7/29/2019 art-3A10.1007-2FPL00004161

1/5

Calcium, Vitamin D and Vitamin K in the Prevention of Fractures due toOsteoporosis

P. J. Meunier

Department of Rheumatology and Bone Diseases and INSERM Unit 403, Edouard Herriot Hospital, Lyon, France

Introduction

Two of the most important nutrients for bone health are

calcium and vitamin D. Calcium has important cellularmetabolic functions and is accumulated as a vast reservein the skeleton. Dietary calcium insufficiency virtuallynever impairs those cellular functions but influences thesize of the calcium reserve through the mobilizationnecessary to maintain a normal blood calcium level. Thisis achieved through an increase in parathyroid function,which accelerates bone remodeling and indirectlyinduces a decrease in bone mass and bone strength.Conversely, in addition to being a substrate for bonemineralization, calcium has an inhibitory effect on boneremodeling through suppression of circulating para-thyroid hormone (PTH). These mechanisms make usrealize that calcium intake plays an important role in the

etiology and pathogenesis of osteoporosis. We literallywalk about on our calcium reserve. It is this uniquefeature of calcium nutrition that is the basis for thelinkage of calcium intake and osteoporosis. It is alsoimportant to understand that calcium functions as athreshold nutrient [1]. This means that below somecritical value about 700800 mg/day bone mass willbe limited by available calcium supplies, whereas abovethat threshold value, no further benefit will accrue fromadditional increases in intake. The current recommendedcalcium intake is 1200 mg/day for adults.

Vitamin D, which facilitates active transport ofcalcium across the intestinal mucosa, is particularlyimportant for adaptation to low calcium intakes. It isgenerally considered that vitamin D status influencesabsorptive performance and that it thereby influences thecalcium requirement [1]. In contrast to the extensiveattention paid to vitamin D as a component of nutritionalhealth in infants and children, for whom vitamin Ddeficiency was synonymous with rickets, the relationship

of vitamin D with the nutritional health of adults orelderly subjects was largely ignored before the mid-1970s and was only shown when the assays for serum25-hydroxyvitamin D (25-OHD) became available. It is

well known that severe and long-lasting vitamin Ddeficiency leads to frank osteomalacia due to a majorinhibition of primary mineralization of bone. In addition,growing evidence demonstrates that a less severereduction in serum 25-OHD levels can already havedeleterious effects on bone density, even if osteomalaciais not present, through an increase in serum PTHconcentration. This vitamin D insufficiency or subclini-cal vitamin D deficiency is a major determinant of serumPTH increase leading to a stimulation of osteoclasticbone resorption and bone remodeling which increasesbone loss and weakens both cortical and trabecular bone.

The vitamin D status of a subject is derived mainly

from cutaneous synthesis initiated by solar irradiation ofthe skin and also from dietary intake. A reduction of oneor both sources unavoidably leads to vitamin Dinsufficiency. Elderly subjects are at high risk of vitaminD insufficiency because they avoid direct sun or takeprotective action to reduce sunlight exposure or areunable to go outdoors because of an inability to walk.Recommendations for reducing the risk of melanomahave worsened the lack of sun exposure. In addition, thecapacity of elderly skin to produce previtamin D3 isreduced. The degree of hypovitaminosis D is greater inwinter and at high latitudes. The main natural sources ofdietary vitamin D are fatty fishes, fish liver oil or to alesser extent eggs. Only small amounts of these foods areconsumed by elderly people in most countries with theexception of Scandinavian countries and Japan in spiteof the need to maintain vitamin D stores during thewintertime by an increase in oral intake. The current USrecommended adequate daily intake for vitamin D is 5mg (200 IU) for people younger than 50 years, 10 mg(400 IU) for those between 51 and 70 years and 20 mg(800 IU) for those over 70 years of age (1977recommendations from the National Academy ofSciences and Institute of Medicine of the USA). Thefortification of milk in North America is only effective

Osteoporos Int (1999) Suppl. 2:S48S52 1999 International Osteoporosis Foundation and National Osteoporosis Foundation Osteoporosis

International

Correspondence and offprint requests to: Prof. Pierre J. Meunier,Department of Rheumatology and Bone Diseases, Pavillon F,Edouard Herriot Hospital, Place dArsonval, F-69437 Lyon cedex 3,France. Tel: +33 4 72117481. Fax: +33 4 72117483. e-mail:meunier@lyon151.inserm.fr.

7/29/2019 art-3A10.1007-2FPL00004161

2/5

for people who actually drink milk and many elderlypeople have completely stopped drinking milk.

