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NDT Advance Access published online on June 10, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn302
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Bone mineral metabolism and its relationship to kidney disease in a residential care home population: a cross-sectional study

Joanne L. Carter1, Shelagh E. O’Riordan2, Gillian L. Eaglestone3, Michael P. Delaney3 and Edmund J. Lamb1

1 Department of Clinical Biochemistry 2 Department of Health Care of the Older Person 3 Department of Renal Medicine, East Kent Hospitals NHS Trust, Canterbury, Kent, CT1 3NG, UK

Correspondence and offprint requests to: Joanne L. Carter, Department of Clinical Biochemistry, East Kent Hospitals NHS Trust, Canterbury, Kent, CT1 3NG, UK. E-mail: joanne.carter{at}ekht.nhs.uk



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Background. Institutionalized older people have a high risk of bone fractures due to osteoporosis. In addition, chronic kidney disease (CKD) is highly prevalent in older people living in residential homes. Secondary hyperparathyroidism, poor calcium intake and deficiency of 1,25-dihydroxyvitamin D may lead to decreased bone mass in people with CKD. The present cross-sectional study assessed the relationship between markers of bone mineral metabolism and kidney function in a residential care home population.

Methods. Older subjects were recruited from residential care homes and kidney function stratified by the estimated glomerular filtration rate (GFR). Parathyroid hormone (PTH), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured in 188 residents not receiving vitamin D/calcium treatment [mean age 85 (range 68– 100) years, 75% female] and in 52 residents receiving vitamin D/calcium supplementation.

Results. Amongst those not receiving vitamin D/calcium, median PTH increased with declining GFR (P < 0.0001), particularly as GFR (mL/min/1.73 m2) fell below 45. PTH concentration was suppressed by increasing 25-hydroxyvitamin D (P < 0.0001), but not 1,25-dihydroxyvitamin D (P > 0.05) concentration. Nearly all residents (92%) had 25-hydroxyvitamin D deficiency or insufficiency and this was uninfluenced by kidney function (P > 0.05). Concentration of 1,25-dihydroxyvitamin D declined with worsening renal function (P < 0.0004) but 1,25-dihydroxyvitamin D deficiency was prevalent at all stages of kidney disease, including amongst residents receiving vitamin D/calcium supplementation.

Conclusion. Vitamin D deficiency and secondary hyperparathyroidism are common in this population irrespective of renal function. However, as GFR falls below 45, the prevalence of secondary hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency increases. Unidentified CKD appears to exacerbate secondary hyperparathyroidism in this at risk population.

Keywords: 1,25-dihydroxyvitamin D; 25-hydroxyvitamin D; chronic kidney disease; older people; parathyroid hormone



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Osteoporotic fracture risk increases in older people, and the rate of falls is three times greater in residential homes compared with those in the community [1] with up to 20% of falls resulting in fracture [2]. Vitamin D deficiency is associated with decreased bone density and additionally with decreased muscle performance favouring an increase in falls [3]. It is well established that chronic kidney disease (CKD), predominantly a disease of the elderly [4–6], is often associated with both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D deficiency and secondary hyperparathyroidism [7,8] that in turn can result in renal osteodystrophy [9]. Growing evidence has highlighted the significant morbidity and economic burden associated with CKD-related fractures [10].

Vitamin D deficiency [11] and CKD associated with a loss of bone mass [12] are common in older people, and recent studies have shown a strong relationship between hip fracture incidence [13,14], osteoporotic fracture [15] and CKD in older community-dwelling adults. However, little is known about the relationship between bone metabolism and the severity of CKD in an institutionalized older population. We recently reported that significant CKD is prevalent and unrecognized in the UK residential care home population [16]. In the present paper, we have assessed the relationship between secondary hyperparathyroidism, 25-hydroxyvitamin D deficiency, 1,25-dihydroxyvitamin D deficiency and kidney function in this population who were predominantly not taking vitamin D and calcium supplements.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Conclusion
 References
 
Recruitment of participants
In this cross-sectional study subjects (n = 250) were recruited over a 9-month period (March to November 2006) from residential care homes in East Kent (total population 3811) using a randomization process as previously described [16]. The number of residents recruited each month was recorded (Figure 1). Residents were weighed and a detailed clinical history recorded, including the presence of co-morbid conditions, medications and smoking. The co-morbidity record was in some cases adjusted following careful review of the individual's medication by a consultant geriatrician. The study had full ethical approval from the East Kent Local Research Ethics Committee (reference 04/Q1803/47).


