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Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN) in adolescent girls and occurs during a critical time in bone development. Little is known about bone metabolism in this patient population. Therefore, we measured bone density (BMD) and body composition by dual energy x-ray absorptiometry, nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent girls with AN (mean +/- SEM, 16.0+/-0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19+/-5 months. Spinal (L1-L4) osteopenia was common in AN. Lumbar anterioposterior BMD was more than 1 SD below the mean in 42% of patients, and lateral spine BMD was more than 1 SD below in 63% of patients compared with controls. Lean body mass significantly predicted lumbar bone mineral content (r = 0.75; P < 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r = -0.44; P = 0.06; lateral: r = -0.59; P = 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2+/-1.9 vs. 23.3+/-1.6 pg/mL (P = 0.01); free testosterone, 0.70+/-0.17 vs. 1.36+/-0.14 pg/mL (P = 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9+/-2.1 vs. 16.5+/-1.8 ng/mL; P < 0.0001). Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels (219+/-41 vs. 511+/-35 ng/mL; P < 0.0001) and correlated with all measures of nutritional status, particularly leptin (r = 0.80; P < 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1+/-6.4 vs. 59.2+/-5.2 ng/mL; BSAP, 27.9+/-4.0 vs. 40.6+/-3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P = 0.002; BSAP: r2 = 0.53; P = 0.01) in stepwise regression analyses. Bone resorption was comparable in patients and controls. These data demonstrate that bone formation is reduced and uncoupled to bone resorption in mature adolescents with AN in association with low bone density. Lean body mass was a significant predictor of BMD in controls, but not AN patients. The major correlate of bone formation in AN was the nutritionally dependent bone trophic factor, IGF-I. Reduced IGF-I during the critical period of bone mineral accumulation may be an important factor in the development of osteopenia in adolescents with AN.
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PMID:The effects of anorexia nervosa on bone metabolism in female adolescents. 1059 7

Identification of a biochemical marker of growth in low birth weight (LBW) infants would be of benefit to rapidly assess the effects of illness and/or therapeutic intervention. The aims of the present study were (1) to measure serially the C-terminal fragment of type I procollagen (PICP), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC) in LBW infants during the first 6 weeks of life; (2) to correlate the changes in PICP, BSAP, and OC with the changes in weight; and (3) to evaluate PICP levels as a marker for bronchopulmonary dysplasia (BPD). Premature neonates (< or =36 weeks of gestation) had cord blood and then weekly blood samples taken from up to 6 weeks after birth. Daily changes in weight were recorded. Measurements of serum PICP, BSAP, and OC were done in duplicate by immunoassay. In a subset population (25-30 weeks), PICP levels in the first 4 weeks of life were evaluated as a marker for subsequent development of BPD. A total of 77 infants had serum PICP and BSAP measured. The mean (+/- SEM) gestational ages of all the infants were 30.4 (+/-0.3) weeks and birth weights 1477 (+/-55) g. Fifteen infants also had measurements of OC done. In these 15 infants, change in weight was correlated significantly with PICP (p<0.0001), but not with either BSAP (p = 0.8) or OC measurements (p = 0.9). In appropriate for gestational age (AGA) infants (n = 66), the PICP values decreased from the cord blood values to the week 1 measurement, coinciding with the fall in weight over the same time period. BSAP values, on the other hand, continued to increase from birth onwards. Over the first 6 weeks of postnatal life in these infants, change in weight had a stronger positive correlation with PICP (R2 = 0.43, p<0.0001) than BSAP (R2 = 0.03, p<0.01). In the subset population, PICP levels at week 4 were significantly lower (p<0.04) in those infants who subsequently developed BPD. PICP measurements are correlated with somatic growth in premature infants and could be used as a biochemical marker in infants who develop BPD.
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PMID:Potential biochemical growth markers in premature infants. 1061 1

