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Intermittent zoledronic Acid prevents bone loss in adults after allogeneic hematopoietic cell transplantation.
Hari, P, DeFor, TE, Vesole, DH, Bredeson, CN, Burns, LJ
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2013;(9):1361-7
Abstract
Bone mineral density (BMD) loss is common in survivors of allogeneic hematopoietic cell transplantation (alloHCT). We performed a multicenter, phase II, randomized open-label trial of intravenous zoledronic acid (ZA) to prevent BMD loss in adult recipients of alloHCT with osteopenia before HCT. The treatment group received ZA 4 mg intravenously within 28 days pre-HCT and at 3 and 6 months after HCT. Both treatment and control groups received calcium carbonate and vitamin D supplements. Of 61 patients, 32 were randomized to the ZA cohort and 29 to the control cohorts. More patients in the ZA group had an HCT comorbidity index high-risk score of ≥3 (50% versus 21%, P < .01). Baseline BMD, T-scores, serum osteocalcin, bone alkaline phosphatase, and urine N-telopeptide (UNTX) levels were similar in both cohorts. Thirty patients were evaluable for outcomes (11 from the treatment and 19 from the control group). At 12 months, subjects in the treatment group had an improvement in BMD at the femoral neck (mean change, .018 for ZA group versus -.054 for controls; P = .04) and a significant decline in levels of UNTX (-56 for ZA group versus -9 for control; P = .04) compared with baseline. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw or renal impairment. Lower survival observed in the ZA cohort was likely related to baseline imbalance in HCT-CI scores. Intermittent ZA is effective in preserving long-term bone health in adult alloHCT recipients at risk for osteoporosis.
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A diet high in meat protein and potential renal acid load increases fractional calcium absorption and urinary calcium excretion without affecting markers of bone resorption or formation in postmenopausal women.
Cao, JJ, Johnson, LK, Hunt, JR
The Journal of nutrition. 2011;(3):391-7
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Abstract
Our objective in this study was to determine the effects of a high-protein and high-potential renal acid load (PRAL) diet on calcium (Ca) absorption and retention and markers of bone metabolism. In a randomized crossover design, 16 postmenopausal women consumed 2 diets: 1 with low protein and low PRAL (LPLP; total protein: 61 g/d; PRAL -48 mEq/d) and 1 with high protein and high PRAL (HPHP; total protein: 118 g/d; PRAL 33 mEq/d) for 7 wk each separated by a 1-wk break. Ca absorption was measured by whole body scintillation counting of radio-labeled (47)Ca. Compared with the LPLP diet, the HPHP diet increased participants' serum IGF-I concentrations (P < 0.0001), decreased serum intact PTH concentrations (P < 0.001), and increased fractional (47)Ca absorption (mean ± pooled SD: 22.3 vs. 26.5 ± 5.4%; P < 0.05) and urinary Ca excretion (156 vs. 203 ± 63 mg/d; P = 0.005). The net difference between the amount of Ca absorbed and excreted in urine did not differ between 2 diet periods (55 vs. 28 ± 51 mg/d). The dietary treatments did not affect other markers of bone metabolism. In summary, a diet high in protein and PRAL increases the fractional absorption of dietary Ca, which partially compensates for increased urinary Ca, in postmenopausal women. The increased IGF-I and decreased PTH concentrations in serum, with no change in biomarkers of bone resorption or formation, indicate a high-protein diet has no adverse effects on bone health.
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Impact of dialysate calcium concentration on the progression of aortic stiffness in patients on haemodialysis.
