Osteoporos Int (1999) Suppl.

2:S48S52 1999 International Osteoporosis Foundation and National Osteoporosis Foundation

Osteoporosis
International

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

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 cellular metabolic functions and is accumulated as a vast reserve in the skeleton. Dietary calcium insufciency virtually never impairs those cellular functions but inuences the size of the calcium reserve through the mobilization necessary to maintain a normal blood calcium level. This is achieved through an increase in parathyroid function, which accelerates bone remodeling and indirectly induces a decrease in bone mass and bone strength. Conversely, in addition to being a substrate for bone mineralization, calcium has an inhibitory effect on bone remodeling through suppression of circulating parathyroid hormone (PTH). These mechanisms make us realize that calcium intake plays an important role in the etiology and pathogenesis of osteoporosis. We literally walk about on our calcium reserve. It is this unique feature of calcium nutrition that is the basis for the linkage of calcium intake and osteoporosis. It is also important to understand that calcium functions as a threshold nutrient [1]. This means that below some critical value about 700800 mg/day bone mass will be limited by available calcium supplies, whereas above that threshold value, no further benet will accrue from additional increases in intake. The current recommended calcium intake is 1200 mg/day for adults. Vitamin D, which facilitates active transport of calcium across the intestinal mucosa, is particularly important for adaptation to low calcium intakes. It is generally considered that vitamin D status inuences absorptive performance and that it thereby inuences the calcium requirement [1]. In contrast to the extensive attention paid to vitamin D as a component of nutritional health in infants and children, for whom vitamin D deciency was synonymous with rickets, the relationship
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.

of vitamin D with the nutritional health of adults or elderly subjects was largely ignored before the mid1970s and was only shown when the assays for serum 25-hydroxyvitamin D (25-OHD) became available. It is well known that severe and long-lasting vitamin D deciency leads to frank osteomalacia due to a major inhibition of primary mineralization of bone. In addition, growing evidence demonstrates that a less severe reduction in serum 25-OHD levels can already have deleterious effects on bone density, even if osteomalacia is not present, through an increase in serum PTH concentration. This vitamin D insufciency or subclinical vitamin D deciency is a major determinant of serum PTH increase leading to a stimulation of osteoclastic bone resorption and bone remodeling which increases bone 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 of the skin and also from dietary intake. A reduction of one or both sources unavoidably leads to vitamin D insufciency. Elderly subjects are at high risk of vitamin D insufciency because they avoid direct sun or take protective action to reduce sunlight exposure or are unable to go outdoors because of an inability to walk. Recommendations for reducing the risk of melanoma have worsened the lack of sun exposure. In addition, the capacity of elderly skin to produce previtamin D3 is reduced. The degree of hypovitaminosis D is greater in winter and at high latitudes. The main natural sources of dietary vitamin D are fatty shes, sh liver oil or to a lesser extent eggs. Only small amounts of these foods are consumed by elderly people in most countries with the exception of Scandinavian countries and Japan in spite of the need to maintain vitamin D stores during the wintertime by an increase in oral intake. The current US recommended adequate daily intake for vitamin D is 5 mg (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 (1977 recommendations from the National Academy of Sciences and Institute of Medicine of the USA). The fortication of milk in North America is only effective

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

49

for people who actually drink milk and many elderly people have completely stopped drinking milk. Vitamin D insufciency is often combined with low dietary calcium intake and is increasingly recognized to be a cause of secondary hyperparathyroidism and indirectly of bone fragility. This is true not only in elderly people living in institutions where it was rst described, but also in free-living old people, normal adults and children. Several authors have demonstrated the reversibility of the senile secondary hyperparathyroidism after administration of calcium alone, after vitamin D alone, or more effectively after supplements combining calcium and vitamin D, but as long as it had not been demonstrated that the correction of the low vitamin D and calcium status was capable of preventing fractures, the role of senile secondary hyperparathyroidism as a causal determinant of fracture risk remained to be proven. In the last 6 years two randomized control trials have shown that combined supplements of calcium and vitamin D were capable of preventing nonvertebral fractures in elderly people living either in institutions [2,3] or at home [4]. In the meantime other recent studies have demonstrated a high incidence of vitamin D insufciency and secondary hyperparathyroidism in independent French [5] and American [6] elderly subjects, in normal French adults [7] and in Spanish children [8]. This is relevant to the possibility of calciumvitamin D supplements for correcting these nutritional decits and preventing bone loss and fractures not only in the elderly population but in younger patients. Interestingly, several studies have shown a signicant relationship between femoral neck bone mineral density (BMD), serum 25-OHD levels and PTH, not only in elderly people [911] but also in middle-aged women [12,13].