Vitamin D insufficiency is often combined with lowdietary calcium intake and is increasingly recognized tobe a cause of secondary hyperparathyroidism andindirectly of bone fragility. This is true not only inelderly people living in institutions where it was firstdescribed, but also in free-living old people, normaladults and children. Several authors have demonstratedthe reversibility of the senile secondary hyperparathy-roidism after administration of calcium alone, aftervitamin D alone, or more effectively after supplementscombining calcium and vitamin D, but as long as it hadnot been demonstrated that the correction of the lowvitamin D and calcium status was capable of preventingfractures, the role of senile secondary hyperparathyroid-ism as a causal determinant of fracture risk remained tobe proven. In the last 6 years two randomized controltrials have shown that combined supplements of calciumand vitamin D were capable of preventing nonvertebralfractures in elderly people living either in institutions

[2,3] or at home [4]. In the meantime other recent studieshave demonstrated a high incidence of vitamin Dinsufficiency and secondary hyperparathyroidism inindependent French [5] and American [6] elderlysubjects, in normal French adults [7] and in Spanishchildren [8]. This is relevant to the possibility ofcalciumvitamin D supplements for correcting thesenutritional deficits and preventing bone loss andfractures not only in the elderly population but inyounger patients. Interestingly, several studies haveshown a significant relationship between femoral neckbone mineral density (BMD), serum 25-OHD levels andPTH, not only in elderly people [911] but also inmiddle-aged women [12,13].

Effects of Calcium, Vitamin D and CalciumVitamin D Combination on Bone Metabolism,Bone Density and Fractures

Calcium Supplementation

Effects on Parathyroid Function. A recent study found asignificant negative relationship between dietary calciumintake and iPTH in a population of 58 healthypostmenopausal women (mean age 64 + 5.3 years)who had a dietary calcium intake lower than 786 mg/day

(r = 70.48; p = 0.0002). No relationship was found in apopulation of 58 women who had a daily calcium intakehigher than 786 mg [14]. This confirms the role ofcalcium as a threshold nutrient, with a rise in PTHbeginning at calcium intake values lower than thisthreshold.

Short- and long-term studies have shown that calciumsupplements are capable of inducing a significantdecrease in serum PTH. In young healthy malevolunteers, four calcium preparations induced a markedsuppression of PTH (737% to 757%) in the 6 hfollowing the administration of 1000 mg calcium [15]. Ina 4-year placebo-controlled clinical trial in 236 normalpostmenopausal women, calcium supplementation of1600 mg/day induced an 18.9% reduction in serum PTH(calcium group vs placebo group). Fifty percent of thispopulation had a dietary calcium intake lower than 714mg/day. A small but significant decrease in bone losswas observed in parallel [16].

Effects on Bone Mineral Density. Eleven studies

involving about 2000 postmenopausal women comparedcalcium supplements (5002600 mg/day for 1.54 years)with a placebo or a control group [1626]. These studieshave shown that women whose diets were supplementedwith calcium had a lower rate of bone loss than untreatedwomen. In most of the studies women with calciumsupplementation had BMDs that were 13% higher thanthe BMDs of women who did not receive calcium.Calcium supplements usually have a smaller effect onBMD in women within the first 5 years after menopausethan in women more than 5 years after menopause.

Effects on Fracture Incidence. The effects of calcium onfracture incidence have been assessed in three rando-

mized trials (Table 1) with a reduction in the fractureprobability of about one-third, but the range ofuncertainty is too wide to make a definitive statementabout the magnitude of the effect or to perform a validcost-effectiveness analysis [28].

Vitamin D Supplementation

Few studies have evaluated the effects of vitamin Dalone, without combined calcium, on fractures, BMDand parathyroid function. In a population of 1186Finnish men and women living independently or in

Table 1. Effects of calcium supplementation on fractures

Dose/day (mg) Duration (yrs) Population (mean age) Effects on Fractures (Fx)

Chevalley 1994 [24] 800* 1.5 93 healthy M and F (72.1) Fewer new vert.Fx (p=0.05)

Recker 1996 [27] 1200 4.3 251 F (73.5) Fewer new vert.Fx in the subsetwith prior vert.Fx (p=0.023)

Reid 1995 [26] 1000 4.0 78 healthy F (58.5) Fewer new Fx (all) (p=0.037)

* vitamin D replete

Calcium, Vitamin D and Vitamin K in the Prevention of Fractures 49

7/29/2019 art-3A10.1007-2FPL00004161

3/5

nursing homes (mean age 82.8 years) Heikinheimo et al.[29] injected 150 000 or 300 000 IU of vitamin D2 once ayear for 4 years. They found fewer fractures of all typesin the vitamin D group (16%) than in the control group(22%) (p = 0.034). A breakdown of the results byfracture site showed a significant reduction in upper-limbfractures combined (p = 0.025) but not in hip fractures.

