Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration.

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

Higher mineralized bone volume is associated with a lower plain X-Ray vascular calcification score in hemodialysis patients.

BACKGROUND AND OBJECTIVES: In dialysis patients, there is an increasing evidence that altered bone metabolism is associated with cardiovascular calcifications. The main objective of this study was to analyse, in hemodialysis patients, the relationships between bone turnover, mineralization and volume, evaluated in bone biopsies, with a plain X-ray vascular calcification score. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In a cross-sectional study, bone biopsies and evaluation of vascular calcifications were performed in fifty hemodialysis patients. Cancellous bone volume, mineralized bone volume, osteoid volume, activation frequency, bone formation rate/bone surface, osteoid thickness and mineralization lag time were determined by histomorphometry. Vascular calcifications were assessed by the simple vascular calcification score (SVCS) in plain X-Ray of pelvis and hands and, for comparison, by the Agatston score in Multi-Slice Computed Tomography (MSCT). RESULTS: SVCS≥3 was present in 20 patients (40%). Low and high bone turnover were present in 54% and 38% of patients, respectively. Low bone volume was present in 20% of patients. In multivariable analysis, higher age (p = 0.015) and longer hemodialysis duration (p = 0.017) were associated with SVCS≥3. Contrary to cancellous bone volume, the addition to this model of mineralized bone volume (OR = 0.863; 95%CI: 0.766, 0.971; p = 0.015), improved the performance of the model. For each increase of 1% in mineralized bone volume there was a 13.7% decrease in the odds of having SVCS≥3 (p = 0.015). An Agatston score>400 was observed in 80% of the patients with a SVCS≥3 versus 4% of patients with a SVCS<3, (p<0.001). CONCLUSION: Higher mineralized bone volume was associated with a lower plain X-ray vascular calcification. This study corroborates the hypothesis of the existence of a link between bone and vessel and reinforces the clinical utility of this simple and inexpensive vascular calcification score in dialysis patients.

Adynamic bone disease: clinical and therapeutic implications.

PURPOSE OF REVIEW: Adynamic bone disease has recently been associated with increased risk of vascular calcification. This review focuses on the emerging data in adynamic bone disease, its clinical consequences and therapeutic implications. RECENT FINDINGS: There is a lack of good biochemical markers of parathyroid status, bone formation and reabsorption to allow a secure diagnosis of bone disease. Recent data have suggested a possible link between bone activity and vascular calcification. Cardiovascular calcification is an independent predictor of mortality. Adynamic bone is associated with a very low capacity of bone to incorporate calcium in the bone compartment and inability to handle an extra calcium load. A positive association between vascular calcifications and low bone turnover has been suggested. Calcium-containing phosphate binders, active vitamin D therapy and high calcium dialysate may enhance vascular calcifications in the presence of adynamic bone disease. SUMMARY: There is recent evidence suggesting a negative impact of calcium load in the progression of vascular calcification in dialysis patients with chronic kidney disease stage 5 with adynamic bone disease. The current therapeutic approach to these patients should focus on reduction of calcium and vitamin D load to restore parathyroid activity.

Low bone volume--a risk factor for coronary calcifications in hemodialysis patients.

BACKGROUND AND OBJECTIVES: There is increasing evidence that altered bone metabolism is associated with cardiovascular calcifications in patients with stage 5 chronic kidney disease on hemodialysis (HD). This study was conducted to evaluate the association between bone volume, turnover, and coronary calcifications in HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study, bone biopsies and multislice computed tomography were performed in 38 HD patients. Bone volume/total volume, activation frequency, and bone formation rate/bone surface were determined by histomorphometry and coronary calcifications were quantified by Agatston scores. RESULTS: Prevalence of low bone turnover was 50% and of low bone volume was 16%. Among the studied traditional cardiovascular risk factors, only age was found to be associated with coronary calcifications. Lower bone volume was a significant risk factor for coronary calcifications during early years of HD, whereas this effect was not observed in patients with dialysis duration >6 yr. Histomorphometric parameters of bone turnover were not associated with coronary calcifications. CONCLUSIONS: Low bone volume is associated with increased coronary calcifications in patients on HD.

Cardiovascular risk in dialysis patients: an X-ray vision on vascular calcifications.

