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Geert J Behets

Publications and source records attributed to Geert J Behets.

9 recordsLinked to original sources
PubMed2006

Development and reversibility of impaired mineralization associated with lanthanum carbonate treatment in chronic renal failure rats.

BACKGROUND: We have previously shown that administration of the new phosphate binder lanthanum (La) carbonate at high doses during 12 weeks induces a mineralization defect (MD) in chronic renal failure (CRF) rats most likely due to the powerful phosphate binding. In this study, we want to investigate the fate and possible biological activities of La once it is accumulated in bone. METHODS: CRF animals (5/6th nephrectomy) received La carbonate (2,000 mg/kg/day) via oral gavage for 2 or 6 weeks and were sacrificed immediately at the end of the treatment period and after a wash out period of 2 and 8 weeks. Bone histomorphometry and measurement of bone La content were performed. Control CRF animals received vehicle only. RESULTS: After 2 weeks of La treatment, 75% of the animals showed signs of MD compared to 14% in CRF controls despite similar bone La levels. Two weeks after arrest of La treatment, bone La levels remained unchanged, yet 87% showed normal bone histology. A similar evolution was noted in the animals treated for 6 weeks. Bone histology showed a reduction of number of animals with a MD from 62.5% at 6 weeks of La treatment to 20% and 28% 2 and 8 weeks after arrest of La treatment respectively. CONCLUSION: The phosphate-binder-induced MD may appear and disappear without any change in either the perimeter of active osteoblasts or in bone La levels. Bone histology in CRF animals normalized after arrest of the La administration, thereby presenting further arguments for the MD in La-treated animals to result from the high phosphate binding capacity of La rather than being the consequence of a direct effect of La on bone.

Animals↗
PubMed2005

Time-evolution and reversibility of strontium-induced osteomalacia in chronic renal failure rats.

BACKGROUND: Patients with impaired renal function can accumulate strontium in the bone, which has been associated with the development of osteomalacia. A causal role for strontium in the development of the disease was presented in chronic renal failure (CRF) rats. Strontium-ranelate has been put forward as a therapeutic agent in the treatment of osteoporosis. Since the target population for strontium treatment consists mainly in postmenopausal osteoporotic women, who may have a reduced renal function, the risk for osteomalacia should be considered. METHODS: To determine the time evolution and reversibility of the strontium-induced mineralization defect, CRF rats were loaded with strontium (2 g/L) (+/- 200 mg/kg/day) during 2, 6, and 12 weeks, followed by a washout period of 0, 2, 4, or 8 weeks. RESULTS: Histologic examination of the bone of the animals treated with strontium revealed signs of osteomalacia already after 2 weeks. Animals that received strontium during 6 and 12 weeks had a significantly higher osteoid perimeter, area and thickness as compared to CRF controls. After 12 weeks, the mineralization was significantly affected, as evidenced by a lower double-labeled surface, mineral apposition and bone formation rate in combination with an increased osteoid maturation time and mineralization lag time. The osteoblast perimeter was significantly lower in the strontium-treated animals. After the washout periods, these effects were reversed and the bone lesions evolved to the values of CRF controls. This went along with an 18% reduction of the bone strontium content. A significant rise in serum alkaline phosphatase (ALP) activity was apparent in the strontium-treated animals as compared to CRF controls. This was not only due to higher levels of the bone ALP but also to those of the liver and the intestinal isoenzymes. Serum parathyroid hormone (PTH) levels decreased during strontium treatment. After cessation of the treatment, the serum ALP activity and PTH concentration reversed to control levels. CONCLUSION: In this study evidence is provided for the rapid development of a mineralization defect in strontium-loaded CRF rats, accompanied by a reduced osteoblast number, reduced PTH synthesis or secretion, and increased serum ALP levels. These effects can be rapidly reversed after withdrawal of the compound.

Alkaline Phosphatase↗
PubMed2005

Localization of lanthanum in bone of chronic renal failure rats after oral dosing with lanthanum carbonate.

