Biochemical Responses of Bone Metabolism to 1,25-Dihydroxyvitamin D Administration in Black and White Women

The basis for the racial difference in bone mass between black and white women is not known. Lower bone turnover, better renal calcium conservation, and decreased sensitivity to parathyroid hormone (PTH) have been proposed as explanations. A dynamic comparison of osteoblast function, utilizing stimulation by 1,25-dihydroxyvitamin D [1,25(OH)₂D], has not been tested between these two ethnic groups. We compared well-matched black (n= 15) and white (n= 15) premenopausal women, before and during 5 days of 1,25(OH)₂D administration (1.0 μg/day) in order to assess dynamic indices of bone metabolism. As expected, at baseline, black women had lower levels of serum 25-hydroxyvitamin D and biochemical markers of bone turnover with slightly higher levels of PTH. Black women also had superior renal calcium conservation than white women at baseline. In response to 1,25(OH)₂D administration, black women had a slightly greater increase in serum calcium and greater decrement in PTH. Moreover, black women showed a lesser increment in urinary calcium than white women and a more robust increase in two markers of bone formation – osteocalcin and carboxyterminal propeptide of type 1 procollagen – than white women. There were no changes in bone resorption indices in either race upon 1,25(OH)₂D administration. These data provide preliminary evidence that black women conserve calcium more efficiently under both static and dynamic conditions, and also appear to have better osteoblastic functional reserve than white women. Received: 22 June 1999 / Accepted: 6 September 1999     

Changes in Bone and Calcium Metabolism Following Hip Fracture in Elderly Patients

Although hip fracture is one of the most common causes of acute immobilization in elderly patients, little is known about the influence of immobilization on changes in bone and calcium metabolism following this event. We therefore compared serum biochemical indices of bone and calcium metabolism in 20 elderly subjects with hip fracture with those measured in 20 healthy age-matched controls. Rankin scores, a measure of functional dependence with 0 representing independence and 5 representing total dependence, were assigned. We also examined serial changes in these biochemical indices from shortly following the fracture to the early recovery period. Ionized calcium, intact parathyroid hormone (PTH), intact bone Gla protein (BGP), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), 25-hydroxyvitamin D (25-OHD), and 1,25-dihydroxyvitamin D (1,25-[OH]₂D) were measured. One week after the fracture, mean serum concentrations of calcium and ICTP were elevated in correspondence to degree of immobilization (mean Rankin score; 4.4), while serum concentrations of BGP, PTH, 25-OHD, and 1,25-[OH]₂D were depressed. Rankin score (mean: 4.4) correlated positively with ICTP and negatively with BGP at this time. At 2 months, calcium and ICTP elevation decreased and BGP, PTH and 1,25-[OH]₂D were less depressed, coinciding with a decline in Rankin score from 4.2 to 2.2. Indices were further improved at 3 months (mean Rankin score, 1.3), with calcium and BGP returning to normal. We concluded that increased bone resorption, and decreased bone formation, and hypercalcemia are present by 1 week following the hip fracture, and some resorption increase persists for at least 3 months. These changes could explain in part the high risk of another hip fracture. Received: 3 April 2000 / Accepted: 15 December 2000     

High Prevalence of Hypovitaminosis D among Free-Living Postmenopausal Women Referred to an Osteoporosis Outpatient Clinic in Northern Italy for Initial Screening

To establish the prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in Northern Italy, we evaluated 25-hydroxyvitamin D (25(OH)D) levels in 570 postmenopausal women who had been consecutively referred to our clinic in the 12 months beginning October 1995. Parathyroid hormone (PTH), serum calcium (Ca), creatinine (Cr) and osteocalcin (OC), urinary calcium (Ca24h) and creatinine (Cr24h), and the bone mineral density of the lumbar spine (LBMD) and femur (FBMD) were also measured. 1,25-Dihydroxyvitamin D (1,25(OH)₂D) concentrations were measured in 23 women. All women had normal electrolyte serum concentrations and kidney function. Mean ± SD 25(OH)D concentration was 18.3 ± 8.3 ng/ml. A significant (p<0.001) seasonal variation was seen for both 25(OH)D and PTH. Women were divided into two groups based on their vitamin D status: low vitamin D status (25(OH)D <12 ng/ml, n= 161, 28%) and normal vitamin D status (25(OH)D ≥12 ng/ml, n= 409, 72%). Hypovitaminosis D was found in 38.5% of all the women in the time period December–May and in 12.5% in the other half-year; among women >70 years old 51% had hypovitaminosis D in the time period December–May and 17% in the other half-year. PTH was significantly (p<0.05) increased, and Ca24h, OC and FBMD significantly (p<0.05) decreased in women with hypovitaminosis D. 1,25(OH)₂D positively correlated with 25(OH)D (p<0.0001), but did not correlate with PTH, age or creatinine clearance. In conclusion, hypovitaminosis D is an important, underestimated problem in Italian free-living postmenopausal women referred to an outpatient osteoporosis clinic. Received: 9 February 1998 / Accepted: 8 July 1998     