In dialysis patients, there is an association between vascular calcifications and mortality. Hyperphosphatemia and calcium overload are associated with development of vascular calcifications, especially in the presence of low bone turnover. Different plain X-ray methods are now available to evaluate vascular calcifications in dialysis patients. The presence of vascular calcifications is an alert sign for increased cardiovascular risk, and this information is important for choosing the most suitable treatment for dialysis patients.

Treatment of hyperphosphatemia with sevelamer hydrochloride in dialysis patients: effects on vascular calcification, bone and a close look into the survival data.

In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Vascular calcifications have been associated with low bone turnover, low bone volume and lower activation frequency. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact parathyroid hormone and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. A randomized, prospective, open label study, evaluated patients with bone biopsies at the beginning and after 1 year treatment period with sevelamer hydrochloride or calcium carbonate. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years.In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a non-calcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations.

Evaluation of parathyroid gland angiogenesis in chronic kidney disease associated with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. Increased parathyroid hormone (PTH) synthesis and secretion is associated with parathyroid cell hyperplasia. The exact mechanisms involved in parathyroid gland (PTG) hyperplasia are still poorly understood. There is no available data on angiogenesis in PTG of patients with chronic kidney disease and SHPT. The aim of this study is to evaluate angiogenesis and expression of the angiogenic factors, basic fibroblastic growth factor (b-FGF) and vascular endothelial growth factor A (VEGF), in secondary PTG hyperplasia. METHODS: This study was performed on formalin-fixed paraffin-embedded archival tissues of 21 SHPT glands from haemodialysis (n = 19) and kidney transplanted (n = 2) patients submitted to surgical parathyroidectomy. For control, eight normal human parathyroid glands (NPG) encountered in surgical specimens of total thyroidectomy were used. We evaluated the immunohistochemical expression of the proliferation cell marker Ki67. Angiogenesis was evaluated by immunohistochemistry staining with anti-endoglin (CD105) antibody in 21 SPH and 5 NPG by stereological analysis. Levels of b-FGF and VEGF were determined by semi-quantitative analysis in 21 SPH and 8 NPG. RESULTS: The SHPT patients present a mean iPTH of 1314 +/- 750 pg/ml, a corrected serum calcium of 10.3 +/- 1.2 mg/dl and a serum phosphorus of 6.1 +/- 1.4 mg/dl. SHPT glands displayed a significantly higher immunoreactivity against Ki67, compared to NPG. With CD105, a significantly higher number and volume of microvessels were observed in SHPT compared to NPG. Both VEGF and b-FGF expression were increased in SHPT compared to NPG. Using the predefined subdivision into negative and positive only the b-FGF expression was significantly increased in the SHPT glands compared to NPG. CONCLUSION: These results suggest that PTGs in this group of patients with SHPT have a significantly higher number of vessels expressing CD105, which has been reported to preferentially label activated endothelial cells associated with angiogenesis. SHPT glands have a significantly increased expression of b-FGF compared to NPG. VEGF-A expression is also increased in the examined SHPT glands but could be less relevant for angiogenesis.

Calcimimetic agents: review and perspectives.

BACKGROUND: Recognition of the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and, ultimately, bone turnover. METHODS: The cloning of the CaR and the discovery of mutations that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary disorders characterized by either hyperparathyroidism or hypoparathyroidism. The CaR, able to amplify the sensitivity of the CaR to Ca++ and suppress PTH levels with a resulting decrease in blood Ca++, became an ideal target for the development of compounds, the calcimimetics. Experience with the calcimimetic R-568 in patients with primary and secondary hyperparathyroidism and parathyroid carcinoma are summarized. RESULTS: The first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic, AMG 073, having a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, suppressing PTH levels while simultaneously reducing serum phosphorus levels and the calcium x phosphorus product. CONCLUSION: The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium x phosphorus product is very promising.

The calcimimetic agents: perspectives for treatment.

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca++), and control of urinary calcium excretion with small changes in blood Ca++. The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca++ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca++, can suppress PTH levels with a resultant fall in blood Ca++. Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca++, with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively short-term except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further long-term controlled studies are underway to further confirm the effectiveness and safety of these compounds.