BACKGROUND: Lanthanum carbonate has been shown to be a safe, effective phosphate-binding agent. We have shown that an impaired mineralization in chronic renal failure rats treated with high doses of lanthanum carbonate develops secondary to phosphate depletion and is therefore pharmacologically mediated rather than a direct effect of lanthanum on bone. Although bulk bone lanthanum concentrations are low, it is important to consider the localization within a given tissue. METHODS: Using the scanning x-ray micro-fluorescence set-up at beamline ID21 of the European Synchrotron Radiation Facility, calcium and lanthanum distributions in bone samples were mapped. RESULTS: In chronic renal failure rats loaded orally with lanthanum carbonate (12 weeks) (2000 mg/kg/day), bulk bone lanthanum concentrations reached values up to 5 microg/g wet weight. Lanthanum could be demonstrated at the edge of the mineralized bone, at both actively mineralizing and quiescent sites, independent of the type of bone turnover. In the presence of hyperparathyroid bone disease, lanthanum was also distributed throughout the mineralized trabecular bone. No correlation with the presence of osteoid, or the underlying bone pathology could be demonstrated. After a 2- or 4-week washout period before sacrifice, lanthanum localization did not change significantly. CONCLUSION: The comparable localization of lanthanum in different types of bone turnover, and the unchanged localization after washout and consequent disappearance of the mineralization defect, indicates no relationship between the localization of lanthanum in bone and the presence of a mineralization defect.

Administration, Oral↗
PubMed2005

Effects of efficient phosphate binding on bone in chronic renal failure rats.

BACKGROUND: We recently reported that administration of high doses of lanthanum carbonate (1000 mg/kg/day) to chronic renal failure (CRF) rats can result in a mineralization defect. Our results suggested, however, that the impaired mineralization was not due to a direct toxic action of lanthanum on the bone, but rather was an indirect consequence of a phosphate depletion resulting from the compound's high phosphate-binding capacity. To further substantiate these results, in the present study, the effects of lanthanum carbonate on bone were compared to the effects of sevelamer, a nonabsorbed, non-metal-containing polymeric phosphate-binding agent. METHODS: Male Wistar rats underwent a 5/6th nephrectomy to induce chronic renal failure, after which they were treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) by oral gavage for 12 weeks. RESULTS: CRF animals treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) developed a phosphate depletion after 4 weeks of treatment, as evidenced by a marked reduction in phosphaturia. At sacrifice after 12 weeks of treatment, bone histomorphometry showed that a mineralization defect had developed in two out of six animals in the lanthanum-carbonate-treated group, in four out of seven animals in the 1000 mg/kg/ day sevelamer group, and in one out of nine animals in the 500 mg/kg/day sevelamer group. CONCLUSIONS: These results corroborate our previous findings that the administration of a powerful phosphate-binding agent to CRF rats can induce phosphate depletion, resulting in a mineralization defect.

Animals↗
PubMed2004

Does the phosphate binder lanthanum carbonate affect bone in rats with chronic renal failure?

Adequate control of phosphate levels remains an important issue in patients with chronic renal failure (CRF). Lanthanum carbonate has been proposed as a new phosphate binder. Previous studies have shown a high phosphate binding capacity (>97%) and low gastrointestinal absorption of lanthanum, without serious toxic side effects in the presence of a normal renal function (NRF). Because of lanthanum's physicochemical resemblance to calcium, the possible effects of it on bone have to be considered. The aim of this study was to investigate the effects of lanthanum carbonate on bone histology in NRF and CRF rats after oral administration of the compound with doses of 100, 500, or 1000 mg/kg per d for 12 wk. Bone histomorphometry showed that CRF animals that received vehicle developed secondary hyperparathyroidism. Urinalysis of lanthanum-loaded CRF animals showed a dose-dependent decrease in urinary phosphorus excretion, which was clearly more pronounced in the CRF groups compared with NRF animals. Phosphatemia, however, remained normal. Lanthanum carbonate administration induced a dose-dependent decrease in bone formation rate and increase in osteoid area in CRF animals. Three of seven animals in the CRF-1000 group and one of eight animals in the NRF-100 group were classified as having a mineralization defect. The number of cuboidal osteoblasts, however, was not affected, indicating that bone changes were not due to a toxic effect of lanthanum on the osteoblast. Furthermore, lanthanum concentrations in the femur remained low and did not correlate with histomorphometric parameters. These findings suggest that the administration of high doses of phosphate binder (1000 mg/kg per d lanthanum carbonate), in combination with decreased 25-(OH) vitamin D(3) in the uremic state, resulted in phosphate depletion and followed by an increased mobilization of phosphorus out of bone and/or reduced incorporation into bone. There was no evidence that lanthanum had a direct toxic effect on osteoblasts.

Alkaline Phosphatase↗
PubMed2004

Lanthanum carbonate: a new phosphate binder.

