Responses of parathyroid hormone to vitamin D supplementation: A systematic review of clinical trials

Archives of Gerontology and Geriatrics 48 (2009) 160–166

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Responses of parathyroid hormone to vitamin D supplementation: A systematic review of clinical trials Mikko Bjo¨rkman a,*, Antti Sorva b, Rejo Tilvis a a b

Clinics of Internal Medicine and Geriatrics, Helsinki University Central Hospital, POB 340, FI-00290 HUS, Helsinki, Finland Department of Long-Term Care, Helsinki City Hospital, Laakso, POB 6600, FI-00099 Helsinki City, Finland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 16 July 2007 Received in revised form 4 December 2007 Accepted 8 December 2007 Available online 19 February 2008

The beneficial bone effects of vitamin D supplementation have been attributed to suppression of secondary hyperparathyroidism by 25-hydroxyvitamin D (25-OHD) levels at least 50 nmol/l. In this systematic review, we have analyzed the results of 52 clinical trials, including 72 intervention groups and 6290 patients, on vitamin D supplementation in order to evaluate the experimental evidence and the effects of age and chronic immobility on responses of parathyroid hormone (PTH). The papers for this systematic review were selected through a search in PubMed and through a review of the reference lists of articles. Negative logarithmic (R2 = 0.318, p < 0.001) and linear (R2 = 0.294, p < 0.001) correlations were found between 25-OHD and PTH levels, when all pre- and post-trial values were scattered. Negative linear (R2 = 0.385, p < 0.001) and logarithmic (R2 = 0.406, p < 0.001) correlations were also found between the changes in 25-OHD and PTH levels. Age correlated negatively with changes in PTH (r = 0.476, p < 0.001). The vitamin D supplementation of the chronically immobile patients resulted in a smaller decrease in PTH levels ( 8.4 vs. 17.4%, p < 0.001) despite a larger increase in 25-OHD levels (187.2% vs. 109.8%, p < 0.001). According to the multiple regression analysis the changes in PTH were independently predicted by pre-trial PTH, changes in 25-OHD, age and chronic immobility, explaining 53.2% (R2 = 0.532) of the variation. This meta-analysis shows that responses of PTH to vitamin D supplementation are not only determined by the baseline PTH levels and changes in vitamin D status, but also by age and mobility of the patients. Our results also suggest that PTH decreases quite linearly during vitamin D supplementation at any given 25-OHD level. Longitudinal vitamin D supplementation studies on populations with wide range of mobility and age are needed to further elucidate their confounding effects. In determining the sufficient doses of vitamin D supplementation and adequate 25-OHD levels, these confounding effects and the inter-individual variation in responses of PTH to vitamin D supplementation should be taken into account. ß 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Parathyroid hormone Vitamin D Chronic immobility in older age

1. Introduction Vitamin D deficiency causes secondary hyperparathyroidism (SHPT) accelerating senile bone loss (Parfitt et al., 1982). The deficiency is especially common in aging institutionalized patients (Lips, 2001; Mosekilde, 2005). Vitamin D supplementation has been shown to decrease plasma levels of PTH, to temper the elevations of biochemical bone turnover markers and to increase bone mineral density (Lips, 2001). These beneficial bone effects have been attributed to suppression of SHPT through a decrease in PTH. The estimates of 25-OHD levels needed to prevent SHPT have been between 25 nmol/l and 122 nmol/l (Aloia et al., 2005).

* Corresponding author. Tel.: +358 50 3414 022; fax: +358 9 4717 4693. E-mail address: mikko.bjorkman@helsinki.fi (M. Bjo¨rkman). 0167-4943/$ – see front matter ß 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2007.12.005

Recently, it has, however, become commonly held that the serum level of 25-OHD should be 50 nmol/l or greater, below which PTH increases above the optimally low plateau level (Malabanan et al., 1998; Heaney et al., 2003; Lips, 2004; Mosekilde, 2005; Need, 2006). Vitamin D supplementation reaching these 25-OHD levels has been shown to reduce the risk of falls and osteoporotic fractures (Bischoff-Ferrari et al., 2004; Tang et al., 2007). In this systematic review, we have analyzed the results of 52 clinical trials, including 72 intervention groups and 6290 patients, on vitamin D supplementation in order to evaluate the experimental evidence on responses of PTH to vitamin D supplementation. The second aim of this literature analysis was to find out the possible factors affecting the responses of PTH and 25-OHD to vitamin D supplementation. In addition to vitamin D status and PTH levels the emphasis was laid on the impact of age and chronic immobility.

