The effects of calcitriol on falls and fractures and physical performance tests

https://doi.org/10.1016/j.jsbmb.2004.03.059Get rights and content

Abstract

There is an increase in the incidence of falls with aging and about 10% of falls lead to fractures. Nearly all hip fractures are due to falls and hip fractures are the most severe of the osteoporotic fractures because they lead to a 20% mortality rate and a loss of independent living in 50% of cases. Although there are multiple factors associated with falls, our interest is the role that vitamin D metabolism plays in the pathogenesis of falls. Recent clinical trials show that both vitamin D and the metabolite calcitriol reduce the number of falls by 30–40% in elderly subjects. This should also reduce the number of fractures. In European studies, the decrease in falls could be attributed to an improvement in the muscle weakness that often accompanies vitamin D deficiency. However, in the studies using calcitriol there was no vitamin D deficiency, so the mechanism of its efficacy is less clear. It could be due to increased muscle strength, an improvement in the neurological control of balance or both. Understanding these mechanisms would allow us to search for analogs of vitamin D that act more selectively on muscle and on the central nervous system.

Introduction

Elderly people fall more often as they age. Falls occur in 30% of people over the age of 65 years and in 50% of people over age 80 years [1], [2], [3]. Increased falling is associated with subsequent admission to a nursing home [4]. About 20% of fall incidents require medical attention, and approximately 10% result in fractures [1], [4], [5], [6], [7], [8], [9]. About 50% of osteoporotic fractures are non-vertebral, and falls appear to be the biggest contributor to a non-vertebral fracture [10]. The most serious fracture due to a fall is hip fracture because it results in a mortality of 15–20% of patients and as many as 50% of hip fracture patients are so physically impaired that they never leave the nursing homes. There are several risk factors for falls in elderly people such as poor general health, diabetes, poor vision, urinary incontinence, a previous history of stroke, Parkinson’s disease, dementia, poor cognitive function, depression, poor balance, decreased muscle strength, difficulty with the activities of daily living, medication use (particularly sedatives and anticonvulsants) and environmental obstacles and barriers [1]. Some of these risk factors are modifiable. A meta-analysis of several studies showed that different types of interventions could reduce the number of falls and multiple targeted interventions were shown to reduce the incidence of falls by about 10% [11]. In the present double blind randomized trial we examined prospectively the effect of calcitriol or estrogen therapy on bone mineral density and the incidence of falls and fractures.

Section snippets

Materials and methods

489 subjects were randomly assigned to one of the following four groups: conjugated equine estrogens (Premarin) 0.625 mg daily plus medroxyprogesterone acetate (Provera) 2.5 mg daily (HT); calcitriol (Rocaltrol) 0.25 μg twice daily; the combination of HT plus calcitriol; or placebo. Hysterectomized women (n=290) assigned to estrogen were not given the progestin, but received estrogen alone (ET) [12]. Calcium intake was maintained at or below 1000 mg per day. On entry into the study, women underwent

Results

The mean age of the women was 72 years at baseline and 75 years at the end of study. Mean serum 25OHD was 80 nmol/L (31 ng/ml), mean serum PTH was 37 pg/ml (normal <60). The effects of the therapy on BMD have previously been described [12].

The cumulative number of fallers was 64% in the placebo group versus 50% on calcitriol (P<0.0382), 58% on ET/HT and 57% on ET/HT + calcitriol. Because of the multiple comparisons test the difference between placebo and calcitriol was not significant.

However, the

Discussion

The results of this study raise questions about the present approach to fracture prevention in the elderly which focuses on the effects of pharmacological agents that increase bone mineral density (BMD). An analysis of the MORE trial showed that an increase in BMD could account for only 4% of the reduction in vertebral fractures [16]. Another analysis of all the large osteoporosis trials showed that only 16% of the decrease in vertebral fracture reduction could be accounted for by an increase

Acknowledgements

This study was primarily supported by the National Institutes of Health (UO1-AG10373 and RO1 AG10373). Other support was provided by Wyeth Pharmaceuticals, Hoffman La Roche and Pharmacia Upjohn.

References (33)

  • S.R. Cummings et al.

    Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs

    Am. J. Med.

    (2002)
  • B. Dawson-Hughes et al.

    Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older

    N. Engl. J. Med.

    (1997)
  • M.E. Tinetti et al.

    Risk factors for falls among elderly persons living in the community

    N. Engl. J. Med.

    (1988)
  • J.L. O’Loughlin et al.

    Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly

    Am. J. Epidemiol.

    (1993)
  • A.J. Blake et al.

    Falls by elderly people at home: prevalence and associated factors

    Age Ageing

    (1998)
  • S. Reinsch et al.

    Attempts to prevent falls and injury: a prospective community study

    Gerontologist

    (1992)
  • M.E. Tinetti et al.

    A multifactorial intervention to reduce the risk of falling among elderly people living in the community

    N. Engl. J. Med.

    (1994)
  • W.P. Berg et al.

    Circumstances and consequences of falls in independent community-dwelling older adults

    Age Ageing

    (1997)
  • A.J. Campbell et al.

    Circumstances and consequences of falls experienced by a community population 70 years and over during a prospective study

    Age Ageing

    (1990)
  • C.I. Gryfe et al.

    A longitudinal study of falls in an elderly population: I. incidence and morbidity

    Age Ageing

    (1977)
  • M.E. Tinetti et al.

    Falls, injuries due to falls, and the risk of admission to a nursing home

    N. Engl. J. Med.

    (1997)
  • B.L. Riggs et al.

    Involutional osteoporosis

    N. Engl. J. Med.

    (1986)
  • L.D. Gillespie, W.J. Gillespie, R. Cumming, S.E. Lamb, B.H. Rowe, Interventions for preventing fall in the elderly...
  • J.C. Gallagher et al.

    Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss

    J. Clin. Endocrinol. Metab.

    (2001)
  • P.H. Thiyyari et al.

    Serum 25-hydroxy vitamin D2 and D3 in elderly subjects

    Bone

    (1998)
  • E.L. Frome

    The analysis of rates using Poisson regression models

    Biometrics

    (1989)
  • Cited by (95)

    View all citing articles on Scopus

    Presented at the 12th Workshop on Vitamin D (Maastricht, The Netherlands, 6–10 July 2003).

    View full text