Total-body bone mineral content in non-corticosteroid-treated postpubertal females with juvenile rheumatoid arthritis: frequency of osteopenia and contributing factors.

OBJECTIVE: To determine the extent of low total-body bone mineral content (BMC) in non-corticosteroid-treated white postpubertal females with juvenile rheumatoid arthritis (JRA) compared with healthy age- and race-matched female controls, and to identify variables that significantly contribute to total-body BMC. METHODS: Thirty-six females with definite JRA who had never received corticosteroids and 51 healthy female controls were evaluated. All subjects had had their first menstrual period at least 2 years prior to enrollment. Total-body BMC, lumbar spine bone mineral density, and body composition were determined by dual x-ray absorptiometry. Total-body BMC Z-scores were calculated for JRA patients using data from controls. JRA patients were dichotomized into those with "normal" bone mass (total-body BMC at or above the mean or no more than 1 SD below the mean) and those with "low" bone mass (total-body BMC more than 1 SD below the mean). Comparisons of anthropometric measurements, laboratory measurements of bone metabolism, disease activity, dietary intake, and physical activity were performed. Stepwise logistic regression was utilized to determine the presence or absence of low total-body BMC and to identify associated contributing factors. RESULTS: Total-body BMC was 4.5% lower in JRA patients than in controls (mean +/- SD 2,050 +/- 379 gm versus 2,143 +/- 308 gm; P = 0.21). Twenty-five of 36 patients (69.4%) had "normal" and 11 of 36 (30.6%) had "low" total-body BMC. Comparison of JRA patients with "normal" versus those with "low" total-body BMC revealed significant differences in disease characteristics, anthropometric and physical development characteristics, laboratory measures of bone mineralization, and dietary intake. The final regression model contained only lean mass (P = 0.01), which accounted for 76.3% of the variance in total-body BMC. The odds ratio for lean mass was 0.4451 (95% confidence interval 0.2374-0.8348). CONCLUSION: In this study, approximately 30% of the subjects in a sample of postpubertal female patients with mild-to-moderate, non-corticosteroid-treated JRA had low bone mass. The predictor variable that significantly contributed to total-body BMC was lean mass, which demonstrated a protective effect of 0.56 risk reduction for low total-body BMC.

Low total body bone mineral content and high bone resorption in Korean winter-born versus summer-born newborn infants.

Seasonal differences in newborn total body bone mineral content (TBBMC) have not been studied, particularly in relation to alterations in vitamin D status in winter. In vitamin D deficiency bone resorption may be high and bone mineralization low. Bone resorption may be assessed by serum cross-linked carboxyterminal telopeptide of type I collagen (ICTP) measures. Because vitamin D supplements throughout pregnancy are uncommon in Korea, we hypothesized that in Korean winter newborns, TBBMC is low and serum ICTP high from high bone resorption and low 25-hydroxyvitamin D (25-OHD) compared with those in summer newborns. Seventy-one Korean term infants were studied prospectively in summer (July through September, n = 37) versus winter (January through March, n = 34); TBBMC was measured before 3 days of age by dual-energy x-ray absorptiometry. Significant seasonal differences were found: winter newborns had 6% lower TBBMC (least squares means +/- SD; 86.7 +/- 7.7 gm vs 93.9 +/- 7.8 gm, p = 0.0002), lower cord serum 25-OHD (10.7 +/- 8 nm vs 30 +/- 15 nm, p = 0.0001) and 1,25-dihydroxyvitamin D, and higher ICTP (96.4 +/- 20.3 microg/L vs 74.8 +/- 24 microg/L, p = 0.0002) and calcium than summer newborns. TBBMC correlated with serum 25-OHD (r = 0.243, p = 0.047) and inversely with ICTP (r = -0.333, p = 0.008). We suggest that in Korea low maternal vitamin D status in winter results in marked reduction in newborn TBBMC.

Predictors of total body bone mineral density in non-corticosteroid-treated prepubertal children with juvenile rheumatoid arthritis.