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2. Materials and methods 2.1. Search for trials The papers for this systematic review were selected through a search in PubMed using the terms ‘‘vitamin D’’ and ‘‘parathyroid hormone’’. The search was limited to clinical or randomized controlled trials that were performed on adults and reported in English. The primary search was done in February 2007 and the search disclosed 519 articles. The flow chart of the articles is presented in Fig. 1. By scanning the abstracts of the articles, a total of 102 trials adressing cholecalciferol or ergocalciferol supplementation with or without calcium was found. Supplementation trials lasting less than 2 weeks or performed on patients with medication, chronic illness, or condition (other than chronic immobilization or osteoporosis) known to markedly affect calcium metabolism were excluded. The authors of the largest trials with insufficiently reported data were contacted in order to include all possible data. However, to avoid the distortion of the analyses we were forced to exclude two trials: one trial (Barger-Lux et al., 1998) with 25-OHD levels widely outside the range of all the other trials and another trial (Aloia et al., 1991) that reported decreases in mean 25-OHD levels despite vitamin D supplementation. In addition to these two trials, five small trials (Scragg et al., 1995; Patel et al., 2001; Aloia et al., 2005; Bauman et al., 2005; Johnson et al., 2005) were also excluded, because all the variables used in our analyses were not reported and we were not able to contact the authors of these papers. Thus, we were able to obtain sufficient data from 41 trials included to the primary search (Chapuy et al., 1987, 1992, 1996, 2002; Himmelstein et al., 1990; Khaw et al., 1994; Sorva et al., 1994; Sebert et al., 1995; Francis et al., 1996; Kamel et al., 1996; Prestwood et al., 1996; Van Der Klis et al., 1996; Chel et al., 1998; Heikkinen et al., 1998; Theiler et al., 1998; Krieg et al., 1999; Hunter et al., 2000; Kurland et al., 2000; Kenny et al., 2001, 2003; Lips et al., 2001; Pfeifer et al., 2001; Harris and Dawson-Hughes, 2002; Deroisy et al., 2002; Jensen et al., 2002; Gannage-Yared et al., 2003; Tangpricha et al., 2003; Harwood et al., 2004; Meier et al., 2004; Brazier et al., 2005; Diamond et al., 2005; Goussous et al., 2005; Magno et al., 2005; Serhan and Holland,

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2005; Barnes et al., 2006; Law et al., 2006; Mastaglia et al., 2006; Natri et al., 2006; Schleithoff et al., 2006; Viljakainen et al., 2006; Zubillaga et al., 2006). In addition to these, 11 papers were found from reference lists of other articles and from our personal archives and these articles were also included to this systematic review (Brazier et al., 1995; Ooms et al., 1995; Dawson-Hughes et al., 1997; Malabanan et al., 1998; Lips et al., 1998; Adams et al., 1999; Grados et al., 2003; Dhesi et al., 2004; Vieth et al., 2004; Daly et al., 2005; Bjo¨rkman et al., 2007). 2.2. Data collection From each trial the number and mean age of the patients in every intervention group were gathered. The mean baseline and post-trial levels of 25-OHD and PTH were collected as well. The daily doses of vitamin D and calcium supplementation were also obtained. If the supplementation was not dosed daily or the dose was changed during intervention, a mean daily dose was calculated. Articles were reviewed in order to be able to classify patients as ambulatory or chronically immobile. All units of measures of 25-OHD were converted to nmol/l (mg/l was multiplied by 2.5) and those of PTH to ng/l (pmol/l was divided by 0.11). For the calculation of the percentage changes in 25-OHD and PTH we used the closest analyses to 6 months in all the trials. In seven papers the results were not given in the text or tables and we were forced to estimate the levels of 25-OHD and/or PTH from figures. 2.3. Statistics The data were analyzed using Windows SPSS, release 12.0.1 (SPSS for Windows, Chicago: SPSS Inc.). Univariate analyses were performed by independent samples T-test for continuous variables and by x2-test for the dichotomous variables. Linear and logarithmic curve estimation regression models for baseline and post-trial levels of PTH as well as for changes in PTH were produced. Series of multivariate linear regression models were also created, respectively, to determine the R2 changes and their levels of significance by entering each of the potential determinants stepwise into the models. All variables were weighted by the number of patients in each intervention group. 3. Results 3.1. Intervention groups The selected 52 vitamin D supplementation trials (42 randomized controlled trials, 10 clinical trials) addressing PTH responses included a total of 72 intervention groups with 6290 patients. The mean age of the subjects ranged from 22 years to 86 years, the average being 71.5 years. The daily doses of cholecalciferol and ergocalciferol varied from 200 IU to 4930 IU and from 750 IU to 14286 IU, respectively. The daily calcium doses varied from 0 mg to 1500 mg. The length of supplementation was described as the time interval between laboratory analyses, the shortest being 3 weeks and the longest 3 years. However, 71.5% of the patients were supplemented for 6 months. 3.2. Baseline 25-OHD and PTH levels

Fig. 1. Flow chart of the articles disclosed in the primary search.

The baseline 25-OHD and PTH levels varied widely from 6.5 nmol/l to 85 nmol/l and from 19 ng/l to 139 ng/l, the average values being 49.5 nmol/l and 43.8 ng/l, respectively. Negative logarithmic (R2 = 0.318, p < 0.001) and linear (R2 = 0.294, p < 0.001) correlations were found between 25-OHD and PTH

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102%, p < 0.001) and PTH ( 18.9% vs. 17.1%, p = 0.017) were larger in these patients. Furthermore, they were slightly younger (69.6.0 vs. 71.8, p < 0.001), more commonly chronically immobile (10.8% vs. 1.4%, p < 0.001) and supplemented with ergocalciferol (19.2% vs. 3.5%, p < 0.001) as well. 3.4. Age and chronic immobility

Fig. 2. Correlations between serum levels of 25-hydroxyvitamin D and parathyroid hormone in 72 intervention groups of 52 vitamin D supplementation trials (n = 6290) when all pre- and post-trial values were scattered. R2 for linear correlation is 0.294 (p < 0.001) and for logarithmic correlation 0.318 (p < 0.001).

