VITAMIN D ACTS THROUGH several pathways to influence

Transcription

1 JOURNAL OF BONE AND MINERAL RESEARCH Volume 22, Supplement 2, 2007 doi: /JBMR.07S American Society for Bone and Mineral Research Therapy of Osteoporosis With Calcium and Vitamin D Bess Dawson-Hughes 1 and Heike A Bischoff-Ferrari 2 ABSTRACT: Inadequate intakes of vitamin D and calcium lead to reduced calcium absorption, higher bone remodeling rates, and increased bone loss. Vitamin D insufficiency has also been linked to reduced muscle function and increased risk of falling. The mechanisms for the performance and muscle effects are not well understood. Administering vitamin D to those with inadequate vitamin D status has been shown to lower fracture rates in some trials but not in others. The purpose of this presentation is (1) to examine how calcium and vitamin D work in concert, (2) to consider key evidence that increasing vitamin D intake will affect risk of falls and fractures, and (3) to estimate the 25-hydroxyvitamin D [25(OH)D] level needed to achieve maximum fracture protection. J Bone Miner Res 2007;22:S2;V59 V63. doi: /JBMR.07S209 Key words: vitamin D, calcium, falls, fractures, muscle performance INTRODUCTION VITAMIN D ACTS THROUGH several pathways to influence risk of fracture. It influences calcium handling in ways that result in reduced rates of bone loss and improvements in bone mass in adults. Vitamin D can also improve muscle performance and lower risk of falling. The mechanisms for the performance and muscle effects are not well understood. Administering vitamin D to those with inadequate vitamin D status has been shown to lower fracture rates in some trials but not in others. The purpose of this presentation is to consider how calcium and vitamin D work in concert, to examine the evidence for an effect of vitamin D on falls and fracture risk, and to estimate the 25-hydroxyvitamin D [25(OH)D] level needed to achieve fracture protection. CALCIUM AND VITAMIN D: POTENTIAL INTERACTIONS Calcium is a threshold nutrient, with respect to its impact on calcium balance or skeletal retention of calcium. In a re-examination of the calcium balance data originally published in men consuming a wide range of calcium intakes ( mg/d), (1) balance became more positive (or less negative) as calcium intake increased up to an intake of 1200 mg/d, after which it remained constant at the plateau. This observation weighed significantly in the deliberations about the optimal calcium intake, which is set at 1200 mg/d for men and women 50 yr of age. (2) Increasing vitamin D intake and the circulating 25(OH)D level increases levels of the metabolites 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D, (3) and in turn The authors state that they have no conflicts of interest. increases calcium absorption (4) and the circulating ionized calcium concentration. The lower PTH level removes the stimulus for bone resorption and has long been considered an important mechanism by which vitamin D improves bone strength and mass. However, increasing calcium intake will also increase calcium absorption, increase the circulating ionized calcium concentration, and suppress PTH and biochemical markers of bone turnover. One question often asked is whether the vitamin D requirement is dependent on calcium intake. Steingrimsdottir et al. (5) have recently examined the relative contributions of 25(OH)D and calcium intake to serum PTH levels in a cross-sectional study in adults. In that study, calcium seemed to suppress serum PTH in subjects with 25(OH)D levels 25 nm but not in subjects with higher 25(OH)D levels. In contrast, 25(OH)D was inversely associated with serum PTH throughout the range of 25(OH)D levels in this study. With regard to other potential interactions of calcium and vitamin D, it is reasonable to consider whether the calcium intake influences the 25(OH)D level achieved in subjects on a fixed dosage of vitamin D. This was examined in healthy adults treated with 800 IU of vitamin D 3 daily during the wintertime. These men and women were randomized to 1000 mg/d of calcium as the carbonate or to placebo. The change in serum 25(OH)D in response to daily supplementation with 800 IU of vitamin D 3 in the calcium and placebo groups was the same, (6) indicating that calcium intake has no impact on the link between vitamin D intake and the serum 25(OH)D level. In conclusion, the evidence cited above suggests that the vitamin D requirement is largely independent of calcium intake. Vitamin D levels have been associated with bone mass in young and old adults, (7) and vitamin D supplementation has been shown to reduce rates of bone loss in adults. (8) The 1 Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; 2 Department of Rheumatology and Institute for Physical Medicine, University Hospital Zurich, Zurich, Switzerland. V59