LeBoeuf, A, Mac-Way, F, Utescu, MS, De Serres, SA, Douville, P, Desmeules, S, Lebel, M, Agharazii, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2011;(11):3695-701
Abstract
BACKGROUND Higher dialysate calcium (DCa) can result in an acute and transient increase in arterial stiffness. The aim of the present study is to evaluate the impact of DCa on the progression of arterial stiffness, calcium balance and bone metabolism in haemodialysis (HD) patients over a 6-month period. Method. We randomly assigned 30 patients on chronic HD to be dialysed with a DCa of 1.12 or 1.37 mmol/L for a period of 6 months. Aortic stiffness and brachial stiffness were respectively measured by carotid-femoral pulse wave velocities (cf-PWV) and carotid-radial pulse wave velocity (cr-PWV) at baseline and at 3 and 6 months. Central pulse pressure (PP) and augmentation index were determined by radial artery tonometry. Dialysis calcium balance and parathyroid hormone (PTH) were measured monthly. Procollagen type-1 amino-terminal propeptide (P1NP) and C-terminal telopeptide of type-I collagen (CTX) were measured as markers of bone formation and resorption, respectively. Data was analysed by linear mixed model. RESULTS Twenty-seven patients (66 ± 13 years old) with a mean duration of HD of 5.8 ± 3.6 months completed the study. At baseline, the groups were similar with respect to age, serum levels of calcium, phosphate and PTH, blood pressure (BP), cf-PWV and cr-PWV. The cf-PWV at baseline and 3 and 6 months were, respectively, 13.4 ± 4.2, 14.7 ± 3.31 and 13.6 ± 2.5 m/s in the DCa 1.12 group and 14.6 ± 5.9, 15.8 ± 7.8 and 17.0 ± 7.0 m/s in the DCa 1.37 group. After correction for mean BP, cf-PWV increased with DCa 1.37 as compared to DCa 1.12 (Time-DCa interaction P = 0.002). However, there were no significant effects of DCa on progression of cr-PWV, central PP or augmentation index. During the intervention period, the mean PTH was slightly higher in the DCa 1.12 group as compared to the DCa 1.37 group (325 ± 185 versus 211 ± 128 ng/L, P = 0.054), and dialysis calcium balance was -8.1 ± 4.4 versus -0.2 ± 4.7 mmol/session, respectively, in groups with DCa 1.12 and DCa 1.37 (P = 0.0001). Treatment with DCa 1.12 mmol/L resulted in increasing levels of CTX as compared to DCa 1.37 (P = 0.02), whereas the P1NP levels did not change significantly in either group. CONCLUSIONS In this study, aortic stiffness progressed with DCa 1.37, while it remained stable with DCa 1.12 over a 6-month period. These results suggest that higher DCa concentrations could be a risk factor for the progression of aortic stiffness in HD patients. In the context of limited oral calcium, the long-term safety of DCa 1.12 on bone metabolism remains to be established.
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A comparison of the acute effects of calcium and strontium ranelate on the serum marker of bone resorption.
Maresova, KB, Franek, T, Vondracek, T, Stepan, JJ
Clinical chemistry and laboratory medicine. 2011;(2):333-5
Abstract
BACKGROUND To investigate the mechanism by which strontium ranelate (SrR) inhibits the bone resorption, this study compared the effects of SrR and calcium on parathyroid hormone (PTH) and the biochemical marker of bone resorption (serum type 1 collagen cross-linked C-telopeptide, βCTX). METHODS In 10 healthy young subjects, after overnight fasting, 1000 mg of elemental calcium and 2000 mg of SrR containing 600 mg Sr²⁺ were administered consecutively with a 1 week washout period. During the control period no drug was given. Fasting blood samples were drawn at baseline and throughout the next 5-h period. RESULTS After the ingestion of either calcium or SrR, there was a significant increase in serum calcium and strontium concentrations, and a decrease in serum βCTX and intact PTH concentrations as compared to the baseline values (p<0.05). In the fasting subjects, no significant differences in the variable were found as compared to the baseline values. CONCLUSIONS The decrease in PTH and the marker of bone resorption observed after the SrR administration is comparable to the decrease observed after the calcium administration in young adults.
