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Relationship between Vitamin D, Parathyroid Hormone, and Bone Health (vit D insufficiently defined)- publication pdf attached
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This version published online on December 15, 2010
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2010-1886
"The accumulation of these findings support the concept that a serum 25OHD greater than 20 ng/ml (50 nmol/liter) is adequate for bone health, and there are no bone data supporting the need for a higher serum 25OHD of 30 ng/ml (75 nmol/liter)......In summary, the practice of defining vitamin D insuf- ficiency as a serum 25OHD less than 30 ng/ml (75 nmol/ liter) (3) based on serum PTH suppression is not supported by the literature review. Taking into account our own results on bone markers, the five large hip fracture studies and the bone loss data from Osteoporotic Fractures in Men, the totality of the data show that vitamin D insuf- ficiency as it relates to bone occurs at a serum 25OHD less than 20 ng/ml (50 nmol/liter). Whether this threshold is higher for diseases other than bone remains to be estab- lished by clinical trials."
A. J. Sai*, R. W. Walters, X. Fang, and J. C. Gallagher
Bone Metabolism Unit (A.J.S., X.F., J.C.G.), Department of Medicine, Creighton University School of Medicine, Omaha Nebraska 68131; and Division of Clinical Research and Evaluative Sciences (R.W.W.), Department of Medicine, Creighton University Medical Center, Omaha, Nebraska 68131
* To whom correspondence should be addressed. E-mail: adarshsai@creighton.edu.
ABSTRACT
Context: There is a controversy regarding the definition of vitamin D insufficiency as it relates to bone health.
Objective: The objective of the study was to examine the evidence for a threshold value of serum 25-hydroxyvitamin D (25OHD) that defines vitamin D insufficiency as it relates to bone health.
Design and Participants: This was a cross-sectional analysis of baseline data in 488 elderly Caucasian women, mean age 71 yr, combined with a literature review of 70 studies on the relationship of serum PTH to serum 25OHD.
Setting: The study was conducted in independent-living women in the midwest United States.
Main Outcome Measure: The relationship between serum 25OHD, serum PTH, and serum osteocalcin and 24-h urine N-telopeptides was evaluated.
Results: Serum PTH was inversely correlated with serum 25OHD (r = -0.256, P < 0.0005), but no threshold as defined by suppression of serum PTH was found within the serum 25OHD range 6-60 ng/ml (15-150 nmol/liter). However, in contrast, there was a threshold for bone markers, serum osteocalcin and urine N-telopeptides, that increased only below a serum 25OHD of approximately 18 ng/ml (45 nmol/liter). Calcium absorption was not correlated with serum PTH and serum 25OHD, and no threshold was found. A literature review of 70 studies generally showed a threshold for serum PTH with increasing serum 25OHD, but there was no consistency in the threshold level of serum 25OHD that varied from 10 to 50 ng/ml (25-125 nmol/liter).
Conclusions: Vitamin D insufficiency should be defined as serum 25OHD less than 20 ng/ml (50 nmol/liter) as it relates to bone.
INTRODUCTION
Serum 25-hydroxyvitamin D (25OHD) is considered to be the best indicator of overall vitamin D status of an individual. Severe vitamin D deficiency [serum 25OHD < 10 ng/ml (25 nmol/liter)] is associated with malabsorption of calcium, secondary hyperparathyroidism, leading to in- creased bone resorption, accelerated cortical bone loss, and increased fractures. Very low levels of serum 25OHD can also cause osteomalacia.
The definition of vitamin D insufficiency is less clear- cut. The World Health Organization originally defined it as a serum 25OHD less than 20 ng/ml (50 nmol/liter) (1). There have been many publications describing the relationship of serum PTH to serum 25OHD, and some but not all papers defined a level of serum 25OHD at which serum PTH levels decreased and reached a plateau. This threshold has been used to define vitamin D insufficiency. Recent influential reviews stated that a serum 25OHD level of 30 ng/ml (75 nmol/liter) should be used as the defining level for vitamin D insufficiency because in the studies analyzed in those reviews, serum PTH showed a plateau at serum 25OHD of approximately 30 ng/ml (75 nmol/liter) (2, 3). Clinical chemistry laboratories now de- fine vitamin D insufficiency as a serum 25OHD level less than 30 ng/ml (75 nmol/liter) and normal values as greater than 30 ng/ml (75 nmol/liter) on their report forms and have adopted this view unquestioningly. This has led to an epidemic of vitamin D insufficiency, and it has been sug- gested that 1 billion people worldwide have vitamin D deficiency or insufficiency (3).
A critical question, however, is what levels of serum PTH are harmful to bone because it was assumed that elevated serum PTH was related to bone loss (3). Independent of vitamin D metabolism, there is an age-related decrease in calcium absorption that probably contributes to secondary hyperparathyroidism (4).
We examined the relationship between serum PTH and serum 25OHD in our own data for evidence of a threshold or plateau and also examined the relationship between bone markers and serum 25OHD. A literature review of studies relating serum PTH and serum 25OHD was performed to determine whether serum PTH showed a plateau or was maximally suppressed in relation to serum 25OHD and whether we could find supporting evidence for a threshold value of serum 25OHD of 30 ng/ml (75 nmol/liter) (3).