Lips et al. [30], in a 4-year randomized trial, comparedthe effects of 400 IU/day of vitamin D3 with those of aplacebo in 2578 Dutch subjects, 25% of whom weremen. Their mean dietary calcium intake from dairyproducts was 868 mg/day and no calcium was given. Nodecrease in the incidence of hip fractures and otherperipheral fractures was observed in the group receivingthe vitamin D supplementation. A small and non-significant decrease in serum PTH (about 715%) wasobserved in a nonrandom sample of the subjects who hadreceived vitamin D.

In a more recent study by Lips group [31], ultravioletirradiation in 45 psychogeriatric women (mean age 85years) was performed 3 times per week and compared

with an oral supplement of 400 IU/day of vitamin D3.The irradiation was as effective as oral vitamin D inincreasing serum 25-OHD and suppressing secondaryhyperparathyroidism (decrease in sPTH greater than30% in both group after 3 months).

Calcium and Vitamin D Combination

Two controlled studies performed in French institutio-nalized elderly women [2,3] and in independent elderlyAmerican men and women [4] have demonstrated asignificant protective effect against hip and othernonvertebral fractures by a combined supplement ofcalcium and vitamin D, with, in parallel, significantincreases in BMD and a decrease in serum PTH (Table2). The effective prevention of fractures observed withcalciumvitamin D combination in independent elderlywomen and men [4] is of particular interest because theconcept of calcium and vitamin D insufficienciesinducing secondary hyperparathyroidism has beenextended from the institutionalized elderly populationto free-living elderly subjects and younger people.During the Euronut Seneca study, serum 25-OHDconcentrations were measured during wintertime infree-living elderly people from 11 European countries

[32]: 36% of men and 47% of women had values below30 nmol/l (12 ng/ml). In free-living healthy Frenchelderly women from the EPIDOS cohort we found inwinter 39% of subjects with a vitamin D insufficiency defined as a serum 25-OHD concentration below 12 ng/ml associated with biochemical indices of secondaryhyperparathyroidism and an increase in biochemicalmarkers of bone remodeling [5]. A clearcut vitamin Dinsufficiency inducing a PTH response was also foundrecently in 57% of 290 patients 152 men and 138women consecutively admitted to general medicalwards at the Massachusetts General Hospital in Boston[6], and in 14% of a healthy younger population of 1569French volunteers 765 men and 804 women with amean age of 50 + 6 years recruited in 20 cities fromthe SU.VI.MAX. cohort [7]. From these two recentstudies it appears that the threshold 25-OHD concentra-tion below which PTH secretion begins to increase ismuch higher than the classical one of 12 ng/ml. InSU.VI.MAX. volunteers [7] this threshold was about 28ng/ml and in the medical inpatients from Boston [6], it

was about 26 ng/ml.If vitamin D insufficiency is defined as a status of

hypovitaminosis D influencing calcium homeostasis andbone remodeling through stimulation of PTH secretion,this condition is much more common than waspreviously believed. This may indicate that a widespreadincrease in vitamin D and calcium intake is likely tohave a greater effect on osteoporosis and fractures thanmany interventions. Correction of calcium and vitaminD insufficiency should be the first step in any therapeuticstrategy in osteoporosis. It should be implementedbefore the introduction of any other active drug. Inaddition, the European population is at high risk forvitamin D insufficiency because of the high latitude,their lifestyle and a low nutritional supply of vitamin D.The fortification of food, which is done in only fewcountries of Northern Europe, should be encouraged inSouthern Europe (Greece, Italy, France, Spain, etc).

Other Nutritional Factors: Vitamin K

Since the first report on the role of vitamin K in speedingfracture healing [33], many data have suggested a role ofvitamin K in bone metabolism. Vitamin K1 is a majordietary form of vitamin K and is present in the green

Table 2. Effects of calcium and vitamin D supplementation on fractures and serum parathormone (PTH)

Daily dose Duration Population Mean Effects on Change in(yrs) (mean age) Ca intake/day fractures (Fx) sPTH (%)

Ca (mg) vit D (iu) (mg)