Association of increased active PTH(1–84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D

Summary As the serum calcium and glomerular filtration rate decreased, the proportion of active PTH(1–84) molecules in PTH immunoreactivity increased in serum from predialysis uremic patients, particularly those with vitamin D insufficiency. Introduction The PTH(1–84) fraction was altered in predialysis patients with chronic renal failure (CRF). Methods Serum PTH in predialysis CRF patients without any medication was measured by PTH(1–84)-specific whole PTH assay and intact PTH assay cross-reacting with N-truncated PTH. Results In CRF patients, the glomerular filtration rate (GFR) correlated positively with serum Ca and 1,25-dihydroxyvitamin D (1,25(OH)₂D), and inversely with serum Pi, log intact PTH, and log whole PTH. In multiple regression analysis, including age, gender, body mass index, GFR, Ca, and Pi and 1,25(OH)₂D as independent variables, serum Ca and GFR associated significantly with serum log whole PTH and intact PTH. Serum log whole PTH/intact PTH ratio, which increased as serum Ca and GFR decreased, retained a negative correlation in those with serum 25-hydroxyvitamin D levels below 20 ng/ml, but not in those above 20 ng/ml. The ratio also correlated positively with serum log tartrate-resistant acid-phosphatase-5b, log cross-linked N-telopeptide of type-I collagen, and log bone alkaline-phosphatase. Conclusion As GFR declined with suppression of serum Ca, the proportion of active PTH molecules increased in predialysis CRF patients, particularly those with vitamin D insufficiency.     

The Association between Parathyroid Hormone, Vitamin D and Bone Mineral Density in 70-Year-Old Icelandic Women

Parathyroid hormone (PTH) may be an important determinant of cortical bone remodeling in the elderly. Vitamin D status is one of the determining factors in this relationship. The aim of this study was to quantify the relationship between serum PTH, vitamin D and bone mineral density (BMD) in elderly women in Reykjavik (64° N), where daily intake of cod liver oil is common and mean calcium intake is high. ln PTH correlated inversely with 25(OH)D (r=−0.26, p<0.01). In multivariate analysis PTH correlated inversely with whole body BMD (mostly cortical bone) (R ²= 2.2%, p = 0.04) but not with the lumbar spine BMD, reflecting more cancellous bone. No association was found between 25(OH)D levels and BMD at any site in univariate or multivariate analysis. Osteocalcin, a measure of bone turnover, was negatively associated with BMD and this association remained significant when corrected for PTH levels. In summary, in this fairly vitamin D replete population with high calcium intake, PTH was negatively associated with total body BMD. We infer that suppression of PTH may reduce cortical bone loss, but other factors are likely to contribute to age-related bone remodeling and osteoporosis. Received: 3 January 2000 / Accepted: 10 April 2000     

Parathyroid Hormone Secretory Response to EDTA-Induced Hypocalcemia in Black and White Premenopausal Women

One consistent racial difference in mineral homeostasis is increased efficiency of renal calcium conservation in blacks which could account, in part, for differences in bone density and fracture risk. Since parathyroid hormone (PTH) is the major regulator of calcium homeostasis, we investigated its secretion in black and white women in response to hypocalcemia. Two hour EDTA infusions (50 mg/kg) were performed in 34 premenopausal women (17 black, 17 white). Blood was sampled at 30-minute intervals during the infusion, at 60-minute intervals for 3 more hours, and at 24 hours. Serum ionized calcium decreased identically in both groups with a nadir at 2 hours and returned to baseline within 24 hours. Serum 1-84 PTH levels rose similarly in both groups with a peak PTH level that was slightly higher in black women, and on average, slightly earlier than that in white women. Serum PTH levels remained elevated in both groups at 24 hours with no overall group differences in PTH response. In black, but not white women, serum 25OHD levels correlated negatively with both basal PTH and peak PTH level, achieved with infusion. Serum 1,25(OH)₂D levels rose and osteocalcin levels decreased, with no group differences. We conclude that overall, premenopausal black women show no clear differences in PTH secretory activity to an EDTA-induced hypocalcemic stimulus. Basal vitamin D status appeared to be a determinant of the degree of the PTH response in black women, with the peak PTH level being inversely correlated with levels of 25OHD. Since we have previously shown that the skeleton contributes less to acute calcium needs in blacks than in whites, the lack of a racial difference in PTH secretory responsivity suggests that calcium homeostasis is more likely maintained in blacks through greater PTH sensitivity at extraskeletal sites, such as the kidney. Received: 31 August 1998 / Accepted: 12 March 1999     