2 V60 effect of vitamin D on bone loss varies with season. In a study conducted at latitude 42 N, prevention of the wintertime decline in serum 25(OH)D with supplementation has been shown to decrease wintertime bone loss and to improve net bone change in healthy older women. (9) MUSCLE, MUSCLE PERFORMANCE, AND RISK OF FALLING Vitamin D receptors (VDRs) are known to be present in muscle tissue. (10,11) In muscle, vitamin D activates protein kinase C, which promotes calcium release, (12,13) increasing the calcium pool that is essential for muscle contraction. With aging, the number of VDRs in muscle decreases and the number of type II fibers also decreases. (14) Type II muscle fibers are fast and are the first to be recruited to avoid falls. In adults with profound vitamin D deficiency (osteomalacia), muscle biopsies show atrophy of type II fibers with enlarged interfibrillar spaces and infiltration of fat, fibrosis, and glycogen granules. (15) In a small uncontrolled study, Sorenson et al. (16) obtained muscle biopsies from elderly women after treatment with 1- -hydroxyvitamin D for 3 mo, and they showed a relative increase in the number and size of type IIa, fast-twitch muscle fibers. More recently, treatment of elderly stroke survivors with 1000 IU of vitamin D 2 daily increased mean type II muscle fiber diameter by 2.5-fold over a 2-yr period. (17) The clinical impact of vitamin D on muscle is indicated in studies that link lower extremity performance and serum 25(OH)D levels. In an analysis of men and women 60 yr of age who participated in the NHANES III survey, subjects with higher 25(OH)D levels were able to walk faster and to get out of a chair (sit-to-stand test) faster. (18) Performance improved rapidly as 25(OH)D levels rose from very low to about the midpoint of the reference range (60 nm). Performance continued to improve, although more slowly, as levels reached the upper end of the reference range (90 nm). A recent controlled trial revealed that supplementation with 1000 IU of vitamin D 2 significantly improved performance on the sit-to-stand test in 302 men and women (mean age, 72 yr) who had a mean baseline 25(OH)D level of 44.5 nm. (19) Given the effect of vitamin D deficiency on muscle and muscle performance, it is natural to expect that supplementation in vitamin D deficient older subjects may lower risk of falling. In 2004, Bischoff-Ferrari et al. (20) published the results of a meta-analysis of vitamin D intervention trials and falls. Five studies met the criteria for inclusion in the analysis. These trials used different vitamin D compounds and different dosages. Collectively, vitamin D lowered risk of falling by 22%. At the time, there were too few studies available to do meaningful subset analyses. Since that analysis, two additional trials have been completed in Australia. Flicker et al. (21) treated 625 assisted living residents (mean age, 83.4 yr) over a 2-yr period with either vitamin D 2 (initially 10,000 IU once weekly and then 1000 IU daily) or placebo. To be eligible, the subjects had to have baseline 25(OH)D levels in the lower one half of the reference range (25 90 nm). The relative risk of a first fall was 0.82 (95% CI, ) in all 625 subjects and 0.70 (95% CI, 0.50 DAWSON-HUGHES AND BISCHOFF-FERRARI 0.99) in the 540 subjects who took at least one half of the study pills. All subjects received 600 mg of elemental calcium daily as calcium carbonate. Vitamin D decreased the total number of falls significantly in all subjects and in the more compliant subset. In a more recent trial, published in abstract form to date, (19) supplementation with 1000 IU/d of vitamin D 2 over a 1-yr period lowered risk of first fall (OR, 0.50; 95% CI, ) in 302 men and women (mean age, 72 yr). In this study, both the vitamin D and placebo groups received 500 mg of calcium as calcium carbonate daily. The mean 25(OH)D level in this study at baseline was 44.6 nm. In the stroke survivor trial cited above, (17) the 1000 IU/d of vitamin D 2 lowered risk of falling (33 of 48 subjects in placebo group fell and 11 of 48 in the vitamin D group fell at least once). In the vitamin D group, mean serum 25(OH)D increased from 25 to 61 nm. Calcium was not provided in this trial. In a secondary analysis of our