The Free Hormone Hypothesis: Is Free Serum 25‐Hydroxyvitamin D a Better Marker for Bone Mineral Density in Older Women?

Michaëlsson, Karl; Rasmusson, Annica J.; Wolk, Alicja; Byberg, Liisa; Mitchell, Adam; Melhus, Håkan

doi:10.1002/jbm4.10059

Cited by 10 publications

(13 citation statements)

References 34 publications

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“…There are several reports where the directly measured free fraction of 25(OH)D has been compared with total 25(OH)D regarding biological effects of vitamin D. Thus, Johnsen et al found a better correlation for free than for total 25(OH)D regarding bone density (24), whereas that was not found in study by Michaelsson et al (38). For PTH similar relations have been found for free and total 25(OH)D in most studies (24, 39–41), whereas Lopez-Molina et al in healthy children found better correlation with markers of phosphocalcic metabolism for free than for total 25(OH)D (42).…”

Section: T2dmmentioning

confidence: 99%

The Role of Vitamin D Binding Protein, Total and Free 25-Hydroxyvitamin D in Diabetes

Jorde

2019

Front. Endocrinol.

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Vitamin D is important for bone health, but may also have extra-skeletal effects. Vitamin D and its binding protein DBP have immunological effects and may therefore be important in the development of type 1 diabetes (T1DM), and low serum levels of 25-hydroxyvitamin D (25(OH)D) are associated with later development of type 2 diabetes (T2DM). However, it has so far been difficult to convincingly show an effect of vitamin D supplementation on prevention or treatment of diabetes. The serum level of 25(OH)D has traditionally been used as a marker of a subject's vitamin D status. This measurement includes both 25(OH)D bound to DBP and albumin as well as the free from of 25(OH)D. However, according to the free hormone hypothesis, the free form is the biologically active. Previously the free form of 25(OH)D had to be calculated based on measurements of 25(OH)D, DBP, and albumin, but recently a method for direct measurement of free 25(OH)D has become commercially available. This is important in clinical conditions where the amount of DBP is affected, and has caused a renewed interest in which vitamin D metabolite to measure in clinical situations. In the present review the relations between DBP, total and free 25(OH)D in T1DM and T2DM are described.

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Section: T2dmmentioning

confidence: 99%

The Role of Vitamin D Binding Protein, Total and Free 25-Hydroxyvitamin D in Diabetes

Jorde

2019

Front. Endocrinol.

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“…In contrast, in a cross-sectional analysis comparing the correlations between free vs. total serum 25(OH)D with BMD and composite indices of femoral neck strength, Alwan reported that higher free 25(OH)D levels were correlated with greater BMD (lumbar spine, femoral neck, total hip), and femoral neck strength ( r = 0.24–0.34, p < 0.05), but total 25(OH)D was not (152). On the flip side, Michaelsson et al reported that in women from Sweden (mean age 68 years) higher total, but not free, serum 25(OH)D was associated with greater BMD (153).…”

Section: Human Clinical Studies Of Free 25(oh)d and Bonementioning

confidence: 99%

Vitamin D Binding Protein and the Biological Activity of Vitamin D

et al. 2019

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Vitamin D has a long-established role in bone health. In the last two decades, there has been a dramatic resurgence in research interest in vitamin D due to studies that have shown its possible benefits for non-skeletal health. Underpinning the renewed interest in vitamin D was the identification of the vital role of intracrine or localized, tissue-specific, conversion of inactive pro-hormone 25-hydroxyvitamin D [25(OH)D] to active 1,25-dihydroxyvitamin D [1,25(OH)2D]. This intracrine mechanism is the likely driving force behind vitamin D action resulting in positive effects on human health. To fully capture the effect of this localized, tissue-specific conversion to 1,25(OH)2D, adequate 25(OH)D would be required. As such, low serum concentrations of 25(OH)D would compromise intracrine generation of 1,25(OH)2D within target tissues. Consistent with this is the observation that all adverse human health consequences of vitamin D deficiency are associated with a low serum 25(OH)D level and not with low 1,25(OH)2D concentrations. Thus, clinical investigators have sought to define what concentration of serum 25(OH)D constitutes adequate vitamin D status. However, since 25(OH)D is transported in serum bound primarily to vitamin D binding protein (DBP) and secondarily to albumin, is the total 25(OH)D (bound plus free) or the unbound free 25(OH)D the crucial determinant of the non-classical actions of vitamin D? While DBP-bound-25(OH)D is important for renal handling of 25(OH)D and endocrine synthesis of 1,25(OH)2D, how does DBP impact extra-renal synthesis of 1,25(OH)2D and subsequent 1,25(OH)2D actions? Are their pathophysiological contexts where total 25(OH)D and free 25(OH)D would diverge in value as a marker of vitamin D status? This review aims to introduce and discuss the concept of free 25(OH)D, the molecular biology and biochemistry of vitamin D and DBP that provides the context for free 25(OH)D, and surveys in vitro, animal, and human studies taking free 25(OH)D into consideration.