Discussion
In our own study of 488 postmenopausal Caucasian women, we found that serum PTH decreased continuously as serum 25OHD increased from 6 to 60 ng/ml (15-150 nmol/liter) without evidence of a plateau, whereas the bone markers serum osteocalcin and uNTx/Cr initially decreased between a serum 25OHD of 6 -18 ng/ml (15- 45 nmol/liter) but then plateaued between serum 25OHD of 18 to 60 ng/ml (45-150 nmol/liter).
We did not find any significant effect of the interaction of calcium intake and serum 25OHD on serum PTH. This might be explained by the relatively few number of subjects (n = 69) with serum 25OHD levels less than 20 ng/ml. However, the few studies that looked at the interaction between calcium intake and serum 25OHD in terms of serum PTH suppression found that at low levels of serum 25OHD (<20 ng/ml), calcium intake was associated with serum PTH (13, 69 -71). In a study from Iceland, subjects with low serum 25OHD less than 10 ng/ml (25 nmol/liter) had significantly higher serum PTH associated with cal- cium intake less than 800 mg/d but above a serum 25OHD of 18 ng/ml (45 nmol/liter), calcium intake had no effect on serum PTH (13). In a study of elderly subjects (85 yr), vitamin D 400 IU/d increased serum 25OHD from 19 to 25 ng/ml (47.4-62.4 nmol/liter) but failed to produce a significant change in serum PTH and serum osteocalcin; however, the mean calcium intake was low (450 mg/d) (69). In a study from Australia of postmenopausal women, 1000 IU/d of vitamin D3 and 1000 mg/d calcium significantly increased serum 25OHD from 18.5 to 23 ng/ml (46.2-57.4 nmol/liter) and significantly suppressed serum PTH and serum C-terminal telopeptides (70). Neither cal- cium nor vitamin D alone suppressed serum PTH, although calcium alone but not vitamin D alone signifi- cantly suppressed serum C-terminal telopeptides.
In a placebo-controlled study of healthy subjects, aged 55 yr, with baseline serum 25OHD level of 26.8 ng/ml (67 nmol/liter), calcium 1200 mg/d alone significantly re- duced the bone turnover markers serum C-terminal te- lopeptides of type 1 collagen and serum amino-terminal propeptide of type I procollagen compared with placebo (71), whereas vitamin D alone (4000 IU/d) had no signif- icant effect on markers; there was no significant effect of calcium or vitamin D on serum PTH. In a study of healthy females aged 47 yr from England and a mean calcium intake of 570 mg/d, vitamin D3 800 IU/d increased serum 25OHD from 29 to 39 ng/ml (72.4 -97.3 nmol/liter) with no change in serum PTH and bone markers, but serum PTH decreased significantly only in the lowest quartile of serum 25OHD (< 24 ng/ml (60 nmol/liter; n = 18) (36).
In a 4-yr randomized, placebo-controlled trial of el- derly women aged 75 yr and baseline serum 25OHD of 23.6 ng/ml (59 nmol/liter), treatment with 750 mg/d of calcium or 15 ug of 25OH vitamin D3 significantly re- duced serum PTH. Calcium intervention was more effec- tive than 25-hydroxyvitamin D3 with the effect of latter seen only at lower calcium intake (<716 mg/d) but not at higher calcium intake (<716 mg/d) (72). Also, bone markers serum osteocalcin and uNTx/Cr did not decrease in any groups; on the contrary, bone markers increased in the vitamin D and placebo groups and stayed the same in the calcium group.
Many other studies in which serum PTH declined significantly after vitamin D and calcium intervention started with low baseline serum 25OHD levels less than 20 ng/ml (50 nmol/liter) (73-75).
Calcium absorption was not associated with serum PTH or serum 25OHD but was associated significantly with serum 1,25(OH)2D. Another recent study showed no correlation between calcium absorption and serum 25OHD levels [mean serum 25OHD 21 ng/ml (52.4 nmol/ liter)] (76). In contrast, Heaney (77) suggested that cal- cium absorption increased with increasing serum 25OHD and did not reach a plateau until 32 ng/ml (80 nmol/liter); these results were derived from a heterogeneous group of five studies, three of which did not directly measure cal- cium absorption. One study showed that calcium absorption was positively correlated with serum 25OHD only when serum 25OHD level was less than 4 ng/ml (10 nmol/ liter), and absorption did not increase with higher serum 25OHD (78). So in studies in which serum 25OHD was greater than 5 ng/ml (12.5 nmol/liter), a threshold effect might have been missed.
