Calcium and Vitamin D in Promotion of Postmenopausal Bone Health

“One reason for the small effects in RCTs may be that most of the studies have been conducted on affluent Western populations with a high baseline Ca intake.”

The state of knowledge regarding the need and dosage of calcium and vitamin D supplementation for postmenopausal women is changing Recently, it has become evident that former vitamin D supplementation recommendations have been too low to attain serum 25(OH)D levels of approximately 75 nmol/l, which is currently held as the optimal vitamin D repletion status for minimization of bone loss and fractures. To attain this level, a vitamin D supplementation of 800 IU daily in the absence of sufficient sunlight exposure is required. Calcium intake recommendations vary from 700 to 1500 mg a day thus reflecting uncertainty regarding optimal calcium intake. A few recent studies suggest that in vitamin D replete women a lower calcium intake (e.g., 800 mg/day) may be sufficient, whereas in vitamin D insufficiency, the need for calcium intake is higher. However, this opinion should be corroborated with a few new well-conducted studies

Calcium (Ca) is the main mineral of bone tissue. Ca intake recommendations for postmenopausal women in western countries vary from 700 to 1500 mg per day reflecting the uncertainty regarding optimal Ca intake.

Vitamin D (Dvit) regulates Ca and bone metabolism. For example, it promotes Ca absorption from the intestine, mediates bone mineralization and lowers bone resorption. Dvit is required for the optimal functioning of several extraskeletal tissues such as muscle [1]. Muscle functioning is related to falls and fractures. Natural sources of Dvit are sunlight and nutrition. Food fortification and Dvit supplementation have been used to ensure adequate intakes. However, Dvit insufficiency is still common in the elderly.

In this article the present state of knowledge regarding the value of Ca and Dvit supplementation in promoting the bone health of postmenopausal women is discussed.

Bone mineral density effects

Former randomized clinical trials (RCTs) have usually shown beneficial (although minor) effects of Ca supplementation on bone mineral density (BMD) in postmenopausal women [2–4]. However, observational studies have often not found that nutritional Ca prevents bone loss. The reason may be the compromised accuracy of the self-reported Ca intake [5].

More recent RCTs have usually used a combination of Ca and Dvit. These studies have also usually shown a moderate bone loss preventing effect in postmenopausal women. For example, Dawson-Hughes et al. conducted a 3-year RCT on persons aged 65 years and over, living at home with a regimen of Ca 500 mg of and cholecalciferol 700 IU, which moderately reduced bone loss; however, only the total body BMD change at the end of the follow-up differed from that of the placebo group [6]. Previously, the recommended daily Dvit intake for postmenopausal women as well as the dose used in Dvit RCTs tended to be low. For example, the large Women's Health Initiative (WHI) study used a Dvit dose of 400 IU with Ca 1000 mg on postmenopausal women with a mean baseline Ca intake of 1150 mg/day and found a small positive effect of 1% in 8 years only at the proximal femur BMD [7]. Peacock et al. formed Ca and Dvit supplementation groups of their own in their 4-year RCT on women aged 60 years or older with a low mean baseline Ca intake of 574 mg/day, which enabled the comparison of the Ca (750 mg) and Dvit₃ (600 IU) effects on femoral bone loss [8]. The Ca group maintained femoral BMD and medullary width as well as reduced bone turnover better than Dvit or placebo groups. Another 5-year RCT on elderly women from Australia with plain Ca supplementation found that Ca improved ultra sound broadband alternation and stiffness but not speed of sound values, and decreased serum parathyroid hormone values [9].

Our 3-year open Ca (1000 mg) and Dvit (800 IU) supplementation RCT to prevent bone loss in 593 Finnish women aged 65–74 years (Kuopio, Finland [located on the northern latitude –63°]) with a total baseline Ca intake of 1200 mg/day) displayed a moderate effect in the total body and ward BMDs but not at other femoral sites [10]. In adherent women, effects were larger (0.5–1.2%) and were found to be significant (p < 0.002 – 0.0001) at every measurement site except spine.

One reason for the small effects in RCTs may be that most of the studies have been conducted on affluent Western populations with a high baseline Ca intake. For example, in our study [10] the mean dairy, total nutritional and total Ca intakes have been on average 800, 1100 and 1200 mg/day, respectively, during the last 20 years. Awareness of risk factors has also improved. In Kuopio, this has not increased the population dairy Ca intake, but has increased serum 25(OH)D of 65–74 year old women from 30 to 50 nmol/l between 1985 and 2003 and has greatly improved the dairy Ca intake of certain specific risk groups such as women with lactose intolerance. Conversely, studies on women with lower baseline Ca intake [2,8] displayed a fair Ca effect.

A recent cross-sectional study found that serum 25(OH)D was associated with hip BMD more closely than dietary Ca, which was related to BMD only in women with low serum 25(OH)D suggesting that Dvit-repleted women may need Ca less (~600 mg/day) than Dvit-deficient women [11]. Longitudinal studies are required for corroboration of these results. Nonetheless, the true value of high Ca intakes as well as the optimal Ca intake levels still remain to be determined.