Hyperthyroid patients have high bone turnover and negative calcium and phosphorus balance often associated with mild osteopenia. Early during antithyroid treatment bone turnover decreases, the mineral balance is converted to positive, and sometimes hypocalcemia occurs. The aim of this investigation was to study the mechanisms of the changes in some parameters of bone and mineral metabolism after treatment of thyrotoxicosis. Thirteen newly diagnosed patients with Graves' disease (seven postmenopausal women, four premenopausal women, and two men) were studied longitudinally, every 6 weeks, for 1 yr after commencing antithyroid treatment with methimazole. Mean serum calcium and phosphorus were both slightly above the normal mean at week 0 and decreased significantly (by 10% and 24%, respectively) during treatment. Fasting urinary calcium was 236 +/- 4 (mean +/- SEM) mg/g creatinine, and the fractional excretion of Ca was 2.0 +/- 0.33% before treatment; both fell significantly to minimums of 61 +/- 20 mg/g and 0.6 +/- 0.16%, respectively. Urinary phosphorus was 282 +/- 60 mg/g creatinine, and the fractional excretion of phosphorus was 3.3 +/- 0.6% before treatment; both increased significantly to 452 +/- 40 mg/g and 8.4 +/- 1.0%, respectively, during treatment. The z-scores were calculated from the mean and SD ofthe respective control groups. The z-score of urinary N-telopeptides of type I collagen (U.NTx) was 9.3 +/- 1.3 at week 0 and declined exponentially, but failed to normalize after 1 yr of antithyroid treatment. The serum alkaline phosphatase (ALP) z-score was initially 2.2 +/- 0.2, increased to 6.0 +/- 1.0 at week 6, and declined slowly there after to 1.0 +/- 1.1 at week 54. The serum osteocalcin (OC) z-score showed a temporal pattern similar to that of ALP. It was initially 2.2 +/- 0.2, increased to 4.0 +/- 0.6 at week 6, and later declined slowly to 0.7 +/- 0.5 at week 54. The failure of the markers of bone turnover to normalize after 1 yr of therapy indicates an on-going high rate of bone turnover despite the attained euthyroidism. The uncoupling index (UI = z-score of U.NTx minus z-score of OC) was 7.1 +/- 1.2 before treatment, indicating unbalanced bone turnover in favor of bone resorption, and fell close to zero at week 30 of treatment. Pretreatment plasma PTH was suppressed slightly to 2.17 +/- 0.47 pmol/L and rose significantly during treatment, reaching a plateau of 5.27 +/- 0.78 at week 12. In all postmenopausal women PTH increased above the upper limit of normal (6.84 pmol/L). Pretreatment serum 25-hydroxyvitamin D was normal and remained unchanged during treatment, whereas 1,25-dihydroxyvitamin D was initially subnormal and rose to normal level after treatment. There was a significant positive linear correlation between PTH and U.NTx after week 12. PTH was also significantly correlated with ALP, but not with OC. ALP and OC were significantly correlated. A significant positive correlation was found between T3 and U.NTx, and a negative correlation was found between T3 and each of the formation markers (ALP and OC) over the 0- to 12-week interval. The latter correlations and the very high pretreatment UI indicate some inhibitory effect of the high thyroid hormone levels on the osteoblasts. The marked and sustained elevation of PTH, more pronounced in the postmenopausal women, during the first year of treatment of hyperthyroidism seems to play a pivotal role in maintaining a relatively high rate of bone turnover despite euthyroidism, and in the conservation of calcium by reducing renal calcium excretion and increasing calcium absorption (via 1,25-dihydroxyvitamin D). It may also account in part for the additional rise of the bone formation markers by an anabolic effect on the osteoblasts. Endogenous PTH may be important in the restoration of bone mineral density of treated hyperthyroid patients.
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PMID:Changes in parameters of bone and mineral metabolism during therapy for hyperthyroidism. 1072 46