Figure 1
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  		Fig. 1 Description of the study cohort. The primary study group included 188 residents not receiving vitamin D/calcium. A secondary analysis was undertaken on a group of 52 residents being actively treated with vitamin D/calcium. Residents were recruited over a 9-month period (March to November 2006).

 
From this sample two cohorts of patients were selected (Figure 1). The primary analysis focused on 188 residents not receiving vitamin D/calcium supplements suitable for examining the native relationship between bone mineral metabolism and kidney function. A secondary analysis was undertaken in which a cohort of residents receiving vitamin D/calcium supplementation (n = 52) was compared against those not receiving treatment. Information about the exact dose of vitamin D and calcium supplementation being administered to residents was not always available. However, standard practice in the UK is to supplement with a daily dose of 800 IU of 25-hydroxyvitamin D (typically cholecalciferol) complemented with calcium (1000–1200 mg) [17].

Laboratory analyses
Blood was collected into vacutainer devices, transported to the laboratory within 4 h of venepuncture and analysed on the same day, with the exception of the 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) measurements, where samples were stored for a maximum of 3 months at –80°C. Serum electrolytes, calcium, phosphate, magnesium, alkaline phosphatase (ALP), alanine transaminase (ALT), {gamma}-glutamyl transferase (GGT) and C-reactive protein (CRP) were measured using an Integra 800 analyser (Roche Diagnostics plc, Lewes, East Sussex, UK). Thyroid function was assessed by measuring free thyroxine and thyroid stimulating hormone on an ADVIA Centaur analyser (Bayer, Newbury, Berkshire, UK). CRP concentrations (mg/L) <1.0 were recorded in this study as 0.9 for subsequent statistical analysis. Haemoglobin was measured using a SYSMEX XE-2100 (Sysmex, Kobe, Japan) analyser. Serum creatinine was measured using a compensated rate Jaffe method on an Integra 800 analyser with standardization traceable to isotope-dilution mass spectrometry. The reference ranges for serum creatinine concentration were 44–80 µmol/L in women and 62–106 µmol/L in men. GFR was estimated (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) study equation [18]. Prior to GFR estimation, creatinine values were adjusted so that the method yielded comparable values to those produced by the laboratory serving the MDRD study [19].

Plasma concentrations of intact PTH were determined by a direct chemiluminescent two-site sandwich immunoassay on an ADVIA Centaur analyser. The between-day coefficients of variation (CVs) were 5.8%, 1.5% and 2.8% for PTH concentrations of 40 ng/L, 224 ng/L and 859 ng/L, respectively. The reference range for this assay is 14–72 ng/L. Plasma concentrations of bio-intact PTH were analysed by a Human Bioactive PTH 1–84 enzyme-linked immunosorbent assay (ELISA) kit (Immutopics Inc., San Clemente, USA). Within-batch CVs were 2.9% and 2.4% at concentrations of 24 ng/L and 192 ng/L, respectively. This assay is validated for research only but the manufacturers suggest an indicative reference range of 2–40 ng/L.