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Long-term cinacalcet HCl treatment improved bone metabolism in Japanese hemodialysis patients with secondary hyperparathyroidism.
Shigematsu, T, Akizawa, T, Uchida, E, Tsukamoto, Y, Iwasaki, M, Koshikawa, S, ,
American journal of nephrology. 2009;(3):230-6
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Abstract
BACKGROUND/AIMS: Few clinical trials conducted with cinacalcet have thoroughly addressed its effects of on bone metabolism. We assessed the effects of cinacalcet on bone markers in Japanese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). METHODS 200 Japanese HD patients with intact PTH (iPTH) levels > or = 300 pg/ml were enrolled. The dose of cinacalcet was titrated from 25 up to 100 mg/day to achieve iPTH levels < or = 250 pg/ml for 52 weeks. RESULTS At the end of the study visit, 57.8% of patients (115/199) had achieved iPTH levels < or = 250 pg/ml. Serum Ca, phosphorus (P) and Ca x P levels decreased rapidly and were maintained throughout the study. At week 52, all bone metabolic markers levels had decreased significantly from baseline. Although bone resorption markers gradually decreased throughout the study period, bone alkaline phosphatase significantly increased during the first 4 weeks and then gradually decreased. CONCLUSIONS The time courses of changes in bone markers after cinacalcet treatment resembled those observed after surgical parathyroidectomy (PTx), sometimes described as the hungry bone syndrome, indicating that cinacalcet treatment induces a rapid recovery in bone response to calcium. In addition, long-term efficacy and safety of cinacalcet were also observed in Japanese patients undertaking long-term hemodialysis (167.0 +/- 81.4 months).
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Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women.
Henriksen, DB, Alexandersen, P, Hartmann, B, Adrian, CL, Byrjalsen, I, Bone, HG, Holst, JJ, Christiansen, C
Bone. 2007;(3):723-9
Abstract
We have previously shown that a single subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women results in a dose-dependent decrease in the nocturnal serum and urine concentrations of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX and u-CTX) and u-DPD, markers of bone resorption. In contrast, bone formation, as assessed by serum osteocalcin and procollagen type I N-terminal propeptide (PINP), appeared to be unaffected by treatment with exogenous GLP-2. These effects were further investigated in a 14-day study. The aim was to demonstrate that a parenteral formulation of GLP-2 is safe and well tolerated after repeated dosing in healthy postmenopausal women for 14 days. It was further investigated whether the effects on bone turnover markers were sustained throughout the study period. The study was a double-blind placebo-controlled trial with 60 postmenopausal women and 2 different doses of GLP-2 (1.6 mg and 3.2 mg GLP-2) against a saline control. The data for bone resorption revealed a similar reduction on Day 1 and Day 14, both based on time course and AUC. There were no signs of tachyphylaxis and no serious adverse reaction. Both GLP-2 doses resulted in similar and significant (p<0.001) reduction in bone resorption indicating that the maximum efficacious dose has been approached. Osteocalcin and PINP levels were unaffected at Day 1 and Day 14, suggesting a disassociation between bone resorption and bone formation during GLP-2 treatment.
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Effects of calcitriol on type 5b tartrate-resistant acid phosphatase and interleukin-6 in secondary hyperparathyroidism.
