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Age and Ageing Advance Access originally published online on October 25, 2007
Age and Ageing 2008 37(1):25-31; doi:10.1093/ageing/afm141
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Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

Vitamin D supplementation has minor effects on parathyroid hormone and bone turnover markers in vitamin D–deficient bedridden older patients

Mikko Björkman1,, Antti Sorva2, Juha Risteli3 and Reijo Tilvis1

1 Clinics of Internal Medicine and Geriatrics, Helsinki University Central Hospital, Helsinki, Finland, POB 340, FI-00290 HUS
2 Department of Long-Term Care, Helsinki Health Center, Helsinki, Finland, POB 6600, FI-00099
3 Department of Clinical Chemistry, University of Oulu, Oulu, Finland, POB 5000, FI-90014

Address correspondence to: B. Mikko. Fax: (+35) 894 717 4693. Email: mikko.bjorkman{at}helsinki.fi


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
 Key points
 Conflict of interest
 Supplementary Data
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Objectives: to evaluate the effects of vitamin D supplementation on parathyroid function and bone turnover in aged, chronically immobile patients.

Design: a randomised double-blind controlled trial.

Subjects: two hundred and eighteen long-term inpatients aged over 65 years.

Intervention: the patients were randomised into treatment groups of I-III, each receiving 0 IU, 400 IU and 1200 IU cholecalciferol per day, respectively. In case of inadequate consumption of dairy products, patients received a daily calcium substitution of 500 mg.

Measurements: plasma concentrations of 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (PTH), amino-terminal propeptide of type I procollagen (PINP), a marker of bone formation, and carboxy-terminal telopeptide of type I collagen (ICTP), a marker of bone resorption, were measured at baseline and after 6 months.

Results: the patients (age 84.5 years) were chronically bedridden. The baseline 25-OHD was low (23 nmol/l), correlated inversely with PINP, and tended to associate inversely with PTH. The prevalence of vitamin D deficiency (VDD) (25-OHD < 50 nmol/l) was 98% and PTH was elevated in 23% of the patients. Vitamin D supplementation significantly increased 25-OHD concentrations (124% group II, 204% group III) and decreased PTH (–7% group II, –8% group III). PINP tended to decrease, but ICTP tended to increase, and only their ratio decreased significantly. The tendency of ICTP to increase was inconsistent. Changes in 25-OHD correlated inversely with those in PTH and PINP.

Conclusions: vitamin D supplementation has minor effects on PTH and bone turnover in chronically immobilised aged patients with VDD. Further comparative studies and meta-analyses are warranted to elucidate the confounding effects of different mobility levels on the benefits of vitamin D supplementation in patients with differing baseline PTH levels.

Keywords: vitamin D, parathyroid hormone, bone resorption, chronic immobilisation, aged, elderly


   Introduction
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 Introduction
Methods
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Senile bone loss is accentuated by subtle chronic secondary hyperparathyroidism (SHPT) resulting from vitamin D deficiency (VDD) [1–3]. Low serum 25-hydroxyvitamin D (S-25-OHD) levels are very common among the elderly, particularly in long-term care [4]. Vitamin D supplementation has been shown to decrease parathyroid hormone (PTH) levels, to temper the elevations of biochemical bone turnover markers, and to increase bone mineral density [5]. Vitamin D supplementation has been shown to prevent falls and subsequent hip fractures in nursing home residents [6–10]. The beneficial effects of vitamin D supplementation have been attributed to the suppression of SHPT. This knowledge is based mainly on studies on mobile persons.

Acute mechanical unloading of bones increases bone resorption [11]. However, the possible confounding influence of chronic immobility on vitamin D metabolism and on SHPT has been studied in few elderly patients. Chronic immobilisation could increase bone resorption with a constant tendency to elevate serum ionized calcium that lowers PTH levels, thus inhibiting the bone effects of VDD [12–15].

In this randomised double-blind controlled trial, we compared the effects of the recommended daily cholecalciferol dose (400 IU) and a three-fold dose (1200 IU) in chronically bedridden patients. We hypothesised that correcting S-25-OHD levels with vitamin D supplementation corrects SHPT and suppresses bone turnover markers in chronically immobile patients.


