Peter D. O'loughlin

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.

Calcium absorption in normal and osteoporotic postmenopausal women

SummaryHourly fractional absorption of radiocalcium (alpha), serum calcitriol, and a number of other variables were measured in 152 normal and 148 osteoporotic postmenopausal women. Alpha, body weight, and serum albumin were all significantly lower in the osteoporotic than in the normal women, and plasma alkaline phosphatase, fasting urinary calcium, sodium, and hydroxyproline were all significantly higher in the osteoporotic than in the normal group. The most significant determinant of alpha in each group was the serum calcitriol concentration, but calcium absorption relative to serum calcitriol was significantly lower in the osteoporotic than in the normal women. The serum calcitriol level was slightly but not significantly lower in the osteoporotic than in the normal group and accounted for only 20% of the difference in alpha between them. The implied “resistance” to calcitriol in the osteoporotic group was significantly related to serum albumin and body weight but independent of age. Urinary hydroxyproline was an inverse function of alpha and a positive function of fasting urinary calcium in the osteoporotic group.

Vitamin D action and regulation of bone remodeling : suppression of osteoclastogenesis by the mature osteoblast

Vitamin D acts through the immature osteoblast to stimulate osteoclastogenesis. Transgenic elevation of VDR in mature osteoblasts was found to inhibit osteoclastogenesis associated with an altered OPG response. This inhibition was confined to cancellous bone. This study indicates that vitamin D–mediated osteoclastogenesis is regulated locally by OPG production in the mature osteoblast.

Osteoporosis and Klinefelter’s Syndrome

objective We wanted to measure forearm mineral density and bone‐related biochemical variables in patients with Klinefelters syndrome.

Malabsorption of calcium in corticosteroid-induced osteoporosis

SummaryWe have examined the relation between radiocalcium absorption and serum 1,25-dihydroxy-vitamin D [1,25(OH)2D3] levels in a set of 60 postmenopausal women on corticosteroid therapy (29 with and 31 without vertebral compression fractures) and compared these results with those from 31 normal postmenopausal women age-matched with the “normal” corticosteroid-treated women. Radiocalcium absorption was a function of serum 1,25(OH)2D3 in both corticosteroid-treated groups and in the set as a whole, but the impaired calcium absorption in the corticosteroid-treated patients with osteoporosis was not accounted for by their slightly reduced serum 1,25(OH)2D3 levels. This apparent resistance to the intestinal action of 1,25(OH)2D3 was quantified by a Z score which expresses, in standard deviation units, the difference between the measured calcium absorption and that predicted from the 1,25(OH)2D3 level. The Z score was significantly reduced in the osteoporotic group. Vertebral mineral density (VMD) was measured by quantitative computed tomography in 43 of the corticosteroid-treated cases and in all the normal postmenopausal women; analysis by VMD yielded similar conclusions.

Oestrogen deficiency impairs intestinal calcium absorption in the rat

1 The effects of ovariectomy on the relationships between calcium consumption and calcium balance and its components were assessed in adult (10‐14 months) sham‐operated and ovariectomized (Ovx) rats fed a semi‐synthetic diet with the calcium content varying between 0·02 and 0·4 %. 2 Adaptation to dietary calcium restriction was monitored for 47 days from commencement of a 0·02 % Ca diet. 3 Response to 1,25‐dihydroxyvitamin D (20 ng kg−1 day−1) administration in sham and Ovx rats and oestradiol (E2) (20 μg kg−1 day−1) replacement in Ovx rats was assessed in rats fed a 0·05 % Ca diet. 4 Ovx rats had lower intercepts for the relationships between calcium consumption and both calcium balance (P < 0·005) and intestinal calcium absorption (P < 0·005) compared with sham rats, but 1,25‐dihydroxyvitamin D was not reduced in Ovx rats. 5 The magnitude of adaptation to dietary calcium restriction was unaffected by ovariectomy. 6 Intestinal calcium absorption was stimulated by an equivalent amount in sham and Ovx rats following 1,25‐dihydroxyvitamin D administration, although this did not reach statistical significance for sham (sham, t= 1·91, n.s.; Ovx, t= 3·18, P < 0·05). 7 Oestradiol replacement in Ovx rats induced a marked increase in intestinal calcium absorption (t= 8·25, P < 0·005), without stimulating circulating 1,25‐dihydroxyvitamin D levels and led to a marked increase in calcium balance (t= 6·89, P < 0·005). 8 These data indicate that the impairment of intestinal calcium absorption following ovariectomy is not the result of reduced circulating 1,25‐dihydroxyvitamin D or reduced intestinal responsiveness to 1,25‐dihydroxyvitamin D. Moreover E2 stimulates intestinal calcium absorption probably by a direct effect on the intestine.

Longitudinal Changes in Testosterone Over Five Years in Community-Dwelling Men

CONTEXT There are few population-based studies reporting longitudinal changes in total T, LH, FSH, and SHBG levels, and there is limited information on risk factors for their change. OBJECTIVE The objective of the study was to examine 5-year changes in serum T, LH, FSH, and SHBG levels among Australian men. DESIGN The study initially included a randomly selected, community-based cohort of 1588 men age 35 years or older at recruitment (mean age, 54 ± 11 y) with available data at 2 visits. Men on medications known to affect, or with established pathology of, the hypothalamo-pituitary gonadal axis were excluded, leaving 1382 for analysis. RESULTS Mean baseline and follow-up T levels were 16.2 ± 1.4 and 15.6 ± 1.4 nmol/L, a change of -0.13 nmol/L/y. Annualized T changes were associated with obesity, being unmarried, and smoking at baseline, but not with diabetes, hypertension, or cardiovascular disease. T declined in men who had persistent depression or developed chronic disease, and it increased in men who were married, as compared to unmarried, at both time points. In the multivariate analysis, smoking cessation, development of central obesity (waist ≥ 100 cm), or generalized obesity (body mass index ≥ 30 kg/m(2)) resulted in T decreases of 0.36, 0.25, and 0.20 nmol/L/y, respectively. Quitting smoking, developing obesity, and having persisting depression were inversely related to SHBG change. CONCLUSIONS An age-related decline in T levels is not inevitable but is largely explained by smoking behavior and intercurrent changes in health status, particularly obesity and depression.

Vitamin D Depletion Induces RANKL-Mediated Osteoclastogenesis and Bone Loss in a Rodent Model†

The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. We used a rodent model of vitamin D depletion to quantify the 25‐hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10‐wk‐old male Sprague‐Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D3 for 4 mo to achieve stable mean serum 25D levels ranging between 10 and 115 nM. At 7 mo of age, animals were killed, and the histomorphometry of distal and proximal femora and L2 vertebra was analyzed. Total RNA was extracted from whole femora for real‐time RT‐PCR analyses. In the distal femoral metaphysis, trabecular bone mineral volume (BV/TV) showed a significant positive association with circulating 25D levels (r2 = 0.42, p < 0.01) in the animals with serum 25D levels between 20 and 115 nM. Osteoclast surface (Oc.S) levels were positively associated with RANKL:OPG mRNA ratio, higher in groups with lower serum 25D levels, and were independent of serum 1,25D levels. Serum 25D levels <80 nM gave rise to osteopenia as a result of increased osteoclastogenesis, suggesting that levels of 25D >80 nM are needed for optimal bone volume. These data indicate that serum 25D levels are a major determinant of osteoclastogenesis and bone mineral volume and are consistent with the levels of 25D recommended to reduce the risk of fracture in humans.

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.