Management of hyperphosphatemia in patients with end-stage renal disease: focus on lanthanum carbonate

Elevated serum phosphate levels as a consequence of chronic kidney disease (CKD) contribute to the increased cardiovascular risk observed in dialysis patients. Protein restriction and dialysis fail to adequately prevent hyperphosphatemia, and in general treatment with oral phosphate binding agents is necessary in patients with advanced CKD. Phosphate plays a pivotal role in the development of vascular calcification, one of the factors contributing to increased cardiovascular risk in CKD patients. Treatment of hyperphosphatemia with standard calcium-based phosphate binders and vitamin D compounds can induce hypercalcemic episodes, increase the Ca × PO4 product and thus add to the risk of ectopic mineralization. In this review, recent clinical as well as experimental data on lanthanum carbonate, a novel, non-calcium, non-resin phosphate binding agent are summarized. Although lanthanum is a metal cation no aluminium-like toxicity is observed since the bioavailability of lanthanum is extremely low and its metabolism differs from that of aluminium. Clinical studies now document the absence of toxic effects of lanthanum for up to 6 years of follow-up. The effects of lanthanum on bone, vasculature and brain are discussed and put in perspective with lanthanum pharmacokinetics

The Wellesley News (04-20-1933)

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Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG <sub>2</sub> ) <sub>2</sub> -IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG <sub>2</sub> ) <sub>2</sub> -IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG <sub>2</sub> ) <sub>2</sub> -IP4 disrupts the nucleation and growth of pathological calcification

Androgens inhibit the osteogenic response to mechanical loading in adult male mice

Androgens are well known to enhance exercise-induced muscle hypertrophy, however whether androgens also influence bone's adapative response to mechanical loading remains unclear. We studied the adaptive osteogenic response to unilateral in vivo mechanical loading of tibia in adult male mice in both a long and a short term experimental set-up. Mice were divided in 4 groups: sham-operated, orchidectomized (ORX), testosterone (ORX+T) or non-aromatizable dihydrotestosterone (ORX+DHT) replacement. Significant interactions between androgen status and osteogenic response to mechanical loading were observed. Cortical thickness increased by T (0.14 vs. 0.11 mm sham, p<0.05) and DHT (0.17 vs. 0.11 mm sham, p<0.05). However, T partially (+36%) and DHT completely (+10%) failed to exhibit the loading-related increase observed in sham (+107%) and ORX (+131%, all p<0.05) mice. ORX decreased periosteal bone formation (PsBFR), which was restored to sham levels by T and DHT. However, both androgens completely suppressed the loading-related increase in PsBFR. Short term loading decreased the number of sclerostin positive osteocytes in sham, whereas in control fibulas, ORX decreased and T increased the number of sclerostin positive osteocytes. Loading no longer downregulated sclerostin in ORX or T groups. In conclusion, both T and DHT suppress the osteogenic response to mechanical loading.status: publishe

A distinct bone phenotype in ADPKD patients with end-stage renal disease.

Autosomal dominant polycystic kidney disease (ADPKD) is among the most common hereditary nephropathies. Low bone turnover osteopenia has been reported in mice with conditional deletion of the PKD1 and PKD2 genes in osteoblasts, and preliminary clinical data also suggest suppressed bone turnover in patients with ADPKD. The present study compared the bone phenotype between patients with end stage renal disease (ESRD) due to ADPKD and controls with ESRD due to other causes. Laboratory parameters of bone mineral metabolism (fibroblast growth factor 23 and sclerostin), bone turnover markers (bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b) and bone mineral density (BMD, by dual energy x-ray absorptiometry, DXA) were assessed in 518 patients with ESRD, including 99 with ADPKD. Bone histomorphometry data were available in 71 patients, including 10 with ADPKD. Circulating levels of bone alkaline phosphatase were significantly lower in patients with ADPKD (17.4 vs 22.6 ng/mL), as were histomorphometric parameters of bone formation. Associations between ADPKD and parameters of bone formation persisted after adjustment for classical determinants including parathyroid hormone, age, and sex. BMD was higher in skeletal sites rich in cortical bone in patients with ADPKD compared to non-ADPKD patients (Z-score midshaft radius -0.04 vs -0.14; femoral neck -0.72 vs -1.02). Circulating sclerostin levels were significantly higher in ADPKD patients (2.20 vs 1.84 ng/L). In conclusion, patients with ESRD due to ADPKD present a distinct bone and mineral phenotype, characterized by suppressed bone turnover, better preserved cortical BMD, and high sclerostin levels