levels, when all pre- and post-trial values were scattered (Fig. 2). In 58 intervention groups consisting of 51.7% of the patients mean serum 25-OHD levels were below 50 nmol/l at baseline. In these vitamin D deficient intervention groups the average PTH level was significantly higher (53.1 ng/l vs. 34.0 ng/l, p < 0.001), patients were older (76.2 years vs. 66.6 years, p < 0.001), and more commonly chronically immobile (5.2% vs. 0.0%, p < 0.001) than patient in groups with adequate mean 25-OHD levels. 3.3. Determinants of 25-OHD responses Vitamin D supplementation increased 25-OHD in every intervention group from 3% to 1025%, reaching the levels between 34 nmol/l and 114 nmol/l. A total of 57 intervention groups including 90.8% (5668) of the patients had post-trial 25OHD levels 50 nmol/l or greater. A dose above 3300 IU of ergocalciferol and 800 IU of cholecalciferol was needed to ensure post-trail 25-OHD levels at least 50 nmol/l. The respective doses to ensure mean post-trial 25-OHD levels at least 75 nmol/l were 5000 IU/d and 2850 IU/d. In the 14 post-trail vitamin D deficient patient groups, the average level of PTH was again higher (41.1 ng/l vs. 33.7 ng/l, p < 0.001) than in vitamin D replete patient groups. The baseline 25-OHD levels were lower (16.8 nmol/l vs. 53.1 nmol/l, p < 0.001), PTH levels higher (53.6 ng/l vs. 42.8 ng/l, p < 0.001), and daily doses of vitamin D supplementation lower (cholecalciferol: 520 IU vs. 730 IU, p < 0.001; ergocalciferol: 2260 IU vs. 3640 IU, p = 0.001) in the non-responding groups. The changes in serum 25-OHD (204% vs.

A strong negative correlation was found between baseline 25OHD levels and age (Table 1). However, even though the changes in 25-OHD levels were positively correlated with age no significant correlation was found between post-trail 25-OHD levels and age. Baseline PTH levels as well as post-trail PTH levels correlated positively and changes negatively with age. There were two trials on chronically immobile patients including four intervention groups with 2.7% (169/6290) of all patients. The immobile patients were older (84.0 years vs. 71.2 years, p < 0.001), had lower 25-OHD levels (21.3 nmol/l vs. 50.3 nmol/l, p < 0.001), higher PTH levels (55.8 ng/l vs. 43.5 ng/l, p < 0.001) and the supplementation resulted in smaller decrease in PTH levels ( 8.4% vs. 17.4%, p < 0.001) despite larger increase in 25-OHD levels (187.2% vs. 109.8%, p < 0.001). 3.5. Determinants of PTH responses PTH appeared to decrease consistently in most (63/72) of the intervention groups. Negative linear (R2 = 0.385, p < 0.001) and logarithmic (R2 = 0.406, p < 0.001) correlations between the changes in 25-OHD and PTH levels were found (Fig. 3). A total of 300 patients (4.8%) were included in the non-responding intervention groups. These patients had similar baseline 25-OHD (48.9 nmol/l vs. 49.6 nmol/l, p = 0.607), lower baseline PTH (33.4 ng/l vs. 44.4 ng/l, p < 0.001) as well as smaller changes in 25-OHD (88.2% vs. 113.1%, p < 0.001) compared to the patients in intervention groups resulting in decreased PTH levels. Furthermore, these patients were markedly younger (56.6 years vs. 72.3 years, p < 0.001), calcium was less frequently (47.3% vs. 88.6%, p < 0.001) combined with a lower dose (cholecalciferol: 600 IU/d vs. 720 IU/d, p = 0.001) vitamin D supplementation. However, no difference was found in the length of vitamin D supplementation and all the patients were mobile outpatients. In eight of these trials that did not report a decrease in PTH the changes in PTH were from 0% to 7%. However, in one trial including 41 postmenopausal women living in Curacao, PTH was markedly increased up to 95% by 9-week 800 IU cholecalciferol supplementation without calcium. In this study the baseline PTH was the lowest (19 ng/l) and the 25-OHD the highest (85 mol/l) of all the selected trials. According to the multiple regression analysis the pre-trial PTH levels were independently predicted by pre-trial 25-OHD, age and immobility (Table 2). Post-trial PTH levels were predicted by baseline PTH, age and chronic immobility and changes in PTH also by changes in 25-OHD in addition to the baseline PTH, age and chronic immobility (Table 2). These independent predictors

Table 1 Pearson’s correlations between age, 25-hydrovitamin D and parathyroid hormone in 72 treatment groups of 52 vitamin D supplementation trials (n = 6290) Age Age Baseline 25-OHD Post-trial 25-OHD Changes in 25-OHD Baseline PTH Post-trial PTH Changes in PTH a

1

Baseline 25-OHD 0.432 1

a

Correlation is significant at the 0.01 level (two-tailed).