Fracture risk effects

Low BMD is a risk factor for fractures; therefore, it would be logical that Ca would protect from fracture. However, fracture studies have left us uncertain if adequate or abundant Ca and/or Dvit intakes prevent fractures and what are the preventive intake levels. Some osteoporotic fracture studies have found a preventive Ca effect [12,13] but some others have not [7,14]. Reasons for these discrepant results may include age, race, source and amount of Ca intake and type of fracture. For example, low dairy Ca intake predicted early postmenopausal wrist fracture [12] and postmenopausal hip fracture [Honkanen R, Unpublished data; ASBMR Honolulu abstract, 2007] in a prospective cohort study but failed to predict hip fracture in older US women in a prospective cohort study [14]. Other reasons for discrepant results might include differences in the accuracy of Ca intake self-reports, differences in the use of Ca supplements or in Dvit repletion statuses, which may be due to latitude, nutrition or fortification of foods with Dvit. For example, the proportion of the dairy Ca intake of the total Ca intake was high (75%) in our study [12]. It might be that dairy Ca intake is fairly stable and its self-report quite accurate. Finally, race or low population Ca intake may affect results; low Ca intake of below 400 mg per day was a strong (threefold) predictor of osteoporotic fractures in Chinese postmenopausal women [13].

In RCTs on fracture risk, sufficient baseline Ca and Dvit intakes, low compliance and power problems are causes of negative results [7,9,15]. Yet even recent well-powered large RCTs have often not shown an effect. For example, the huge WHI trial [7], on the role of Ca (1000 mg/day) and Dvit (400 IU/day) on fracture risk did not register an effect on the risks of hip, vertebral, wrist or total fractures. However, the hip fracture preventing effect was found in WHI subgroup analyses: in compliant women (29%), in women 60 years of age or older (21%) and in women not using personal Ca supplements (30%).

“There is also some evidence that Ca supplements might increase the risk of coronary heart disease.”

Regarding fracture risk, falling tendency is an important factor besides reduced bone strength, and Dvit seems to prevent falls as well [1].

Most of the Dvit studies on the risk of fracture related to Dvit have included Ca in the supplementation regimen. Previously, the Dvit dose has tended to be rather low. For example, in the WHI study, the daily dose was 400 IU [7]. The small effect in that study may primarily be due to the high baseline Ca intake of 1150 mg per day and small Dvit dose as well as to low compliance. In fact, the effect was 2.5-fold and statistically significant in compliant women.

The meta-analysis on 12 Dvit RCTs by Bischoff-Ferrari et al. showed that a higher Dvit dose (>400 IU/day) prevented fractures (20%) but a lower dose did not [16]. However, seven out of nine of the high-dose studies but only one-third of the low-dose studies included Ca supplementation. In fact, a new meta-analysis showed that Dvit in combination with Ca is effective in fracture prevention [17]. Our open 3-year Ca (1000 mg) and Dvit (800 IU) RCT on 3432 women aged 65–74 years did not register a fracture preventive effect [15]. Reasons for our negative result include low fracture incidence, high baseline Ca and moderate Dvit repletion (25[OH]D = 50 nmol/l), open design and low compliance.

Disadvantages of Ca & Dvit supplementation

Gastrointestinal complaints are well-known side-effects of Ca supplements. Dvit is more prone to cause hypercalcemia, hypercalciuria and urinary tract stones than Ca alone. A recent study suggests that very high doses of Dvit orally may increase the risk of falls and fractures [18]. There is also some evidence that Ca supplements might increase the risk of coronary heart disease [19,20].

Conclusion

For postmenopausal women, the total Ca intake from nutrition and supplements should be about 800–1200 mg/day depending on the body size, health and osteoporosis situation. If sunlight exposure is scanty, Dvit supplementation of 800 IU/day is needed with the aim to attain a 25(OH) D serum level of 75 nM. The opinion that this Dvit level makes high Ca intake of 800 mg or more unnecessary still requires large and well-conducted studies for corroboration. We hope that new investigations will shed light on reciprocal Ca and Dvit relationships regarding metabolism and skeletal and extraskeletal effects. Affluent Western postmenopausal populations often have such high Ca intakes that, in the future, care should be taken to also recruit low-intake subjects into studies and to also conduct studies in Southeast Asia where intakes are low and the majority of elderly females live. Inclusion of extraskeletal health indicators in these new studies is well founded.

Future perspective

Vitamin D repletion of western populations will be better than it is at present. New studies conducted in western and Asian countries will show if the improvement of Dvit repletion in postmenopausal women decreases the need of high Ca intakes

Executive summary

• The need and dosage of calcium and vitamin D supplementation in postmenopausal women is discussed.

• Calcium intake recommendations vary greatly (i.e., 700–1500 mg/day).

• Vitamin D replete status seems to be 75 nml/l or more of serum 25(OH)D.

• To attain vitamin D replete status, a supplementation of 800 IU/day may be required.

• Calcium and vitamin D strengthen the effects of each other: In vitamin D replete women, the need for calcium may be lower than in vitamin D deficient women