Effect of immobilization upon renal synthesis of 1,25-dihydroxyvitamin D in disabled elderly stroke patients

A 1,25-dihydroxyvitamin D [1,25-(OH)2D] deficiency and immobilization-related increased serum calcium concentration have been observed in hemiplegic stroke patients. To elucidate the influence of increased serum calcium concentration on bone metabolism, we measured serum biochemical indices and bone mineral density (BMD) in the second metacarpals of 170 elderly subjects with hemiplegic stroke and 72 age-matched healthy controls. Serum concentrations of 25-hydroxyvitamin D [25-(OH)D], 1,25-(OH)2D, ionized calcium, intact parathyroid hormone (PTH), intact bone Gla protein (BGP), and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were measured. An increased serum calcium concentration (mean 2.543 mEq/L) was observed in this population and correlated negatively with the Barthel index (mean 66), indicating immobilization-induced bone resorption with consequent increased serum calcium. Decreased serum concentrations of 1,25-(OH)2D (mean 25.0 pg/mL) and serum 25-OHD concentration (mean 11.6 ng/mL) were noted. Serum PTH was not increased (mean 34.8 pmol/L). Serum levels of BGP were decreased significantly, whereas serum ICTP concentrations were elevated (mean 15.2 ng/mL). A strong negative correlation was seen between the serum calcium concentration and 1,25-(OH)2D (p < 0.0001). BMD of the second metacarpal in patients was decreased significantly compared with control subjects and highly correlated with 25-(OH)D and 1,25-(OH)2D concentrations. Immobilization-related increased serum calcium levels may inhibit PTH secretion, and thus 1,25-(OH)2D production. In addition, 25-(OH)D insufficiency also may contribute to decreased concentration of 1,25-(OH)2D.     

Longitudinal Evaluation of Vitamin D Status in Healthy Subjects from Southern Italy: Seasonal and Gender Differences

Vitamin D status is currently considered among the relevant determinants of skeletal integrity. Since vitamin D levels present seasonal variations, we longitudinally studied young healthy men and women in order to investigate the related physiologic modifications of both calcium homeostasis and bone remodeling. Thirty-two men (mean age 39.4 ± 7.8 years) and 58 premenopausal women (aged 36.9 ± 6.4 years) from southern Italy were studied. In all subjects the following parameters were measured both in winter and in summer: serum calcium, phosphorus, creatinine, total alkaline phosphatase activity, 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), osteocalcin (BGP), together with urinary calcium (Ca/Cr), total pyridinoline (Pyr/Cr) and deoxypyridinoline (d-Pyr/Cr), corrected for creatinine excretion. In both sexes 25OHD levels were significantly higher in summer, while PTH values were lower, than in winter. The prevalence of hypovitaminosis D, defined by concentrations of 25OHD lower than 30 nmol/l, was 17.8% in winter and 2.2% in summer in the whole sample, while it was 27.8% and 3.4%, respectively, among female subjects. Indeed male subjects did not display hypovitaminosis D, having throughout the year significantly higher calcium and 25OHD levels together with lower PTH values, than the women. Moreover, alkaline phosphatase total activity was more elevated in men both in winter and in summer. In women, during winter, bone remodeling markers levels were higher while urinary calcium levels were lower than in summer. In the whole sample serum 25OHD correlated positively with serum calcium and inversely with PTH. The seasonal percentage variations in PTH were inversely correlated with those of Ca/Cr. Our results show a relatively high prevalence of subclinical vitamin D deficiency among young healthy women from southern Italy. Significant gender-specific differences have been demonstrated in both calcium homeostasis and skeletal remodeling indexes; the seasonal fluctuations in the vitamin D–PTH axis are accompanied by cyclical variations of bone turnover rate, which were more pronounced in women. Received: 11 January 2001 / Accepted: 6 July 2001     

Increased Serum 1,25-Dihydroxyvitamin D after Growth Hormone Administration is not Parathyroid Hormone-Mediated