Post-trial 25-OHD 0.016 0.609a 1

Changes in 25-OHD a

0.475 0.806a 0.249 a 1

Baseline PTH a

0.430 0.593a 0.159a 0.590a 1

Post-trial PTH a

0.207 0.366a 0.196a 0.261a 0.792a 1

Changes in PTH 0.476 a 0.562 a 0.043a 0.621 a 0.639 a 0.113 a 1

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Fig. 3. Correlations between changes in levels of 25-hydroxyvitamin D and parathyroid hormone in 72 intervention groups of 52 vitamin D supplementation trials (n = 6 290). R2 for linear correlation is 0.385 (p < 0.001) and for logarithmic correlation 0.406 (p < 0.001).

explained (R2) 53.2% of the variation in the responses of PTH to vitamin D supplementation. The respective figures for the variation in baseline and post-trial PTH levels were 39.0% and 70.6%. 4. Discussion We have done our best to include all the available vitamin D supplementation trials, in which 25-OHD and PTH levels were determined, to this systematic review. However, we were forced to exclude seven of the found vitamin D supplementation trials. This literature analysis shows that responses of PTH to vitamin D supplementation are not only determined by the baseline PTH levels and changes in vitamin D status, but also by age and mobility of the patients. Our results also suggest that PTH decreases quite linearly during vitamin D supplementation at any given baseline 25-OHD

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level. This observation accords well with the results of single papers of this literature analysis including the largest trial (Lips et al., 2001) and the latest experiment (Bjo¨rkman et al., 2007) as well as with a large cross-sectional study concluding that no plateau relationship between PTH and 25-OHD exists (Vieth et al., 2003). Thus, the concept of a vitamin D-dependent optimally low plateau level of PTH remains speculative despite the numerous estimated threshold levels of 25-OHD (Aloia et al., 2005), below which PTH is presumed to start to increase. Furthermore, to be able to determine this hypothetical plateau level, it would require ethically questionable prospective vitamin D depletion trials on vitamin D replete subjects rather than vitamin D supplementation trials on vitamin D deficient patients. However, the optimal bone protection and fracture prevention by suppression of PTH to levels, seen in healthy young vitamin D replete subjects, has been the rationale for ever higher recommendations of adequate 25-OHD level. The leading vitamin D researchers are now calling for the elevation of the recommended adequate 25-OHD level from 50 nmol/l to 75 nmol/l or greater—also partly because of other beneficial effects of vitamin D, not related to PTH (Vieth et al., 2007). This meta-analysis emphasizes that age of the patients also contributes to the elevation of PTH levels independently. The mechanisms of age-related increase in parathyroid function and elevated PTH are multi-factorial and partly well-established. The intake of calcium and vitamin D, exposure to sunlight, cutaneous production of vitamin D3, renal production of 1,25-dihydroxyvitamin D, and the ability to adapt to a low calcium diet may all be reduced in elderly subjects (Bouillon et al., 1997). Furthermore, the decreased intestinal calcium absorption, reduced renal tubular function, declined response of the kidney to PTH and impaired capacity of 1,25-dihydroxyvitamin D to stimulate calcium absorption are changes of calcium metabolism seen in aging patients (Van Abel et al., 2006). However, the exact mechanisms for the elevation of PTH in aged patients are beyond the scope of this literature analysis. Two major causes of elevated PTH of aged people, impaired renal function (Lips, 2001) and primary hyperparathyroidism (Sorva et al., 1992) were also excluded from these analyses, if clearly indicated in the text of the manuscript. However, the effect of high age should be interpreted with caution, because it most probably reflects merely the presence of frailty and illnesses in these patients. In this series PTH was higher in the chronically immobile than ambulatory patients suggesting increased bone loss in the

Table 2 Multiple linear regression analyses of average pre- and post-trail parathyroid hormone levels and their changes in 72 treatment groups of 52 vitamin D supplementation trials (n = 6290) R2

Added variable

Dependent variable: pre-trial PTH Pre-trial 25-OHD (nmol/l) Age (year) Immobility

Adjusted R2

Change statistics R2 change

p for change

a

0.352 0.389 0.390

0.352 0.389 0.390

0.352 0.037 0.001

<0.001 <0.001 0.005

Dependent variable: post-trial PTHb Pre-trial PTH (ng/l) Immobility Age (year)

0.627 0.672 0.706

0.627 0.672 0.706

0.627 0.045 0.034

<0.001 <0.001 <0.001

Dependent variable: changes in PTHc Pre-trial PTH (ng/l) Changes in 25-OHD (nmol/l) Immobility Age (year)

0.408 0.499 0.531 0.559

0.408 0.499 0.531 0.558

0.408 0.091 0.031 0.028

<0.001 <0.001 <0.001 <0.001

a b c

Pre-trial 25-OHD, immobility, and age were entered to the analysis. Post-trial 25-OHD, pre-trial PTH, immobility, and age were entered to the analysis. Changes in 25-OHD, pre-trial PTH, immobility, and age were entered to the analysis.