Vitamin D metabolites were measured by established in-house assays [20,21]. Briefly, serum was extracted using acteonitrile followed by application of the protein-free supernatant to C18 Silica Sep-Pak cartridges for solid phase extraction. Initial separation of metabolites was performed by straight-phase HPLC (Waters Associates, Milford, MA, USA) using a Hewlett Packard Zorbax-Sil Column (4.6 x 250 mm, 5 µm) (Hicrom Ltd, Reading, Berkshire, UK), eluted with hexane:propan-2-ol:methanol (92:4:4). 25-Hydroxyvitamin D2 and 25-hydroxyvitamin D3 were collected together and measured separately by application to a second Zorbax-Sil Column eluted with hexane:propan-2-ol (98:2) and quantified by UV absorbance at 265 nm. Total (D2 plus D3) 25-hydroxyvitamin D concentrations were reported. Within-batch and between-day CVs were 4% and 7%, respectively. Residents were classified as being 25-hydroxyvitamin D replete (>30 µg/L), insufficient (10–30 µg/L), or deficient (<10 µg/L) [22]. Following separation by straight-phase HPLC, 1,25-dihydroxyvitamin D was quantified using an established, well-validated sensitive radioimmunoassay (RIA) [21]. The RIA employs a monoclonal antibody (mAb 5F2) and 3H 1,25-dihydroxyvitamin D3 tracer. Within-batch and between-day CVs were 7.8% at 8 ng/L and 10.7% at 34 ng/L, respectively. The reference range for 1,25-dihydroxyvitamin D was 20–50 ng/L.

Statistics and data analysis
Data were analysed using Analyse-It (Analyse-It Software Ltd, Yorkshire, UK) and Instat (GraphPad.com). P < 0.05 was considered significant. Kidney function was stratified by MDRD eGFR into GFR > 60 mL/min/1.73 m2, stage 3 CKD (30–59 mL/min/ 1.73 m2) or stage 4 CKD (GFR 15–29 mL/min/1.73 m2) according to the internationally agreed system [23]. Stage 3 CKD was further divided into two sub-stages: stage 3A CKD (GFR 45–59 mL/min/1.73 m2) and stage 3B CKD (GFR 30– 44 mL/min/1.73 m2) [24].

The Kruskal–Wallis test [non-parametric analysis of variance (ANOVA)] was used to assess the significance of differences amongst more than two groups: if a significant effect was observed, Dunn's multiple comparison test was used to assess pairwise comparisons. Categorical variables were analysed using the chi-squared test for trend. In most cases the non-parametric Mann–Whitney U-test was used for comparison between two groups. For variables that showed a Gaussian distribution, the significance of differences between more than two groups was analysed using one-way ANOVA: if a significant effect was observed, the Tukey–Kramer multiple comparison test was used to assess pairwise comparisons. Spearman rank analysis was used to test for univariate relationships between vitamin D metabolites/PTH with clinical variables.

Multiple linear regression analysis was performed to investigate the independent effect of clinical variables [age, gender, body mass index (BMI), smoking history, number of medications, length of residence, haemoglobin, diabetes mellitus, vascular disease (comprising cardiovascular disease, stroke and hypertension), dementia, osteoporosis, joint replacement, thyroid disease and eGFR] on vitamin D metabolites in residents not receiving vitamin D/calcium treatment. In multiple regression analyses using serum 1,25-dihydroxyvitamin D as the dependent variable, serum 25-hydroxyvitamin D was included as an independent variable, since this metabolite is a substrate for 1,25-dihydroxyvitamin D. Further multiple regression analysis was performed to investigate the independent effect of clinical variables (age, gender, BMI, vascular disease, smoking history, thyroid disease, osteoporosis, joint replacement, number of medications, length of residence, eGFR, albumin-adjusted calcium, phosphate, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D) on PTH concentration in the same cohort (n = 188). Residuals were found to be normally distributed when the dependent outcome (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D or PTH) was log10 transformed. Multicollinearity was not detected in any models used. Manual backward elimination was performed; clinical variables that were not significant (P > 0.05) were excluded from the analysis.