OBJECTIVE: To determine the extent of significant osteopenia in prepubertal patients with juvenile rheumatoid arthritis (JRA) not treated with corticosteroids and to identify variables that are highly related to bone mineralization in this population. METHODS: In a cross-sectional study, 48 JRA patients and 25 healthy control subjects ages 4.6-11.0 years were evaluated. Total body bone mineral density (TB BMD) was determined by Hologic dual energy x-ray absorptiometry. All patients were prepubertal (Tanner stage I or II) and had never taken corticosteroids. For comparison, JRA patients were divided into "low" TB BMD (Z score < or =-1) or "normal" TB BMD (Z score >-1). RESULTS: The overall mean +/- SD TB BMD scores did not differ between the JRA subjects (0.75 +/- 0.06 gm/cm2) and controls (0.73 +/- 0.07 gm/cm2; P > 0.30). However, 29.2% of the JRA patients had low TB BMD, whereas only 16% would be expected to have low TB BMD based on the standard normal distribution (goodness of fit chi(2) = 4.84, P = 0.01). The mean Z score for the JRA patients with low TB BMD was -1.43, and for those with normal TB BMD, it was 0.32. The JRA subjects with low TB BMD were significantly younger, had more active articular disease, greater physical function limitation, higher erythrocyte sedimentation rate, higher joint count severity score, lower body mass index, lower lean body mass, less participation in organized sports, and more protein and vitamin D in their diet compared with JRA patients with normal TB BMD (all P < 0.05). Using logistic regression, a model including age at JRA onset, Juvenile Arthritis Functional Assessment Report (JAFAR) score, triceps skin-fold percentiles, percentage US recommended daily allowance for dietary magnesium intake, and serum 1,25-dihydroxyvitamin D levels was able to accurately segregate 79.6% of the JRA subjects into either the low or normal TB BMD groups (chi(2) = 20.5, P = 0.001). CONCLUSION: This study demonstrated that in a mildly to moderately ill prepubertal JRA population that had never been exposed to corticosteroids, almost 30% had significantly low TB BMD. The patients with low TB BMD had more active and severe articular disease and greater physical function limitation. Disease-related parameters in JRA appear to exert a negative effect on bone mineralization even in prepubertal children, which can be demonstrated despite the exclusion of corticosteroid-treated patients.

The role of magnesium in the pathogenesis of bone disease in childhood cholestatic liver disease: a preliminary report.

BACKGROUND: Magnesium deficiency may contribute to the metabolic bone disease that complicates chronic cholestatic liver disease. We hypothesized that magnesium deficiency alters vitamin D metabolism by decreasing parathyroid hormone (PTH) response, resulting in decreased serum osteocalcin and decreased bone accretion. METHODS: Nine subjects, age 3-22 years, with cholestatic liver disease were evaluated with the magnesium retention test. The response of PTH, 1,25(OH)2 vitamin D, and osteocalcin to provocative stimuli and dual x-ray absorptiometry measurement of bone mineral density (BMD) of the lumbar spine were assessed. Thereafter, subjects were treated with oral magnesium supplements. RESULTS: All nine subjects were magnesium depleted. Repletion with magnesium was successful in seven subjects, and required 4 to 31 (median 14) months with doses of 6 to 34 (median 11) mg/kg/day. Baseline serum PTH was significantly reduced in the cholestatic subjects compared to 15 age-matched controls. Comparison of baseline to repleted provocative testing was performed in six Mg-repleted subjects. Osteocalcin response increased significantly (p = 0.048) with repletion, while PTH response increased (p = 0.061). Lumbar spine BMD increased modestly with repletion (p = 0.093). CONCLUSIONS: This preliminary report suggests that magnesium depletion is extremely common in children with chronic cholestasis. We speculate that magnesium supplementation may be warranted to forestall the progression of metabolic bone disease in chronic cholestasis.

Biochemical bone markers, bone mineral content, and bone mineral density in rats with experimental nephrotic syndrome.