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chronically immobile patients. This observation is also supported by some earlier cross-sectional studies (Lips et al., 1990; Bischoff et al., 1999; Sato et al., 1999; Chen et al., 2006). The importance of acute immobilization and mobility, in general, as a regulator of bone resorption and parathyroid function has also been advocated by several studies (Bikle and Halloran, 1999). Probably, a constant increased flux of calcium from bones in chronically immobile patients attenuates the elevation of PTH. The results of this systematic review also support this hypothesis. The decreases in PTH were smaller in two trials (Sorva et al., 1994; Bjo¨rkman et al., 2007) on chronically immobile than in ambulatory patients groups despite the fact that their baseline PTH was higher and that the supplementation caused more marked increase in serum 25-OHD. However, the chronically immobile patients were also markedly older than the mobile patients. Thus, the age-related confounding mechanisms of vitamin D and calcium metabolism discussed above may also partly contribute to the blunted responses of PTH in the chronically immobile patients included to these analyses. Furthermore, possible differences in classification of ambulatory and chronically immobile patients in single papers may cause bias to these analyses. Cholecalciferol and ergocalciferol supplementation has also been shown to have a wide safety margin (Vieth, 1999). Thus, to ensure adequate vitamin D status and optimal suppression of PTH markedly larger vitamin D doses than those conventionally used have been recommended (Vieth et al., 2007). In this literature analysis, the doses of cholecalciferol and ergocalciferol supplementation needed to ensure mean 25-OHD levels at least 50 nmol/l were higher than 800 IU/d and 3300 IU/d, respectively. The respective doses to ensure mean post-trial 25-OHD levels at least 75 nmol/l were 2850 IU/d and 5000 IU/d. In our previous study, however, the 50 nmol/l level of 25-OHD was not reached in 16% of the patients (n = 73) even with a 6-month 1200 IU/d cholecalciferol supplementation that resulted in mean 25-OHD level of 73 nmol/l (Bjo¨rkman et al., 2007). However, one patient developed mild hypercalcaemia (ionized calcium from 1.24 mmol/l to 1.40 mmol/l), accompanied by decrease in PTH far below the levels seen in replete young subjects (from 54 ng/l to 7 ng/l) despite rather moderate increase in 25-OHD (from 15 nmol/l to 47 nmol/l). This observation suggests that the vitamin D supplementation induced changes in vitamin D and calcaemic status are individual. Six months after the cessation of the supplementation ionized calcium (1.24 mmol/l) and PTH (30 ng/l) of this patient returned within normal limits. The patient had no evidence of diseases causing increased 1,25-hydroxylation of vitamin D. Furthermore, the transient mild hypercalcemia also attests against progressive granulomatous or malignant diseases. Furthermore, in a recent fracture risk study on postmenopausal women (n = 36,282) even a moderate dose (400 IU/d) vitamin D supplementation combined with calcium substitution (1000 mg/d) increased the risk of urolithiasis (OR: 1.17; 95% CI: 1.02–1.34) However, in this study the mean 25-OHD level was almost 50 nmol/l and the calcium intake relatively high at baseline. Very large doses of vitamin D can certainly increase 25-OHD to levels high enough to cause hypercalcemia suppressing PTH to infraphysiological levels and undoubtedly far below the levels seen in young vitamin D replete subjects. However, the literature on high levels of 25-OHD is lacking. It has been estimated that vitamin D intoxication occurs when 25-hydroxyvitamin D levels are greater than 375 nmol/l (Holick, 2006), but in aged frail patients the safety margin could be narrower than in other populations. However, the elderly are claimed to need even more vitamin D than younger adults to produce the higher 25-OHD concentrations required to overcome the hyperparathyroidism associated with their diminishing renal function (Vieth et al., 2003).

In general practice, vitamin D supplementation with conventional daily doses up to 20 mg or 800 IU does not usually necessitate calcemic follow-up of the patient. However, the individual differences in responses of vitamin D and calcemic status to vitamin D supplementation and the possibility of narrowed safety margin especially in older bedridden patients should temper the enthusiasm for much higher doses unless calcemic follow-up is provided. Considering the possible adverse effects and the shown beneficial anabolic bone effects of PTH analogues, the concept of ‘‘the lower PTH, the better’’ seems questionable. Longitudinal vitamin D supplementation studies on populations with wide range of mobility and age are needed to further elucidate their confounding effects. In determining the sufficient doses of vitamin D supplementation and adequate 25-OHD levels, these confounding effects and the inter-individual variation in responses of PTH to vitamin D supplementation should be taken to account. Acknowledgement The study was funded by a special governmental subsidy for health sciences research and training to Helsinki University Central Hospital. References Adams, J.S., Kantorovich, V., Wu, C., Javanbakht, M., Hollis, B.W., 1999. Resolution of vitamin D insufficiency in osteopenic patients results in rapid recovery of bone mineral density. J. Clin. Endocrinol. Metab. 84, 2729–2730. Aloia, J.F., Vaswani, A., Yeh, J.K., McGowan, D.M., Ross, P., 1991. Biochemical shortterm changes produced by hormonal replacement therapy. J. Endocrinol. Invest. 14, 927–934. Aloia, J.F., Talwar, S.A., Pollack, S., Yeh, J., 2005. A randomized controlled trial of vitamin D3 supplementation in African American women. Arch. Intern. Med. 165, 1618–1623. Barger-Lux, M.J., Heaney, R.P., Dowell, S., Chen, T.C., Holick, M.F., 1998. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos. Int. 8, 222–230. Barnes, M.S., Robson, P.J., Bonham, M.P., Strain, J.J., Wallace, J.M., 2006. Effect of vitamin D supplementation on vitamin D status and bone turnover markers in young adults. Eur. J. Clin. Nutr. 60, 727–733. Bauman, W.A., Morrison, N.G., Spungen, A.M., 2005. Vitamin D replacement therapy in persons with spinal cord injury. J. Spinal Cord. Med. 28, 203–207. Bischoff, H., Stahelin, H.B., Vogt, P., Friderich, P., Vonthein, R., Tyndall, A., Theiler, R., 1999. Immobility as a major cause of bone remodeling in residents of a longstay geriatric ward. Calcif. Tissue Int. 64, 485–489. Bischoff-Ferrari, H.A., Dawson-Hughes, B., Willett, W.C., Staehelin, H.B., Bazemore, M.G., Zee, R.Y., Wong, J.B., 2004. Effect of vitamin D on falls. A meta-analysis. J. Am. Med. Assoc. 291, 1999–2006. Bikle, D., Halloran, B., 1999. The response of bone to unloading. J. Bone Miner. Metab. 17, 233–244. Bjo¨rkman, M., Sorva, A., Risteli, J., Tilvis, R., 2007. Vitamin D supplementation has minor effects on parathyroid hormone and bone turnover markers in vitamin Ddeficient bedridden older patients. Age Ageing [Epub ahead of print]. Bouillon, R., Carmeliet, G., Boonen, S., 1997. Ageing and calcium metabolism. Baillieres Clin. Endocrinol. Metab. 11, 341–365. Brazier, M., Kamel, S., Maamer, M., Agbomson, F., Elesper, I., Garabedian, M., Desmet, G., Sebert, J.L., 1995. Markers of bone remodeling in the elderly subject: effects of vitamin D insufficiency and its correction. J. Bone Miner. Res. 10, 1753–1761. Brazier, M., Grados, F., Kamel, S., Mathieu, M., Morel, A., Maamer, M., Sebert, J.L., Fardellone, P., 2005. Clinical and laboratory safety of one year’s use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study. Clin. Ther. 27, 1885–1893. Chapuy, M.C., Chapuy, P., Meunier, P.J., 1987. Calcium and vitamin D supplements: effects on calcium metabolism in elderly people. Am. J. Clin. Nutr. 46, 324–328. Chapuy, M.C., Arlot, M.E., Duboeuf, F., Brun, J., Crouzet, B., Arnaud, S., Delmas, P.D., Meunier, P.J., 1992. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N. Engl. J. Med. 327, 1637–1642. Chapuy, M.C., Chapuy, P., Thomas, J.L., Hazard, M.C., Meunier, P.J., 1996. Biochemical effects of calcium and vitamin D supplementation in elderly, institutionalized, vitamin D-deficient patients. Rev. Rhum. Engl. Ed. 63, 135–140. Chapuy, M.C., Pamphile, R., Paris, E., Kempf, C., Schlichting, M., Arnaud, S., Garnero, P., Meunier, P.J., 2002. 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. 13, 257–264.

