Prevention of Falls and Fractures in Old People by Administration of Calcium and Vitamin D. Randomized Clinical Trial (ANVITAD)

• Consequence of falls. [ Time Frame: 24 months. ] [ Designated as safety issue: No ]
  Bone fractures at any location, need for healthcare, need for hospitalization, bed-ridden.
• Change in calcidiol [25(OH)D3] plasma levels [ Time Frame: 18 months. ] [ Designated as safety issue: No ]
  Determined by RIA (Vitamin D deficiency is defined as a calcidiol plasma level lower than 10ng/ml).
• Change in bone mass (bone density or mineral content). [ Time Frame: 24 months. ] [ Designated as safety issue: No ]
  By densitometry (risk of fracture). Osteoporosis will be diagnosed based on a densitometry T-score of less than 2.5 in the vertebral column, according to WHO criteria.
• Change in muscle strength in the dominant hand. [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Determined by dyanometry (with a mean of 3 attempts to obtain a muscle strength measurement).
• Changes in musculoskeletal function. [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  By the timed up and go test (the elderly person gets up from a chair with arms, walks three meters, turns round, walks back and sits down again). Taking more than 20 seconds indicates a high risk for falls.
• Serious adverse events or any other adverse event. [ Time Frame: 24 months. ] [ Designated as safety issue: Yes ]
  An adverse event is considered as any untoward medical occurrence in any patient included in the study which does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product.

The first objective is to determine the efficacy of calcium and vitamin D supplementation at doses of 1200 mg and 800 IU, respectively, to reduce the incidence of falls and fractures in non-institutionalized elderly people.

The second objective is to measure and compare treatment groups (calcium and vitamin D vs placebo) as regards muscle strength and musculoskeletal function, bone mineral density, calcidiol level and treatment safety.

Background:

There are many studies that associate vitamin D serum levels in older persons with muscle strength, physical performance and risk of fractures and falls. However, current evidence is insufficient to make a general recommendation for administrating calcium and vitamin D to older persons. The objective of this study is to determine the effectiveness of calcium and vitamin D supplementation in improving musculoskeletal function and decreasing the number of falls in person aged over 65 years.

Design:

Phase III, randomized, double blind, placebo-controlled trial to evaluate the efficacy of already marketed drugs in a new indication. It will be performed at Primary Care doctor visits at several Healthcare Centers in different Spanish Health Areas. A total of 704 non-institutionalized subjects aged 65 years or older will be studied (sample size calculated for a statistical power of 80%, alpha error 0.05, annual incidence of falls 30% and expected reduction of 30% to 20% and expected loss to follow up of 20%). The test drug containing 800 IU of vitamin D and 1000 mg of calcium will be administered daily. The control group will receive a placebo. The subjects will be followed up over two years. The primary variable will be the incidence of spontaneous falls. The secondary variables will include: consequences of the falls (fractures, need for hospitalization), change in calcidiol plasma levels and other analytical determinations (transaminases, PTH, calcium/phosphorous, albumin, creatinine, etc.), change in bone mass by densitometry, change in muscle strength in the dominant hand and change in musculoskeletal strength, risk factors for falls, treatment compliance, adverse effects and socio-demographic data.

• Fall
• Fractures

• Bischoff HA, Stähelin HB, Dick W, Akos R, Knecht M, Salis C, Nebiker M, Theiler R, Pfeifer M, Begerow B, Lew RA, Conzelmann M. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 2003 Feb;18(2):343-51.
• Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005 May 11;293(18):2257-64. Review.
• Campbell AJ, Robertson MC, Gardner MM, Norton RN, Tilyard MW, Buchner DM. Randomised controlled trial of a general practice programme of home based exercise to prevent falls in elderly women. BMJ. 1997 Oct 25;315(7115):1065-9.
• Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992 Dec 3;327(23):1637-42.
• Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, Garnero P, Meunier PJ. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int. 2002 Mar;13(3):257-64.
• del Campo MT, Aguado P, Martínez ME. [Vitamin D and bone health: is there a need to review supplementation in osteoporosis risk population?]. Med Clin (Barc). 2005 Dec 3;125(20):788-93. Review. Spanish.
• Dhesi JK, Bearne LM, Moniz C, Hurley MV, Jackson SH, Swift CG, Allain TJ. Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status. J Bone Miner Res. 2002 May;17(5):891-7.
• Gillespie WJ, Avenell A, Henry DA, O'Connell DL, Robertson J. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2001;(1):CD000227. Review. Update in: Cochrane Database Syst Rev. 2005;(3):CD000227.
• Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr. 2002 Apr;75(4):611-5. Review.
• Latham NK, Anderson CS, Reid IR. Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review. J Am Geriatr Soc. 2003 Sep;51(9):1219-26. Review.
• Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1996 Feb 15;124(4):400-6.
• NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001 Feb 14;285(6):785-95. Review.
• Pfeifer M, Begerow B, Minne HW. Vitamin D and muscle function. Osteoporos Int. 2002 Mar;13(3):187-94. Review.
• Simon J, Leboff M, Wright J, Glowacki J. Fractures in the elderly and vitamin D. J Nutr Health Aging. 2002;6(6):406-12. Review.
• Vallecillo G, Díez A, Carbonell J, González Macías J. [Treatment of osteoporosis with calcium and vitamin D. Systematic review]. Med Clin (Barc). 2000 Jun 10;115(2):46-51. Review. Spanish.
• van der Wielen RP, Löwik MR, van den Berg H, de Groot LC, Haller J, Moreiras O, van Staveren WA. Serum vitamin D concentrations among elderly people in Europe. Lancet. 1995 Jul 22;346(8969):207-10.
• Zamboni M, Zoico E, Tosoni P, Zivelonghi A, Bortolani A, Maggi S, Di Francesco V, Bosello O. Relation between vitamin D, physical performance, and disability in elderly persons. J Gerontol A Biol Sci Med Sci. 2002 Jan;57(1):M7-11.
• Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003 May;89(5):552-72. Review.
• López-Torres Hidalgo J; ANVITAD Group. Prevention of falls and fractures in old people by administration of calcium and vitamin D. randomized clinical trial. BMC Public Health. 2011 Dec 9;11:910.

Inclusion Criteria:

• Aged over 65 years with normal renal function
• Normal transaminase levels
• Normal calcium blood levels
• Not homebound (not immobilized) nor in socio-healthcare institutions.

Exclusion Criteria:

• Need for medical treatment with calcium or vitamin D
• Hypersensitivity to or contraindication for calcium or vitamin D
• Medical treatment that includes calcium or vitamin D
• Physical disability that impedes their collaboration
• Taking thiazide diuretics
• Oral anticoagulants
• Hormone replacement therapy
• Digitalis drugs
• Anticonvulsants or barbiturates

• Having any of the following diseases:

  • Lithiasis
  • Renal impairment (serum creatinine >1.4 mg/dl)
  • Hypo or hyperthyroidism
  • Paget's disease
  • Chronic liver disease
  • Tumors
  • Sarcoidosis
  • Impaired intestinal absorption or chronic alcoholism (>40 g/day).