Effects of Race on Diurnal Patterns of Renal Conservation of Calcium and Bone Resorption in Premenopausal Women

Previous studies showed differences in bone and mineral metabolism in African-Americans and Caucasians: reductions in serum 25-hydroxyvitamin D [25(OH)D], urinary calcium and skeletal remodeling and moderate secondary hyperparathyroidism. Diurnal studies were carried out in 7 African-American and 7 white normal premenopausal women matched for age, weight and height to further characterize these racial differences in calcium homeostasis. Serum 25(OH)D was significantly lower and serum intact parathyroid hormone (PTH) was significantly higher in the African-American compared with the white women, whereas serum total calcium, Ca²⁺, phosphorus and 1,25-dihydroxyvitamin D [1,25(OH)₂D] were not different in the two groups. Serum intact PTH increased significantly at night in the white women and did not change in the African-American women. Urinary calcium was 47% lower in the African-American than in the white women during the day but was not different at night. Urinary calcium declined at night by 53% in the white women and by 40% in the African-American women. Stepwise multivariate analysis showed that determinants of urinary calcium were mean 24 h serum intact PTH and serum Ca²⁺ in the two groups together, mean 24 h serum intact PTH, body mass index (BMI) and serum 25(OH)D in the white women, and BMI in the African-American women. Urinary N-telopeptide of type I collagen, a marker of bone resorption, increased by over 60% at night in both groups and was 25% lower in African-American compared with white women, but the difference was not statistically different. Urinary free deoxypyridinoline also increased at night in both groups and was not racially different. Thus, African-American women show higher serum intact PTH and greater conservation of calcium than white women throughout the day. In both groups, maintenance of serum calcium at night is achieved by increased bone resorption and renal conservation of calcium. Received: 15 April 1999 / Accepted: 6 July 1999     

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     

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     

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     

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     

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     

Relationship Between Disease Activity and Serum Levels of Vitamin D Metabolites and PTH in Rheumatoid Arthritis

In several studies on patients with rheumatoid arthritis, an association of bone loss with a persistently high disease activity has been found. The aim of our study was to investigate the relation between disease activity and serum levels of vitamin D metabolites, parathyroid hormone (PTH), and parameters of bone turnover in patients with rheumatoid arthritis. A total of 96 patients (83 women and 13 men) were divided into three groups according to disease activity measured by serum levels of C-reactive protein (CRP). In the whole group, serum levels of 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) (P < 0.001) and PTH (P < 0.05) were negatively correlated to disease activity. The urinary excretion of collagen crosslinks—pyridinoline (Pyd) (P < 0.001) and deoxypyridinoline (Dpd) (P < 0.05)—showed a positive correlation with disease activity. The inverse correlation between serum 1,25(OH)₂D₃ and disease activity was separately evident in patients with (P < 0.001) and without (P < 0.01) glucocorticoid treatment, in pre- (P < 0.01) and postmenopausal (P < 0.001) women, and in men (P < 0.01). 1,25(OH)₂D₃ and PTH serum levels were positively correlated to serum bone alkaline phosphatase (ALP) (P < 0.01). The results indicate that high disease activity in patients with rheumatoid arthritis is associated with an alteration in vitamin D metabolism and increased bone resorption. The decrease of 1,25(OH)₂D₃ levels in these patients may contribute to a negative calcium balance and inhibition of bone formation. Furthermore, low levels of 1,25(OH)₂D₃ as an endogenous immunomodulator suppressing activated T cells and the proliferation of cells may accelerate the arthritic process in rheumatoid arthritis. Received: 3 February 1997 / Accepted: 26 June 1997     