Lu, KC, Tseng, CF, Wu, CC, Yeung, LK, Chen, JS, Chao, TY, Janckila, AJ, Yam, LT, Chu, P
Blood purification. 2006;(5-6):423-30
Abstract
BACKGROUND/AIMS: Secondary hyperparathyroidism (SHP) is characterized by high bone turnover and elevated serum bone remodeling markers. Elevation of serum interleukin-6 (IL-6) levels is also characteristic of end-stage renal disease. This study investigates the effects of intravenous calcitriol on serum bone resorptive markers, namely, type 5b tartrate-resistant acid phosphatase (TRACP5b) and IL-6 in patients with SHP. METHODS Intravenous calcitriol therapy was given for 16 weeks to 24 patients on maintenance hemodialysis with plasma intact parathyroid hormone (iPTH) levels >300 pg/ml. Blood was drawn at baseline and every 4 weeks for 16 weeks for determination of the levels of biochemical parameters, iPTH, IL-6 and bone remodeling markers, including bone-specific alkaline phosphatase (bAP) and TRACP5b. RESULTS Only 21 patients responded to the calcitriol therapy, with significant decrements in serum iPTH after 4 weeks of therapy and thereafter. After 16 weeks of calcitriol therapy, 21 patients had significant decrements in serum iPTH (707.9 +/- 317.8 vs. 205.0 +/- 63.1 pg/ml, p < 0.01). Prior to treatment, a significant correlation was found between increased levels of serum iPTH and IL-6 levels (r = 0.45, p < 0.05). After treatment, there was also a significant and parallel lowering of levels of serum iPTH, IL-6 (8.52 +/- 3.59 vs. 7.24 +/- 2.81 pg/ml, p < 0.01), bAP (54.68 +/- 36.17 vs. 24.55 +/- 13.84 U/l, p < 0.01) and TRACP5b (3.41 +/- 1.89 vs. 1.80 +/- 0.55 U/l, p < 0.01). Our results additionally showed significant positive correlationsbetween baseline levels of serum IL-6 and those of iPTH, bAP and TRACP5b. After 16 weeks of calcitriol treatment, the correlation between IL-6 and iPTH levels lost significance but levels of serum IL-6, bAP and TRACP5b remained significantly correlated. CONCLUSIONS Elevated levels of serum IL-6 and bone remodeling markers, namely, bAP and TRACP5b which are common features of SHP, are effectively suppressed by calcitriol therapy. This indicates that hyperparathyroidism not only accelerates bone remodeling but may also aggravate inflammation in patients on maintenance hemodialysis.
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Effects of treatment of hyperthyroidism on glucose homeostasis, insulin secretion, and markers of bone turnover.
Al-Shoumer, KA, Vasanthy, BA, Al-Zaid, MM
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2006;(2):121-30
Abstract
OBJECTIVE To study glucose and bone metabolism in hyperthyroidism, assess their changes after treatment, and investigate their interrelationships. METHODS Thirty patients with hyperthyroidism matched with 32 normal control subjects were studied. After a 10- to 12-hour overnight fast, blood samples were collected for measurement of glucose, insulin, C-peptide, and intact proinsulin levels as well as for measurement of bone markers: serum alkaline phosphatase (ALP), osteocalcin, and procollagen type I C-terminal peptide (PICP) as markers of bone formation and serum C-terminal cross-linked telopeptide of type I collagen (ICTP) as a marker of bone resorption. A 3-hour 75-g oral glucose tolerance test was then performed, with measurement of glucose, insulin, and C-peptide levels every 30 minutes. Patients were studied at baseline and after treatment with an antithyroid drug (carbimazole) for 1 month and 6 months. RESULTS Pretreatment fasting glucose, insulin, C-peptide, and intact proinsulin levels were significantly higher in patients with hyperthyroidism than in control subjects. During the 3-hour oral glucose tolerance test, the area under the curve of glucose was significantly elevated in the patients, whereas the 3-hour areas under the curve of insulin and C-peptide were not significantly different between patients and control subjects. Fasting glucose, insulin, C-peptide, and intact proinsulin levels decreased significantly to levels similar to those of the control subjects after 1 month of antithyroid therapy and remained so at 6 months. Pretreatment ALP, osteocalcin, PICP, and ICTP were significantly higher in the patients than in the control subjects. After treatment, all markers of bone turnover decreased significantly to levels similar to those of the control subjects at 1 month (except ALP) and 6 months. Within the study group of patients, baseline PICP, osteocalcin, and ICTP demonstrated positive correlation trends with free triiodothyronine and free thyroxine. CONCLUSION Abnormal glucose metabolism and increased bone turnover are hallmarks of untreated hyperthyroidism. These factors normalize as early as 4 weeks after initiation of antithyroid therapy. Changes in bone markers, particularly those of resorption, are related to the degree of thyroid hyperactivity.