STOP/IT study of 389 community-dwelling men and women 65 yr of age, supplementation with vitamin D 3 and calcium (700 IU/500 mg as citrate malate), when compared with double placebo, lowered risk of falling in the women but not the men. (22) Furthermore, the risk reduction was greatest in the more sedentary women. The baseline mean 25(OH)D levels were 83 nm in the men and 66.5 nm in the women. Two recent studies have found no significant impact of supplementation with 800 IU of vitamin D 3 daily on falling in free-living subjects. (23,24) These findings should be interpreted with caution, however, because compliance was poor, and fall assessment was not optimal in these pragmatic trials. Additionally, one of the trials (24) had an open design (no placebo in the control group). From the available evidence, it is difficult to determine the level of 25(OH)D needed to minimize risk of falling, but supplementation with IU of vitamin D 3 per day in subjects with initial 25(OH)D levels well within the reference range seems to lower risk of falling in freeliving and institutionalized elderly subjects. (21,19,22) The impact of calcium intake on the relationship between vitamin D and falls is not certain. FRACTURE RISK The impact of supplementation with vitamin D was examined in 2005 in a meta-analysis of available randomized, controlled clinical trials. (25) Trials using ergocalciferol or cholecalciferol and involving a total of 9820 subjects were included in the analysis. Heterogeneity was present in the analysis of the five trials that examined hip fracture and the seven trials that examined nonvertebral fracture; heterogeneity disappeared when the trials were pooled by dose of vitamin D administered ( 400 and IU/d). Therefore, the two dosage groups were analyzed separately. No benefit was observed in the two trials that used 400 IU/d for hip or nonvertebral fractures. (26,27) In contrast, in the higher dose trials, supplementation significantly lowered risk of hip fracture (RR, 0.74; 95% CI, ) and nonvertebral fracture (RR, 0.77; 95% CI, ). Since the publication of this meta-analysis, the results of two large randomized, placebo-controlled trials have been published. The RECORD trial was a secondary prevention

3 THERAPY OF OSTEOPOROSIS WITH CALCIUM AND VITAMIN D V61 TABLE 1. SERUM 25(OH)D, PTH, AND NONVERTEBRAL FRACTURE RESPONSES TO SUPPLEMENTATION WITH VITAMIN D 3 :SUMMARY OF RANDOMIZED, PLACEBO-CONTROLLED TRIALS Study (reference) Dose (IU/d) 25(OH)D (nm) PTH (%) Significant effect on nonvertebral fracture Chapuy et al. (34) 800* Yes Chapuy et al. (35) 800* Yes Dawson-Hughes et al. (36) 700* Yes Trivedi et al. (37) ? Yes Grant et al. (RECORD Trial Group) (23) 800* No Jackson et al. (WHI) (28) 400* 59? No Lips et al. (27) No Meyer et al. (26) ? No * Supplemental calcium given to the vitamin D and placebo group. Measured in a subset of subjects. trial in 5292 ambulatory men and women >70 yr of age with a history of a low-trauma fracture in the last 10 yr. (23) Subjects were randomized to treatment with 1000 mg of calcium as calcium carbonate, 800 IU of vitamin D 3, combined calcium and vitamin D, or placebo. The supplements were delivered by mail every 4 mo. Compliance was measured by a mailed questionnaire every 4 mo. During the study, 698 (13%) of participants had a new fracture; of these, 183 (26%) were hip fractures. In this study, supplementation with calcium, vitamin D, or the two combined had no effect on the risk of fracture, either hip or all fractures. At the 2-yr point in this 5-yr trial, only 54.5% of subjects were still taking any study pills. The serum 25(OH)D level in a nonrandom subset of 60 subjects after 1 yr on vitamin D supplements was 62 nm. The second placebo-controlled trial published since the meta-analysis is the Women s Health Initiative. (28) More than 36,000 women (mean age, 62.4 yr) participated in this 7-yr study. They were randomized to 1000 mg of calcium as calcium carbonate plus 400 IU of vitamin D 3 or placebo daily. At the end of the study, 59% of the women were taking at least 80% of their study pills. In the group as a whole, supplementation did not significantly reduce fracture risk, although there was a trend toward lower risk of hip fracture (HR, 0.88; 95% CI, ). In the subset of women who had 25(OH)D measured, the initial 25(OH)D level was 47 nm and the intrastudy level was 28% higher (59 nm). A recent meta-analysis by Avenell et al. (29) concluded that older people confined to institutions had reduced hip and other nonvertebral fracture rates if given vitamin