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Conclusion
 References
 
Demographic information
Characteristics for the whole primary study cohort (n = 188) and by CKD stage are listed in Table 1. Subjects ranged in age from 68 to 100 years, were exclusively Caucasian and predominantly (75%) female. Age and percentage female increased across the CKD stages whereas haemoglobin and serum bicarbonate concentrations decreased. The mean number of medications per resident was 6. A high prevalence of co-morbidities was observed in this cohort (Table 1), but only the number of residents with diabetes mellitus increased significantly across the CKD stages (P = 0.0187). Seventeen residents were receiving bisphosphonates and one was receiving strontium randate.


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  		Table 1 Demographic details of primary study cohort not receiving vitamin D/calcium (n = 188) stratified by the Modification of Diet in Renal Disease (MDRD)-estimated glomerular filtration rate (eGFR)

 
Characteristics of the cohort receiving vitamin D/calcium supplementation (n = 52) were essentially similar [mean age 87 years, 48% were hypertensive, 40% had cardiovascular disease, 29% had joint replacement, 29% had dementia, 25% had a history of stroke, 23% had thyroid disease, 13% had diabetes mellitus (type 1 and type 2), 2% were smokers, 11.5% had an eGFR ≥60 mL/min/1.73 m2, 44% had stage CKD 3A, 37% had CKD stage 3B and 8% had CKD stage 4] (P > 0.05) except that a history of osteoporosis (37%) was more common, the percentage of females was higher (90%) and vascular disease was slightly less prevalent (62%) (P < 0.05). Nine residents were receiving bisphosphonates and one was receiving strontium randate. Fifteen of the 52 residents receiving vitamin D/calcium supplements had suffered a fracture in the previous 10 years compared to 36 of the 188 in the primary study cohort (P = 0.1308).

The association between each of PTH, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with GFR
Amongst residents not receiving vitamin D/calcium supplementation (n = 188) nearly all (92%) had 25-hydroxyvitamin D deficiency (<10 µg/L) or insufficiency (10–30 µg/L) and this was not influenced by kidney function (P > 0.05) as demonstrated by the absence of a progressive change in median values for 25-hydroxyvitamin D across the CKD stages (Table 2, Figure 2). Concentrations of 1,25-dihydroxyvitamin D declined with worsening renal function (P < 0.0004) (Table 2, Figure 2) but 1,25-dihydroxyvitamin D deficiency (<20 ng/L) was prevalent at all stages of kidney disease and in half of patients with stage 3B and 4 CKD. Median intact and bio-intact PTH concentrations increased significantly with declining eGFR, particularly as eGFR fell below 45 mL/min/1.73 m2 (Table 2). The relative increase in bio-intact PTH was ~0.6-fold less than that observed for intact PTH. The prevalence of secondary hyperparathyroidism increased at CKD stage 3B or worse, whichever PTH measurement (i.e. intact or bio-intact PTH) was used. There were no significant changes (P > 0.05) in serum calcium, phosphate, calcium x phosphate product and ALP across the CKD stages (Table 2).


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  		Table 2 Biochemical markers of bone metabolism in primary study cohort not receiving vitamin D/calcium treatment (n = 188) stratified by the Modification of Diet in Renal Disease (MDRD)-estimated glomerular filtration rate (eGFR)

 

Figure 2
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  		Fig. 2 Median concentrations of 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and intact parathyroid hormone (PTH) by Modification of Diet in Renal Disease-estimated glomerular filtration rate (GFR) stages in residents not receiving vitamin D/calcium treatment (n = 188).

 
Effect of clinical variables on vitamin D metabolites
Univariate analyses amongst residents not being treated with vitamin D/calcium treatment demonstrated weak positive correlations between 25-hydroxyvitamin D concentration and both 1,25-dihydroxyvitamin D and calcium x phosphate product and a stronger negative association with PTH (Table 3). However, in a multiple regression model none of these investigated clinical variables were significantly and independently associated with 25-hydroxyvitamin D concentration (data not shown). Amongst these individuals, seasonal variation did not affect 25-hydroxyvitamin D concentration as demonstrated by the absence of the significant difference (P > 0.05) across the 9-month recruitment period: March to November 2006 (data not shown). Further, median (interquartile range) 25-hydroxyvitamin D (µg/L) did not differ (P = 0.2519) between those residents recruited during March and April [10.5 (10.2), n = 36] and those recruited during October and November [12.6 (7.6), n = 34].