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     

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     

Effects of continuous glucocorticoid infusion on bone metabolism in the rat

The effects of continuous administration of supraphysiologic doses of dexamethasone (DEX) on bone metabolism were examined in rats. Adult, male, Sprague Dawley rats were infused with DEX at a constant rate of 16.25 μg/day for 19 days. Despite soft tissue catabolism, DEX treatment led to a significant increase in bone volume in all experiments. This was accompanied by a significant gain in femoral weight and calcium content. These findings were also observed in DEX-treated parathyroidectomized animals indicating that intact parathyroid function was not required for this effect. DEX treatment did not affect mean levels of serum calcium or phosphorus but led to significant declines in circulating levels of PTH and 1,25(OH)₂D and in the urinary calcium/creatinine ratio. This latter finding was also observed in PTX animals in which 1,25(OH)₂D levels did not change. Serum concentrations of osteocalcin and tartrate-resistant acid phosphatase both declined in a time-dependent manner with DEX treatment suggesting a slowing of bone turnover with the net effect favoring formation. However, histomorphometric findings were variable. Two of three experiments demonstrated a decrease in cellular parameters of formation and resorption and in one experiment, these indices increased. Mineralized surface increased with DEX treatment. We conclude that, in marked contrast to the findings in man and certain other species, DEX treatment increases bone mass in rats. This may in part relate to a relatively greater suppression of resorption vis à vis formation. Received: 28 September 1995 / Accepted: 23 February 1996     

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.     

Bone Mineral in Pre- and Postmenopausal Women with Insulin-Dependent and Non-insulin-Dependent Diabetes Mellitus

We have recently shown that bone radiogrammetric dimensions are associated with vitamin D receptor gene polymorphism. Since parathyroid hormone (PTH) plays a central role in maintaining calcium homeostasis and in bone remodeling, we investigated whether bone radiogrammetric dimensions are associated with a PTH gene polymorphism in 91 healthy Caucasian women, who were premenopausal at entry into the study. These women had assessments of bone by radiogrammetry every five years for a median period of 20 years (range 4–27). DNA was extracted from white blood cells. A segment of the PTH gene with a polymorphism at a BstBI restriction site was amplified by polymerase chain reaction. Diameter, cortical thickness and cross-sectional area at standard sites of the metacarpals, radius and femur were measured with radiogrammetry. Higher metacarpal diameter and cross-sectional cortical area, and a slower decrease in radial cortical area with age, were associated with the absence of the BstBI restriction site of the PTH gene. PTH gene polymorphism accounts for about 7–9% of the total variances of bone dimensional variables. These findings suggest that the dimensions of long bones are influenced by allelic variations in the PTH gene or in genes nearby. Received: 29 January 1998 / Accepted: 3 August 1998     

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 Bone Mineral Density in Ambulatory Women Living in Buenos Aires, Argentina

The aim of this study was to determine possible associations between bone mineral density (BMD), 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (PTH). In a retrospective study we examined the case notes of free-living postmenopausal women living in our city (34° S). We also report a low prevalence of vitamin D deficiency (25(OH)D <25 nmol/l, 5.6%) and of secondary hyperparathyroidism (intact PTH >65 pg/ml, 7.5%). Age was correlated with BMD at the lumbar spine (r=−0.25, p = 0.00038) and femoral neck (r=−0.252, p = 0.0003). Body mass index (BMI) was correlated with BMD at the femoral neck (r= 0.177, p = 0.021) but not at the lumbar spine. 25(OH)D was positively correlated with BMD at the femoral neck (r = 0.149, p=0.036) but not at the lumbar spine. PTH was positively correlated with age (r= 0.279, p = 0.012) and negatively correlated with 25(OH)D (r=−0.322, p = 0.0036). PTH was also negatively correlated with BMD at the lumbar spine (r=−0.258, p=0.02) and the femoral neck (r=−0.282, p = 0.011). Forward stepwise multiple regression showed that BMI, age and 25(OH)D made significant contributions to BMD at the femoral neck. PTH also showed a significant contribution to BMD at both sites. In conclusion, weak correlations found between PTH and 25(OH)D and BMD suggest these biochemical variables, among other factors, contribute to lumbar spine and femoral neck BMD. Received: 19 February 2000 / Accepted: 20 June 2000     

Age-Related Decline of Bone Mass and Intestinal Calcium Absorption in Normal Males