D and calcium but that the impact of these supplements in free-living older subjects is unclear. How can the mixed results of the vitamin D intervention trials be reconciled? One approach is to examine the results in relation to the 25(OH)D level achieved and the degree of PTH suppression occurring with supplementation (Table 1). In the trials that achieved higher 25(OH)D levels, PTH suppression was greater. There seems to be a threshold level of 25(OH)D at 75 nm that is needed to lower fracture risk. The trials that had positive results achieved this mean level or higher; those that did not reach this threshold level were null. From available evidence, it seems that individuals will benefit by having their 25(OH)D levels no lower than 75 nm. A higher level may provide additional benefit, but this has not been established. Supplemental calcium, used in many of the trials, both positive and negative, may be essential for benefit, (30) but this remains uncertain because the positive trials that used calcium plus vitamin D achieved mean 25(OH)D levels >75 nm (Table 1). In any event, the recommended intake of 1200 mg/d of calcium for the general population should cover calcium needs. The level of vitamin D needed to increase serum 25(OH)D by given increments has been examined. One microgram (or 40 IU) will increase serum 25(OH)D by nm. (31) A bigger increment is observed in subjects with lower starting levels. Age does not seem to influence the increment. (32) In Toronto, Canada, in the wintertime, an intake of 1000 IU of vitamin D 3 brought the mean 25(OH)D value to near 75 nm and 4000 IU per day brought each participant s level to 75 nm or higher. (33) In conclusion, the vitamin D requirement does not seem to be highly dependent on calcium intake. Vitamin D protects against fracture by decreasing PTH and increasing bone mass and also by lowering risk of falling. A 25(OH)D level of 75 nm or greater seems to be needed to lower risk of fracture. An intake of 1000 IU/d will bring the average individual s level to 75 nm, but more will be needed by many adults. ACKNOWLEDGMENTS This work was supported by the U.S. Department of Agriculture under Agreement Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture. REFERENCES 1. Spencer H, Kramer L, Lesniak M, De Bartolo M, Norris C, Osis D 1984 Calcium requirements in humans. Report of original data and a review. Clin Orthop 184: Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1997 Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Institute of Medicine, Washington, DC, USA.

4 V62 3. Carpenter TO, Keller M, Schwartz D, Mitnick M, Smith C, Ellison A, Carey D, Comite F, Horst R, Travers R, Glorieux FH, Gundberg CM, Poole AR, Insogna KL ,25 Dihydroxyvitamin D supplementation corrects hyperparathyroidism and improves skeletal abnormalities in X-linked hypophosphatemic rickets a clinical research center study. J Clin Endocrinol Metab 81: Devine A, Wilson SG, Dick IM, Prince RL 2002 Effects of vitamin D metabolites on intestinal calcium absorption and bone turnover in elderly women. Am J Clin Nutr 75: Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G 2005 Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA 294: Goussous R, Song L, Dallal GE, Dawson-Hughes B 2005 Lack of effect of calcium intake on the 25-hydroxyvitamin D response to oral vitamin D3. J Clin Endocrinol Metab 90: Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B 2004 Positive association between 25-hydroxy vitamin D levels and bone mineral density: A population-based study of younger and older adults. Am J Med 116: Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P 1995 Prevention of bone loss by vitamin D supplementation in elderly women: A randomized double-blind trial. J Clin Endocrinol Metab 80: Dawson-Hughes B, Dallal GE, Krall EA, Harris S, Sokoll LJ, Falconer G 1991 Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med 115: Zanello SB, Collins ED, Marinissen MJ, Norman AW, Boland RL 1997 Vitamin D receptor expression in chicken muscle tissue and cultured myoblasts. Horm Metab Res 29: Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Staehlin H, Dick W 2001 In situ detection of 1,25-dihydroxyvitamin D 3 receptor in human skeletal muscle tissue. Histochem J 33: de Boland ARBoland RL 1987 Rapid changes in skeletal muscle calcium uptake induced in vitro by 1,25-dihydroxyvitamin D3 are suppressed by calcium channel blockers. Endocrinology 120: Capiati DA, Vazquez G, Boland RL 2001 Protein kinase C alpha modulates the Ca2+ influx phase of the Ca2+ response to 