non-traumatic was not determined.
  • Self-reported fractures could not be collected from participants who withdrew or died before the 2007 questionnaire. This may have caused survivor bias and underestimation of self-reported fracture rates.
  • The number of fractures was relatively low. The authors suggest this may be due to participants' younger age and the high proportion of men.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Wittenoom, Western Australia

All asbestos mines

Topics

Medical terms in this study, explained in our Lexicon: Crocidolite, Cumulative Dose.

Related studies

• Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial — G.S. Omenn, G.E. Goodman, et al. (1996)
• Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene — N.H. de Klerk, A.W. Musk, et al. (1998)
• The protective effect of beta-carotene and retinol on ventilatory function in an asbestos-exposed cohort — P. Chuwers, S. Barnhart, et al. (1997)
• Research cost analyses to aid in decision making in the conduct of a large prevention trial, CARET. Carotene and Retinol Efficacy Trial — M.D. Thornquist, N. Urban, et al. (1993)
• Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke — X.D. Wang, C. Liu, et al. (1999)
• The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements — G.E. Goodman, M.D. Thornquist, et al. (2004)

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