To assess the effects of growth hormone (GH) on serum 1,25-dihydroxyvitamin D [1,25(OH)₂D], we performed the following prospective crossover study in six healthy, young, adult, white men. During each of two admissions for 2? days to a general clinical research center, subjects were placed on a daily dietary calcium intake of 400 mg. Serum calcium, phosphorus, 1,25(OH)₂D, immunoreactive intact parathyroid hormone (PTH), insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP3), tubular reabsorption of phosphate (TRP), and maximum tubular reabsorption of phosphate (TMP/GFR) were measured. Recombinant human GH (rhGH, Humatrope) (25 μg/kg/day subcutaneously for 1 week) was administered prior to and during one of the admissions. Results are expressed as mean ± SEM. Whereas serum 1,25(OH)₂D (58.9 ± 7.7 versus 51.6 ± 7.4 pg/ml, P < 0.01), serum phosphorus (4.5 ± 0.1 versus 3.7 ± 0.1 mg/dl, P < 0.01), TRP (92.0 ± 0.5 versus 87.8 ± 0.7 mg/dl, P < 0.005), TMP/GFR (4.6 ± 0.1 versus 3.5 ± 0.2, P < 0.005), and urinary calcium (602 ± 49 versus 346 ± 25 mg/day, P < 0.001) increased significantly, serum PTH decreased significantly (19.9 ± 1.9 versus 26.8 ± 4.0 pg/ml, P < 0.05) and serum calcium did not change when subjects received rhGH. These findings indicate that in humans, GH affects serum 1,25(OH)₂D independently of circulating PTH and that this effect is mediated by IGF-I. We propose, therefore, that one potential mechanism by which GH stimulates increases in bone mass is via modest increases in serum 1,25(OH)₂D. Received: 2 May 1996 / Accepted: 18 October 1996     

Threshold value of serum 25-hydroxyvitamin D concentration in relation to elevated serum parathyroid hormone concentrations in elderly Japanese women

This study was designed to determine the threshold value for 25-hydroxyvitamin D [25(OH)D] concentration in relation to elevated serum parathyroid hormone (PTH) concentrations in elderly Japanese women. The subjects were 582 noninstitutionalized, ambulant women who lived in a community in Japan. Serum 25(OH)D concentrations were determined using the Nichols Advantage chemiluminescent assay, and serum intact PTH concentrations were determined with a two-site immunoradiometric assay. Demographic characteristics, calcium intake, and serum 1,25(OH)₂D levels were also determined. The average age, body mass index (BMI), and calcium intake of the subjects were 74.5 years (SD 4.5), 23.3 kg/m² (SD 3.4), and 579 mg/day (SD 248), respectively. The serum log-transformed intact PTH concentration was significantly predicted by the serum 25(OH)D concentration (r = −0.147, P = 0.0004), but not by age, BMI, the serum log-transformed 1,25(OH)₂D concentration, or the log-transformed calcium intake. Analysis of variance with Dunnett's multiple comparisons showed that mean serum intact PTH concentrations with serum 25(OH)D concentrations less than 30 nmol/l (mean intact PTH = 5.89 pmol/l, P < 0.0001) and in the range 30–39 nmol/l (mean intact PTH = 4.54 pmol/l, P = 0.0067) were significantly higher than mean intact PTH concentrations for serum 25(OH)D concentrations greater than 50 nmol/l (mean intact PTH = 3.65 pmol/l, the baseline level), but the mean serum intact PTH concentration for 25(OH)D concentrations in the range 40–49 nmol/l (mean intact PTH = 3.70 pmol/l, P = 0.9975) was not. We conclude that serum 25(OH)D for ambulant elderly Japanese women should be maintained at 40 nmol/l or higher.     

Parathyroid hormone and rates of bone formation are raised in perimenopausal rural Gambian women

To investigate rates of bone turnover and calcium homeostasis in Gambian women, we recruited 103 peri- and postmenopausal women, aged 45 to 80+ years and 11 women of reproductive age. Fasting blood was analyzed for plasma osteocalcin, PTH, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], total- and bone-specific alkaline phosphatase. Plasma and urinary calcium, inorganic phosphate, sodium, potassium, creatinine, and albumin and urine free deoxypyridinoline (Dpd) was also measured. Samples from 20 premenopausal and 31 postmenopausal women from Cambridge, UK were analyzed, using the same methodology for comparison. For the Gambian women, peak calcium excretion occurred at around 50 years of age. For women aged > or =45 years, calcium excretion decreased by 3.0% per year of age (SE 1%; P < 0.005). In this age group, 25(OH)D also decreased with age (P < 0.005). Urinary sodium output, pH, and titratable acid output decreased (all P < 0.05) and total alkaline phosphatase (P < 0.005), osteocalcin (P < 0.005), and PTH (P < 0.05) increased with age. Comparisons were made between the following groups of Gambian and British women: premenopausal, early (age 55-64 years)- and late (age 65+ years)-postmenopausal. Gambian women of all ages were lighter (P < 0.001), shorter (P < 0.01), and had higher plasma bone-specific alkaline phosphatase activity (P < 0.05) and higher concentrations of osteocalcin (P < 0.05), PTH (P < 0.001), 1,25(OH)(2)D (P < 0.001), and 25(OH)D (P < 0.001). There were no consistent differences in calcitonin, while urinary free Dpd outputs were lower in the Gambians (P < 0.001). Plasma calcium, phosphate, and albumin (P < 0.01) were significantly lower. Urinary calcium, phosphate, sodium, and potassium excretion were lower, particularly in the postmenopausal group (P < 0.001). Although Gambian urine pH was more acidic, titratable acid output was lower (P < 0.01). These data show that Gambian women with low dietary calcium intakes and good vitamin D status have low urinary calcium excretion and that menopausal changes in calcium and bone metabolism among Gambian women are similar to those seen in other populations. In addition, they demonstrate that Gambian women of all ages have raised plasma PTH and 1,25(OH)(2)D concentrations and raised markers of osteoblast activity. We postulate that high endogenous PTH concentrations may be beneficial to bone health in Gambian women, removing fatigue damage and improving bone quality.     