   Methods
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Subjects
Long-term inpatients from municipal hospitals in Helsinki, Finland were screened between September and December 2005 for this randomised double-blind controlled trial. The inclusion criteria were age over 65 years, chronically impaired mobility, stable general condition, and no known present disease (except osteoporosis) or medication (vitamin D supplements, glucocorticoids, antiepileptics, etc.) affecting calcium or bone metabolism. Large majority of the patients were excluded during screening because of their present medication. After baseline laboratory analyses patients with markedly elevated creatinine levels (>125 µmol/l), hypercalcaemia (ionised calcium >1.32 mmol/l), hypothyroidism (thyrotropin >5.3 mU/l) or hyperthyroidism (thyrotropin <0.2 mU/l) were also excluded. A flow chart for screening patients appears in Figure 1.


Figure 1
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  		Figure 1. Flow chart for screening patients.

 
Intervention
Eligible patients (n = 218) were randomised into three treatment groups receiving cholecalciferol (Vigantol, Merck KGaA, Darmstadt, Germany 20,000 IU/ml in Migliol oil) in doses of 0 µg, Formula g or Formula g (groups I, II, III) every 2 weeks, equivalent with average daily intakes of 0 IU, 400 IU or 1200 IU respectively. To ensure that all three groups received identical volumes (26drops = ~0.84 ml), medication oil was diluted three-fold with Migliol oil in group II, and group I received plain Migliol oil. Furthermore, the oil was swallowed entirely in the presence of the nurse and given with a small amount of food or drink, if necessary. Each bottle was individually coded to blind the patients and the ward nurses of not only the content of the bottles but also of the group labels (I, II, III). Before the start of the intervention, the use of dairy products was roughly evaluated to be insufficient among 40 patients, who received a daily calcium carbonate substitution of 500 mg during the intervention. Three other patients also received a previous daily medication of 500 mg calcium carbonate at baseline, which they continued to receive through the intervention. The study protocol was approved by the local ethics committee and all participants provided an informed consent before the start of the trial. If the patient was severely cognitively impaired, the informed consent was obtained from the participant's surrogate or health care power of attorney.

Measurements
In addition to routine laboratory analyses, plasma intact PTH was determined at baseline and after 6 months. Plasma 25-hydroxyvitamin D (25-OHD), amino-terminal propeptide of type I procollagen (PINP), and carboxy-terminal telopeptide of type I collagen (ICTP) levels were measured from deep-frozen (–20°C) EDTA-plasma samples collected at baseline and after 6 months. Vacuum tubes were used to draw venous blood from patients in a supine position the morning after an overnight fast.

The PTH levels were determined with a solid-phase, two-site chemiluminescent enzyme-labelled immunometric assay (Immulite 2000 intact PTH). The intra-assay coefficient of variation (CV) (n = 20) was 5.7% at 72 ng/l and 4.3% at 258 ng/l [16]. The inter-assay CV (n = 10) was 6.3% at 54 ng/l and 8.8% at 387 ng/l.

High performance liquid chromatography was used to measure plasma 25-OHD levels [17]. The method's limit of quantification, defined as the lowest concentration with a signal-to-noise ratio of 10:1, was 10 nmol/l. The within-assay CV was 5.6% at 21.6 nmol/l (n = 14) and 3.7% at 138 nmol/l (n = 15). The total CV was 7.3% at 16.4 nmol/l (n = 12) and 5.7% at 167 nmol/l (n = 15).

Plasma ICTP levels were determined by radioimmunoassay (RIA) [18]. The method yielded CVs between 3 and 8% for a wide range of concentrations. The levels of PINP were also analysed using RIA [19]. The inter- and intra-assay CVs ranged from 3.1 to 9.3% (n = 191) for values within the reference intervals (mean ± 2SD) for intact PINP in serum, which ranged from 19 to 84 µg/l for women and from 20 to 76 µg/l for men.

Mobility was evaluated at baseline and after 6 months by the ward nurses using the Resident Assessment Instrument (RAI) Minimum Data Set (MDS) 2.0 assessments [20]. Glomerular filtration rate (GFR) was also estimated by Cockcroft–Gault equation [21]. All subjects had a creatinine level 125 µmol/l or less, and impaired estimated GFR was not subsequently used to exclude any subjects from this pragmatic intervention trial.

