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Concept: Parathyroid hormone

169

Tertiary hyperparathyroidism is a common cause of hypercalcemia after kidney transplant. We designed this 12-month, prospective, multicenter, open-label, randomized study to evaluate whether subtotal parathyroidectomy is more effective than cinacalcet for controlling hypercalcemia caused by persistent hyperparathyroidism after kidney transplant. Kidney allograft recipients with hypercalcemia and elevated intact parathyroid hormone (iPTH) concentration were eligible if they had received a transplant ≥6 months before the study and had an eGFR>30 ml/min per 1.73 m(2). The primary end point was the proportion of patients with normocalcemia at 12 months. Secondary end points were serum iPTH concentration, serum phosphate concentration, bone mineral density, vascular calcification, renal function, patient and graft survival, and economic cost. In total, 30 patients were randomized to receive cinacalcet (n=15) or subtotal parathyroidectomy (n=15). At 12 months, ten of 15 patients in the cinacalcet group and 15 of 15 patients in the parathyroidectomy group (P=0.04) achieved normocalcemia. Normalization of serum phosphate concentration occurred in almost all patients. Subtotal parathyroidectomy induced greater reduction of iPTH and associated with a significant increase in femoral neck bone mineral density; vascular calcification remained unchanged in both groups. The most frequent adverse events were digestive intolerance in the cinacalcet group and hypocalcemia in the parathyroidectomy group. Surgery would be more cost effective than cinacalcet if cinacalcet duration reached 14 months. All patients were alive with a functioning graft at the end of follow-up. In conclusion, subtotal parathyroidectomy was superior to cinacalcet in controlling hypercalcemia in these patients with kidney transplants and persistent hyperparathyroidism.

Concepts: Chronic kidney disease, Kidney, Nephrology, Vitamin D, Parathyroid hormone, Organ transplant, Hypoparathyroidism, Hyperparathyroidism

167

OBJECTIVE: The 1-34 amino acid segment of the parathyroid hormone (PTH [1-34]) mediates anabolic effects in chondrocytes and osteocytes. The aim of this study was to investigate whether systemic application of PTH [1-34] improves the repair of non-osteoarthritic, focal osteochondral defects in vivo. DESIGN: Standardized cylindrical osteochondral defects were bilaterally created in the femoral trochlea of rabbits (n = 8). Daily subcutaneous injections of 10 μg PTH [1-34]/kg were given to the treatment group (n = 4) for 6 weeks, controls (n = 4) received saline. Articular cartilage repair was evaluated by macroscopic, biochemical, histological and immunohistochemical analyses. Reconstitution of the subchondral bone was assessed by micro-computed tomography. Effects of PTH [1-34] on synovial membrane, apoptosis, and expression of the PTH receptor (PTH1R) were determined. RESULTS: Systemic PTH [1-34] increased PTH1R expression on both, chondrocytes and osteocytes within the repair tissue. PTH [1-34] ameliorated the macro- and microscopic aspect of the cartilaginous repair tissue. It also enhanced the thickness of the subchondral bone plate and the microarchitecture of the subarticular spongiosa within the defects. No significant correlations were established between these coexistent processes. Apoptotic levels, synovial membrane, biochemical composition of the repair tissue, and type-I/II collagen immunoreactivity remained unaffected. CONCLUSIONS: PTH [1-34] emerges as a promising agent in the treatment of focal osteochondral defects as its systemic administration simultaneously stimulates articular cartilage and subchondral bone repair. Importantly, both time-dependent mechanisms of repair did not correlate significantly at this early time point and need to be followed over prolonged observation periods.

Concepts: Bone, Calcitonin, Collagen, Extracellular matrix, Parathyroid hormone, Cartilage, Autologous chondrocyte implantation, Articular cartilage repair