(r = 70.48; p = 0.0002). No relationship was found in a population of 58 women who had a daily calcium intake higher than 786 mg [14]. This conrms the role of calcium as a threshold nutrient, with a rise in PTH beginning at calcium intake values lower than this threshold. Short- and long-term studies have shown that calcium supplements are capable of inducing a signicant decrease in serum PTH. In young healthy male volunteers, four calcium preparations induced a marked suppression of PTH (737% to 757%) in the 6 h following the administration of 1000 mg calcium [15]. In a 4-year placebo-controlled clinical trial in 236 normal postmenopausal women, calcium supplementation of 1600 mg/day induced an 18.9% reduction in serum PTH (calcium group vs placebo group). Fifty percent of this population had a dietary calcium intake lower than 714 mg/day. A small but signicant decrease in bone loss was observed in parallel [16]. Effects on Bone Mineral Density. Eleven studies involving about 2000 postmenopausal women compared calcium supplements (5002600 mg/day for 1.54 years) with a placebo or a control group [1626]. These studies have shown that women whose diets were supplemented with calcium had a lower rate of bone loss than untreated women. In most of the studies women with calcium supplementation had BMDs that were 13% higher than the BMDs of women who did not receive calcium. Calcium supplements usually have a smaller effect on BMD in women within the rst 5 years after menopause than in women more than 5 years after menopause. Effects on Fracture Incidence. The effects of calcium on fracture incidence have been assessed in three randomized trials (Table 1) with a reduction in the fracture probability of about one-third, but the range of uncertainty is too wide to make a denitive statement about the magnitude of the effect or to perform a valid cost-effectiveness analysis [28].

Effects of Calcium, Vitamin D and Calcium Vitamin D Combination on Bone Metabolism, Bone Density and Fractures
Calcium Supplementation
Effects on Parathyroid Function. A recent study found a signicant negative relationship between dietary calcium intake and iPTH in a population of 58 healthy postmenopausal women (mean age 64 + 5.3 years) who had a dietary calcium intake lower than 786 mg/day
Table 1. Effects of calcium supplementation on fractures Dose/day (mg) Chevalley 1994 [24] Recker 1996 [27] Reid 1995 [26] * vitamin D replete 800* 1200 1000 Duration (yrs) 1.5 4.3 4.0

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

Population (mean age) 93 healthy M and F (72.1) 251 F (73.5) 78 healthy F (58.5)

Effects on Fractures (Fx) Fewer new vert.Fx (p=0.05) Fewer new vert.Fx in the subset with prior vert.Fx (p=0.023) Fewer new Fx (all) (p=0.037)

50

P. J. Meunier

nursing homes (mean age 82.8 years) Heikinheimo et al. [29] injected 150 000 or 300 000 IU of vitamin D2 once a year for 4 years. They found fewer fractures of all types in the vitamin D group (16%) than in the control group (22%) (p = 0.034). A breakdown of the results by fracture site showed a signicant reduction in upper-limb fractures combined (p = 0.025) but not in hip fractures. Lips et al. [30], in a 4-year randomized trial, compared the effects of 400 IU/day of vitamin D3 with those of a placebo in 2578 Dutch subjects, 25% of whom were men. Their mean dietary calcium intake from dairy products was 868 mg/day and no calcium was given. No decrease in the incidence of hip fractures and other peripheral fractures was observed in the group receiving the vitamin D supplementation. A small and nonsignicant decrease in serum PTH (about 715%) was observed in a nonrandom sample of the subjects who had received vitamin D. In a more recent study by Lips group [31], ultraviolet irradiation in 45 psychogeriatric women (mean age 85 years) 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 in increasing serum 25-OHD and suppressing secondary hyperparathyroidism (decrease in sPTH greater than 30% in both group after 3 months).