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  		Table 3 Correlation between bone metabolism markers (PTH, 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D) and clinical variables in the primary study cohort (n = 188)

 
Univariate analysis demonstrated that 1,25-dihydroxyvitamin D correlated positively with eGFR and haemoglobin and negatively with BMI, although these latter two associations only just achieved significance (Table 3). In a multiple regression model (Table 4) decreased eGFR and the presence of thyroid disease were found to be significant predictors of decreased 1,25-dihydroxyvitamin D concentration. Conversely, female gender was associated with increased 1,25-dihydroxyvitamin D concentration. The model explained 11.0% of the variance in 1,25-dihydroxyvitamin D (P < 0.0001).


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  		Table 4 Independent effect of clinical variables on 1,25-dihydroxyvitamin D concentration by multiple linear regression analysis

 
Effect of clinical variables on intact PTH
Univariate analyses revealed that intact PTH correlated positively with age, BMI and ALP and negatively with 25-hydroxyvitamin D (Figure 3), haemoglobin, calcium and eGFR (Table 3). Declining eGFR, a fall in 25-hydroxyvitamin D concentration and an increase in number of medications were all found to be significant independent predictors of increased PTH concentration using multiple regression analysis (Table 5). Conversely, the presence of diabetes and dementia independently decreased PTH concentration, although the latter only just achieved statistical significance. The model explained 39.7% of the variance in PTH (P < 0.0001). 1,25-Dihydroxyvitamin D had no independent effect on PTH concentration (P > 0.05).


Figure 3
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  		Fig. 3 Relationship between 25-hydroxyvitamin D and PTH concentration in residents not receiving vitamin D/calcium treatment (n = 188).

 

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  		Table 5 Independent effect of clinical variables on parathyroid hormone (PTH) by multiple linear regression analysis

 
Effect of vitamin D supplementation on PTH, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations
PTH concentration was significantly decreased and 25-hydroxyvitamin D significantly increased amongst residents receiving vitamin D/calcium supplementation (n = 52) compared to those not receiving supplementation (n = 188), whereas there was no significant difference in 1,25-dihydroxyvitamin D concentration (Table 6). Amongst the group receiving supplementation (n = 52), the median (interquartile range) 1,25-dihydroxyvitamin D concentration (ng/L) did not differ (P = 0.1382) between those residents who were 25-hydroxyvitamin D replete (>30 µg/L) [20.0 (11.8), n = 34] and those who were not (≤30 µg/L) [25.5 (11.5), n = 18]. Further, amongst the sub-group of those receiving treatment and being 25-hydroxyvitamin D replete (n = 34), when stratified by their median eGFR the median (interquartile range) 1,25-dihydroxyvitamin D concentration (ng/L) did not differ (P = 0.1624) between those with eGFR above [18.0 (9.0), n = 17] and below [22.0 (17.0), n = 17] 45.5 mL/min/1.73 m2.


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  		Table 6 Comparison of circulating parathyroid hormone (PTH) and vitamin D metabolites in residents currently treated and untreated with vitamin D/calcium supplementation

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Conclusion
 References
 
Association of vitamin D metabolite and PTH concentration with kidney function
It is well documented that mineral and bone abnormalities occur during the progression of CKD [25]. However, this is the first study to examine such a relationship in a UK residential care home population, amongst whom covert moderate CKD has only recently been recognized as an extremely prevalent condition [16]. The high prevalence of 1,25-dihydroxyvitamin D deficiency (33%) and secondary hyperparathyroidism (53%) is perhaps not surprising in this population, given that >80% of the residents had CKD stage 3 or worse. These observations were exacerbated as GFR fell below ~45 mL/min/1.73 m2, consistent with recent studies of community-dwelling individuals [8,26]. There were no significant changes in 25-hydroxyvitamin D concentration across the CKD stages. The absence of any significant changes in the serum calcium and phosphate concentrations as GFR declines probably reflects an appropriate physiological increase in PTH in response to declining kidney function and vitamin D deficiency. Significant changes in phosphate and calcium concentrations in CKD patients tend to occur when GFR falls below 20 mL/min/1.73 m2 [8,26], which only applied to two of our cohort.