Statistics
The data were analysed using Windows SPSS, release 12.0.1 (SPSS for Windows, Chicago: SPSS Inc). The frequencies and their levels of significance for dichotomous variables were determined by the chi-square test. An adjusted ratio (PINP/(ICTP x 7) x 100) of bone turnover markers was also calculated to denote overall bone turnover. A multiplier of 7 was used because of the difference in molecular weight between PINP and ICTP. The analysis of variance was carried out by the one-way ANOVA procedure, and the bivariate correlations procedure was used to compute Pearson's correlation coefficients.


   Results
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 Introduction
 Methods
 Results
Discussion
 Key points
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 References
 
All patients (n = 218) were aged (65–104 years), frail and chronically bedridden (Table 1). They required assistance of at least two persons in almost all activities of daily living. Only 11 patients were able to walk short distances with the physical assistance of one person. Nine patients had severely decreased estimated glomerular filtration rate (<30 ml/min) despite creatinine levels below 125 µmol/l.


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  		Table 1. Characteristics of patients

 
The mean baseline 25-OHD was low (23 nmol/l) and only four patients (2%) had 25-OHD level higher than 50 nmol/l. In 12 patients (6%), 25-OHD was under the measurement threshold (=10 nmol/l); they received a value of 9 nmol/l. The mean PTH level was 61 ng/l and the PTH upper reference value of the laboratory (73 ng/l) was exceeded in 51 (23%) patients. The randomisation succeeded well and the baseline characteristics were very similar in all three study groups with one exception (Table 1). PINP was the highest in group II.

Baseline plasma 25-OHD correlated inversely with PINP (r = –0, 171, P = 0.011) and tended to associate inversely with PTH (r = –0.126, P = 0.064) and positively with ICTP (r = 0.125, P = 0.065). The ratio of PINP to ICTP, however, correlated with baseline 25-OHD (r = –0.270, P < 0.001). Baseline PINP correlated positively with ICTP (r = 0.217, P = 0.001).

The 6-month vitamin D supplementation significantly increased 25-OHD concentrations and decreased PTH levels (Table 2). It also increased serum Ca2+, but the increase was very small. Nine patients exhibited slightly elevated Ca2+ (≤1.40 mmol/l). However, in one of these patients the mild hypercalcaemia (ionised calcium from 1.24 to 1.40 mmol/l) was accompanied by a decrease in PTH level (from 54 to 7 ng/l) below the lower reference value (8 ng/l) of the laboratory and an increase in 25-OHD (from 15 to 47 nmol/l). Closer analyses showed that 25-OHD increased in dose-dependent fashion (+8% group I, +124% group II, +204% group III, P<0.001). The supplementation also decreased the levels of PTH (+7.8% group I, –6.9% group II, –8.3% group III, P = 0.021) and tended to decrease PINP (–3.6% group I, –12.7% group II, –15.7% group III, P = 0.194). Changes in ICTP (–7.3% group I, –1.0% group II, +13.7% group III, P = 0.078) were minor and inconsistent. The ratio of PINP to ICTP, however, decreased significantly (0.2% group I, –11.8% group II, –19.0% group III, P = 0.025). The highest 25-OHD value was 116 nmol/l in group III. The lower the baseline 25-OHD, the more marked was the increase after vitamin D supplementation (r = –0.259, P<0.001). The proportion of patients with 25-OHD higher than 50 nmol/l after 6-month supplementation was 47% in group II and 84% in group III. The respective figures for patients with PTH falling below 73 ng/l were 83% and 87%. Vitamin D supplementation also resulted in minor and inconsistent changes in creatinine levels. However, no significant differences were found in estimated GFRs between groups, and the randomisation of patients with GFR below 50 ml/min also succeeded well (n = 25 in group I, n = 26 in group II, and n = 22 in group III, P = 0.705). Furthermore, the changes of the biochemical variables were also similar and parallel in patients with impaired estimated GFR (<50 ml/min) compared with those in other patients (please see Appendix 1 in the supplementary data on the journal website http://www.ageing.oxfordjournals.org/). The responses to vitamin D supplementation in a subgroup of patients with baseline PTH levels within laboratory reference values (8–73 ng/l) despite 25-OHD levels below 50 nmol/l (‘functional hypoparathyroidism’) were similar and parallel with rest of the patients as well, despite the larger increase in 25-OHD concentrations (Appendix 1 available online).


