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Predictive Power of Bone Turnover Biomarkers to Estimate Bone Mineral Density after Kidney Transplantation with or without Denosumab: A post hoc Analysis of the POSTOP Study.
Heimgartner, N, Graf, N, Frey, D, Saleh, L, Wüthrich, RP, Bonani, M
Kidney & blood pressure research. 2020;(5):758-767
Abstract
BACKGROUND Low bone mineral density (BMD) represents a major risk factor for bone fractures in patients with chronic kidney disease (CKD) as well as after kidney transplantation. However, modalities to solidly predict patients at fracture risk are yet to be defined. Better understanding of bone turnover biomarkers (BTMs) may close this diagnostic gap. This study strives to correlate BTMs to BMD in kidney transplant recipients. METHODS Changes in BTMs - procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSAP), β-isomer of the C-terminal telopeptide of type I collagen, and urine deoxypyridinoline/Cr - at the time of transplant and 3 months were correlated to changes in BMD measured by dual-energy X-ray absorptiometry at the time of transplant, 6, and 12 months, respectively. Half of the collective was treated with denosumab twice yearly in addition to the standard treatment with calcium and vitamin D. RESULTS Changes in bone formation markers BSAP and P1NP within 3 months showed a significant negative correlation to changes in BMD at the hip within 6 months in denosumab-naïve patients. This correlation was abrogated by denosumab treatment. CONCLUSIONS Changes in BSAP and P1NP showed promise in short-term prediction of BMD. We suggest further trials expanding on the knowledge of these BTMs with assessment of fracture risk, sequential measurements of BTMs within the first 6 months, and the additional use of computed tomography to assess BMD.
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Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization.
Fratzl-Zelman, N, Valta, H, Pereira, RC, Misof, BM, Roschger, P, Jalanko, H, Wesseling-Perry, K, Klaushofer, K, Mäkitie, O
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017;(5):1116-1125
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Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross-sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age-appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients' clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10-fold, both p < 0.0001) and in heterogeneity of mineralization (+26,5% and +27.8%, both p < 0.0001), respectively. Moreover, the BMDD parameters were nonsignificantly distinct from CKD5D cohort except that the heterogeneity in mineralization was higher posttransplantation. There was a strong inverse correlation between the average calcium content of the bone matrix and patients' biochemical ALP levels, histomorphometric indices of bone formation and resorption. The abnormally high bone matrix mineralization in transplant recipients, consistent with serum and histomorphometric outcomes, suggests a history of low bone turnover with accumulation of fully mineralized bone packets. Additionally, the increased heterogeneity of mineralization suggests local alterations in mineralization kinetics, which may be linked to dysfunctional osteocytes that were recently shown to accumulate within the bone matrix during organ failure and concomitant glucocorticoid and immunosuppressive medication. © 2017 American Society for Bone and Mineral Research.
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Greater change in bone turnover markers for efavirenz/emtricitabine/tenofovir disoproxil fumarate versus dolutegravir + abacavir/lamivudine in antiretroviral therapy-naive adults over 144 weeks.
Tebas, P, Kumar, P, Hicks, C, Granier, C, Wynne, B, Min, S, Pappa, K
AIDS (London, England). 2015;(18):2459-64
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OBJECTIVE Antiretroviral therapy initiation has been linked to bone mineral density and bone biomarker changes. We assessed long-term bone turnover biomarker effects over 144 weeks in patients initiating dolutegravir (DTG) + abacavir/lamivudine (ABC/3TC) versus efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). METHODS Patients randomized in SINGLE received DTG (50 mg once daily) + ABC/3TC or fixed-dose combination EFV/FTC/TDF. We evaluated vitamin D serum levels and bone turnover markers (BTMs), including type 1 collagen cross-linked C-telopeptide (CTx), osteocalcin, bone-specific alkaline phosphatase (BSAP), and procollagen type 1 N-terminal propeptide (P1NP), at baseline and weeks 48, 96, and 144. RESULTS Among the 833 enrolled patients (68% white, 85% men), baseline median age was 35 years (range 18-85), median CD4 was 338 cells/μl, and median BMI was 24 kg/m. Fifty-three percent of patients smoked, and 6% reported baseline vitamin D use, with no meaningful differences between groups. Relative to baseline, CTx, osteocalcin, BSAP, and P1NP increased; vitamin D decreased in both groups at weeks 48, 96, and 144. Changes from baseline typically peaked at weeks 48 or 96 and for the four analytes, excluding vitamin D, with the EFV/FTC/TDF group having significantly greater changes from baseline at all time points. CONCLUSION DTG + ABC/3TC in antiretroviral therapy-naive patients resulted in significantly lower increases in BTMs (CTx, osteocalcin, BSAP, P1NP) compared with EFV/FTC/TDF over 144 weeks. The observed changes are consistent with results from other smaller, randomized trials. These differences in BTMs likely correlate with changes in bone mineral density over time.
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Romosozumab in postmenopausal women with low bone mineral density.
McClung, MR, Grauer, A, Boonen, S, Bolognese, MA, Brown, JP, Diez-Perez, A, Langdahl, BL, Reginster, JY, Zanchetta, JR, Wasserman, SM, et al
The New England journal of medicine. 2014;(5):412-20
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BACKGROUND Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).
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Effect of calcium phosphate and vitamin D₃ supplementation on bone remodelling and metabolism of calcium, phosphorus, magnesium and iron.