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Variable deficits of bone mineral despite chronic glucocorticoid therapy in pediatric patients with inflammatory diseases: a Glaser Pediatric Research Network study.
von Scheven, E, Gordon, CM, Wypij, D, Wertz, M, Gallagher, KT, Bachrach, L
Journal of pediatric endocrinology & metabolism : JPEM. 2006;(6):821-30
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OBJECTIVE To evaluate the relationship between chronic glucocorticoid (GC) exposure and bone mineral density (BMD) in children with rheumatic diseases and inflammatory bowel disease. STUDY DESIGN Lumbar spine BMD was measured by DXA in 86 GC-treated children (66% female, age 8-20 years, mixed ethnicity) screened for a multi-center intervention trial. Predictors of spine BMD z-score and vitamin D [25(OH)D] were examined by multivariable linear regression. RESULTS Mean prior year and lifetime cumulative GC exposure was 77.8 mg/kg and 224.6 mg/kg, respectively. BMD z-scores ranged from -3.7 to 2.2 SD (-1.1 +/- 1.2, mean +/- SD). Lower BMD z-scores were associated with increased prior year average daily GC dose (p = 0.03), decreased height z-score (p = 0.003), and decreased 25(OH)D concentrations (p = 0.03), but explained only a small proportion of BMD variability (adjusted R2 = 0.29). The 25(OH)D levels were <20 ng/ml in 45% of patients, and low 25(OH)D was associated with non-Caucasian ethnicity (p <0.001), increased age (p = 0.004), increased parathyroid hormone (p = 0.03), and residing in the Boston area (p <0.001). CONCLUSIONS Although GC exposure is significantly associated with BMD z-score, the association is too variable to serve as a consistent predictor of reduced BMD in children. Vitamin D insufficiency is common and may contribute to skeletal deficits in this population.
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Effects of thickened beverages fortified with inulin on beverage acceptance, gastrointestinal function, and bone resorption in institutionalized adults.
Dahl, WJ, Whiting, SJ, Isaac, TM, Weeks, SJ, Arnold, CJ
Nutrition (Burbank, Los Angeles County, Calif.). 2005;(3):308-11
Abstract
OBJECTIVES We wanted to develop thickened beverages that contain soluble fiber (inulin) with acceptable consistency, taste, and texture and to determine the effects of these beverages on bone resorption markers (to determine calcium retention), bowel frequency, and indicators of gastrointestinal function in institutionalized adults bound to wheelchairs. METHODS A double-blind, 3-wk, cross-over study testing 13-g/d inulin-fortified versus isocaloric standard modified starch-thickened beverages was conducted in institutionalized adults who were bound to wheelchairs and had dysphagia or did not have dysphagia. Beverage acceptability, as assessed by discriminative and descriptive sensory testing, bowel frequency, fecal output, and laxative use, were determined by direct testing or by nursing charts. Bone resorption was measured by using the urinary excretion of fasting calcium and of cross-linked N-telopeptides of collagen. RESULTS Sensory panelists were unable to detect a difference between beverages thickened with modified starch and those fortified with inulin. Few differences were found between the control and inulin-fortified beverages for sensory descriptors. No significant difference was found in frequency of bowel movements between treatments; however, weighted bowel movement frequency increased by 13% with inulin (P < 0.01), whereas enema and laxative administration decreased by 13% (P < 0.05). Bone resorption, as an indicator of calcium retention, remained unchanged. CONCLUSIONS Inulin was incorporated into thickened beverages, with no decrease in acceptability; when consumed, perceived stool output increased in residents of long-term care facilities.