M. Bjo¨rkman et al. / Archives of Gerontology and Geriatrics 48 (2009) 160–166 Chel, V.G., Ooms, M.E., Popp-Snijders, C., Pavel, S., Schothorst, A.A., Meulemans, C.C., Lips, P., 1998. Ultraviolet irradiation corrects vitamin D deficiency and suppresses secondary hyperparathyroidism in the elderly. J. Bone Miner. Res. 13, 1238–1242. Chen, J.S., Cameron, I.D., Cumming, R.G., Lord, S.R., March, L.M., Sambrook, P.N., Simpson, J.M., Seibel, M.J., 2006. Effect of age-related chronic immobility on markers of bone turnover. J. Bone Miner. Res. 21, 324–331. Daly, R.M., Brown, M., Bass, S., Kukuljan, S., Nowson, C., 2005. Calcium- and vitamin D3-fortified milk reduces bone loss at clinically relevant skeletal sites in older men: a 2-year randomized controlled trial. J. Bone Miner. Res. 21, 397–405. Dawson-Hughes, B., Harris, S.S., Krall, E.A., Dallal, G.E., 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, 670–676. Deroisy, R., Collette, J., Albert, A., Jupsin, I., Reginster, J.Y., 2002. Administration of a supplement containing both calcium and vitamin D is more effective than calcium alone to reduce secondary hyperparathyroidism in postmenopausal women with low 25(OH) vitamin D circulating levels. Aging Clin. Exp. Res. 14, 13–17. Dhesi, J.K., Jackson, S.H., Bearne, L.M., Moniz, C., Hurley, M.V., Swift, C.G., Allain, T.J., 2004. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing 33, 589–595. Diamond, T.H., Ho, K.W., Rohl, P.G., Meerkin, M., 2005. Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med. J. Aust. 183, 10–12. Francis, R.M., Boyle, I.T., Moniz, C., Sutcliffe, A.M., Davis, B.S., Beastall, G.H., Cowan, R.A., Downes, N., 1996. A comparison of the effects of alfacalcidol treatment and vitamin D2 supplementation on calcium absorption in elderly women with vertebral fractures. Osteoporos. Int. 6, 284–290. Gannage-Yared, M.H., Azoury, M., Mansour, I., Baddoura, R., Halaby, G., Naaman, R., 2003. Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy postmenopausal women. J. Endocrinol. Invest. 26, 748–753. Goussous, R., Song, L., Dallal, G.E., 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, 707–711. Grados, F., Brazier, M., Kamel, S., Mathieu, M., Hurtebize, N., Maamer, M., Garabedian, M., Sebert, J.L., Fardellone, P., 2003. Prediction of bone mass density variation by bone remodeling markers in postmenopausal women with vitamin D insufficiency treated with calcium and vitamin D supplementation. J. Clin. Endocrinol. Metab. 88, 5175–5179. Harris, S.S., 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, 357–362. Harwood, R.H., Sahota, O., Gaynor, K., Masud, T., Hosking, D.J., 2004. The Nottingham Neck of Femur (NONOF) Study. A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. Age Ageing 33, 45–51. Heaney, R.P., Dowell, M.S., Hale, C.A., Bendich, A., 2003. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J. Am. Coll. Nutr. 22, 142–146. Heikkinen, A., Parviainen, M.T., Tuppurainen, M.T., Niskanen, L., Komulainen, M.H., Saarikoski, S., 1998. Effects of postmenopausal hormone replacement therapy with and without vitamin D3 on circulating levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. Calcif. Tissue Int. 62, 26–30. Himmelstein, S., Clemens, T.L., Rubin, A., Lindsay, R., 1990. Vitamin D supplementation in elderly nursing home residents increases 25(OH)D but not 1,25(OH)2D. Am. J. Clin. Nutr. 52, 701–706. Holick, M.F., 2006. The role of vitamin D for bone health and fracture prevention. Curr. Osteoporos. Rep. 4, 96–102. Hunter, D., Major, P., Arden, N., Swaminathan, R., Andrew, T., MacGregor, A.J., Keen, R., Snieder, H., Spector, T.D., 2000. A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs. J. Bone Miner. Res. 15, 2276–2283. Jensen, C., Holloway, L., Block, G., Spiller, G., Gildengorin, G., Gunderson, E., Butterfield, G., Marcus, R., 2002. Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Am. J. Clin. Nutr. 75, 1114–1120. Johnson, J.L., Mistry, V.V., Vukovich, M.D., Hogie-Lorenzen, T., Hollis, B.W., Specker, B.L., 2005. Bioavailability of vitamin D from fortified process cheese and effects on vitamin D status in the elderly. J. Dairy Sci. 88, 2295–2301. Kamel, S., Brazier, M., Rogez, J.C., Vincent, O., Maamer, M., Desmet, G., Sebert, J.L., 1996. Different responses of free and peptide-bound cross-links to vitamin D and calcium supplementation in elderly women with vitamin D insufficiency. J. Clin. Endocrinol. Metab. 81, 3717–3721. Kenny, A.M., Prestwood, K.M., Gruman, C.A., Marcello, K.M., Raisz, L.G., 2001. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J. Gerontol. A: Biol. Sci. Med. Sci. 56, M266– M272. Kenny, A.M., Biskup, B., Robbins, B., Marcella, G., Burleson, J.A., 2003. Effects of vitamin D supplementation on strength, physical function, and health perception in older, community-dwelling men. J. Am. Geriatr. Soc. 51, 1762–1767. Khaw, K.T., Scragg, R., Murphy, S., 1994. Single-dose cholecalciferol suppresses the winter increase in parathyroid hormone concentrations in healthy older men and women: a randomized trial. Am. J. Clin. Nutr. 59, 1040–1044.

