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Long-term treatment with lanthanum carbonate reduces mineral and bone abnormalities in rats with chronic renal failure.

Damment S, Secker R, Shen V, Lorenzo V, Rodriguez M - Nephrol. Dial. Transplant. (2010)

Bottom Line: Lanthanum carbonate (FOSRENOL(®), Shire Pharmaceuticals) is an effective non-calcium, non-resin phosphate binder for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD).Hyperphosphataemia, hypocalcaemia, elevated calcium × phosphorus product and secondary hyperparathyroidism were evident in CRF + vehicle animals.Treatment with lanthanum carbonate reduced hyperphosphataemia and secondary hyperparathyroidism in CRF animals (P < 0.05), and had little effect in NRF animals.

View Article: PubMed Central - PubMed

Affiliation: Shire Pharmaceuticals, Basingstoke, UK. sdamment@shire.com

ABSTRACT

Background: Lanthanum carbonate (FOSRENOL(®), Shire Pharmaceuticals) is an effective non-calcium, non-resin phosphate binder for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). In this study, we used a rat model of chronic renal failure (CRF) to examine the long-term effects of controlling serum phosphorus with lanthanum carbonate treatment on the biochemical and bone abnormalities associated with CKD-mineral and bone disorder (CKD-MBD).

Methods: Rats were fed a normal diet (normal renal function, NRF), or a diet containing 0.75% adenine for 3 weeks to induce CRF. NRF rats continued to receive normal diet plus vehicle or normal diet supplemented with 2% (w/w) lanthanum carbonate for 22 weeks. CRF rats received a diet containing 0.1% adenine, with or without 2% (w/w) lanthanum carbonate. Blood and urine biochemistry were assessed, and bone histomorphometry was performed at study completion.

Results: Treatment with 0.75% adenine induced severe CRF, as demonstrated by elevated serum creatinine. Hyperphosphataemia, hypocalcaemia, elevated calcium × phosphorus product and secondary hyperparathyroidism were evident in CRF + vehicle animals. Treatment with lanthanum carbonate reduced hyperphosphataemia and secondary hyperparathyroidism in CRF animals (P < 0.05), and had little effect in NRF animals. Bone histomorphometry revealed a severe form of bone disease with fibrosis in CRF + vehicle animals; lanthanum carbonate treatment reduced the severity of the bone abnormalities observed, particularly woven bone formation and fibrosis.

Conclusions: Long-term treatment with lanthanum carbonate reduced the biochemical and bone abnormalities of CKD-MBD in a rat model of CRF.

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Histomorphometry of trabecular bone from rats with normal renal function or chronic renal failure after 22 weeks of treatment with vehicle or lanthanum carbonate. *P < 0.05 vs all other groups, † P < 0.05 vs NRF + LC, ‡ P < 0.05 vs NRF groups. Data are presented as mean ± standard error of the mean. CRF, chronic renal failure; LC, lanthanum carbonate; NRF, normal renal function; Veh, vehicle. (A) Trabecular bone volume (%) = [trabecular bone area (mm2)/total tissue area (mm2)] × 100. (B) Osteoid thickness (μm). (C) Osteoid volume (%) = [osteoid area (mm2)/trabecular bone area (mm2)] × 100. (D) Osteoid surface (%) = [osteoid perimeter (mm)/trabecular bone perimeter (mm)] × 100. (E) Osteoblast surface (%) = [osteoblast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (F) Osteoclast surface (%) = [osteoclast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (G) Woven bone volume = [woven bone area (mm2)/total tissue area (mm2)] × 100. (H) Fibrosis tissue volume = [fibrosis tissue area (mm2)/total tissue area (mm2)] × 100.
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fig5: Histomorphometry of trabecular bone from rats with normal renal function or chronic renal failure after 22 weeks of treatment with vehicle or lanthanum carbonate. *P < 0.05 vs all other groups, † P < 0.05 vs NRF + LC, ‡ P < 0.05 vs NRF groups. Data are presented as mean ± standard error of the mean. CRF, chronic renal failure; LC, lanthanum carbonate; NRF, normal renal function; Veh, vehicle. (A) Trabecular bone volume (%) = [trabecular bone area (mm2)/total tissue area (mm2)] × 100. (B) Osteoid thickness (μm). (C) Osteoid volume (%) = [osteoid area (mm2)/trabecular bone area (mm2)] × 100. (D) Osteoid surface (%) = [osteoid perimeter (mm)/trabecular bone perimeter (mm)] × 100. (E) Osteoblast surface (%) = [osteoblast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (F) Osteoclast surface (%) = [osteoclast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (G) Woven bone volume = [woven bone area (mm2)/total tissue area (mm2)] × 100. (H) Fibrosis tissue volume = [fibrosis tissue area (mm2)/total tissue area (mm2)] × 100.

Mentions: Undecalcified histology preparation of the metaphysis of the proximal tibia was performed, and samples were analysed for abnormalities. The parameters described in the Materials and methods section were quantified (Figure 5). There were no statistically significant differences between vehicle and lanthanum carbonate treatment groups in the NRF rats. Vehicle-treated CRF rats had significantly increased trabecular bone volume, osteoid thickness, osteoblast surface, woven bone volume and fibrosis tissue volume compared with NRF animals (P < 0.05). Trabecular bone volume, osteoid thickness, woven bone volume and fibrosis tissue volume were significantly lower in lanthanum-carbonate-treated CRF animals, compared with vehicle-treated controls (P < 0.05). Despite lanthanum carbonate treatment, osteoid surface and volume, and osteoblast and osteoclast surfaces remained elevated. Representative images are shown in Figure 6.