PURPOSE OF REVIEW: Hyperphosphatemia remains an important aspect in the management of end-stage renal disease patients. Consequently, there is a need for new, efficient and well-tolerated phosphate binders. In this review, a new phosphate-binding drug, lanthanum carbonate, with an attractive preclinical efficacy profile compared with existing binders, is discussed. Although the available human efficacy and safety data over 3 years are encouraging, the consequences of low-level tissue deposition continue to be evaluated in longer-term clinical studies. RECENT FINDINGS: Lanthanum carbonate has been shown in clinical studies of up to 3 years to be an effective, well-tolerated phosphate binder. Reported adverse effects are mainly gastrointestinal, and do not differ from those of calcium carbonate. The gastrointestinal absorption of lanthanum is very low. Whereas the element is mainly excreted by the liver, renal excretion of the absorbed fraction is less than 2%. Bone lanthanum levels seen after long-term treatment (up to 4 years) seem not to affect the physicochemical process of mineralization, or osteoblast number/function. Preliminary data on the localization of lanthanum in bone have shown the element to be present at both active and quiescent sites of bone mineralization, independent of the type of renal osteodystrophy, a profile distinct from aluminum, as well as diffusely distributed throughout the mineralized bone matrix especially in rats/humans with an increased bone turnover. A randomized, comparator-controlled, parallel group, open-label study comparing lanthanum carbonate with calcium carbonate in dialysis patients showed no evolution towards low bone turnover in the lanthanum group, and no aluminum-like effect on bone. SUMMARY: Lanthanum carbonate seems to be a potent phosphate-binding drug, minimally absorbed from the gut, with an encouraging safety profile, and no deleterious effects on bone.

Bone and Bones↗
PubMed2003

Useful biochemical markers for diagnosing renal osteodystrophy in predialysis end-stage renal failure patients.

BACKGROUND: Various biochemical markers have been evaluated in dialysis patients for the diagnosis of renal osteodystrophy (ROD). However, their value in predialysis patients with end-stage renal failure (ESRF) is not yet clear. METHODS: Bone histomorphometric evaluation was performed and biochemical markers of bone turnover were determined in serum of an unselected predialysis ESRF population (N = 84). RESULTS: Significant (P < 0.005) differences between the five groups with ROD (ie, normal bone [N = 32], adynamic bone [ABD; N = 19], hyperparathyroidism [N = 8], osteomalacia [OM; N = 10], and mixed lesion [N = 15]) were noted for intact parathyroid hormone, total (TAP) and bone alkaline phosphatase (BAP), osteocalcin (OC), and serum calcium levels. Serum creatinine and (deoxy)pyridinoline levels did not differ between groups. For the diagnosis of ABD, an OC level of 41 microg/L or less (< or =7.0 nmol/L) had a sensitivity of 83% and specificity of 67%. The positive predictive value (PPV) for the population under study was 47%. The combination of an OC level of 41 ng/L or less (< or =7.0 nmol/L) with a BAP level of 23 U/L or less increased the sensitivity, specificity, and PPV to 72%, 89%, and 77%, respectively. ABD and normal bone taken as one group could be detected best by a BAP level of 25 U/L or less and TAP level of 84 U/L or less, showing sensitivities of 72% and 88% and specificities of 76% and 60%, corresponding with PPVs of 89% and 85%, respectively. In the absence of aluminum or strontium exposure, serum calcium level was found to be a useful index for the diagnosis of OM. CONCLUSION: OC, TAP, BAP, and serum calcium levels are useful in the diagnosis of ABD, normal bone, and OM in predialysis patients with ESRF.

Adult↗
PubMedDate not supplied

Lanthanum: a safe phosphate binder.

Accumulation of inorganic phosphate due to renal functional impairment contributes to the increased cardiovascular mortality observed in dialysis patients. Phosphate plays a causative role in the development of vascular calcification in renal failure; treatment with calcium-based phosphate binders and vitamin D can further increase the Ca x PO(4) product and add to the risk of ectopic mineralization. The new generation of calcium-free phosphate binders, sevelamer and lanthanum, can control hyperphosphatemia without adding to the patients calcium load. In this article, the metabolism of lanthanum carbonate and its effects in bone, liver and brain are discussed. Although lanthanum is a metal cation its effects are not comparable to those of aluminum. Indeed, in clinical studies no toxic effects of lanthanum have been reported after up to four years of follow-up. The bioavailability of lanthanum is extremely low. The effects observed in bone are due to phosphate depletion, with no signs of direct bone toxicity yet observed in rats or humans. The liver is the main route of excretion for lanthanum carbonate, which can be localized in the lysosomes of hepatocytes. No lanthanum could be detected in brain tissue.

Animals↗