Along with the full-length (1–84) peptide, C-terminal fragments of PTH lacking the biologically active N-terminal region are both directly secreted by the parathyroid gland and also arise from peripheral metabolism. These fragments accumulate in renal impairment [27]. Widely used, so-called intact PTH assays cross react with these fragments and may potentially be misleading in the presence of kidney disease [28]. Consequently, we also used a PTH assay reported to detect only the full-length (1–84) ‘bio-intact’ PTH molecule. Due to a lack of common standardization direct comparison between these assays is difficult [29]. However, the relative increase in intact PTH (1–84 full-length peptide plus C-terminal fragments) observed across advancing CKD stages was only slightly more pronounced than that of the specific bio-intact PTH (1–84 full-length peptide only) assay. Furthermore, the prevalence of secondary hyperparathyroidism using both PTH measurements was comparable. Thus, although the data presented here suggest the presence of cross-reacting C-terminal fragments that accumulate with declining GFR, both assays seemed to define the same population with hyperparathyroidism.

In our study, a high prevalence (92%) of 25-hydroxyvitamin D deficiency/insufficiency (<30 µg/L) was observed across all CKD stages. This is consistent with a recent study of bone metabolism in 1814 non-institutionalized CKD patients across the United States (mean age 70 years) in which 86% had inadequate 25-hydroxyvitamin D concentrations [8]. However, in the present study, more residents (36%) were identified with 25-hydroxyvitamin D deficiency (<10 µg/L) compared with the aforementioned study [7] in which only 12% of CKD patients were deficient. The higher prevalence of 25-hydroxyvitamin D deficiency in the present study probably reflects our older (median age 86 years) institutionalized population with lower sunlight exposure related to poor mobility and/or lack of outdoor space in combination with nutritional deprivation as health worsens [11,30].

Effect of clinical variables on vitamin D metabolites
Multiple regression analysis was undertaken to establish factors independently associated with both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations. None of the investigated variables including kidney function were significantly associated with 25-hydroxyvitamin D concentration, whereas kidney function and the presence of thyroid disease were found to be associated with 1,25-dihydroxyvitamin D concentration, although the latter was only just significant. Although sunlight exposure and diet were not directly investigated in the present study, the effects of seasonal variation were explored. The nadir for 25-hydroxyvitamin D concentration was defined between March and April and the peak between October and November [31]. Seasonal variation did not affect the concentration of 25-hydroxyvitamin D during the recruitment period.

Although some previous studies have demonstrated positive relationships between 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in elderly women [32], postmenopausal women [33] and in CKD patients [34], others have reported that 25-hydroxyvitamin D concentrations do not affect circulating 1,25-dihydroxyvitamin D in healthy adults [35], outpatients ranging in age from 19 to 97 years [36] and CKD patients [7,8]. In the present study, using a multiple regression analysis approach, 25-hydroxyvitamin D did not significantly and independently predict 1,25-dihydroxyvitamin D concentration.

Vitamin D deficiency/insufficiency is common amongst CKD patients [6] but the present study found no relationship between 25-hydroxyvitamin D and advancing kidney disease consistent with recent data [7,8,26,34,37]. In contrast, 1,25-dihydroxyvitamin D was significantly associated with worsening kidney function as previously reported [7,8,37], probably reflecting reduced renal 1{alpha}-hydroxylase activity, due to decreased functional renal mass.