The effect of oral pamidronate on bone mineral density and its adverse effect profile was investigated by a double-masked placebo-controlled study of 122 patients aged 55-75 years with established vertebral osteoporosis. Patients on active therapy received disodium pamidronate 300 mg/day (group A) for 4 weeks every 16 weeks, 150 mg/day (group B) for 4 weeks every 8 weeks or placebo (group C). All patients additionally received 500 mg of calcium and 400 IU vitamin D daily. Dual-energy X-ray absorptiometry measurements of the spine, hip, forearm and total body were performed at baseline and 6-monthly for 2 years using a Hologic QDR 1000 device at two sites. Serum osteocalcin and urinary deoxypyridinoline were measured at the above visits and at 3 months. The percentage change (SEM) in spine bone mineral density (BMD) at 2 years based on intention-to-treat analysis was 4.64 (1.01) in group A, 6.10 (0.87) in group B and 1.13 (1.32) in group C. Analysis of variance showed significant increases in group A and B compared with placebo (p < 0.01). There were also significant rises in femoral neck BMD for group A (p = 0.005), trochanter BMD for groups A and B (p < 0.01) and total-body BMD for groups A and B (p < 0.001). There was a significant reduction in serum osteocalcin and urinary deoxypyridinoline for groups A and B (p < 0.01). There was an excess of gastrointestinal side-effects in the treated groups, particularly group A. We conclude that intermittent pamidronate therapy can prevent bone loss at both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although due to gastrointestinal side-effects the 300 mg dose in particular does not appear suitable for clinical usage.
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PMID:Intermittent oral disodium pamidronate in established osteoporosis: a 2 year double-masked placebo-controlled study of efficacy and safety. 1079 77

Primary disturbances in mineral metabolism and deficiencies in insulin and insulin-like growth factor-I (IGF-I) have been implicated in the pathogenesis of diabetic osteopenia. This prompted us to investigate whether normal bone minerals and bone morphology are preserved after pancreas transplantation. To this end, 8 inbred rats (transplants) were compared with 9 sham-operated rats (controls) 20 months after orthotopic pancreas transplantation. While basal levels of insulin remained unaffected by transplantation, an oral glucose load elicited hyperinsulinemia (integrated incremental response: mean +/- SEM, 62+/-8 nmol l(-1) 60 min in transplants vs. 32+/-6 nmol l(-1) 60 min in controls; p<0.01) in the presence of normal glucose levels. Fecal and urinary excretion and fractional intestinal absorption of calcium, magnesium and phosphorus, net calcium absorption and the respective serum mineral levels were unchanged after transplantation, as were those of the calciotropic hormones. Serum osteocalcin and bone alkaline phosphatase remained unaffected, and urinary excretion of pyridinium and deoxypyridinium were unchanged. Fasting plasma IGF-I concentration was significantly decreased in transplants (930+/-42 ng ml(-1)) vs. control rats (1074+/-49 ng ml(-1); p < 0.05). Despite similar physical and chemical properties of bone in both groups, histomorphometry revealed slight osteopenia in transplant rats, as reflected by a 38% reduction in the cancellous bone area of the proximal tibial metaphysis. Plasma IGF-I levels were significantly correlated with bone mineral apposition rate (r=0.70, p<0.02), osteoblast perimeter (r=0.60, p<0.05) and osteoid perimeter (r=0.60, p<0.05). In conclusion, pancreas transplantation preserves physical and chemical properties of bone, but bone metabolism is not completely normal after transplantation, as evidenced by decreased cancellous bone. This might have resulted from the insulin resistance associated with the lowering of the plasma IGF-I level, which was correlated with the mineral apposition rate.
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PMID:High insulin and low IGF-I plasma levels following pancreas transplantation in rats. Implications for bone and mineral metabolism. 1088 89