167

BACKGROUND: Until now the exact biochemical processes during healing of metaphyseal fractures of healthy and osteoporotic bone remain unclear. Especially the physiological time courses of 25(OH)D3 (Vitamin D) as well as PTH (Parathyroid Hormone) the most important modulators of calcium and bone homeostasis are not yet examined sufficiently. The purpose of this study was to focus on the time course of these parameters during fracture healing. METHODS: In the presented study, we analyse the time course of 25(OH)D3 and PTH during fracture healing of low BMD level fractures versus normal BMD level fractures in a matched pair analysis. Between March 2007 and February 2009 30 patients older than 50 years of age who had suffered a metaphyseal fracture of the proximal humerus, the distal radius or the proximal femur were included in our study. Osteoporosis was verified by DEXA measuring. The time courses of 25(OH)D3 and PTH were examined over an eight week period. Friedmann test, the Wilcoxon signed rank test and the Mann-Withney U test were used as post-hoc tests. A p-value <= 0.05 was considered significant. RESULTS: Serum levels of 25(OH)D3 showed no differences in both groups. In the first phase of fracture healing PTH levels in the low BMD level group remained below those of the normal BMD group in absolute figures. Over all no significant differences between low BMD level bone and normal BMD level bone could be detected in our study. CONCLUSIONS: The time course of 25(OH)D3 and PTH during fracture healing of patients with normal and low bone mineral density were examined for the first time in humans in this setting and allowing molecular biological insights into fracture healing in metaphyseal bones on a molecural level. There were no significant differences between patients with normal and low BMD levels. Hence further studies will be necessary to obtain more detailed insight into fracture healing in order to provide reliable decision criteria for therapy and the monitoring of fracture healing.

Concepts: Osteoporosis, Bone, Vitamin D, Calcitonin, Bone fracture, Parathyroid hormone, Calcium, Hyperparathyroidism

166

The survival rate of dialysis patients, as determined by risk factors such as hypertension, nutritional status, and chronic inflammation, is lower than that of the general population. In addition, disorders of bone mineral metabolism are independently related to mortality and morbidity associated with cardiovascular disease and fracture in dialysis patients. Hyperphosphatemia is an important risk factor of, not only secondary hyperparathyroidism, but also cardiovascular disease. On the other hand, the risk of death reportedly increases with an increase in adjusted serum calcium level, while calcium levels below the recommended target are not associated with a worsened outcome. Thus, the significance of target levels of serum calcium in dialysis patients is debatable. The consensus on determining optimal parathyroid function in dialysis patients, however, is yet to be established. Therefore, the contribution of phosphorus and calcium levels to prognosis is perhaps more significant. Elevated fibroblast growth factor 23 levels have also been shown to be associated with cardiovascular events and death. In this review, we examine the associations between mineral metabolic abnormalities including serum phosphorus, calcium, and parathyroid hormone and mortality in dialysis patients.

Concepts: Bone, Epidemiology, Metabolism, Demography, Parathyroid hormone, Calcium metabolism, Parathyroid gland, Hyperparathyroidism

165

Chronic renal failure (CRF) is associated with the development of secondary hyperparathyroidism and vascular calcifications. We evaluated the efficacy of PA21, a new iron-based non-calcium phosphate binder, in controlling phosphocalcic disorders and preventing vascular calcifications in uremic rats. Rats with adenine-diet-induced CRF were randomized to receive either PA21 0.5%, 1.5% or 5% or calcium carbonate (CaCO3) 3% in the diet, for 4 weeks and were compared with uremic and non-uremic control groups. After 4 weeks' phosphate binder treatment, serum calcium, creatinine and body weight were similar between all CRF groups. Serum phosphorus was reduced with CaCO3 3% (2.06 mmol/l, P≤0.001), PA21 1.5% (2.29 mmol/l, P<0.05) and PA21 5% (2.21 mmol/l, P≤0.001) versus CRF controls (2.91 mmol/l). Intact parathyroid hormone was strongly reduced in the PA21 5% and CaCO3 3% CRF groups to a similar extent (1138 and 1299 pg/ml, respectively) versus CRF controls (3261 pg/ml, both P≤0.001). A lower serum fibroblast growth factor 23 concentration was observed in the PA21 5%, compared with CaCO3 3% and CRF, control groups. PA21 5% CRF rats had a lower vascular calcification score compared with CaCO3 3% CRF rats and CRF controls. In conclusion, PA21 was as effective as CaCO3 at controlling phosphocalcic disorders but superior in preventing the development of vascular calcifications in uremic rats. Thus, PA21 represents a possible alternative to calcium-based phosphate binders in CRF patients.