Although about 25% of all hip fractures occur in men, little is known about the pattern of their age-related bone loss and its main determinants. The aim of this cross-sectional study was to evaluate the age-related changes of intestinal calcium absorption, bone mass, and bone turnover in normal men. In 70 normal males (age 17–91 years), we measured spinal and forearm bone density (FBD) (by DXA), fractional intestinal calcium absorption (by oral test), serum immunoreactive parathyroid hormone (PTH), dietary calcium intake (diet records), biochemical markers of bone turnover (serum alkaline phosphatase (ALP), osteocalcin, urine calcium, creatinine, and hydroxyproline), and 1,25(OH)₂D₃ serum levels. Vertebral bone density (VBD) showed a modest decline before age 50 and a greater decline after age 50, whereas FBD presented a significant decrease with advancing age starting at age 40, suggesting a predominant age-related cortical bone loss. Intestinal calcium absorption (⁴⁷CaFA) and serum 1,25(OH)₂D₃ also presented an age-related decline similar to FBD. Simple correlation analysis revealed that age was significantly related to ⁴⁷CaFA (r = 0.60), calcium intake (r = 0.32), VBD and FBD (r = 0.79 and 0.63, respectively), serum 1,25(OH)₂D₃ (r = 0.69), and serum iPTH (r = 0.72). No significant correlation was found between age and biochemical markers of bone remodeling. Partial correlation and stepwise variable selection analyses, using ⁴⁷CaFA and bone mass as dependent variables, showed that in normal males, serum 1,25(OH)₂D₃ and dietary calcium intake were the main contributors (64%) to ⁴⁷CaFA variability, whereas only age accounted for 63% of VBD and age and dietary calcium accounted for 45% of FBD variability. These results indicate that bone loss in men accelerates after age 50 years and that among other factors, intestinal calcium malabsorption and 1,25(OH)₂D₃ serum levels play a role. Received: 19 November 1996 / Accepted: 26 January 1998     

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     

The importance of genetic and nutritional factors in responses to vitamin D and its analogs in osteoporotic patients

The effects of vitamin D and its analogs on fractures and bone mass have been clarified by clinical observations for more than 10 years. Reviewing the results of six clinical trials on osteoporotic fractures using activated vitamin D analogs, there appeared to be a negative correlation between basal levels of calcium intake and the incidence of vertebral fractures in the control groups. For example, when daily calcium intake was about 600 mg, there were approximately 800 vertebral fractures per 1000 persons a year in the controls. When daily calcium intake was above 1000 mg, the incidence was less than 400 fractures per 1000 persons a year. The incidence of fractures decreased by about half in the activated vitamin D-treated group compared with the control group, but the most marked preventive effects of activated vitamin D on fractures were obtained in clinical studies, with daily calcium intakes of 400–800 mg. The effects of vitamin D analogs on bone mass were reported in the clinical studies, but the results are not consistent. However, these studies suggest that the effects of both 1,25(OH)₂D₃ and 1-alpha(OH)D₃ on bone mass were dose dependent, and the doses were low in clinical studies in which good results were not obtained. Significant effects on bone mass were obtained when more than 0.6 μg of 1,25(OH)₂D₃, or more than 0.75 μg of 1-alpha(OH)D₃ was administered, with increase in the urinary calcium level being within the acceptable range. Reported data indicate that both nonactivated vitamin D and activated vitamin D reduce the serum parathyroid hormone level. However, activated vitamin D administration is more effective, and is able to reduce bone resorption in postmenopausal, osteoporotic patients with a vitamin D-sufficient status. Recent studies concerning the polymorphism of the vitamin D-receptor gene emphasize that sensitivity to active vitamin D varies between genotypes. In the bb type, sensitivity to active vitamin D is high, and calcium absorption efficiency in the intestine under low calcium conditions increases with increase in the serum 1,25(OH)₂D level. A significant increase in lumbar bone mineral density was obtained after administration of activated vitamin D to osteoporotic patients of bb type. However, in the genotype with the B factor, sensitivity to active vitamin D was low, and the rate of increase of bone density was low. These data suggest that nutritional and genetic factors are critical when using active vitamin D and its analogs in the treatment of osteoporosis.     