Surprisingly, the presence of thyroid disease was also found to be an independent predictor of decreased serum 1,25-dihydroxyvitamin D concentration. To date, there have been no other reports of a similar relationship. Female gender significantly predicted increased 1,25-dihydroxyvitamin D although this only just achieved statistical significance. Unlike other studies [7,8] the presence of diabetes mellitus was not independently associated with reduced 1,25-dihydroxyvitamin D concentration. Notably, only 11.0% of the variance in 1,25-dihydroxyvitamin D concentration could be explained by the model indicating that other factors not assessed here must account for the variability in 1,25-dihydroxyvitamin D concentration.

Effect of clinical variables on PTH concentration
Kidney function, 25-hydroxyvitamin D and presence of diabetes were the most significant factors affecting PTH concentration. Surprisingly, only 25-hydroxyvitamin D was a significant predictor of increased PTH concentration whereas 1,25-dihydroxyvitamin D, the active hormone classically associated with homeostatic feedback, had no independent effect. Similarly, amongst patients receiving vitamin D/calcium supplementation, a PTH-lowering effect appeared to be attributable to increased 25-hydroxyvitamin D concentration alone (see below). We were surprised that 1,25-dihydroxyvitamin D had no independent effect on PTH concentration, although such an observation has been made previously [38]. In vitro and in vivo animal models have demonstrated that 1,25-dihydroxyvitamin D decreases PTH gene transcription [39,40]. In uraemic individuals, intravenous administration of 1,25-dihydroxyvitamin D has been shown to cause marked reductions in circulating PTH concentration [41]. However, this appears to have been in association with supraphysiological concentrations of circulating 1,25-dihydroxyvitamin D (e.g. >100 ng/L). In uraemic children, administration of 1.25 ug 1,25-dihydroxyvitamin D either orally or intraperitoneally three times weekly had little effect on PTH concentration despite achieving serum 1,25-dihydroxyvitamin D concentrations within their reference range (20–80 ng/L) [42]. The majority (75%) of our primary study cohort had low concentrations of 1,25-dihydroxyvitamin D (<30 ng/L): it is possible that such concentrations are below the threshold at which an inverse relationship between PTH and 1,25-dihydroxyvitamin D concentrations will be seen.

Many studies have shown an inverse correlation between PTH and 25-hydroxyvitamin D amongst the elderly [36,43], in CKD patients [37], in dialysis [38] and in renal transplant patients [44]. Ghazali et al. [38] also observed that this effect was independent of 1,25-dihydroxyvitamin D. Two hypotheses have been put forward to explain the mechanism by which 25-hydroxyvitamin D could suppress PTH. The parathyroid gland expresses vitamin D receptors [45] and expression of 25-hydroxyvitamin D 1{alpha}-hydroxylase has been demonstrated in human parathyroid tissue [46]. Thus, circulating 25-hydroxyvitamin D could affect PTH secretion by the conversion of this substrate extra-renally to the active form within the parathyroid gland [36]. Secondly, there is evidence that 25-hydroxyvitamin D can suppress PTH synthesis in bovine parathyroid cells by direct activation of vitamin D receptors [47].

Diabetes mellitus was shown to be independently associated with decreases in PTH concentration. Although some earlier studies [7,48] reported no differences in PTH concentrations between nondialyzed CKD patients with and without diabetes mellitus, others have demonstrated that PTH was less responsive to phosphate administration in diabetic patients compared with controls [49].

As expected worsening kidney function was significantly and independently associated with increases in PTH concentration [50]. The number of medications and the presence of dementia also emerged as independent predictors of PTH although these only just achieved statistical significance. Only 39.7% of the variance in PTH concentration could be explained by the model indicating that other factors not assessed here significantly account for the variability in PTH concentration.