The human nephrotic syndrome (NS) is accompanied by important alterations of mineral and bone metabolism. The purpose of the present study was to examine bone metabolism in rats with experimental NS and normal creatinine clearance, and to evaluate the reversibility of this alteration. NS was induced by three injections of puromycin aminonucleoside (PAN) on days 0, 21, and 35 (10, 5, and 5 mg/100 g body weight, respectively). The biochemical markers of bone formation (osteocalcin and alkaline phosphatase) and bone resorption (hydroxyproline and pyridinoline), bone mineral content (BMC), and bone mineral density (BMD), determined by dual-energy x-ray absorptiometry (DEXA), were studied on days 0, 7, 14, 28, 42, 56, 84, and 112. Proteinuria was present throughout the study. Hypoproteinemia was seen on days 7, 28, 42, and 56, returning to control values on days 84 and 112. In serum, osteocalcin (OC) concentration increased (p < 0.001), and alkaline phosphatase (ALP) decreased (p = 0.002). In urine, hydroxyproline increased (p < 0.001), but urinary pyridinoline was not different from the control group throughout the study. Increased serum parathyroid hormone concentration and decreased levels of 25-hydroxy and 1,25-dihydroxyvitamin D were found from day 7. During the intense proteinuria, bone resorption predominates and decreased BMC and BMD ensues in PAN-nephrotic rats. PAN-nephrotic rats showed low BMC and BMD compared to control group (p < 0.001). At the end of the study, when proteinuria persisted but total serum protein returned to control values, the biochemical bone markers, BMC, and BMD returned to normal. In conclusion, PAN-nephrotic rats had reversible bone alterations that were related to the magnitude of proteinuria and the concentration of total serum protein.

Normal serum indices of bone collagen biosynthesis and degradation in small for gestational age infants.

Serum carboxyterminal propeptide of type I procollagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP), new markers of bone collagen type I biosynthesis and degradation, have not been studied in small for gestational age (SGA) infants. In an earlier study, we found a lower bone mineral content (BMC) and decreased serum osteocalcin in SGA than in appropriate for gestational age (AGA) infants, supporting the thesis that decreased fetal bone formation is a cause of lower BMC in SGA. In view of the role of insulin-like growth factor-I (IGF-I) in the regulation of collagen type I synthesis and degradation, and low serum IGF-I concentrations in SGA infants, we hypothesized that serum PICP would be lower and serum ICTP would be higher in SGA than in AGA infants, reflecting decreased bone collagen type I biosynthesis or enhancement of bone collagen type I degradation in SGA. We studied 19 term SGA and 38 term AGA infants that were matched specifically 1:2 by gestation and birth month. There were no differences between SGA and AGA infants in serum PICP nor ICTP concentrations. Serum ICTP was correlated with osteocalcin and with PICP in SGA infants but not in AGA infants. Thus, serum biochemical indices of bone collagen type I biosynthesis and degradation in term SGA infants are similar to those in term AGA infants. These findings are not consistent with the thesis of altered fetal bone collagen type I biosynthesis or degradation in SGA. We suggest that the reduced bone mineral content in SGA infants is predominantly related to a lower supply of minerals rather than defective regulation of bone collagen type I metabolism.

Carboxy-terminal propeptide of human type I collagen and pyridinium cross-links as markers of bone growth in infants 1 to 18 months of age.

Serum carboxy-terminal propeptide of human type I collagen (PICP) concentrations, as a marker for bone formation, and urinary pyridinium (Pyd) cross-link concentrations, as a marker of bone resorption, were determined in 66 healthy infants aged 1-18 months who are being studied longitudinally. We hypothesized that there would be a positive correlation of growth velocity, increase in bone area, and bone mass accretion rates with PICP and Pyd cross-link concentrations. Since osteocalcin is currently used as a marker of bone formation, serum osteocalcin concentrations were also measured. Mean serum PICP and urinary Pyd cross-link concentrations were significantly greater than adult concentrations. Future growth velocity, increase in bone area, and bone mass accretion rates were not associated with PICP, Pyd cross-link, or osteocalcin concentrations. Growth velocity during the 3 months preceding sample collection correlated with serum PICP, Pyd/kg, and osteocalcin concentrations (r = 0.474, p < 0.001; r = 0.379, p < 0.001; and r = 0.516, p < 0.001, respectively). Previous increase in bone area correlated with serum PICP concentrations (r = 0.359, p = 0.01). The relationship between the infant's previous bone mass accretion rate and PICP was of borderline significance (r = 0.281, p = 0.055). In summary, normative data for PICP, Pyd cross-link concentrations, and parameters of bone growth are provided for infants 1-18 months of age and indicate that these markers reflect past and current bone metabolism and may be helpful in monitoring bone disorders in infants.