Gastric Fundectomy in the Rat: Effects on Mineral and Bone Metabolism, with Emphasis on the Gastrin–Calcitonin–Parathyroid Hormone–Vitamin D Axis

In humans, gastric surgery results in in osteopenia via mechanisms that are insufficiently understood; surgery-induced changes in the hormonal axes involving the stomach, thyroid, and the parathyroids may play a role. To study this in more detail, we evaluated calcium (Ca), magnesium (Mg), and phosphorus (P) metabolism as well as physical, chemical, and histomorphometric bone parameters in rats rendered hypergastrinemic by fundectomy (FX). In independent experiments, the response to an oral Ca challenge was investigated in intact rats versus FX, and in thyroidectomized versus thyroid-intact FX rats. Sixteen weeks following FX, body weight was approximately 80% that of sham-operated controls. In urine, P excretion was elevated fivefold, the pH was significantly decreased, and cAMP excretion was elevated as compared with controls; serum parathyroid hormone (PTH), calcitonin, 25OHD, Ca, Mg, and P were normal; gastrin and 1,25(OH)₂D were elevated. On the basis of bone ash mineral content, FX rats developed significant osteopenia, and histomorphometry indicated only slightly elevated bone turnover and mineralization. Following oral Ca, thyroid-intact FX rats developed hypercalcemia, serum gastrin decreased, and calcitonin increased significantly; in thyroidectomized FX rats, calcitonin remained at baseline levels although there was a similar degree of hypercalcemia; PTH decreased during the hypercalcemic period in both groups. Serum gastrin did not correlate with calcitonin or PTH, and in multivariate regression analysis the only predictor of serum 1,25(OH)₂D was urinary phosphorus. It was concluded that in the FX rat (1) osteopenia is not caused by intestinal Ca malabsorption, vitamin D, Ca deficiency, or secondary hyperparathyroidism; (2) osteopenia may be related to PTH-independent urinary hyperexcretion of P, followed by a rise of serum 1,25(OH)₂D; (3) the existence of endocrine axes among gastrin, calcitonin, and PTH cannot be substantiated. FX osteopenia appears to be related to gastric acid abolition, and the reactive hypergastrinemia probably stabilizes the mass and turnover of bone. Received: 12 August 1997 / Accepted: 26 January 1998     

Relationship Between Disease Activity and Serum Levels of Vitamin D Metabolites and Parathyroid Hormone in Ankylosing Spondylitis

Vertebral fractures due to osteoporosis are a common but frequently unrecognized complication of ankylosing spondylitis (AS) and various factors may contribute to the development of osteoporosis in AS. It is known that inflammatory activity in rheumatic disease (i.e., proinflammatory cytokines) itself plays a possible role in the pathophysiology of bone loss. 1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) seems to be another possible candidate for mediatory function in regulating both the inflammatory process and bone turnover. The aim of this study was to evaluate the relation between disease activity, bone turnover and calciotropic hormones. In 70 patients with established AS and an age- and sex-matched control group, the relation between disease activity (erythrocyte sedimentation rate, C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index), and serum levels of vitamin D metabolites, parathyroid hormone (PTH), bone alkaline phosphatase (bAP) and urinary pyridinium crosslinks were determined. Serum levels of 1,25(OH)₂D₃ (p<0.01) and PTH (p<0.01) were negatively correlated with disease activity, the excretion of urinary pyridinium crosslinks showed a positive correlation with disease activity (p<0.01), and 1,25(OH)₂D₃ and PTH were positively correlated with bAP (p<0.01). These results indicate that high disease activity in AS is associated with an alteration in vitamin D metabolism and increased bone resorption. Furthermore, the decreased levels of 1,25(OH)₂D₃ may contribute to a negative calcium balance and inhibition of bone formation. Our results suggest further research is necessary to determine whether low levels of 1,25(OH)₂D₃ as an endogenous immune modulator suppressing activated T cells and cell proliferation may accelerate the inflammation process in AS. Received: 29 January 2001 / Accepted: 3 August 2001     

Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: Analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV‐3, 2009 and KNHANES V‐1, 2010)