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  		Table 2. Changes in biochemical variables after 6-month vitamin D supplementation

 
Changes in plasma 25-OHD correlated inversely with changes in PTH (r = –0.209, P = 0.005), PINP (r = –0.224, P = 0.002), and the adjusted ratio of PINP to ICTP (r = –0.240, P = 0.001). However, no correlation occurred between changes in 25-OHD and ICTP. The changes in PTH correlated inversely with the changes in Ca2+ (r = –0.255, P = 0.001), but the changes in PTH showed no association with changes in bone turnover markers.

Vitamin D supplementation showed no measurable effects on changes in mobility. Altogether 36 patients died during the intervention and 9 deaths occurred in group I, 17 deaths in group II and 10 deaths in group III (P = 0.262). The most common causes of death in each group were pneumonia, Alzheimer's disease and vascular dementia. The baseline PTH values of the deceased tended to be elevated (59 versus 71 ng/l, P = 0.058).


   Discussion
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Vitamin D supplementation in doses of 400 IU/d and 1200 IU/d strongly increased plasma levels of 25-OHD and slightly decreased PTH levels. The recommended dose of 400 IU/d did not, however, elevate vitamin D levels to the recently advocated adequate level of at least 50 nmol/l [2, 3, 22, 23], and PTH also remained elevated in several patients, even with the highest vitamin D dose (1200 IU/d). The changes in 25-OHD (+124%) and PTH (–7%) observed with the dose of 400 IU/d accord well with those of an earlier study on elderly women (n = 177, mean age 80 years), in which 1 year of vitamin D supplementation resulted in a 130% increase in 25-OHD concentration and a 6% decrease in PTH level [24]. The dose of vitamin D was identical to that of the present study and the baseline 25-OHD levels were similarly low. The patients were not bedridden, however, and the baseline PTH was low (32 ng/l) compared with the level (61 ng/l) in the present study. In another randomised controlled trial on elderly ambulatory community-dwelling women (n = 74, mean age 75 years) with low baseline 25-OHD, an 8-week supplementation of 800 IU/d vitamin D and 1200 mg/d calcium resulted in a 156% increase in 25-OHD concentration and in a 26% decrease in PTH level [25]. The respective changes in the present study were +204% and –8% with vitamin D dose of 1200 IU/d. Interestingly, in these elderly vitamin D–deficient patients, vitamin D supplementation resulted in the stronger suppression of PTH in the group of younger mobile patients when baseline PTH levels were identical—even with a smaller vitamin D dose and milder increase in 25-OHD. Plausibly, immobilisation due to frailty causes bone resorption, leading to excess flux of calcium from bones and subsequent suppression of parathyroid function and blunted responses of PTH to VDD and vitamin D supplementation. Absence of SHPT in presence of hypovitaminosis D has also been described as ‘functional hypoparathyroidism’ and documented in patients with a recent hip fracture [26]. Up to 75% of the patients in the present study had PTH levels below 73 ng/l, despite inadequate vitamin D status. However, the responses of these patients to vitamin D supplementation were similar and parallel with the other patients despite larger increase in 25-OHD concentrations.

Vitamin D supplementation was well tolerated. One patient, however, developed a mild hypercalcaemia (ionised calcium from 1.24 to 1.40 mmol/l) in group III, accompanied by decrease in PTH (from 54 to 7 ng/l) far below the levels seen in replete subjects and increase in 25-OHD (from 15 to 47 nmol/l) that did not even exceed the target level of 50 nmol/l. This observation suggests that the vitamin D supplementation–induced changes in the vitamin D level and in the calcaemic status are individual. Six months after the cessation of the supplementation ionized calcium (1.24 mmol/l) and PTH (30 ng/l) returned to normal limits. The patient had no evidence of diseases causing increased 1,25-hydroxylation of vitamin D.

