Allan G. Need

Vitamin D Metabolites and Calcium Absorption in Severe Vitamin D Deficiency

Contrary to frequent claims, vitamin D insufficiency does not generally cause malabsorption of calcium because serum 1,25(OH)2D, which is the major determinant of calcium absorption, is maintained by secondary hyperparathyroidism. Nevertheless, because malabsorption of calcium has been described in osteomalacia, there must be a 25(OH)D level below which the serum 1,25(OH)2D can no longer be sustained, although it has never been defined. This paper seeks to define it. We examined the records of 3661 patients and found 319 with a serum 25(OH)D ≤40 nM, in whom calcium absorption, serum calcium, PTH, bone markers, and vitamin D metabolites had been measured. They were grouped according to their serum 25(OH)D into four categories, 0–10, 11–20, 21–30, and 31–40 nM, and differences between the groups were tested by ANOVA. Correlations between the variables were also examined. Serum calcium, 1,25(OH)2D, and calcium absorption were significantly decreased and serum PTH and alkaline phosphatase (ALP) and urine hydroxyproline were increased in those with 25(OH)D ≤10 nM. Serum ALP and urine hydroxyproline were more strongly related, inversely, to calcium absorption than to the vitamin D metabolites. We conclude that vitamin D deficiency does not reduce serum 1,25(OH)2D, and therefore calcium absorption, until the serum 25(OH)D falls to ∼10 nM. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite despite secondary hyperparathyroidism. Further studies are needed to see how these changes correlate with the histological changes of osteomalacia.

Relationship between fasting serum glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal women

Objective  Because it has been reported that vitamin D, given to mother or infant, can prevent type I diabetes in children, that diabetes is more common in adults with low serum vitamin D and that insulin secretion and action are related to vitamin D levels in healthy young adults we examined the relationship between serum vitamin D metabolites and fasting serum glucose in patients attending our outpatient clinics.

Vitamin D, glucose, insulin, and insulin sensitivity

This review examines available evidence of links between abnormalities of glucose and insulin metabolism and vitamin D deficiency. Possible mechanisms of action of vitamin D include stimulation of insulin secretion and effects on insulin sensitivity. Sun exposure usually implies greater outdoor physical activity, which in itself may have beneficial effects on insulin sensitivity, unrelated to serum 25-hydroxyvitamin D concentrations. The observed associations in humans among vitamin D, insulin, and glucose metabolism have not yet been confirmed by intervention studies and, hence, a causal association has not been established. Clinical trials are needed to determine whether vitamin D treatment of vitamin D-deficient individuals is able to prevent or treat diabetes mellitus.

Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency

It is known that nursing-home patients with vitamin D insufficiency have elevated serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase (ALP). Although it is well known that vitamin D insufficiency and secondary hyperparathyroidism are common among the elderly in western countries, there is continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D] necessary for bone health. We approached this issue by examining the relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the urinary bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr, respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who were referred to our osteoporosis and menopause clinics for investigation. When the patients were divided into two groups with 25(OH)D above and below 20 nmol/L, 30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant differences between the two groups thus derived was found at a serum 25(OH)D level of 60 nmol/L (P < 0.001 for all markers). The most significant difference between groups for serum PTH was found when the patients were divided at a serum 25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a trend for ionized calcium to be positively related to 25(OH)D, but this did not reach statistical significance. We conclude that rises in three bone resorption markers and ALP can be detected in postmenopausal women when the serum 25(OH)D level falls below 60 nmol/L. Levels above this may be required for optimal bone health.

Glucose tolerance and vitamin D: Effects of treating vitamin D deficiency

OBJECTIVE We investigated the effects of vitamin D treatment on plasma glucose, serum insulin, and insulin sensitivity in vitamin D-deficient individuals without diabetes mellitus. METHODS Thirty-three adults with vitamin D insufficiency (serum 25-hydroxyvitamin D concentration < or = 50 nmol/L) and without diabetes (12 with impaired glucose tolerance) were given two oral doses of 100 000 IU of cholecalciferol, 2 wk apart. Before the first dose and 2 wk after the second dose, a 75-g oral glucose tolerance test was performed. Plasma glucose, serum insulin, 25-hydroxyvitamin D, and parathyroid hormone concentrations were measured and insulin sensitivity was calculated from the oral glucose tolerance test. RESULTS Mean serum 25-hydroxyvitamin D increased from 39.9 +/- 1.5 (SEM) to 90.3 +/- 4.3 nmol/L (P < 0.0001) and mean serum parathyroid hormone decreased from 6.7 +/- 1.2 to 4.5 +/- 0.6 pmol/L (P = 0.055). There was no change in blood glucose mean of 0-120 min (6.1 +/- 0.3 before versus 6.2 +/- 0.3 mmol/L, P = 0.63) or insulin mean of 0-120 min (47.8 +/- 5.35 versus 48.9 +/- 5.22 mU/L, P = 0.67) concentrations, and no change in insulin sensitivity (Avignons insulin sensitivity index [SiM], P = 0.97; insulin sensitivity index at 0 and 120 min [ISI(0,120)], P = 0.74; Quantitative Insulin Sensitivity Check Index [QUICKI], P = 0.88; homeostasis model assessment [HOMA], P = 0.99) after vitamin D treatment. Results did not differ between subjects, with and without, impaired glucose tolerance. CONCLUSION In adults without diabetes, correction of vitamin D deficiency is not associated with any effect on blood glucose or insulin concentrations or insulin sensitivity as assessed during an oral glucose tolerance test. These observations do not support an association between glucose/insulin homeostasis and vitamin D, at least in the short term.

Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis

Both raloxifene (RLX) and alendronate (ALN) can treat and prevent new vertebral fractures, increase bone mineral density (BMD), and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis. This phase 3, randomized, double-blind 1-yr study assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis (femoral neck BMD T-score, less than 2). Women (aged 2 yr since their last menstrual period) received placebo, RLX 60 mg/d, ALN 10 mg/d, or RLX 60 mg/d and ALN 10 mg/d combined. At baseline, 6 and 12 months, BMD was measured by dual x-ray absorptiometry. The bone turnover markers serum osteocalcin, bone-specific alkaline phosphatase, and urinary N- and C-telopeptide corrected for creatinine were measured. The effects of RLX and ALN were considered to be independent and additive if the interaction effect was not statistically significant (P > 0.10) in a two-way ANOVA model. All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups, and between the RLX and RLXALN groups (P < 0.05). On average, lumbar spine BMD increased by 2.1, 4.3, and 5.3% from baseline with RLX, ALN, and RLXALN, respectively. The increase in femoral neck BMD in the RLXALN group (3.7%) was greater than the 2.7 and 1.7% increases in the ALN (P 0.02) and RLX (P < 0.001) groups, respectively. The changes from baseline to 12 months in bone markers ranged from 7.1 to 16.0% with placebo, 23.8 to 46.5% with RLX, 42.3 to 74.2% with ALN, and 54.1 to 81.0% in the RLXALN group. RLX and ALN increased lumbar spine and femoral neck BMD, and decreased osteocalcin and C-telopeptide corrected for creatinine in an additive and independent manner, because the interaction effects were not significant. Although the ALN group had changes in BMD and bone markers that were approximately twice the magnitude as in the RLX group, it is not known how well these changes correlate to the clinical outcome of fracture. RLXALN reduced bone turnover more than either drug alone, resulting in greater BMD increment, but whether this difference reflects better fracture risk reduction was not assessed in this study. (J Clin Endocrinol Metab 87: 985–992, 2002)

Misconceptions — Vitamin D insufficiency causes malabsorption of calcium

The negative effect of vitamin D insufficiency on bone is commonly attributed to a decrease in calcium absorption although little evidence has been produced to support this assumption. Using two previously published series of elderly patients we refute this common assumption and present evidence that low circulating levels of 25 hydroxyvitamin D have a direct and deleterious effect on bone.

A longitudinal study of bone-related biochemical changes at the menopause

objective  To evaluate the effects of the menopause on bone‐related biochemical variables in a longitudinal study.

Nutrition, Osteoporosis, and Aging

ABSTRACT: Loss of bone is an almost universal accompaniment of aging that proceeds at an average rate of 0.5‐1% per annum from midlife onwards. There are at least four nutrients involved in this process: calcium, salt, protein, and vitamin D, at least in women. The pathogenesis of osteoporosis in men is more obscure. Calcium is a positive risk factor because calcium requirement rises at the menopause due to an increase in obligatory calcium loss and a small reduction in calcium absorption that persist to the end of life. A metaanalysis of 20 calcium trials shows that this process can generally be arrested by calcium supplementation, although there is some doubt about its effectiveness in the first few years after menopause. Salt is a negative risk factor because it increases obligatory calcium loss; every 100 mmol of sodium takes 1 mmol of calcium out of the body. Restricting salt intake lowers the rate of bone resorption in postmenopausal women. Protein is another negative risk factor; increasing animal protein intake from 40 to 80 g daily increases urine calcium by about 1 mmol/day. Low protein intakes in third world countries may partially protect against osteoporosis. Vitamin D (sometimes called a nutrient and sometimes a hormone) is important because age‐related vitamin D deficiency leads to malabsorption of calcium, accelerated bone loss, and increased risk of hip fracture. Vitamin D supplementation has been shown to retard bone loss and reduce hip fracture incidence in elderly women.

Effects of norethisterone on bone related biochemical variables and forearm bone mineral in post-menopausal osteoporosis

OBJECTIVE Progestogens may be a useful therapeutic alternative to oestrogen in the treatment of post‐menopausal osteoporosis. The purpose of this study was to determine the effects of norethisterone on forearm bone mineral content and bone related biochemical variables in patients with post‐menopausal osteoporosis.