Trautvetter, U, Neef, N, Leiterer, M, Kiehntopf, M, Kratzsch, J, Jahreis, G
Nutrition journal. 2014;:6
Abstract
BACKGROUND The aim of the present study was to determine the effect of calcium phosphate and/or vitamin D₃ on bone and mineral metabolism. METHODS Sixty omnivorous healthy subjects participated in the double-blind, placebo-controlled parallel designed study. Supplements were tricalcium phosphate (CaP) and cholecalciferol (vitamin D₃). At the beginning of the study (baseline), all subjects documented their normal nutritional habits in a dietary record for three successive days. After baseline, subjects were allocated to three intervention groups: CaP (additional 1 g calcium/d), vitamin D₃ (additional 10 μg/d) and CaP + vitamin D₃. In the first two weeks, all groups consumed placebo bread, and afterwards, for eight weeks, the test bread according to the intervention group. In the last week of each study period (baseline, placebo, after four and eight weeks of intervention), a faecal (three days) and a urine (24 h) collection and a fasting blood sampling took place. Calcium, phosphorus, magnesium and iron were determined in faeces, urine and blood. Bone formation and resorption markers were analysed in blood and urine. RESULTS After four and eight weeks, CaP and CaP + vitamin D₃ supplementations increased faecal excretion of calcium and phosphorus significantly compared to placebo. Due to the vitamin D₃ supplementations (vitamin D₃, CaP + vitamin D₃), the plasma 25-(OH)D concentration significantly increased after eight weeks compared to placebo. The additional application of CaP led to a significant increase of the 25-(OH)D concentration already after four weeks. Bone resorption and bone formation markers were not influenced by any intervention. CONCLUSIONS Supplementation with daily 10 μg vitamin D₃ significantly increases plasma 25-(OH)D concentration. The combination with daily 1 g calcium (as CaP) has a further increasing effect on the 25-(OH)D concentration. Both CaP alone and in combination with vitamin D₃ have no beneficial effect on bone remodelling markers and on the metabolism of calcium, phosphorus, magnesium and iron. TRIAL REGISTRATION NCT01297023.
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Profile of changes in bone turnover markers during once-weekly teriparatide administration for 24 weeks in postmenopausal women with osteoporosis.
Sugimoto, T, Nakamura, T, Nakamura, Y, Isogai, Y, Shiraki, M
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2014;(3):1173-80
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SUMMARY Changes in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained. INTRODUCTION This study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis. METHODS The 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week. RESULTS Similar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4-8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks. CONCLUSIONS Twenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same.
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Effects of bazedoxifene on bone mineral density, bone turnover, and safety in postmenopausal Japanese women with osteoporosis.
Itabashi, A, Yoh, K, Chines, AA, Miki, T, Takada, M, Sato, H, Gorai, I, Sugimoto, T, Mizunuma, H, Ochi, H, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;(3):519-29
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This randomized, double-blind, placebo-controlled, dose-response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (-0.65%, p < .001 for both). Both bazedoxifene doses significantly improved BMD at the total hip, femoral neck, and greater trochanter compared with placebo (p < .001 for all). Decreases in bone turnover markers were observed with bazedoxifene 20 and 40 mg as early as 12 weeks (p < .05 for all) and were sustained throughout the study. Total and low-density lipoprotein cholesterol levels were significantly decreased from baseline with both bazedoxifene doses compared with placebo (p < .05 for all). Incidences of new vertebral and nonvertebral fractures were similar among the bazedoxifene and placebo groups. Overall, the incidence of adverse events with bazedoxifene 20 and 40 mg was similar to that with placebo. Bazedoxifene significantly improved BMD, reduced bone turnover, and was well tolerated in postmenopausal Japanese women with osteoporosis.
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Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss.
Conroy, R, Girotra, M, Shane, E, McMahon, DJ, Pavlovich, KH, Leibel, RL, Rosenbaum, M, Korner, J
Metabolism: clinical and experimental. 2011;(9):1222-6
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The objective was to examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover. This was a prospective, single-blinded study of 12 subjects (8 women, 4 men; 2 nonobese, 10 obese; age range, 19-46 years) who were studied on an inpatient basis while maintaining their usual weight [Wt(initial)] and during maintenance of 10% weight loss while receiving twice-daily injections of either a placebo [Wt(-10%P)] or replacement doses of leptin [Wt(-10%L)]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide) and resorption (N-telopeptide) as well as parathyroid hormone, calcium, and 25-hydroxy vitamin D measured from fasting morning serum. As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3% ± 3.9% between Wt(initial) and Wt(-10%P) and remained suppressed after leptin administration (both P < .01 compared with baseline). N-telopeptides increased by 37.2% ± 11.3% from Wt(initial) to Wt(-10%L) (P < .01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium, and 25-hydroxy vitamin D did not change. These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss.
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A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover.
Horwitz, MJ, Tedesco, MB, Sereika, SM, Prebehala, L, Gundberg, CM, Hollis, BW, Bisello, A, Garcia-Ocaña, A, Carneiro, RM, Stewart, AF
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;(9):2287-97
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Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1-34) [hPTH(1-34)] and human parathyroid hormone-related protein(1-36) [hPTHrP(1-36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1-84). The maximal tolerated infused doses over a 7-day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone-formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone-resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT.
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Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women.
Binkley, N, Harke, J, Krueger, D, Engelke, J, Vallarta-Ast, N, Gemar, D, Checovich, M, Chappell, R, Suttie, J
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2009;(6):983-91
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Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double-blind, placebo-controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D(3) supplementation. Serum bone-specific alkaline phosphatase (BSALP) and n-telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.