The effect of homocysteine-lowering with B-vitamins on osteoporotic fractures in patients with cerebrovascular disease: substudy of VITATOPS, a randomised placebo-controlled trial.

Vitatops Trial Study Group ,John Gommans,Helen Rodgers,Graeme J Hankey,John W Eikelboom,Qilong Yi,Christopher Chen

doi:10.1186/1471-2318-13-88

Abstract

BackgroundHomocysteine has been postulated as a novel, potentially reversible risk factor for osteoporosis and related fractures. We evaluated whether homocysteine-lowering therapy with B-vitamins in patients with symptomatic cerebrovascular disease reduced the incidence of osteoporotic fractures.MethodsVITAmins To Prevent Stroke (VITATOPS) was a prospective randomised double-blind placebo-controlled trial in which 8,164 patients with recent (within 7 months) stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of either placebo (n = 4,075) or B-vitamins (folic acid 2 mg, vitamin B6 25 mg, vitamin B12 500 μg; n = 4,089). Patients were reviewed every six months. Any osteoporotic fracture and osteoporotic hip fractures were secondary outcome events, and were reviewed by a masked adjudication committee. Analysis was by intention to treat. Logistic regression was used to identify independent predictors of fracture.ResultsParticipants had a mean age of 62.6 years (SD 12.5 years) and 64% were male, 42% of Western European descent and 75% were functionally independent (Oxford Handicap Scale of two or less). After a median duration of 2.8 years therapy and 3.4 years follow-up, there was no significant difference in the incidence of any osteoporotic fracture between participants assigned B-vitamins (67 [1.64%]) and placebo (78 [1.91%]; risk ratio [RR] 0.86, 95% confidence interval [CI] 0.62-1.18) or the incidence of hip fractures (34 [0.83%] B-vitamins vs. 36 [0.88%] placebo; RR 0.94, 95% CI 0.59-1.5). There was no significant impact of B-vitamin therapy on time to first fracture. Baseline homocysteine levels did not predict any osteoporotic fracture (p =0.43). Independent predictors of any osteoporotic fracture were female sex, age > 64 years, Western European ethnicity and use of anti-osteoporosis medication at randomization (all p < 0.01).ConclusionsOnce daily treatment with B-vitamins had no effect on incidence of osteoporotic fractures during a median of 3.4 years follow-up in patients with cerebrovascular disease. A modest effect of B-vitamin therapy is not excluded due to the low numbers of fracture outcome events.Trial registrationClinicaltrials.gov number: NCT00097669 and isrctn.org number: ISRCTN74743444.

Highlights

Homocysteine has been postulated as a novel, potentially reversible risk factor for osteoporosis and related fractures
As raised total homocysteine (tHcy) can be lowered with B-vitamin therapy, [15,16] it is possible to determine whether tHcy is a causal risk factor for bone fracture by means of randomised controlled trials (RCTs) of B-vitamins vs. placebo
In light of the uncertainty surrounding the role of tHcy in the pathogenesis of osteoporosis and bone fracture, we prospectively examined the occurrence of any osteoporotic fracture and osteoporotic hip fractures in the VITAmins TO Prevent Stroke (VITATOPS) trial of patients with recently symptomatic cerebrovascular disease treated with either B-vitamins or placebo

Summary

Introduction

Homocysteine has been postulated as a novel, potentially reversible risk factor for osteoporosis and related fractures. An increased plasma concentration of total homocysteine (tHcy) has been postulated as a novel, potentially treatable risk factor for osteoporotic fractures, including hip fractures [2,6,7,8]. In one prospective population-based study, the highest quartile of tHcy was associated with a two-fold increase in risk of fracture (risk ratio [RR] 1.9, 95% confidence interval [CI] 1.4-2.6), and the association was continuous; with each standard deviation (SD) increase in tHcy, the risk of fracture increased by 30% (RR 1.3, 95% CI 1.1-1.5) [9]. The only positive intervention study to date was undertaken in 628 elderly Japanese patients with significant residual hemiplegia at least one year following stroke [23] Those treated with combination folate and vitamin B12 had a 75% reduction (adjusted RR 0.24, 95% CI 0.11-0.53) in the incidence of fracture at two years. The study population was highly selected and characterized by severe disability, very high homocysteine concentrations (mean 19.9 μmol/L), and an unusually high fracture rate in the control group, approximately 10 times the rate found in the average Japanese population of the same age [24]

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