It has been suggested that because serum PTH is still elevated at a serum 25OHD of 30 ng/ml (75 nmol/liter), it is an indicator of secondary hyperparathyroidism and because PTH resorbs bone, it must be an adverse finding (2, 3), but many of the studies did not measure bone resorp- tion, bone loss, or fractures. In our study increased bone resorption was associated only with serum 25OHD less than 18 ng/ml (45 nmol/liter). There are other bone studies that confirm this threshold. A nested case-control study from the Women's Health Initiative found that the risk of hip fractures was significantly greater in women with mean serum 25OHD 19 ng/ml or less (47.5 nmol/liter) compared with the group with mean serum 25OHD 28.3 ng/ml or greater (70.7 nmol/liter) [odds ratio 1.71, 95% confidence limits (CL) 1.05-2.79] (79). In another case- cohort study, 436 men with incident nonspine fractures vs. 1608 controls, the group in the lowest quartile of serum 25OHD less than 20 ng/ml (50 nmol/liter) had more hip fractures compared with men in the top quartile of serum 25OHD (>/=28 ng/ml) (70 nmol/liter) [hazard ratio (HR) 2.36, 95% CL 1.08-5.15] (80). In the National Health and Nutrition Examination Survey III study consisting of 1917 white men and women 65 yr of age or older, the risk of hip fracture was significantly lower in the group with serum 25OHD 25 ng/ml or greater (62.5 nmol/liter) than those with serum 25OHD less than 25 ng/ml (62.5 nmol/liter) [relative risk 0.64, 95% CL 0.46-0.89] (81). In another recent study of fractures in 1194 men with a median follow-up of 11 yr, it was found that serum 25OHD levels of less than 16 ng/ml (40 nmol/ liter) were associated with an increased risk of fracture (HR 1.65, 95% CL 1.09 -2.49) (82). In another Swedish study involving 986 ambulatory women, aged 75 yr, the HR for sustaining a fracture was 2.04 (95% CL 1.04 - 4.04) in the group with serum 25OHD less than 20 ng/ml (50 nmol/liter) (84).
In a longitudinal study of bone density from the Osteoporotic Fractures in Men study, the rate of bone loss in the hip was higher in the group with serum 25OHD levels less than 20 ng/ml (50 nmol/liter) compared with greater than 20 ng/ml (50 nmol/liter) (85). A bone biopsy study in Germany performed in 675 autopsies of men and women showed that about 96.5% of osteomalacia cases occurred at a serum 25OHD level of less than 20 ng/ml (50 nmol/ liter), and almost 99% occurred at serum 25OHD levels of less than 25 ng/ml (62.4 nmol/liter) (86).
The accumulation of these findings support the concept that a serum 25OHD greater than 20 ng/ml (50 nmol/liter) is adequate for bone health, and there are no bone data supporting the need for a higher serum 25OHD of 30 ng/ml (75 nmol/liter).
It is not clear what is the clinical significance of higher serum PTH at serum 25OHD levels greater than 20 ng/ml (50 nmol/liter) when bone markers are not increased. Age- related decreases in calcium absorption and renal function and low calcium intake are some of the explanations. Several other factors affect serum PTH levels including race (23), gender (48), weight (20), serum leptin (45), and serum SHBG (8). These factors may play a role in the range of serum 25OHD levels at which serum PTH is maximally suppressed.
We saw a continuous decline in serum PTH over the normal range of serum 25OHD up to 60 ng/ml (150 nmol/ liter), and these are levels that none would suggest represents vitamin D insufficiency. Possibly the decreasing serum PTH is a sign of the pharmacological effect of higher serum 25OHD or 1,25(OH)2D acting on the vitamin D response element in the PTH gene.
With regard to the literature review, there are some limitations in defining a threshold serum 25OHD from various studies. There are different methods for measurement of serum 25OHD and serum PTH among the 70 papers. The study populations are variable in terms of age, race, location, diet, gender, and culture, and these factors may influence the relationship between serum 25OHD and serum PTH. The role of calcium intake might be important in suppressing serum PTH, particularly at low serum 25OHD levels, as discussed above. Most of the studies did not analyze the effect of calcium intake while assessing the relationship between serum PTH and serum 25OHD. Twenty-four studies showed a threshold level for serum PTH at a serum 25OHD between 10 and 20 ng/ml (25-50 nmol/liter), and six studies showed a threshold between 20 and 25 ng/ml (50-62.4 nmol/liter). Thirty studies showed a threshold level of serum 25OHD of less than 25 ng/ml (62.4 nmol/liter) in terms of serum PTH suppression. Several studies including our own failed to find any threshold level of serum 25OHD at which serum PTH plateaus.
What is very clear is that of the 70 studies we reviewed, a serum 25OHD threshold varying between 10 and 50 ng/ml (25-150 nmol/liter) was found.
In summary, the practice of defining vitamin D insufficiency as a serum 25OHD less than 30 ng/ml (75 nmol/ liter) (3) based on serum PTH suppression is not supported by the literature review. Taking into account our own results on bone markers, the five large hip fracture studies and the bone loss data from Osteoporotic Fractures in Men, the totality of the data show that vitamin D insufficiency as it relates to bone occurs at a serum 25OHD less than 20 ng/ml (50 nmol/liter). Whether this threshold is higher for diseases other than bone remains to be established by clinical trials.
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