The relative contributions of calcium and vitamin D to calcium metabolism and bone mineral density (BMD) have been examined previously, but not in a population with very low calcium intake. To determine the relative importance of dietary calcium intake and serum 25‐hydroxyvitamin D [25(OH)D] concentration to calcium metabolism and bone mass in a population with low calcium intake, a total of 4662 adults (2567 men and 2095 women) ≥50 years of age from the 2009–2010 Korea National Health and Nutrition Examination Survey (KNHANES) were divided into groups according to dietary calcium intakes (quintiles means: 154, 278, 400, 557, and 951 mg/d) and serum 25(OH)D concentrations (<50, 50–75, and >75 nmol/L). Serum intact parathyroid hormone (PTH) and femoral neck and lumbar spine BMD were evaluated according to dietary calcium intake and serum 25(OH)D. Mean calcium intake was 485 mg/d; mean serum 25(OH)D concentration was 48.1 nmol/L; PTH was 68.4 pg/mL; femoral neck BMD was 0.692 g/cm²; and lumbar spine BMD was 0.881 g/cm². Lower dietary calcium intakes were significantly associated with higher serum PTH concentrations and lower femoral neck BMD, not only at lower (<50 nmol/L) but also at higher (>75 nmol/L) serum 25(OH)D concentrations. Serum PTH was highest and femoral neck BMD was lowest in the group, with a serum 25(OH)D less than 50 nmol/L. In this low‐intake population, calcium intake is a significant determinant of serum PTH and BMD at higher as well as lower 25(OH)D levels. This finding indicates that low calcium intake cannot be compensated for with higher 25(OH)D levels alone. As expected, serum 25(OH)D levels were inversely associated with serum PTH and BMD. A calcium intake of at least 668 mg/d and a serum 25(OH)D level of at least 50 nmol/L may be needed to maintain bone mass in this calcium deficient population. © 2013 American Society for Bone and Mineral Research.     

Effect of an Intermittent Weekly Dose of Human Parathyroid Hormone (1-34) on Osteoporosis: A Randomized Double-Masked Prospective Study Using Three Dose Levels

To test the effect of amino-terminal peptide 1–34 of human parathyroid hormone (hPTH (1–34)) as a possible bone anabolic agent in the treatment of osteoporosis, weekly subcutaneous injection of 50 units (L group), 100 units (M group) or 200 units (H group) of hPTH (1–34) was started in 220 patients with osteoporosis at 71 institutions randomly divided into three groups in a double-masked system. Lumbar spine bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) increased by 0.6%, 3.6% and 8.1% after 48 weeks in groups L, M and H respectively, responses in groups M and H being significantly higher than in L (p<0.05, Mann–Whitney U-test). Since the coefficient of variation for lumbar spine measurement stayed at 1–2.5%, increases of 3.6% and 8.1% appeared significant. Metacarpal BMD and cortical thickness measured by radiogrammetry did not change significantly. Serum calcium decreased in each group and serum phosphorus decreased in groups M and H. Urinary calcium/creatinine decreased at the 12th week in group H and at the 24th and 48th weeks in groups M and L. Serum 25(OH) vitamin D and 1,25(OH)₂ vitamin D decreased in each group at the 48th week (p<0.05). Serum bone-type alkaline phosphatase was increased at the fourth week in groups H and M and decreased at the 48th week in group H. Urinary hydroxyproline, pyridinoline and deoxypyridinoline declined significantly in each group. Backache improved in 30–40% of each group. No serious adverse effects were found during the test period. Intermittent weekly injection of hPTH (1–34) increased lumbar BMD in osteoporosis, suggesting usefulness in the treatment of osteoporosis. Received: 2 February 1998 / Accepted: 3 August 1998     

Effect of Vitamin D Receptor Genotypes on Calcium Absorption,Duodenal Vitamin D Receptor Concentration,and Serum 1,25 Dihydroxyvitamin D Levels in Normal Women

It is well established that bone mineral density is under strong genetic control. Recently it was reported that the Bsm I restriction fragment length polymorphism of the vitamin D receptor (VDR) gene could account for up to 75% of the genetic variance in bone mineral density. However, the physiological basis for such an effect has not been established. The VDR gene codes for the vitamin D receptor protein which regulates intestinal calcium absorption. In order to assess the biochemical basis we studied the effect of common allelic variation of the VDR gene on intestinal VDR protein concentration, calcium absorption, and serum 1,25 dihydroxyvitamin D (1,25(OH)₂D). Ninety-two Caucasian women were genotyped for Bsm I and Taq I polymorphism at the VDR gene locus. From these we compared 49 young women aged 25–35 years and 43 elderly women aged 65–83 years, who had all three measurements performed. There were no significant differences in intestinal VDR protein concentration, serum 1,25(OH)₂D, or radioactive calcium absorption among VDR genotype groups. Therefore, the small intestine does not seem to be a target for VDR gene polymorphism. Received: 12 August 1996 / Accepted: 3 January 1997     