Evidence of increased intrauterine bone resorption in term infants of mothers with insulin-dependent diabetes.

Infants of diabetic mothers (IDMs) have lower bone mineral content than control subjects at birth. We measured cord blood propeptide of type I procollagen (PICP), a marker of bone formation, and telopeptide of type I collagen (ICTP), a marker of bone resorption, in 25 term IDMs and 20 term control subjects. Concentrations of ICTP were higher in IDMs than in control subjects; there was no difference in PICP concentrations. We conclude that osteoclastic activity appears to be higher in IDMs than in control subjects in utero.

Low bone mineral content and high serum osteocalcin and 1,25-dihydroxyvitamin D in summer- versus winter-born newborn infants: an early fetal effect?

Seasonal differences in bone mineral indices have not been studied in newborn infants. In adults, indicators of bone metabolism may show seasonal variations. In postneonatal infants and possibly in adults, vitamin D metabolism shows seasonal variations. We hypothesized that in winter-born infants, the bone mineral content is low and serum osteocalcin is high, related to increased bone turnover and high serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. We studied 246 healthy, term appropriate-for-gestation infants in winter (January through March; 140 children) and summer (July through September; 106 children). The bone mineral content (BMC) of the one-third distal radius was measured before 3 days of age by photon absorptiometry. Significant seasonal differences were found: summer-born infants had significantly lower BMC, higher serum osteocalcin and 1,25(OH)2D, and lower serum total calcium than winter-born infants. Seasonal differences in BMC remained significant after adjusting for race and sex. BMC was not correlated with serum biochemical measures. Thus, summer-born newborn infants have low BMC and high serum osteocalcin and 1,25(OH)2D than winter-born infants; these findings are the opposite of adult findings. We suggest that seasonal effects on fetal bone operate especially in early pregnancy (approximately 6 months before birth) resulting in a "phase effect" and opposite findings from later life.

Reduced serum osteocalcin and 1,25-dihydroxyvitamin D concentrations and low bone mineral content in small for gestational age infants: evidence of decreased bone formation rates.

In small for gestational age (SGA) infants, bone mineral content (BMC) is low but the reasons are unclear and the possible relationships between calcium-regulating hormones and BMC have not been studied. We hypothesized that BMC would be lower and concentrations of serum parathyroid hormone and 1,25-dihydroxyvitamin D would be higher at birth in SGA infants than in appropriate for gestational age (AGA) infants. Forty-two term SGA infants and 126 term AGA infants, matched 1:3 specifically by gestation (+/- 1 week) and birth month, were studied prospectively. The BMC of the distal one third of the radius was measured before 3 days of age by photon absorptiometry. The BMC was lower in SGA than in AGA infants. Both SGA and AGA infants had lower BMC in summer or spring than in winter; BMC differences between groups remained significant after adjustment for season (p = 0.0001). Cord serum osteocalcin and 1,25-dihydroxyvitamin D values were lower in SGA than in AGA infants. There were no differences between groups in cord serum levels of intact parathyroid hormone, 25-hydroxyvitamin D, calcium, phosphorus, and magnesium. Relationships were positive between BMC and birth weight and were inverse between BMC and intact parathyroid hormone values. We suggest that reduced uteroplacental blood flow in SGA infants may result in reduced fetal-placental production of 1,25-dihydroxyvitamin D, which results in low BMC and low serum osteocalcin values; fetal serum parathyroid hormone values may be relatively elevated because of reduced placental mineral supply.