Osteoporosis in men poses a unique therapeutic challenge. Clinical studies have focused largely on the more prevalent problem of post-menopausal osteoporosis, with few gender-specific studies exploring treatment options in men. Idiopathic osteoporosis in middle-aged men presents an additional dilemma, because in the majority of patients it is a low bone turnover state for which there are currently no available anabolic agents. We conducted an 18-month randomized, double blind, placebo-controlled trial of 23 men with idiopathic osteoporosis, 30-68 yr old (mean age +/- SEM, 50 +/- 1.9 yr). All patients received 1,500 mg calcium and 400 IU vitamin D daily. Ten patients were randomized to receive 400 IU PTH-(1-34), and 13 patients received vehicle, administered by daily sc injection. Serum and urinary biochemistries, including markers of bone turnover were measured every 3 months. Bone densitometry of the lumbar spine, hip, and radius was performed every 6 months. PTH-(1-34) was associated with a marked 13.5% increase in bone mass at the lumbar spine, whereas that in the control group did not change (P < 0.001). The mean lumbar spine T-score improved from -3.5 +/- 0.2 to 2.4 +/- 0.4. Femoral neck bone mineral density in the PTH-treated group increased 2.9% (P < 0.05). The 1/3 site of the distal radius showed no change from baseline in the PTH-treated group. There were no significant changes in serum calcium concentration, 24-h urinary calcium excretion, or 1,25-dihydroxyvitamin D in either group. All markers of bone turnover increased in the PTH-treated patients, with the greatest changes in serum osteocalcin and urinary N-telopeptide (230% and 375% above baseline by 12 months, respectively; P < 0.001). Free pyridinoline and markers of bone formation that showed little correlation with each other at baseline, became highly correlated in the PTH-treated group (r = 0.1; P = 0.29 at baseline; to r = 0.7; P < 0.0001 at 18 months), a pattern absent in the control patients. The best predictor of the lumbar spine response to PTH at 18 months was the combination of pyridinoline at baseline and osteocalcin at 3 months (70% of the variance). PTH is a potent stimulator of skeletal dynamics in men with idiopathic, low turnover osteoporosis; is associated with substantial increases in lumbar spine and hip bone density; and may prove to be an efficacious anabolic agent in men with this disorder.
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PMID:Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. 1099 88

We investigated the concept of using bioactive substrates as templates for in vitro synthesis of bone tissue for transplantation by assessing the osteogenic potential of a melt-derived bioactive glass ceramic (Bioglass 45S5) in vitro. Bioactive glass ceramic and bioinert (plastic) substrates were seeded with human primary osteoblasts and evaluated after 2, 6, and 12 days. Flow cytometric analysis of the cell cycle suggested that the bioactive glass-ceramic substrate induced osteoblast proliferation, as indicated by increased cell populations in both S (DNA synthesis) and G2/M (mitosis) phases of the cell cycle. Biochemical analysis of the osteoblast differentiation markers alkaline phosphatase (ALP) and osteocalcin indicated that the bioactive glass-ceramic substrate augmented osteoblast commitment and selection of a mature osteoblastic phenotype. Scanning electron microscopic observations of discrete bone nodules over the surface of the bioactive material, from day 6 onward, further supported this notion. A combination of fluorescence, confocal, transmission electron microscopy, and X-ray microprobe (SEM-EDAX) examinations revealed that the nodules were made of cell aggregates which produced mineralized collagenous matrix. Control substrates did not exhibit mineralized nodule formation at any point studied up to 12 days. In conclusion, this study shows that Bioglass 45S5 has the ability to stimulate the growth and osteogenic differentiation of human primary osteoblasts. These findings have potential applications for tissue engineering where this bioactive glass substrate could be used as a template for the formation of bioengineered bone tissue.
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PMID:Bioglass 45S5 stimulates osteoblast turnover and enhances bone formation In vitro: implications and applications for bone tissue engineering. 1100 Mar 47