Effects of Different Dress Styles on Vitamin D Levels in Healthy Young Jordanian Women

Jordan is a sunny Middle Eastern country where no vitamin D fortification of milk is undertaken, and where women wear dress styles that cover the body to a variable extent. This may produce variable effects on vitamin D, parathyroid hormone and bone mineralization. The aim of the present study was to evaluate the vitamin D and parathyroid hormone levels in healthy young women of child-bearing age, and to examine the effects of dress style and season, in a survey of the effects of these parameters on vitamin D metabolism, and the possible bone mineralization consequences. One hundred and forty-six subjects (22 men, 124 women) were selected, according to established inclusion criteria. Of the women, 21 wore Western-type dress styles (group 1), 80 wore dress styles covering the whole body but the sparing face and hands (group 2) and 23 wore dress styles covering the whole body including the face and hands (group 3). The study was conducted in summer and winter. All volunteers underwent initial interviews, answered a food frequency questionnaire, and underwent essential laboratory tests (serum 25-hydroxyvitamin D (25(OH)D) by radioimmunoassay, and serum parathyroid hormone (PTH) by chemiluminescent enzyme immunoassay). The 25(OH) D levels in groups 2 and 3 were significantly lower than in the men (p<0.05 in both comparisons). No significant differences were noted between women wearing different dress styles. PTH levels were in the upper limits of normal but failed to show statistical differences between study groups. The prevalence of hypovitaminosis D was 62.3% in the study groups as a whole. Dress styles covering the whole body, totally or nearly totally, have adverse effects on 25(OH)D levels and may produce a state of secondary hyperparathyroidism on the long run. Although Jordan enjoys plenty of sunshine, these data are suggestive of widespread hypovitaminosis D in Jordan. Received: 6 October 2000 / Accepted: 30 May 2001     

The Effect of Season and Vitamin D Supplementation on Bone Mineral Density in Healthy Women: A Double-Masked Crossover Study

Vitamin D status is known to be an important determinant of bone mineral density (BMD). There is a significant seasonal variation in serum vitamin D, and some studies have reported an associated seasonal variation in BMD. The present study was devised to investigate whether a seasonal variation in BMD could be detected in healthy normal subjects, along with associated variations in serum parathyroid hormone (PTH), intestinal calcium absorption and biochemical markers of bone turnover. A second aim was to investigate whether, if such variations were identified, they could be suppressed by vitamin D supplementation. The subjects were 70 healthy female volunteers (mean age 47.2 years, range 24–70 years) recruited into a double-masked crossover study and followed over 2 years. During the first year 35 subjects received a daily oral supplement containing 800 IU (20 mg) cholecalciferol (group 1) and 35 subjects received a placebo preparation (group 2). During the second year the treatment each group received was reversed. Lumbar spine (L1–L4), left proximal femur and total body BMD were measured by DXA at 3-month intervals. Serum 25-hydroxyvitamin D (25-OHD), serum PTH, bone markers (bone-specific ALP (BSAP) and urinary crosslinks (DYPD/creatinine)) and calcium absorption were also measured at each visit. Cholecalciferol treatment increased serum 25-OHD by 25.4 nmol/l (p <0.001), while a reciprocal decrease in serum PTH of 6.6 ng/l (p = 0.011) was seen in subjects in the lowest quartile of baseline serum 25-OHD. The treatment had no significant effect on spine, femur or total body BMD, calcium absorption or bone markers. When Fourier analysis was used to analyze the data for seasonal effect (defined as twice the amplitude of the 1-year period variation) a highly significant effect for 25-OHD of 18 nmol/l (p <0.001) was found. However, no effect was found for BMD, PTH, calcium absorption or bone markers. The analysis set a 95% confidence limit to the seasonal effect of less than 0.6% for spine, total hip and total body BMD. It was concluded that in the population of healthy women studied there was no evidence of seasonal variation in spine, femur or total body BMD, serum PTH, calcium absorption or bone markers. Vitamin D supplementation was found to have no effect on BMD. Received: 7 July 2000 / Accepted: 14 November 2000     

Vitamin D and its Major Metabolites: Serum Levels after Graded Oral Dosing in Healthy Men