165

Krieg, M.A., Jacquet, A.F., Bremgartner, M., Cuttelod, S., Thiebaud, D., Burckhardt, P., 1999. Effect of supplementation with vitamin D3 and calcium on quantitative ultrasound of bone in elderly institutionalized women: a longitudinal study. Osteoporos. Int. 9, 483–488. Kurland, E.S., Cosman, F., McMahon, D.J., Rosen, C.J., Lindsay, R., Bilezikian, J.P., 2000. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J. Clin. Endocrinol. Metab. 85, 3069– 3076. Law, M., Withers, H., Morris, J., Anderson, F., 2006. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Age Ageing 35, 482–486. Lips, P., 2001. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr. Rev. 22, 477–501. Lips, P., 2004. Which circulating level of 25-hydroxyvitamin D is appropriate? J. Steroid. Biochem. Mol. Biol. 89-90, 611–614. Lips, P., Van Ginkel, F.C., Netelenbos, J.C., Wiersinga, A., Van der Vijgh, W.J., 1990. Lower mobility and markers of bone resorption in the elderly. Bone Miner. 9, 49–57. Lips, P., Wiersinga, A., Van Ginkel, F.C., Jongen, M.J., Netelenbos, J.C., Hackeng, W.H., Delmas, P.D., Van der Vijgh, W.J., 1998. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J. Clin. Endocrinol. Metab. 67, 644–650. Lips, P., Duong, T., Oleksik, A., Black, D., Cummings, S., Cox, D., Nickelsen, T., 2001. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J. Clin. Endocrinol. Metab. 86, 1212–1221. Magno, C., Anastasi, G., Morabito, N., Gaudio, A., Maisano, D., Franchina, F., Gali, A., Frisina, N., Melloni, D., 2005. Preventing bone loss during androgen depri-vation therapy for prostate cancer: early experience with neridronate. Eur. Urol. 47, 575–580. Malabanan, A., Veronikis, I.E., Holick, M.F., 1998. Redefining vitamin D insufficiency. Lancet 351, 805–806. Mastaglia, S.R., Mautalen, C.A., Parisi, M.S., Oliveri, B., 2006. Vitamin D2 dose required to rapidly increase 25OHD levels in osteoporotic women. Eur. J. Clin. Nutr. 60, 681–687. Meier, C., Woitge, H.W., Witte, K., Lemmer, B., Seibel, M.J., 2004. Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial. J. Bone Miner. Res. 19, 1221–1230. Mosekilde, L., 2005. Vitamin D and the elderly. Clin. Endocrinol. (Oxf.) 62, 265–281. Natri, A.M., Salo, P., Vikstedt, T., Palssa, A., Huttunen, M., Karkkainen, M.U., Salovaara, H., Piironen, V., Jakobsen, J., Lamberg-Allardt, C.J., 2006. Bread fortified with cholecalciferol increases the serum 25-hydroxyvitamin D concentration in women as effectively as a cholecalciferol supplement. J. Nutr. 136, 123–127. Need, A.G., 2006. Bone resorption markers in vitamin D deficiency. Clin. Chim. Acta 368, 48–52. Ooms, M.E., Roos, J.C., Bezemer, P.D., van der Vijgh, W.J., Bouter, L.M., Lips, P., 1995. Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J. Clin. Endocrinol. Metab. 80, 1052–1058. Parfitt, A.M., Gallagher, J.C., Heaney, R.P., Johnston, C.C., Neer, R., Whedon, G.D., 1982. Vitamin D and bone health in the elderly. Am. J. Clin. Nutr. 36, 1014–1031. Patel, R., Collins, D., Bullock, S., Swaminathan, R., Blake, G.M., Fogelman, I., 2001. The effect of season and vitamin D supplementation on bone mineral density in healthy women: a double-masked crossover study. Osteoporos. Int. 12, 319– 325. Pfeifer, M., Begerow, B., Minne, H.W., Nachtigall, D., Hansen, C., 2001. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J. Clin. Endocrinol. Metab. 86, 1633–1637. Prestwood, K.M., Pannullo, A.M., Kenny, A.M., Pilbeam, C.C., Raisz, L.G., 1996. The effect of a short course of calcium and vitamin D on bone turnover in older women. Osteoporos. Int. 6, 314–319. Sato, Y., Kuno, H., Asoh, T., Honda, Y., Oizumi, K., 1999. Effect of immobilization on vitamin D status and bone mass in chronically hospitalized disabled stroke patients. Age Ageing 28, 265–269. Schleithoff, S.S., Zittermann, A., Tenderich, G., Berthold, H.K., Stehle, P., Koerfer, R., 2006. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am. J. Clin. Nutr. 83, 754–759. Scragg, R., Khaw, K.T., Murphy, S., 1995. Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. Eur. J. Clin. Nutr. 49, 640–646. Sebert, J.L., Garabedian, M., Chauvenet, M., Maamer, M., Agbomson, F., Brazier, M., 1995. Evaluation of a new solid formulation of calcium and vitamin D in institutionalized elderly subjects. A randomized comparative trial versus separate administration of both constituents. Rev. Rheum. Engl. Ed. 62, 288–294. Serhan, E., Holland, M.R., 2005. Calcium and vitamin D supplementation failed to improve bone mineral density in Indo-Asians suffering from hypovitaminosis D and secondary hyperparathyroidism. Rheumatol. Int. 25, 276–279. Sorva, A., Valvanne, J., Tilvis, R.S., 1992. Serum ionized calcium and the prevalence of primary hyperparathyroidism in age cohorts of 75, 80 and 85 years. J. Intern. Med. 231, 309–312. Sorva, A., Valimaki, M., Risteli, J., Risteli, L., Elfving, S., Takkunen, H., Tilvis, R., 1994. Serum ionized calcium, intact PTH and novel markers of bone turnover in bedridden elderly patients. Eur. J. Clin. Invest. 24, 806–812.