Low bone density, fractures, and kyphosis complicate the lives of adults with cystic fibrosis (CF), and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) that may alter bone metabolism have been previously found to be increased in the lungs and serum of CF patients. The objective of this prospective study was to determine the impact of lung infection on bone physiology in 17 adult CF patients. Serum osteocalcin, a marker of bone formation; urine N-telopeptides of type I collagen and free deoxypyridinoline, both of which are markers of bone breakdown; serum cytokines (TNF-alpha, IL-1beta, and IL-6); and general inflammatory markers (serum C-reactive protein [CRP] and chondrex) were measured at the beginning and end of treatment for an acute exacerbation of lung infection and again 3 wk later. After treatment with conventional antibiotics, decreases in N-telopeptides (147.3 +/- 77.5 [mean +/- SEM] versus 95.5 +/- 57.3 bone collagen equivalents (BCE)/mmol creatinine, p = 0.0014), deoxypyridinoline (8.42 +/- 2.8 versus 6.8 +/- 3.0 mmol/mmol creatinine, p = 0.08), IL-1beta (1.43 +/- 1.13 versus 0.65 +/- 0.63 pg/ml, p = 0.03), IL-6 (9.5 +/- 6.5 versus 4.7 +/- 3.2 pg/ml, p = 0. 012), CRP (43.1 +/- 29.3 versus 23.4 +/- 25.3 mg/ml, p = 0.04), and chondrex (151.7 +/- 111.7 versus 101.4 +/- 67.3 ng/ml, p = 0.014), and increases in osteocalcin levels (14.5 +/- 5.4 versus 22.5 +/- 8. 7 ng/ml, p = 0.010) were observed. Three weeks later, the changes in N-telopeptides and osteocalcin persisted. These data indicate that pulmonary infection, through the elaboration of inflammatory cytokines, may be linked to increased bone resorption and diminished bone formation. These results provide insights into the impact of systemic inflammation on bone health, and suggest novel mechanisms for bone disease in CF.
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PMID:Adverse alterations in bone metabolism are associated with lung infection in adults with cystic fibrosis. 1106 95

Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.
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PMID:A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs. 1109 10

Quantitative ultrasound (QUS) of bone is a valuable tool in the assessment of postmenopausal osteoporosis. QUS and new markers of bone turnover have been poorly assessed in Cushing's syndrome, however. Twenty-five patients with Cushing's syndrome (20 women, 3 men; mean age +/- SEM: 38+/-2 years) were studied and compared with 35 age- and sex-matched control patients (mean age +/- SEM: 38+/-2 years). The following variables were measured in both groups: QUS parameters at the heel (BUA; SOS; Stiffness Index, SI); bone mineral density (BMD) at both the lumbar spine (LS) and femoral neck (FN) by dual-energy X-ray absorptiometry; and serum markers of bone turnover (osteocalcin, procollagen type I N- and C-terminal propeptides (PINP and PICP), bone alkaline phosphatase (BAP), procollagen type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopepetide breakdown products (CTX)). Both BUA and SI were decreased in patients with Cushing's syndrome (p<0.01) but not SOS (p=0.08). BMD was also strongly decreased in Cushing's syndrome, at both the LS and FN (p<0.005). The two markers of bone turnover statistically significantly different between the two groups were osteocalcin (mean + SEM: 3.5 + 0.7 ng/ml (Cushing's syndrome) vs 6.4+/-0.5 ng/ml (controls, p<0.01)) and CTX (mean +/- SEM: 148.7+/-17.1 microg/mmol Cr (Cushing's syndrome) vs 220.8+/-22.9 microg/mmol Cr (controls), p<0.05). The areas under the receiver operating characteristic curve (AUC) were 0.72 (BUA), 0.73 (SI), 0.90 (BMD(LS)), 0.81 (BMD(FN)), 0.83 (osteocalcin) and 0.64 (CTX) respectively. AUC was significantly higher for BMD(LS) than for both BUA and SI (p<0.05). Conversely AUC was not statistically significantly different for BMDFN as compared with either BUA or SI. AUC was also higher for osteocalcin than for other markers of bone turnover. In conclusion, QUS of bone seems to be a relevant tool for assessing bone involvement in Cushing's syndrome. QUS does have a lower sensitivity compared with DXA, however, and the relevance of QUS cannot be ascertained until some longitudinal data are forthcoming. Except for CTX, the other new markers of bone turnover assessed in this study (PINP, PICP, BAP and ICTP) do not seem of interest in Cushing's syndrome.
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PMID:Quantitative ultrasound of bone and markers of bone turnover in Cushing's syndrome. 1130 11


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