We determined the quantitative relationships between graded oral dosing with vitamin D₃, 25(OH)D₃, and 1,25(OH)₂D₃ for short treatment periods and changes in circulating levels of these substances. The subjects were 116 healthy men (mean age, 28 + 4 years, with usual milk consumption of 40.47 l/day and mean serum 25(OH)D of 67 + 25 nmol/l). They were distributed among nine open-label treatment groups: vitamin D₃ (25, 250 or 1250 mg/day for 8 weeks), 25(OH)D₃ (10, 20 or 50 mg/day for 4 weeks) and 1,25(OH)₂D₃ (0.5, 1.0 or 1.0 mg/day for 2 weeks). All treatment occurred between January 3 and April 3. We measured fasting serum calcium, parathyroid hormone, vitamin D₃, 25(OH)D and 1,25(OH)₂D immediately before and after treatment. In the three groups treated with vitamin D₃, mean values for circulating vitamin D₃ increased by 13, 137 and 883 nmol/l and serum 25(OH)D increased by 29, 146 and 643 nmol/l for the three dosage groups, respectively. Treatment with 25(OH)D₃ increased circulating 25(OH)D by 40, 76 and 206 nmol/l, respectively. Neither compound changed serum 1,25(OH)₂D levels. However, treatment with 1,25(OH)₂D₃ increased circulating 1,25(OH)₂D by 10, 46 and 60 pmol/l, respectively. Slopes calculated from these data allow the following estimates of mean treatment effects for typical dosage units in healthy 70-kg adults: an 8-week course of vitamin D₃ at 10 mg/day (400 IU/day) would raise serum vitamin D by 9 nmol/l and serum 25(OH)D by 11 nmol/l; a 4-week course of 25(OH)D₃ at 20 mg/day would raise serum 25(OH)D by 94 nmol/l; and a 2-week course of 1,25(OH)₂D₃ at 0.5 mg/day would raise serum 1,25(OH)₂D by 17 pmol/l. Received: 4 August 1997 / Accepted: 14 October 1997     

The Effect of Intermittent Slow-Release Sodium Fluoride and Continuous Calcium Citrate Therapy on Calcitropic Hormones, Biochemical Markers of Bone Metabolism, and Blood Chemistry in Postmenopausal Osteoporosis

A detailed examination of calcitropic hormones and biochemical markers of bone turnover, serum chemistry, and blood hematology was performed in 75 postmenopausal women allocated to two groups: placebo plus calcium citrate (400 mg Ca B.I.D.) (n = 36) or intermittent slow-release sodium fluoride (SRNaF, 25 mg B.I.D.) plus calcium citrate (n = 39). After 2 years of therapy, a significant reduction in serum immunoreactive parathyroid hormone (PTH) was seen for both groups (43 ± 18 SD–30 ± 11 ng/liter, in placebo and 46 ± 24–36 ± 10, in SRNaF P < 0.0001 for both groups). Serum 1,25(OH)₂D significantly fell in placebo-treated patients (91 ± 31–75 ± 34 pmol/liter, P= 0.001) but did not change for SRNaF-treated patients. This difference in response between placebo and SRNaF-treated groups was significant, P= 0.005. Urinary hydroxyproline significantly declined during treatment in both groups (130 ± 61–76 ± 38 μmol/day, for placebo and 138 ± 84–84 ± 38 for SRNaF, P= 0.001). Similar decreases in urinary N-telopeptide of type I collagen were also observed for both groups (305 ± 192–252 ± 197 nmoles BCE/day for placebo and 356 ± 230–220 ± 197, P= 0.0001 for SRNaF). Serum carboxyterminal propeptide of type I collagen (PICP) declined significantly in both the placebo and SRNaF groups (118 ± 38–101 ± 36 μg/liter, and 116 ± 47–105 ± 39, P= 0.0027). Serum osteocalcin did not change significantly for either group, but bone-specific alkaline phosphatase (BS-ALPase), another marker of bone formation, demonstrated a significant fall in the placebo group at 2 years of therapy (16.2 ± 6.7 U/liter–12.1 ± 3.5, P= 0.009) and a small increase in the SRNaF-treated patients (13.0 ± 4.1–15.0 ± 4.5). The observed difference in response of BS-ALPase between the placebo and treated groups was significant (P= 0.007). There were no significant changes within or between treatment groups for blood hematology or serum chemistries. Mean values for all parameters remained within established normal ranges. These findings suggest that administration of calcium citrate inhibited PTH secretion and thereby reduced bone resorption in both groups, indicated by a decline in serum PTH, urinary hydroxyproline, and N-telopeptide. A low turnover state of bone may have been produced in the placebo group taking calcium citrate alone, since serum PICP, BS-ALPase, and 1,25(OH)₂D also decreased. The addition of SRNaF prevented serum 1,25(OH)₂D from falling by an unknown mechanism. However, its anabolic action on the skeleton was best reflected by changes in BS-ALPase. Moreover, SRNaF appeared to exert no deleterious effects on blood chemistries or hematology during 2 years of administration. Received: 28 January 1996 / Accepted: 25 April 1997