Preparación de células paratiroides caninas vivas mediante digestión enzimática: descripción del método / Canine parathyroid cells preparation employing enzyme digestion: description of the method

La secreción de hormona paratiroidea (PTH) se ha caracterizado con una preparación de células individuales, obtenidas mediante digestión enzimática de glándulas paratiroides previamente fragmentadas, obtenidas quirúrgicamente d diferentes especies, incluida la humana. Esta preparación permite establecer condiciones experimentales controladas, imposibles de obtener en vivo. Tiene además la ventaja de conservar todas las funciones secretoras de las células intactas, inclusive, las de los tejidos anormales. Este trabajo describe las modificaciones metodológicas necesarias para obtener una preparación de células paratiroideas a partir de glándulas caninas, especie en la que el metabolismo mineral es muy similar al del humano y que se puede estudiar experimentalmente con facilidad. Demonstramos que, en estas células, tanto el curso temporal como la influencia de las concentraciones extracelulares de calcio influyen de manera normal en la secreción de PTH, misma que aumentó sobre la secreción basal hasta 264.4 ñ 53.9 pg/10 células cuando la concentración extracelular de calcio fue de 0.5 mM y hasta 212 ñ 51.1 pg/10 células a concentración extracelular de calcio de 2.0 mM (p < 0.05). La región linear del incremento temporal en secreción de PTH mostró una correlación altamente significativa en ambas concentraciones de calcio (0.5 mM r = 0.93, 2mM r = 0.97). Concluimos que utilizando este método se obtiene células paratiroideas individuales, viables, que conservan su capacidad secretora intacta, aplicables al estudio del funcionamiento paratiroideo canino in vitro

The duodenal 1 alpha,25-dihydroxyvitamin D3 receptor in rats with experimentally induced diabetes.

Studies in the rat with streptozotocin-induced diabetes of short and long duration revealed decreased circulating 1 alpha,25-dihydroxyvitamin D [1,25-(OH)2D] levels and an intact 1,25-(OH)2D3 duodenal cytosolic receptor with a sedimentation coefficient of 3.3S. Whereas no significant alterations in the equilibrium dissociation constant (Kd) were observed in the diabetic animals, the number of 1,25-(OH)2D3-binding sites was increased in the animals with short term (235 +/- 48 vs. 100 +/- 15 fmol/mg protein) and long term (521 +/- 60 vs. 119 +/- 15 fmol/mg protein) diabetes. The data are consistent with the hypothesis that alterations in intestinal calcium absorption previously observed in the diabetic state are due, at least in part, to dynamic relationships between circulating 1,25-(OH)2D concentrations and the number of intestinal 1,25(OH)2D3-binding sites.

I alpha, 25-Dihydroxyvitamin D3 receptor in the X-linked hypophosphatemic mouse.

We have attempted to determine if the resistance of the X-linked hypophosphatemic mouse to the actions of 1,25(OH)2D3 is due to abnormal cytosolic receptors for this hormone. Cytoplasmic 1,25-dihydroxy-vitamin D3 [1,25(OH)3D3] receptors were demonstrated in hypophosphatemic (HYP) mouse tissues including intestine, kidney and testis. Cytosol preparations from 14 murine tissues were prepared using hypertonic buffer and incubated for three hours at 0 C with 1,25(OH)2 [23,24(n)-(-3)H]D3 ([3H]-1,25(OH)2D3). The results of studies using 5-20% sucrose density gradients revealed th at cytosol preparations from intestine, kidney and testis exhibited a 3.2 S peak which ws specific for 1,25(OH)2D3. Scatchard analysis of intestinal, renal and testicular cytosol preparations of Hyp mice revealed a single class of noninteracting binding sites with a range of equilibrium dissociation constants (KD) of 0.9-3.5 X 10(-10) M, and a range of specific binding sites of 15-317 fmol/mg protein. There were no significant differences in values of KD, and numbers of specific binding sites among Hyp and control mice. We conclude the reported resistance of Hyp mice to vitamin D is not due to abnormal 1,24(OH)2D3 receptor in Hyp mouse.