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“…A woman with a bi-allelic deletion of Gc exhibited a very low level of 25OHD Total and congenital absence of VDBP, but remained normocalcemic, thus exhibiting relatively mild disruption of bone metabolism, supporting the “free hormone hypothesis” [ 43 ]. However, the significance of the relationships between the various 25OHD measures and bone parameters varied by subject age, sex, hormonal and medication status, the methods used to measure vitamin D or VBDP, and the BMD measurement sites [ 15 – 18 , 44 ]. In racially diverse athletic men, Allison et al reported better associations between con-25OHD BioA level derived using a monoclonal VDBP and BMDs at all sites compared to those of the 25OHD Total level [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, this may not be relevant to bone health, as bone structural integrity relies on an adequate Ca supply delivered via the action of 1,25OH 2 D [ 13 ], principally VDBP-bound 25OHD [ 14 ]. A better [ 15 – 17 ] or poorer [ 18 ] association between bone mineral density (BMD) and 25OHD Free and/or 25OHD BioA levels (compared to that of 25OHD Total ) has been reported in adult populations. The vitamin D measure that best reflects bone parameters in healthy children remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Total, bioavailable and free 25-hydroxyvitamin D levels as functional indicators for bone parameters in healthy children

Heo

Lee

et al. 2021

PLoS ONE

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Objectives Vitamin D is essential for bone health. Not only total but also free 25-hydroxyvitamin D (25OHD) may contribute to bone mass. We sought to determine which vitamin D measure best reflected clinical and bone parameters in healthy children. Methods A cross-sectional study including 146 healthy children (71 boys, 9.5 ± 1.9 years) conducted at a tertiary medical center. We used a multiplex liquid chromatography-tandem mass spectrometry-based assay to simultaneously measure vitamin D metabolites. The bioavailable and free 25OHD (25OHDBioA and 25OHDFree) levels were calculated using the genotype-specific or genotype-constant affinity coefficients of vitamin D-binding proteins (yielding spe-25OHDBioA, spe-25OHDFree and con-25OHDBioA, con-25OHDFree respectively). The 25OHDFree level was directly measured (m-25OHDFree). Bone mineral content (BMC) and bone mineral density (BMD) were assessed via dual-energy X-ray absorptiometry. Results The total 25OHD (25OHDTotal), the two forms of 25OHDBioA, the three forms of 25OHDFree, and 24,25-dihydroxyvitamin D3 levels correlated with parathyroid hormone level (all p < 0.01). Serum 25OHDTotal and m-25OHDFree levels were influenced by age, pubertal status, season, body mass index (BMI), daylight hours, and vitamin D intake (all p < 0.05). The con-25OHDBioA and con-25OHDFree levels better reflected pubertal status and daylight hours than did the spe-25OHDBioA and spe-25OHDFree levels (both p < 0.01). The association between the 25OHDTotal level and bone parameters varied according to the BMI (interaction p < 0.05). In 109 normal-weight children, the con-25OHDBioA and con-25OHDFree levels correlated with total body BMC and BMD (both p < 0.05), whereas the 25OHDTotal and 24,25-dihydroxyvitamin D3 levels were associated with total body BMC (both p < 0.05). No such association was found in overweight or obese children. Conclusions In healthy children, total, bioavailable, and free 25OHD levels comparably reflected lifestyle factors. In normal-weight children, the con-25OHDBioA and con-25OHDFree, but not m-25OHDFree levels, reflected bone mass, as did the 25OHDTotal level.

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The Free Hormone Hypothesis: Is Free Serum 25‐Hydroxyvitamin D a Better Marker for Bone Mineral Density in Older Women?

Cited by 10 publications

References 34 publications

The Role of Vitamin D Binding Protein, Total and Free 25-Hydroxyvitamin D in Diabetes

The Role of Vitamin D Binding Protein, Total and Free 25-Hydroxyvitamin D in Diabetes

Vitamin D Binding Protein and the Biological Activity of Vitamin D

Total, bioavailable and free 25-hydroxyvitamin D levels as functional indicators for bone parameters in healthy children

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