Long-term treatment with lanthanum carbonate reduces mineral and bone abnormalities in rats with chronic renal failure.

Damment S, Secker R, Shen V, Lorenzo V, Rodriguez M - Nephrol. Dial. Transplant. (2010)

Histomorphometry of trabecular bone from rats with normal renal function or chronic renal failure after 22 weeks of treatment with vehicle or lanthanum carbonate. *P < 0.05 vs all other groups, † P < 0.05 vs NRF + LC, ‡ P < 0.05 vs NRF groups. Data are presented as mean ± standard error of the mean. CRF, chronic renal failure; LC, lanthanum carbonate; NRF, normal renal function; Veh, vehicle. (A) Trabecular bone volume (%) = [trabecular bone area (mm2)/total tissue area (mm2)] × 100. (B) Osteoid thickness (μm). (C) Osteoid volume (%) = [osteoid area (mm2)/trabecular bone area (mm2)] × 100. (D) Osteoid surface (%) = [osteoid perimeter (mm)/trabecular bone perimeter (mm)] × 100. (E) Osteoblast surface (%) = [osteoblast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (F) Osteoclast surface (%) = [osteoclast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (G) Woven bone volume = [woven bone area (mm2)/total tissue area (mm2)] × 100. (H) Fibrosis tissue volume = [fibrosis tissue area (mm2)/total tissue area (mm2)] × 100.
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fig5: Histomorphometry of trabecular bone from rats with normal renal function or chronic renal failure after 22 weeks of treatment with vehicle or lanthanum carbonate. *P < 0.05 vs all other groups, † P < 0.05 vs NRF + LC, ‡ P < 0.05 vs NRF groups. Data are presented as mean ± standard error of the mean. CRF, chronic renal failure; LC, lanthanum carbonate; NRF, normal renal function; Veh, vehicle. (A) Trabecular bone volume (%) = [trabecular bone area (mm2)/total tissue area (mm2)] × 100. (B) Osteoid thickness (μm). (C) Osteoid volume (%) = [osteoid area (mm2)/trabecular bone area (mm2)] × 100. (D) Osteoid surface (%) = [osteoid perimeter (mm)/trabecular bone perimeter (mm)] × 100. (E) Osteoblast surface (%) = [osteoblast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (F) Osteoclast surface (%) = [osteoclast perimeter (mm)/trabecular bone perimeter (mm)] × 100. (G) Woven bone volume = [woven bone area (mm2)/total tissue area (mm2)] × 100. (H) Fibrosis tissue volume = [fibrosis tissue area (mm2)/total tissue area (mm2)] × 100.
Mentions: Undecalcified histology preparation of the metaphysis of the proximal tibia was performed, and samples were analysed for abnormalities. The parameters described in the Materials and methods section were quantified (Figure 5). There were no statistically significant differences between vehicle and lanthanum carbonate treatment groups in the NRF rats. Vehicle-treated CRF rats had significantly increased trabecular bone volume, osteoid thickness, osteoblast surface, woven bone volume and fibrosis tissue volume compared with NRF animals (P < 0.05). Trabecular bone volume, osteoid thickness, woven bone volume and fibrosis tissue volume were significantly lower in lanthanum-carbonate-treated CRF animals, compared with vehicle-treated controls (P < 0.05). Despite lanthanum carbonate treatment, osteoid surface and volume, and osteoblast and osteoclast surfaces remained elevated. Representative images are shown in Figure 6.

Bottom Line: Lanthanum carbonate (FOSRENOL(®), Shire Pharmaceuticals) is an effective non-calcium, non-resin phosphate binder for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD).Hyperphosphataemia, hypocalcaemia, elevated calcium × phosphorus product and secondary hyperparathyroidism were evident in CRF + vehicle animals.Treatment with lanthanum carbonate reduced hyperphosphataemia and secondary hyperparathyroidism in CRF animals (P < 0.05), and had little effect in NRF animals.

View Article: PubMed Central - PubMed

Affiliation: Shire Pharmaceuticals, Basingstoke, UK. sdamment@shire.com

ABSTRACT

Background: Lanthanum carbonate (FOSRENOL(®), Shire Pharmaceuticals) is an effective non-calcium, non-resin phosphate binder for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). In this study, we used a rat model of chronic renal failure (CRF) to examine the long-term effects of controlling serum phosphorus with lanthanum carbonate treatment on the biochemical and bone abnormalities associated with CKD-mineral and bone disorder (CKD-MBD).

Methods: Rats were fed a normal diet (normal renal function, NRF), or a diet containing 0.75% adenine for 3 weeks to induce CRF. NRF rats continued to receive normal diet plus vehicle or normal diet supplemented with 2% (w/w) lanthanum carbonate for 22 weeks. CRF rats received a diet containing 0.1% adenine, with or without 2% (w/w) lanthanum carbonate. Blood and urine biochemistry were assessed, and bone histomorphometry was performed at study completion.

Results: Treatment with 0.75% adenine induced severe CRF, as demonstrated by elevated serum creatinine. Hyperphosphataemia, hypocalcaemia, elevated calcium × phosphorus product and secondary hyperparathyroidism were evident in CRF + vehicle animals. Treatment with lanthanum carbonate reduced hyperphosphataemia and secondary hyperparathyroidism in CRF animals (P < 0.05), and had little effect in NRF animals. Bone histomorphometry revealed a severe form of bone disease with fibrosis in CRF + vehicle animals; lanthanum carbonate treatment reduced the severity of the bone abnormalities observed, particularly woven bone formation and fibrosis.

Conclusions: Long-term treatment with lanthanum carbonate reduced the biochemical and bone abnormalities of CKD-MBD in a rat model of CRF.

Show MeSH
Related in: MedlinePlus