Calcium and Vitamin D Combination

Two controlled studies performed in French institutionalized elderly women [2,3] and in independent elderly American men and women [4] have demonstrated a signicant protective effect against hip and other nonvertebral fractures by a combined supplement of calcium and vitamin D, with, in parallel, signicant increases in BMD and a decrease in serum PTH (Table 2). The effective prevention of fractures observed with calciumvitamin D combination in independent elderly women and men [4] is of particular interest because the concept of calcium and vitamin D insufciencies inducing secondary hyperparathyroidism has been extended from the institutionalized elderly population to free-living elderly subjects and younger people. During the Euronut Seneca study, serum 25-OHD concentrations were measured during wintertime in free-living elderly people from 11 European countries

[32]: 36% of men and 47% of women had values below 30 nmol/l (12 ng/ml). In free-living healthy French elderly women from the EPIDOS cohort we found in winter 39% of subjects with a vitamin D insufciency dened as a serum 25-OHD concentration below 12 ng/ ml associated with biochemical indices of secondary hyperparathyroidism and an increase in biochemical markers of bone remodeling [5]. A clearcut vitamin D insufciency inducing a PTH response was also found recently in 57% of 290 patients 152 men and 138 women consecutively admitted to general medical wards at the Massachusetts General Hospital in Boston [6], and in 14% of a healthy younger population of 1569 French volunteers 765 men and 804 women with a mean age of 50 + 6 years recruited in 20 cities from the SU.VI.MAX. cohort [7]. From these two recent studies it appears that the threshold 25-OHD concentration below which PTH secretion begins to increase is much higher than the classical one of 12 ng/ml. In SU.VI.MAX. volunteers [7] this threshold was about 28 ng/ml and in the medical inpatients from Boston [6], it was about 26 ng/ml. If vitamin D insufciency is dened as a status of hypovitaminosis D inuencing calcium homeostasis and bone remodeling through stimulation of PTH secretion, this condition is much more common than was previously believed. This may indicate that a widespread increase in vitamin D and calcium intake is likely to have a greater effect on osteoporosis and fractures than many interventions. Correction of calcium and vitamin D insufciency should be the rst step in any therapeutic strategy in osteoporosis. It should be implemented before the introduction of any other active drug. In addition, the European population is at high risk for vitamin D insufciency because of the high latitude, their lifestyle and a low nutritional supply of vitamin D. The fortication of food, which is done in only few countries of Northern Europe, should be encouraged in Southern Europe (Greece, Italy, France, Spain, etc).

Other Nutritional Factors: Vitamin K

Since the rst report on the role of vitamin K in speeding fracture healing [33], many data have suggested a role of vitamin K in bone metabolism. Vitamin K1 is a major dietary 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 Ca (mg) Chapuy 1994 [3] 1200 vit D (iu) 800 3 3270 F (84) Duration (yrs) Population (mean age) Mean Ca intake/day (mg) 512 Effects on fractures (Fx) Change in sPTH (%)

fewer hip and other non vert. Fx (p <0.02) fewer non vert. Fx (p <0.02)

47

Dawson-Hughes 1997 [4]

500

700

380 F+M (71)

725

33 (in F)