Concepts: Renal failure, Nephrology, Carbon dioxide, Parathyroid hormone, Calcium carbonate, Hyperparathyroidism, Organ failure, Phosphate binders

149

A 68-year-old man was hospitalized and examined for renal impairment. A laboratory analysis showed hypercalcemia. Although the serum parathyroid hormone and serum 1-25(OH)2 vitamin D3 levels were not elevated, the serum parathyroid hormone-related peptide (PTHrP) level was increased. Immunoelectrophoresis of the urine and bone marrow aspiration indicated multiple myeloma (MM). He was diagnosed with the coexistence of cast nephropathy and light chain deposition disease by a renal biopsy. Notably, PTHrP expression was detected in the myeloma cells based on immunohistochemistry and in situ hybridization. It is therefore important to examine the PTHrP concentration in MM patients with hypercalcemia.

Concepts: Multiple myeloma, Kidney, Bone, Vitamin D, Cancer, Bone marrow, Parathyroid hormone, Parathyroid hormone-related protein

148

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long-acting PTH analog, [Ala(1,3,12,18,22) , Gln(10) ,Arg(11) ,Trp(14) ,Lys(26) ]-PTH(1-14)/PTHrP(15-36) (LA-PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intra-venous administration of LA-PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near-normal levels for longer than 48 hours, while PTH(1-34) and PTH(1-84), each injected at a dose 80-fold higher than that used for LA-PTH, increased sCa and decreased sPi only modestly and transiently (< 6 hours). LA-PTH also exhibited enhanced and prolonged efficacy versus PTH(1-34) and PTH(1-84) for elevating sCa when administered subcutaneously (SC) into monkeys. Daily SC administration of LA-PTH (1.8 nmol/kg) into TPTX rats for 28-days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long-acting PTH analogs as potential therapies for patients with hypoparathyroidism. This article is protected by copyright. All rights reserved.

Concepts: Bone, Parathyroid hormone, Bone resorption, Calcium metabolism, Parathyroid gland, Hypoparathyroidism, Hyperparathyroidism, Copyright

51

A tight control of magnesium homeostasis seems to be crucial for bone health. On the basis of experimental and epidemiological studies, both low and high magnesium have harmful effects on the bones. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting on the secretion and the activity of parathyroid hormone and by promoting low grade inflammation. Less is known about the mechanisms responsible for the mineralization defects observed when magnesium is elevated. Overall, controlling and maintaining magnesium homeostasis represents a helpful intervention to maintain bone integrity.

Concepts: Bone, Vitamin D, Calcitonin, Parathyroid hormone, Osteoclast, Calcium, Glucocorticoid, Knowledge

29

The aim of this study was to assess the relationship between obesity and vitamin D status cross-sectionally, the relationship between obesity and the incidence of hypovitaminosis D prospectively and inversely the relationship between vitamin D status and incidence of obesity in a population-based cohort study in Spain. At baseline (1996-1998), 1226 subjects were evaluated and follow-up assessments were performed in 2002-2004 and 2005-2007, participants undergoing an interview and clinical examination with an oral glucose tolerance test. At the second visit, 25-hydroxyvitamin D and intact parathyroid hormone concentrations were also measured. Prevalence of obesity at the three visits was 28.1, 36.2 and 39.5%, respectively. The prevalence of vitamin D deficiency (25-hydroxyvitamin D 20 ng/ml (50 nmol/l)) was 34.7%. Neither obesity at baseline (OR=0.98, 95% CI: 0.69-1.40, P=0.93) nor the development of obesity between baseline and the second evaluation (OR=0.80, 95% CI: 0.48-1.33, P=0.39) were significantly associated with vitamin D status. In subjects who were non-obese (BMI <30 kg/m(2)) at the second evaluation, 25-hydroxyvitamin D values 17 ng/ml (42.5 nmol/l) were significantly associated with an increased risk of developing obesity in the next 4 years (OR=2.35, 95% CI: 1.03-5.4, P=0.040 after diverse adjustments). We conclude that vitamin D deficiency is associated with an increased risk of developing obesity.European Journal of Clinical Nutrition advance online publication, 20 February 2013; doi:10.1038/ejcn.2013.48.

Concepts: Vitamin D, Nutrition, Diabetes mellitus, Glucose tolerance test, Parathyroid hormone, Vitamin, Vitamins, Hypovitaminosis D

28

Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.

Concepts: Bone, Calcitonin, Signal transduction, Skeletal system, Parathyroid hormone, Bone resorption, Osteoclast, Enzyme inhibitor