166

M. Bjo¨rkman et al. / Archives of Gerontology and Geriatrics 48 (2009) 160–166

Tang, B.M., Eslick, G.D., Nowson, C., Smith, C., Bensoussan, A., 2007. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370, 657–666. Tangpricha, V., Koutkia, P., Rieke, S.M., Chen, T.C., Perez, A.A., Holick, M.F., 2003. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am. J. Clin. Nutr. 77, 1478–1483. Theiler, R., Bischoff, H., Tyndall, A., Stahelin, H.B., 1998. Elevated PTH levels in hypovitaminosis D are more rapidly suppressed by the administration of 1,25dihydroxy-vitamin D3 than by vitamin D3. Int. J. Vitam. Nutr. Res. 68, 36–41. Van Abel, M., Huybers, S., Hoenderop, J.G., Van der Kemp, A.W., Van Leeuwen, J.P., Bindels, R.J., 2006. Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6. Am. J. Physiol. Renal. Physiol. 291, F1177–F1183. Van Der Klis, F.R., Jonxis, J.H., Van Doormaal, J.J., Sikkens, P., Saleh, A.E., Muskiet, F.A., 1996. Changes in vitamin-D metabolites and parathyroid hormone in plasma following cholecalciferol administration to pre- and postmenopausal women in the Netherlands in early spring and to postmenopausal women in Curacao. Br. J. Nutr. 75, 637–646.

Vieth, R., 1999. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am. J. Clin. Nutr. 69, 842–856. Vieth, R., Ladak, Y., Walfish, P.G., 2003. Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. J. Clin. Endocrinol. Metab. 88, 185–191. Vieth, R., Kimball, S., Hu, A., Walfish, P.G., 2004. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr. J. 19, 8. Vieth, R., Bischoff-Ferrari, H., Boucher, B.J., Dawson-Hughes, B., Garland, C.F., Heaney, R.P., Holick, M.F., Hollis, B.W., Lamberg-Allardt, C., McGrath, J.J., Norman, A.W., Scragg, R., Whiting, S.J., Willett, W.C., Zittermann, A., 2007. The urgent need to recommend an intake of vitamin D that is effective. Am. J. Clin. Nutr. 85, 649–650. Viljakainen, H.T., Palssa, A., Karkkainen, M., Jakobsen, J., Lamberg-Allardt, C., 2006. How much vitamin D3 do the elderly need? J. Am. Coll. Nutr. 25, 429–435. Zubillaga, P., Garrido, A., Mugica, I., Ansa, J., Zabalza, R., Emparanza, J.I., 2006. Effect of vitamin D and calcium supplementation on bone turnover in institutionalized adults with Down’s Syndrome. Eur. J. Clin. Nutr. 60, 605–609.