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Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism.
Behets, GJ, Spasovski, G, Sterling, LR, Goodman, WG, Spiegel, DM, De Broe, ME, D'Haese, PC
Kidney international. 2015;(4):846-56
Abstract
The multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma parathyroid hormone (PTH) levels of 300 pg/ml or more, serum calcium of 8.4 mg/dl or more, bone-specific alkaline phosphatase over 20.9 ng/ml and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6-12 months of cinacalcet treatment. The median PTH decreased from 985 pg/ml at baseline to 480 pg/ml at the end of study (weeks 44-52). Bone formation rate/tissue area decreased from 728 to 336 μm(2)/mm(2)/day, osteoblast perimeter/osteoid perimeter decreased from 17.4 to 13.9%, and eroded perimeter/bone perimeter decreased from 12.7 to 8.3%. The number of patients with normal bone histology increased from none at baseline to 20 at 12 months. Two patients had adynamic bone at the end of study with a PTH under 150 pg/ml, and one patient with overt hypophosphatemia at baseline that reoccurred during follow-up developed osteomalacia. Thus, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate/tissue area, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology. Twenty patients had normal bone histology at follow-up, whereas most had mild hyperparathyroidism or mixed uremic osteodystrophy.
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Effect of lyso-phosphatidylcholine and Schnurri-3 on osteogenic transdifferentiation of vascular smooth muscle cells to calcifying vascular cells in 3D culture.
Castro-Chavez, F, Vickers, KC, Lee, JS, Tung, CH, Morrisett, JD
Biochimica et biophysica acta. 2013;(6):3828-34
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Abstract
BACKGROUND In vitro cell culture is a widely used technique for investigating a range of processes such as stem cell behavior, regenerative medicine, tissue engineering, and drug discovery. Conventional cell culture is performed in Petri dishes or flasks where cells typically attach to a flat glass or plastic surface as a cell monolayer. However, 2D cell monolayers do not provide a satisfactory representation of in vivo conditions. A 3D culture could be a much better system for representing the conditions that prevail in vivo. METHODS AND RESULTS To simulate 3D conditions, vascular smooth muscle cells (VSMCs) were loaded with gold-polyvmer-iron oxide hydrogel, enabling levitation of the cells by using spatially varying magnetic fields. These magnetically levitated 3D cultures appeared as freely suspended, clustered cells which proliferated 3-4 times faster than cells in conventional 2D cultures. When the levitated cells were treated with 10nM lysophosphatidylcholine (LPC), for 3days, cell clusters exhibited translucent extensions/rods 60-80μm wide and 200-250μm long. When 0.5μg/μl Schnurri-3 was added to the culture containing LPC, these extensions were smaller or absent. When excited with 590-650nm light, these extensions emitted intrinsic fluorescence at >667nm. When the 3D cultures were treated with a fluorescent probe specific for calcium hydroxyapatite (FITC-HABP-19), the cell extensions/rods emitted intensely at 518nm, the λmax for FITC emission. Pellets of cells treated with LPC were more enriched in calcium, phosphate, and glycosaminoglycans than cells treated with LPC and Schnurri-3. CONCLUSIONS In 3D cultures, VSMCs grow more rapidly and form larger calcification clusters than cells in 2D cultures. Transdifferentiation of VSMC into calcifying vascular cells is enhanced by LPC and attenuated by Schnurri-3. GENERAL SIGNIFICANCE The formation of calcified structures in 3D VSMC cultures suggests that similar structures may be formed in vivo.
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Blood perfusion and bone formation before and after minimally invasive periacetabular osteotomy analysed by Positron Emission Tomography combined with Computed Tomography.
Mechlenburg, I, Hermansen, F, Thillemann, T, Søballe, K
International orthopaedics. 2013;(5):789-94
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Abstract
PURPOSE Sufficient blood perfusion is essential for successful bone healing after periacetabular osteotomy (PAO). The purpose of this study was to quantify blood perfusion and bone formation before and after PAO analysed by positron emission tomography (PET) combined with computed tomography (CT). METHODS Twelve dysplastic patients (nine women) were included consecutively in the study and all were operated upon by the senior author (KS). Median age was 33 (23-55) years. Initially, two patients were PET scanned in a pilot study to test our models for calculation of the physiological parameters. The following ten patients had their hip joints PET/CT scanned immediately before PAO and three to four weeks after. Oxygen-15-water was used to quantify blood perfusion and Flourine-18-fluoride was used to produce quantitative images interpreted as new bone formation in the acetabular fragment. RESULTS The blood perfusion of the operated acetabulum before surgery was 0.07 ± 0.02 ml/min/ml, and after surgery 0.19 ± 0.03 ml/min/ml (p = 0.0003). Blood perfusion of the non-operated acetabulum was 0.07 ± 0.02 ml/min/ml before PAO and 0.07 ± 0.02 ml/min/ml after surgery (p = 0.47). The fluoride-clearance per volume bone of the operated acetabulum was 0.02 ± 0.01 ml/min/ml preoperatively, and 0.06 ± 0.01 ml/min/ml postoperatively (p = 0.0005). Fluoride-clearance of the non-operated acetabulum was 0.01 ± 0.01 ml/min/ml before PAO and 0.02 ± 0.01 ml/min/ml after PAO (p = 0.49). CONCLUSION Blood perfusion and new bone formation increased significantly in the acetabular fragment. Thus, the results of this study do not support the concern about surgically damaged vascularity after PAO.
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Differential effects of teriparatide on regional bone formation using (18)F-fluoride positron emission tomography.
Frost, ML, Siddique, M, Blake, GM, Moore, AE, Schleyer, PJ, Dunn, JT, Somer, EJ, Marsden, PK, Eastell, R, Fogelman, I
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;(5):1002-11
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Abstract
Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study (18)F-fluoride plasma clearance (K(i)) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1-hour dynamic scan of the lumbar spine and a 10-minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 µg/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine K(i) values evaluated using a three-compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine K(i) values increased by 24% (p = .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k(3)/[k(2) + k(3)]), which increased by 23% (p = .0006). In contrast to K(i) , spine SUVs increased by only 3% (p = .84). The discrepancy between changes in K(i) and SUVs was explained by a 20% decrease in (18)F(-) plasma concentration. SUVs increased by 37% at the femoral shaft (p = .0019), 20% at the total hip (p = .032), and 11% at the pelvis (p = .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by (18)F(-) PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites.
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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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Abstract
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.