Effect of declining renal function on bone density in aging women

Summary The factors that are responsible for trabecular bone loss in aging women are not completely understood. To evaluate declining renal function as a possible factor, we studied 19 Caucasian women (average age 67) who were from 6 to 41 years postmenopausal. Trabecular bone density was quantitated by computerized tomography of the spine. Serum calcium, phosphorus, and creatinine were normal in all subjects. Creatinine clearance averaged 74 ml/min (range 38–122), decreased with age (r=−0.60,P=0.003), and was inversely related to serum creatinine (r=−0.51,P=0.01). Bivariate regression demonstrated that bone density decreased with age (r=−0.59,P=0.004); controlling for the effect of creatinine clearance weakened this correlation to r=−0.45 (P=0.03); controlling additionally for 1,25-dihydroxyvitamin D [1,25(OH)₂D] and parathyroid hormone (PTH) reduced the correlation coefficient to r=−0.34 (P=0.11). Bone density also decreased in direct proportion to the decrement in creatinine clearance (r=0.44,P=0.03); controlling for the effects of 1,25(OH)₂D and PTH reduced this correlation coefficient to r=0.34 (P=0.11). These results suggest that occult renal insufficiency may contribute to bone loss in aging women, and that this effect may be mediated in part by 1,25(OH)₂D and PTH. In this age group renal function should be assessed by measuring creatinine clearance rather than the serum creatinine concentration since renal insufficiency can be masked by apparently normal circulating creatinine levels.     

Effects of a low sodium diet on bone metabolism

Osteoporosis is a serious public health problem, and dietary interventions may potentially be helpful in preventing this disorder. The purpose of this study was to determine the effects of a low sodium diet on bone metabolism in postmenopausal women. This was a longitudinal study to determine the effects of a low sodium (2-g/day) diet on bone. Forty postmenopausal African–American and Caucasian women were enrolled in a 2-g/day sodium diet for 6 months. Sodium and calcium excretion, bone turnover, and calcitropic hormones (intact parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D) were measured before and 6 months after the intervention. In women who had baseline sodium excretions equal to or greater than the average sodium intake in the United States (≥3.4 g/day), the low sodium diet resulted in significant decreases in sodium excretion (P = 0.01), in calcium excretion (P = 0.01), and in a biomarker of bone turnover, aminoterminal propeptide of type I collagen (P = 0.04). However, there were no significant changes in calcitropic hormones, including intact PTH (P = 0.97) or 1,25 dihydroxyvitamin D (P = 0.49) with the low sodium diet. These findings suggest that in postmenopausal women with sodium intakes ≥3.4 g/day, a low sodium diet may have benefits for skeletal health.     

Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy Versus Active Vitamin D Analog (D-Hormone) Therapy

Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. Secondary hyperparathyroidism due to poor intestinal Ca absorption has been implicated not only in senile osteoporosis but also in age-related bone loss. Accordingly, in population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward, which constitutes a maximum increase at 80 years of age of 50% of the basal value seen at 30 years of age. The cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency. There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)₂D₃ resulting from decreased renal production of 1,25(OH)₂D₃; and (3) resistance to 1,25(OH)₂D₃ action owing to decreased responsiveness to 1,25(OH)₂D₃ of target tissues. The cause for the resistance to 1,25(OH)₂D₃ could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and senile osteoporosis. There are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)₂D₃ deficiency/resistance requires active vitamin D analog therapy [1,25(OH)₂D₃ or 1α(OH)D₃] to correct the high serum PTH and the Ca malabsorption. In addition, in the elderly, there are patients with decreased intestinal Ca absorption but with apparently normal vitamin D metabolism. Although the cause of poor intestinal Ca absorption in these patients is unclear, these patients, as well as all other patients with secondary hyperparathyroidism (not due to decreased renal function), show a decrease in serum PTH and an increase in Ca absorption in response to therapy with 1,25(OH)₂D₃ or 1α(OH)D₃. In short, it is clear that some form of vitamin D therapy, either plain vitamin D or 1,25(OH)₂D₃ or 1α(OH)D₃, can be used to correct all types of age-dependent impairments in intestinal Ca absorption and secondary hyperparathyroidism during aging. However, from a clinical standpoint, it is important to recognize the type of vitamin D deficiency in patients with senile osteoporosis so that primary vitamin D deficiency can be appropriately treated with plain vitamin D therapy, whereas 1,25(OH)₂D₃ deficiency/resistance will be properly treated with 1,25(OH)₂D₃ or 1α(OH)D₃ therapy. With respect to postmenopausal osteoporosis, there is strong evidence that active vitamin D analogs (but not plain vitamin D) may have bone-sparing actions. However, these effects appear to be results of their pharmacologic actions on bone formation and resorption rather than through replenishing a deficiency.