Chapuy 1994 [3] 1200 800 3 3270 F (84) 512 fewer hip and 47other non vert.Fx (p

7/29/2019 art-3A10.1007-2FPL00004161

4/5

parts of vegetables such as spinach, cabbage, cauliflowerand green beans, and in pigs liver and calves liver.Vitamin K plays an important role in gamma-carboxyla-tion of bone-specific Gla-containing proteins (mainlyosteocalcin, but also matrix Gla protein and protein S).The circulating levels of vitamin K, and of the vitaminK2 congeners, menaquinones MK7 and MK8, werefound to be significantly reduced in patients who hadsustained a hip or a spine fracture [34]. The degree ofvitamin K deficiency in humans can be assessed bymeasuring the undercarboxylated fraction of osteocalcin,either by the indirect method using hydroxyapatite[35,36], or more recently with a direct immunoassay[37]. Undercarboxylated osteocalcin in serum increaseswith aging in women, is negatively correlated with thehip BMD in elderly women and is a predictor of thesubsequent risk of hip fracture [36,37]. This observation,which was made initially in institutionalized elderlywomen [36], has been confirmed in independent healthyelderly women [37]. In vitro and in vivo data suggestthat the degree of carboxylation of osteocalcin is

dependent not only on vitamin K but also on vitaminD, and both vitamin K and vitamin D insufficiencies arecommon in elderly people. Whether these changes onlyreflect the impaired nutritional status of these patients orare responsible for increased bone fragility in the elderlyis not clear. Bone mineral measurements in patientstaking oral anticoagulants have shown mixed results. Ina short (6 months) placebo-controlled trial in 80osteoporotic patients, Orimo et al. [38] have shownthat in the group receiving 45 mg/day of vitamin K2 a1.3% increase in metacarpal BMD was observed,whereas a decrease of 3.8% was noted in the controlgroup. Further clinical trials are warranted, as vitamin Kappears to play a significant role in bone metabolism.

References

1. Heaney RP. Non-pharmacologic prevention of osteoporosis:nutrition and exercise. In: Meunier PJ, editor. Osteoporosis:diagnosis and management. London: Martin Dunitz, 1998:16174.

2. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calciumto prevent hip fractures in elderly women. N Engl J Med1992;237:163742.

3. Chapuy MC, Arlot ME, Delmas PD, et al. Effect of calcium andcholecalciferol treatment for three years on hip fractures inelderly women. BMJ 1994;308:10812.

4. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calciumand vitamin D supplementation on bone density in men andwomen 65 years of age or older. N Engl J Med 1997;337:6706.

5. Chapuy MC, Schott AM, Garnero P, et al. French women livingat home have secondary hyperparathyroidism and high boneturnover in winter. J Clin Endocrinol Metab 1996;81:112933.

6. Thomas KK, Lloyd-Jones DH, Thadhani RI, et al. Hypovitami-nosis D in medical inpatients. N Engl J Med 1998;338:77783.

7. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitaminD insufficiency in an adult normal population. Osteoporos Int1997;7:43943.

8. Docio S, Riancho JA, Perez A, et al. Seasonal deficiency ofvitamin D in children: a potential target for osteoporosis-preventing strategies? J Bone Miner Res 1998;13:5448.

9. Oooms ME, Roos JC, Bazemer PD, et al. Prevention of bone loss

by vitamin D supplementation in elderly women: a randomizeddouble blind trial. J Clin Endocrinol Metab 1995;80:10528.

10. Meunier PJ, Chapuy MC, Arlot ME, et al. Can we stop bone lossand prevent hip fractures in the elderly? Osteoporos Int1994;4(Suppl)1:716.

11. Rosen CJ, Morrison A, Zhou H, et al. Elderly women in NorthernNew England exhibit seasonal changes in bone mineral densityand calciotropic hormones. Bone Miner 1994;2:8392.

12. Khaw KT, Sheyd MJ, Compston J. Bone density, parathyroid

hormone and 25-hydroxyvitamin D concentrations in middle-aged women. BMJ 1992;305:2737.13. Lukert B, Higgins J, Stoskopf M. Menopausal bone loss is

partially regulated by dietary intake of vitamin D. Calcif TissueInt 1992;51:1739.

14. Fardellone P, Brazier M, Kamel S, et al. Biochemical effects ofcalcium supplementation in postmenopausal women: influence ofdietary calcium intake. Am J Clin Nutr 1998;67:1273-8.

15. Reginster JY, Denis D, Bartsch V, et al. Acute biochemicalvariations induced by four different calcium salts in healthy malevolunteers. Osteoporos Int 1993;3:2715.

16. Riggs BL, OFallon WM, Muhs J, et al. Long-term effects ofcalcium supplementation on serum parathyroid hormone level,bone turnover and bone loss in elderly women. J Bone Miner Res1998;13:16874.

