Gender-Dependent Characteristics of Serum 1,25-Dihydroxyvitamin D/25-Hydroxyvitamin D Ratio for the Assessment of Bone Metabolism
ObjectivesVitamin D deficiency, which is common worldwide, increases the risks of falls and fractures and can lead to increased morbidity and mortality. However, the clinical utility and relevance of vitamin D activation remain unknown. The ...
The results of the present study suggested that vitamin D activities had relevance to clinical parameters, especially bone turnover, with gender-specific correlations with features in age and BMI. The ratio of serum 1,25D/25D as a marker for activation of vitamin D was significantly lower in male patients than in female patients, particularly in older females (≧50 years of age), who are considered to be menopausal women. On the other hand, bone mineral density was significantly lower in older female patients (≧50 years of age) than in male patients. The serum 1,25D/25D ratio was found to be negatively correlated with bone mineral density, negatively correlated with serum inorganic phosphate, and positively correlated with intact PTH, ALP, and BAP in all patients. Of interest, the ratio was negatively correlated with age in male patients but was positively correlated with BMI in female patients, suggesting that vitamin D activation is involved in bone metabolism in a gender-specific manner.
The 1,25D/25D ratio is a putative index of CYP27B1 activity and is considered to be a useful tool for the diagnosis of ocular sarcoidosis . In cases of sarcoidosis or lymphomas, type II IFN enhances the activity of 1α-hydroxylase in macrophages, resulting in increased production of 1,25D and hypercalcemia . Excessive vitamin D activity also has a stimulatory effect on bone turnover and an inhibitory effect on bone mineralization . Vitamin D is a key component of the bone-kidney-parathyroid endocrine axis. 1,25D produced in the kidney binds to VDR in the bone and also activates FGF-23 gene expression. Secreted FGF-23 acts on the Klotho-FGF receptor complex in the kidney and parathyroid gland. In the kidney, FGF-23 down-regulates the Cyp27b1 gene and up-regulates the Cyp24 gene, resulting in suppression of vitamin D activity. In the parathyroid gland, FGF-23 suppresses the expression of PTH, which has the potential function of promoting Cyp27b1 gene expression. Since there is a closed negative feedback loop for vitamin D homeostasis, disruption of the loop regulating CYP27B1 induction results in an increase in 1,25D level [19-21].
Vitamin D level in serum has been reported to decline with aging due to a reduction in the production of vitamin D in the skin [22,23]. In general, a hormonal decline of sex steroids such as androgen and estrogen is important in the aging process . Total testosterone level has been reported to have a slight but significant positive association with serum 25D level, suggesting that both testosterone and vitamin D can be health-related markers for males . A meta-analysis showed that vitamin D status has an inverse relationship with BMI in both diabetic and non-diabetic subjects . Another meta-analysis showed that serum vitamin D level had an inverse association with the risk of abdominal obesity in a dose-response manner . Vitamin D deficiency has been considered to be associated with obesity and metabolic dysregulation by modulating the expression of genes related to adipogenesis and inflammatory and oxidative stress in mature adipocytes .
In the present study, it was also shown that serum levels of creatinine and free thyroxin were negatively correlated with the serum 1,25D/25D ratio. In this regard, patients with chronic kidney disease (CKD) usually have secondary hyperparathyroidism and a low serum 1,25 level . Patients in an advanced stage of CKD have high levels of serum FGF-23 and PTH and a low level of Klotho expression, so-called FGF-23 resistance, leading to impaired activation of vitamin D . Vitamin D also acts on the thyroid through VDR; however, there is no clear consensus about a relationship between vitamin D status and thyroid function in healthy humans , although a study on the role of vitamin D in thyroid diseases indicated that vitamin D deficiency might be an increased risk of autoimmune thyroid diseases . However, based on the present findings, it seems likely that thyroid function is involved in the activation of vitamin D.
Vitamin D activity should be evaluated when vitamin D-related disorders such as hyperparathyroidism or granuloma-forming disorders are suspected. However, our findings presented here indicate the importance of assessing vitamin D activity from the ratio of 1,25D to 25D in general clinical settings. Considering that vitamin D activation can be linked to aging and obesity as well as bone mineral metabolism, measurement of serum 1,25D/25D ratio can be useful for suspecting bone loss, fractures, sarcopenia, or other clinical outcomes associated with frailty. Since the present study showed a negative correlation between serum 1,25D/25D ratio and bone mineral density, serum 1,25D/25D ratio might be a marker for determining the necessity for vitamin D supplementation. However, when a high serum 1,25D/25D ratio is related to increased PTH as in primary hyperparathyroidism, vitamin D supplementation may promote the progression of hypercalcemia. Nevertheless, our findings suggest that a high serum 1,25D/25D ratio is a clue for considering the loss of bone mineral density. There are some limitations of the present study. Patients included in the present study had various pathological conditions possibly associated with hypovitaminosis D. Since we focused on BMI and age, which are physiological parameters potentially influenced by pathological conditions, our study could not show a direct interrelationship between vitamin D metabolism and BMI/age. However, we consider that it is meaningful to assess real-world data obtained from clinical practice in general medicine. Also, serum vitamin D levels can be affected by seasonal changes, lifestyles related to sunlight exposure, nutritional intake, and human race [5,23]. In the present study, serum vitamin D levels might have been affected by seasonal changes or sunlight exposure. All of the patients included in this study were Japanese.
Technically, although free vitamin D and albumin-bound vitamin D (10-15%) are bioavailable, current assays cannot distinguish free vitamin D from vitamin D-binding protein-bound (DPB) vitamin D (85-90%) and albumin-bound vitamin D, the amounts of which are affected by the capability for DPB and albumin synthesis . Another limitation of this study is that it was performed retrospectively at a single center with a relatively small number of patients, and it is, therefore, difficult to draw a solid conclusion. To clarify the precise interaction between vitamin D activity and bone turnover, another study with a larger sample size including a general population or a prospective study using age- and gender-matched cohorts as a multi-center study will be needed.
In the present study, it was notable that the 1,25D/25D ratio is conceivably a useful tool for suspecting bone loss, fractures, or other clinical outcomes associated with frailty.