1alpha,25-dihydroxy-vitamin-D3 in skeletal muscle cells. Horm Metab Res 33: Bischoff-Ferrari HA, Borchers M, Gudat F, Durmuller U, Stahelin HB, Dick W 2004 Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res 19: Yoshikawa S, Nakamura T, Tanabe H, Imamura T 1979 Osteomalacic myopathy. Endocrinol Jpn 26: Sorensen OH, Lund B, Saltin B, Lund B, Andersen RB, Hjorth L, Melsen F, Mosekilde L 1979 Myopathy in bone loss of ageing: Improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Lond) 56: Sato Y, Iwamoto J, Kanoko T, Satoh K 2005 Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: A randomized controlled trial. Cerebrovasc Dis 20: Bischoff-Ferrari HA, Dietrich T, Orav EJ, Zhang Y, Karlson EW, Dawson-Hughes B 2004 Higher 25-hydroxyvitamin D levels are associated with better lower extremity function in both active and inactive adults 60+ years of age. Am J Clin Nutr 80: Zhu K, Dick I, Devine A, Bruce D, Prince R 2006 An RCT of Vitamin D or Placebo on Falls in Elderly Women with Low Vitamin D Status and a Falling History. J Bone Miner Res 21: Bischoff-Ferrari HA, Dawson-Hughes B, Willett W, Staehlin H, Bazemore M, Zee R, Wong J 2004 Effect of vitamin D on falls a meta-analysis. JAMA 291: DAWSON-HUGHES AND BISCHOFF-FERRARI 21. Flicker L, MacInnis RJ, Stein MS, Scherer SC, Mead KE, Nowson CA, Thomas J, Lowndes C, Hopper JL, Wark JD 2005 Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc 53: Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B 2006 Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: A 3-year randomized controlled trial. Arch Intern Med 166: Grant AM, Avenell A, Campbell MK, McDonald AM, Mac- Lennan GS, McPherson GC, Anderson FH, Cooper C, Francis RM, Donaldson C, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA, RECORD Trial Group Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): A randomised placebo-controlled trial. Lancet 365: Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, Baverstock M, Birks Y, Dumville J, Francis R, Iglesias C, Puffer S, Sutcliffe A, Watt I 2005 Randomized controlled trial of calcium and supplementation with cholecalciferol (vitamin D 3 ) for prevention of fractures in primary care. BMJ 330: Bischoff-Ferrari HA, Willett W, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B 2005 Fracture prevention with vitamin D supplementation: A meta-analysis of randomized controlled trials. JAMA 293: Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI 2002 Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 17: Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM 1996 Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 124: Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ockene JK, O Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Stefanick ML, Van Horn L, Wactawski-Wende J, Whitlock E, Anderson GL, Assaf AR, Barad D, Women s Health Initiative Investigators Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354: Avenell A, Gillespie W, Gillespie L, O Connell D 2007 Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 1: Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P Need for additional calcium to reduce risk of hip fracture with vitamin D supplementation: Evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 92: Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ 2003 Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77: Harris SS, Dawson-Hughes B 2002 Plasma vitamin D and 25OHD responses of young and old men to supplementation with vitamin D3. J Am Coll Nutr 21: Vieth R, Chan PC, MacFarlane GD 2001 Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 73: Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ 1992 Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 327: Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, Garnero P, Meunier PJ 2002 Combined calcium

5 THERAPY OF OSTEOPOROSIS WITH CALCIUM AND VITAMIN D V63 and vitamin D3 supplementation in elderly women: Confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: The Decalyos II study. Osteoporos Int 13: Dawson-Hughes B, Harris SS, Krall EA, Dallal GE 1997 Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337: Trivedi DP, Doll R, Khaw KT 2003 Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: Randomised double blind controlled trial. BMJ 326: Address reprint requests to: Bess Dawson-Hughes, MD Bone Metabolism Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University 711 Washington Street Boston, MA 02111, USA Bess.Dawson-Hughes@Tufts.edu Received in original form December 18, 2006; revised form March 8, 2007; accepted March 16, 2007.