Which circulating level of 25-hydroxyvitamin D is appropriate?

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Abstract

Moderate Vitamin D deficiency causes secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures. Controversy exists which circulating level of 25-hydroxyvitamin D (25OH)D is appropriate. The high incidence of hip fractures at northern latitudes suggest a relationship with Vitamin D deficiency. However, international studies show lower serum 25(OH)D levels in southern than in northern Europe. Serum 25(OH)D was not a risk factor for hip fractures in several epidemiological studies. The required serum 25(OH)D is usually established by assessing the point where serum parathyroid hormone (PTH) starts to rise. This point varied in several studies between 30 and 78 nmol/l. However, interlaboratory variation may also influence the apparent required serum 25(OH)D level. Dietary calcium intake influences serum PTH and serum PTH may influence the turnover of Vitamin D metabolites. A low calcium intake causes an increase of serum PTH and serum 1,25(OH)2D thereby decreasing the half life of serum 25(OH)D. While a low calcium intake may aggravate Vitamin D deficiency, a high calcium intake may have a Vitamin D sparing effect. With current knowledge, a global estimate for the appropriate serum 25(OH)D is 50 nmol/l.

Introduction

Vitamin D deficiency causes rickets in children and osteomalacia in adults. Both diseases are relatively uncommon. Moderate Vitamin D deficiency is more frequent and has been associated with the occurrence of hip fractures in the elderly [1]. Moderate Vitamin D deficiency causes secondary hyperparathyroidism, high bone turnover, and may lead to osteoporosis and fractures [2]. Risk groups for Vitamin D deficiency are the elderly, persons with low sunshine exposure, persons with a dark skin in northern climates and patients with diseases interfering with Vitamin D and calcium absorption. Randomized placebo-controlled trials on the effects of Vitamin D supplementation with fracture as outcome criterion have led to discordant results [2]. The different outcomes of these studies and the varying results of epidemiological studies have led to an ongoing discussion on the required serum concentration of 25-hydroxyVitamin D (25(OH)D) in adults. These differences may also be due to differences in assays for serum 25(OH)D and the influence of calcium intake. These subjects will be discussed in this paper.

Section snippets

Is Vitamin D deficiency a risk factor for hip fractures?

The association between the occurrence of hip fractures and Vitamin D deficiency has been known for more than 30 years [1]. Studies in patients with hip fractures showed signs of osteomalacia or high bone turnover in 5–30% of these patients [2], [3]. In addition, serum 25(OH)D levels were lower in these patients than in age-matched controls. Most of these studies are cross-sectional or case-control and these studies may not always be appropriate to establish causal relationships.

In Europe, the

Assessment of the required serum 25(OH)D level

The metabolite 25(OH)D is the main circulating Vitamin D metabolite, but it is not the most active metabolite. Conclusions on the required serum 25(OH)D concentration might be based on homeostatic mechanisms, such as the synthesis of 1,25(OH)2D, the increase of the serum parathyroid hormone (PTH) level in case of Vitamin D deficiency, or the effects of Vitamin D on bone. Several methods to assess the required serum 25(OH)D concentration are summarized in Table 1. These methods are based on

Evidence from epidemiological and intervention studies

In case of Vitamin D deficiency, the synthesis of 1,25(OH)2D becomes dependent on the availability of the substrate 25(OH)D. In that case, a positive correlation has been observed between serum 25(OH)D and serum 1,25(OH)2D. Positive correlations were found in elderly patients with hip fracture [3] and in institutionalized elderly in a study from Belgium [9]. A threshold serum 25(OH)D level was not established in these studies. Vitamin D supplementation may increase serum 1,25(OH)2D in case of a

Comparability of assays for serum 25(OH)D

When comparing the results from large epidemiological and intervention studies, it became clear that the results obtained with different assays for serum 25(OH)D may be very different. An interlaboratory comparison of serum 25(OH)D assays was done between laboratories in Lyon, Boston, Rotterdam and Amsterdam [18]. It appeared from this study that a difference between an older competitive protein binding assay and HPLC analysis differed a factor 2, while radioimmunoassays were in between. When

The influence of calcium intake on the required serum 25(OH)D

The dietary calcium intake influences the serum PTH level. An oral calcium supplement of 1000 mg decreases serum PTH within one hour [19]. Calcium supplementation can reduce serum PTH during 24 h [20]. Serum PTH influences the turnover of Vitamin D metabolites. A low calcium intake due to low dairy intake after gastrectomy caused an increase of serum PTH and serum 1,25(OH)2D, and decreased the half life of serum 25(OH)D thus leading to Vitamin D deficiency [21]. Metabolic studies in rats with a

Classification of Vitamin D replete and deficient states

A safe lower reference limit for serum 25(OH)D applicable under most circumstances is 50 nmol/l. A serum 25(OH)D between 25 and 50 nmol/l may indicate mild Vitamin D deficiency, while moderate Vitamin D deficiency is a level lower than 25 nmol/l and severe deficiency is defined as a serum 25(OH)D lower than 12.5 nmol/l. This classification is summarized in Table 2.

The assessment of the appropriate circulating level of 25(OH)D is hampered by the moderate comparability of assays for 25(OH)D. The

Conclusion

A serum 25(OH)D level of 50 nmol/l or higher can be considered appropriate. This level may be influenced by dietary calcium intake. The required level may be somewhat lower with a high calcium intake, or higher with a very low calcium intake.

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