Implications
Although residents on supplementation had significantly higher 25-hydroxyvitamin D and lower PTH concentrations compared with the untreated group, 1,25-dihydroxyvitamin D concentration did not differ between the two groups. The efficacy of vitamin D supplementation on biochemical (increased 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations, lowered PTH concentration) and clinical (reduced falls risk and fractures) endpoints is controversial, both in the setting of CKD and in the older population more generally. A recent Cochrane meta-analysis of 38 trials revealed the benefit of vitamin D supplementation (700–800 IU) on fracture prevention, which was only significant amongst the institutionalized older population when co-administered with calcium (1000 mg) [51]. Evidence is scant in the predialysis CKD population. Clinical practice guidelines recommend pharmacological doses of vitamin D in stage 3 CKD patients with secondary hyperparathyroidism [52] but, in a relatively small study, Al-Aly et al. found that even such doses were relatively ineffective [53]. Conversely, in the study of Sekkarie [54], secondary hyperparathyroidism and 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D deficiency in patients with CKD stages 3 and 4 was prevented by daily administration of 400 IU 25-hydroxyvitamin D and 500 mg calcium.

Some studies have promoted supplementation with the active form of vitamin D demonstrating that an increase in 1,25-dihydroxyvitamin D concentration is associated with prevention of annual bone mineral density changes in predialysis CKD patients [55] and lower fall rates in older community-dwelling adults [56,57]. Further, only treatment with the active form of vitamin D resulted in increases in circulating 1,25-dihydroxyvitamin D compared with treatment with 25-hydroxyvitamin D in healthy men [35]. The prevalence of 1,25-dihydroxyvitamin D deficiency we observed amongst residents receiving supplementation could reflect poor compliance, although a beneficial effect of treatment on 25-hydroxyvitamin and PTH concentrations was observed in this group. Alternatively, the treatment regimen involving 25-hydroxyvitamin D (800 IU) and calcium supplementation (1000 mg) may be ineffective for increasing 1,25-dihydroxyvitamin D concentration in this population. Adjuvant therapy involving the active form of vitamin D and/or increased doses of 25-hydroxyvitamin D may be more effective in older institutionalized populations amongst whom CKD has been identified and such strategies require evaluation.

Limitations
The effects of sunlight exposure and quality of diet on 25-hydroxyvitamin D were not assessed in this population but the effect of seasonal variation over the recruitment period was assessed. Also we did not have information about any previous vitamin D/calcium supplementation in the group of 188 residents not taking such supplements at the time of the study, or the reasons for such supplementation in the 52 residents who were receiving vitamin D/calcium. As one would expect, individuals receiving supplementation were more likely to have a recorded history of osteoporosis, although they were not more likely to have suffered a recent fracture. Further, bone formation and resorption markers may have been useful in the characterization of bone turnover status although no significant differences in total ALP were observed across stages of kidney disease.



   Conclusion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
References
 
In conclusion, the present study has shown that vitamin D deficiency (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) and secondary hyperparathyroidism are common amongst older residents irrespective of renal function. However, as kidney function declines, the prevalence of secondary hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency increases. This may increase the risk of osteoporosis-related falls and fractures. Covert CKD is an additional risk factor for disturbed mineral metabolism that must be taken into account when contemplating preventive or secondary management of falls and fractures in the residential care home population. Vitamin D replacement with 25-hydroxyvitamin D plus calcium supplementation appears to be at least partially effective in ameliorating secondary hyperparathyroidism, independent of an effect on 1,25-dihydroxyvitamin D and its efficacy in this setting requires further evaluation.



   Acknowledgments
 
The authors are grateful to the managers and residents of East Kent care homes for participating in this study, to Dr S. Burns for initial help with the study and to the staff of the Clinical Biochemistry Department in East Kent Hospitals NHS Trust for their co-operation and help. They are also grateful to Dr J. Berry and laboratory staff at the University Department of Medicine at Manchester Royal Infirmary for processing the samples for vitamin D analysis. The study received statistical advice at the protocol development stage from Dr C. Cryer, Centre for Health Services, University of Kent. The study received financial support from the British Renal Society (grant reference 04-007).

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication: 20.12.07
Accepted in revised form: 5. 5.08


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