To the best of our knowledge, the effects of vitamin D supplementation on the bone turnover markers in aged bedridden patients have not been investigated earlier, except for our previous study [12], which showed a significant decrease in carboxy-terminal propeptide of type I collagen (PICP), a marker for bone formation, in a subgroup of five patients, while no significant changes occurred in ICTP in any of the subgroups. In the present study, PINP, also a marker of bone formation, correlated inversely with 25-OHD at baseline and was significantly decreased by vitamin D supplementation. This observation is in accordance with that of an earlier cross-sectional study in which an inverse association between 25-OHD and PINP occurred in a subgroup of aged women (n = 826) with impaired mobility [15]. A decrease in PINP resulting from vitamin D supplementation also occurred during a raloxifene treatment trial in mobile post-menopausal women with osteoporosis [27]. In that study, a subgroup of patients (n = 366, mean age 68 years) served as controls and received supplements of 400–600 IU/d vitamin D and 500 mg/d calcium for 1 year, resulting in an 11% decrease in PINP, compared to a 41% decrease in the group treated with raloxifene, vitamin D and calcium. The observed tendency of PINP to decrease (13–16%) in this present study, together with the significant decrease in ratio of PINP to ICTP, suggests that vitamin D supplementation decreases bone collagen formation and bone turnover, even in chronically immobilised aged patients.

The levels of baseline plasma ICTP, a marker of bone resorption, in our patients were very high, in keeping with the view that chronic immobility accelerates bone loss. In group III, ICTP levels increased by 13.7% with a 6-month supplementation of 1200 IU/d vitamin D, suggesting a negative net effect on bone turnover given the decrease in PINP. The changes in ICTP, however, were inconsistent and insignificant. ICTP may also reflect the collagen breakdown of other tissues. A correlation between high levels of ICTP and extent of liver fibrosis has been shown in patients with various liver diseases [28]. Therefore, any conclusions suggesting that vitamin D supplementation would increase bone loss should be made with great caution.

There were several patients with impaired renal function in this study. It has been shown that GFR less than 50 ml/min, estimated from plasma creatinine level leads to impaired hydroxylation of 25-OHD to 1,25-(OH)2D [29]. It can be discussed to what extent the minor and partly insignificant changes in bone turnover are resulted by the inclusion of these patients in this trial. However, the responses to vitamin D supplementation in these patients were similar compared to other patients. Thus, it is unlikely that the impaired hydroxylation of 25-OHD to 1,25-(OH)2D related to renal failure and age causes significant bias to these results.

This randomised controlled double-blind clinical trial has several strengths. The analyses were done by intention to treat. The groups of patients were very homogeneous and the number of patients was sufficient to detect changes in biochemical variables. The homogeneity of selected patients is, however, a weakness of this study as well. The patients were too ill and too immobile for the effects of mobility or its potential changes to be detected. Further comparative studies and meta-analyses are warranted to elucidate the confounding effects of different mobility levels on the benefits of vitamin D supplementation in patients with differing baseline PTH levels.


   Key points
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Key points
Conflict of interest
 Supplementary Data
 Funding
 References
 

  • In a double-blind randomised controlled trial of vitamin D supplementation in bedridden aged patients, the prevalence of hypovitaminosis D was high: up to 98% of the patients had baseline vitamin D levels below 50 nmol/l and PTH was elevated above 73 ng/l in 23% of the patients.
  • Vitamin D supplementation resulted in a marked increase in 25-OHD concentrations and in small but significant decrease in PTH levels.
  • The plasma levels of PINP, a marker of bone formation, tended to decrease. The baseline plasma level of ICTP, a marker of bone resorption, was high and response to vitamin D supplementation was inconsistent.
  • The suppression of secondary hyperparathyroidism with vitamin D supplementation has minor effects on bone turnover markers in chronically immobile aged patients.


   Conflict of interest
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 Conflict of interest
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 References
 
There are no conflicts of interest.


   Supplementary Data
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 Supplementary Data
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Supplementary data for this article are available online at http://ageing.oxfordjournals.org


   Funding
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The study was funded by a special governmental subsidy for health sciences research and training to Helsinki University Central Hospital.


   Acknowledgements
 
We gratefully acknowledge the help of Lea Enjala, Ulla Koponen and Jaana Huuskonen on practical matters. We also thank the staff of the long-term care hospitals and Anneli Vertanen from the Helsinki University Central Hospital laboratory for their flexible co-operation.


   References
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 Abstract
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 Methods
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 Conflict of interest
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 References
 

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Received 12 March 2007; accepted in revised form 1 September 2007.


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