ALUMINUM-INDUCED BONE-DISEASE IN UREMIC RATS - EFFECT OF DEFEROXAMINE

We have previously established a rat model of chronic uremia, which is suitable to investigate the effect of various treatment modalities on renal osteodystrophy [1]. Afterfour months subsequent to 5/6 nephrect omy, some animals were treated by gavage for 9 weeks with tap water (c ontrols), or with aluminium (Al-citrate) 3 x 25 mg/week/kg b.wt +/- su bsequent deferoxamine (DFO) 3 x 50 mg/ week/kg b.wt. for 4 weeks. At t ermination of the study, serum clinical chemistry, femoral chemical co mposition and mechanical properties, calvarial parathyroid hormone (PT H)-elicited adenylate cyclase (AC) and phospholipase C (PLC) activitie s, cross-sectional femoral area, as well as bone histomorphometry, wer e analyzed. Animals given Al displayed moderately enhanced serum Al an d bone Al accumulation, however, DFO-treatment did not fully alleviate bone Al retainment. A small increase in serum PTH was seen in all ani mals rendered uremic. Furthermore, a marked fall in serum alkaline pho sphatase (ALP) below normal controls was observed in Al +/- DFO-treate d animals compared with uremic controls. The uremic condition led to r educed femoral ratios of hydroxyproline (HYP) over Ca2+ and phosphate (P-i), while Al-intoxication alone enhanced femoral Hyp contents above values seen for normal controls. The protracted ureamia caused a dete rioration of long bone resilience and brittleness, however, Al +/- DFO -treatment seemed to normalize the latter. Contrastingly, Al +/- DFO-g avage enhanced time to fracture. Uremic rats intoxicated with Al showe d a complete loss of calvarial PTH-sensitive AC and PLC activities. DF O-treatment normalized PTH-elicited PLC, while PTH-susceptible AC rema ined super-normal. Al apparently exerts a long term down-regulation of both PTH-sensitive signaling systems as evidenced by studies of rat U MR 106 osteosarcoma cells in culture. The uremic condition enhanced en dosteal bone resorption as shown by femoral shaft dimension analysis, while Al +/- DFO-treatment insignificantly reversed the condition. Fin ally, histomorphometrical analyses showed that DFO-administration tend ed to normalize aberrant trabecular bone volume, while rectifying both bone resorption and degree of mineralization. In conclusion, we asser t that Al-intoxication hampers both processes (i.e. formation and reso rption) of bone turnover, and that DFO-treatment to a certain extent p revents the uremia- and Al-induced bone disease in rats.