17. Recker RR, Saville PD, Heaney RP. Effect of estrogens andcalcium carbonate on bone loss in postmenopausal women. Ann

Intern Med 1977;87:64955.18. Riis B, Thomsen K, Christiansen C. Does calcium supplementa-

tion prevent postmenopausal bone loss? a double-blind, con-trolled clinical trial. N Engl J Med 1987;316:1737.

19. Hansson T, Roos B. The effect of fluoride and calcium on spinalbone mineral content: a controlled, prospective (3 years) study.Calcif Tissue Int 1987;40:3157.

20. Smith EL, Gilligan C, Smith PE, et al. Calcium supplementationand bone loss in middle-aged women. Am J Clin Nutr1989;50:83342.

21. Dawson-Hughes B, Dallal GE, Krall EA, et al. A controlled trialof the effect of calcium supplementation on bone density inpostmenopausal women. N Engl J Med 1990;323:87883.

22. Elders PJM, Netelenbos JC, Lips P, et al. Calcium supplementa-tion reduces vertebral bone loss in perimenopausal women: acontrolled trial in 248 women between 46 and 55 years of age. J

Clin Endocrinol Metab 1991;73:53340.23. Aloia JF, Vaswani A, Yeh JK, et al. Calcium supplementationwith and without hormone replacement therapy to preventpostmenopausal bone loss. Ann Intern Med 1994;120:97103.

24. Chevalley T, Rizzoli R, Nydegger V, et al. Effects of calciumsupplements on femoral bone mineral density and vertebralfracture rate in vitamin D replete elderly patients. Osteoporos Int1994;4:24552.

25. Prince R, Devine A, Dick I, et al. The effects of calciumsupplementation (milk powder or tablets) and exercise on bonedensity in postmenopausal women. J Bone Miner Res1995;10:106875.

26. Reid IR, Ames RW, Evans MC, et al. Long-term effects ofcalcium supplementation on bone loss and fractures in post-menopausal women: a randomized controlled trial. Am J Med1995;98:3315.

27. Recker RR, Hinders S, Davies KM, et al. Correcting calcium

nutritional deficiency prevents spine fractures in elderly women. JBone Miner Res 1996;11:19616.

28. Osteoporosis: review of the evidence for prevention, diagnosisand treatment and cost effectiveness analysis. Report from theNational Osteoporosis Foundation. Osteoporos Int 1998;8(Suppl4).

29. Heikinheimo RJ, Inkovaara JA, Harju EJ, et al. Annual injectionsof vitamin D and fractures on aged bones. Calcif Tissue Int1992;52:11405.

30. Lips P, Graafmans WC, Ooms ME, et al. Vitamin Dsupplementation and fracture incidence in elderly persons. AnnIntern Med 1996;124:4006.

31. Chel VGM, Ooms ME, Popp-Snijders C, et al. Ultravioletirradiation corrects vitamin D deficiency and suppresses

Calcium, Vitamin D and Vitamin K in the Prevention of Fractures 51

7/29/2019 art-3A10.1007-2FPL00004161

5/5

secondary hyperparathyroidism in the elderly. J Bone Miner Res1998;8:123842.

32. Van der Wielen RP, Lowik MRH, Van der Berg H, et al. Serum25-OHD concentrations among elderly people in Europe. Lancet1995;346:20710.

33. Bouckaert JH, Said AH. Fracture healing by vitamin K. Nature1960;185:849.

34. Hodges SJ, Pilkington MJ, Stam TCB, et al. Depressed levels ofcirculating menaquinones in patients with osteoporotic fractures

of the spine and femoral neck. Bone 1991;12:3879.35. Szulc P, Chapuy MC, Meunier PJ, et al. Serum undercarboxylatedosteocalcin is a marker of the risk of hip fracture in elderlywomen. J Clin Invest 1993;91:176974.

36. Szulc P, Chapuy MC, Meunier PJ, et al. Serum undercarboxylatedosteocalcin is a marker of the risk of hip fracture: a three yearfollow-up study. Bone 1996;5:4878.

37. Vergnaud P, Garnero P, Meunier PJ. Undercarboxylatedosteocalcin measured with a specific immunoassay predicts hipfracture in elderly women: the EPIDOS study. J Clin EndocrinolMetab 1997;82:71924.

38. Orimo H, Shiraki M. Clinical evaluation of menatetrenone(vitamin K2) in the treatment of involutional osteoporosis. In:

Christiansen C, Riis B, editors. Proceedings of the fourthinternational symposium on osteoporosis, Hong Kong,1993:1489.

52 P. J. Meunier