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

51 by vitamin D supplementation in elderly women: a randomized double blind trial. J Clin Endocrinol Metab 1995;80:10528. Meunier PJ, Chapuy MC, Arlot ME, et al. Can we stop bone loss and prevent hip fractures in the elderly? Osteoporos Int 1994;4(Suppl)1:716. Rosen CJ, Morrison A, Zhou H, et al. Elderly women in Northern New England exhibit seasonal changes in bone mineral density and calciotropic hormones. Bone Miner 1994;2:8392. Khaw KT, Sheyd MJ, Compston J. Bone density, parathyroid hormone and 25-hydroxyvitamin D concentrations in middleaged women. BMJ 1992;305:2737. Lukert B, Higgins J, Stoskopf M. Menopausal bone loss is partially regulated by dietary intake of vitamin D. Calcif Tissue Int 1992;51:1739. Fardellone P, Brazier M, Kamel S, et al. Biochemical effects of calcium supplementation in postmenopausal women: inuence of dietary calcium intake. Am J Clin Nutr 1998;67:1273-8. Reginster JY, Denis D, Bartsch V, et al. Acute biochemical variations induced by four different calcium salts in healthy male volunteers. Osteoporos Int 1993;3:2715. Riggs BL, OFallon WM, Muhs J, et al. Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover and bone loss in elderly women. J Bone Miner Res 1998;13:16874. Recker RR, Saville PD, Heaney RP. Effect of estrogens and calcium carbonate on bone loss in postmenopausal women. Ann Intern Med 1977;87:64955. Riis B, Thomsen K, Christiansen C. Does calcium supplementation prevent postmenopausal bone loss? a double-blind, controlled clinical trial. N Engl J Med 1987;316:1737. Hansson T, Roos B. The effect of uoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study. Calcif Tissue Int 1987;40:3157. Smith EL, Gilligan C, Smith PE, et al. Calcium supplementation and bone loss in middle-aged women. Am J Clin Nutr 1989;50:83342. Dawson-Hughes B, Dallal GE, Krall EA, et al. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1990;323:87883. Elders PJM, Netelenbos JC, Lips P, et al. Calcium supplementation reduces vertebral bone loss in perimenopausal women: a controlled trial in 248 women between 46 and 55 years of age. J Clin Endocrinol Metab 1991;73:53340. Aloia JF, Vaswani A, Yeh JK, et al. Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med 1994;120:97103. Chevalley T, Rizzoli R, Nydegger V, et al. Effects of calcium supplements on femoral bone mineral density and vertebral fracture rate in vitamin D replete elderly patients. Osteoporos Int 1994;4:24552. Prince R, Devine A, Dick I, et al. The effects of calcium supplementation (milk powder or tablets) and exercise on bone density in postmenopausal women. J Bone Miner Res 1995;10:106875. Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995;98:3315. Recker RR, Hinders S, Davies KM, et al. Correcting calcium nutritional deciency prevents spine fractures in elderly women. J Bone Miner Res 1996;11:19616. Osteoporosis: review of the evidence for prevention, diagnosis and treatment and cost effectiveness analysis. Report from the National Osteoporosis Foundation. Osteoporos Int 1998; 8(Suppl4). Heikinheimo RJ, Inkovaara JA, Harju EJ, et al. Annual injections of vitamin D and fractures on aged bones. Calcif Tissue Int 1992;52:11405. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. Ann Intern Med 1996;124:4006. Chel VGM, Ooms ME, Popp-Snijders C, et al. Ultraviolet irradiation corrects vitamin D deciency and suppresses

parts of vegetables such as spinach, cabbage, cauliower and green beans, and in pigs liver and calves liver. Vitamin K plays an important role in gamma-carboxylation of bone-specic Gla-containing proteins (mainly osteocalcin, but also matrix Gla protein and protein S). The circulating levels of vitamin K, and of the vitamin K2 congeners, menaquinones MK7 and MK8, were found to be signicantly reduced in patients who had sustained a hip or a spine fracture [34]. The degree of vitamin K deciency in humans can be assessed by measuring 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 increases with aging in women, is negatively correlated with the hip BMD in elderly women and is a predictor of the subsequent risk of hip fracture [36,37]. This observation, which was made initially in institutionalized elderly women [36], has been conrmed in independent healthy elderly women [37]. In vitro and in vivo data suggest that the degree of carboxylation of osteocalcin is dependent not only on vitamin K but also on vitamin D, and both vitamin K and vitamin D insufciencies are common in elderly people. Whether these changes only reect the impaired nutritional status of these patients or are responsible for increased bone fragility in the elderly is not clear. Bone mineral measurements in patients taking oral anticoagulants have shown mixed results. In a short (6 months) placebo-controlled trial in 80 osteoporotic patients, Orimo et al. [38] have shown that in the group receiving 45 mg/day of vitamin K2 a 1.3% increase in metacarpal BMD was observed, whereas a decrease of 3.8% was noted in the control group. Further clinical trials are warranted, as vitamin K appears to play a signicant role in bone metabolism.

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17. 18. 19. 20. 21. 22.

23.

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