ABSTRACT
Interventions that alter PTH levels in an animal model of chronic kidney disease have effects on the perfusion of bone and bone marrow. INTRODUCTION: Patients with chronic kidney disease (CKD) have accelerated bone loss, vascular calcification, and abnormal biochemistries, together contributing to an increased risk of cardiovascular disease and fracture-associated mortality. Despite evidence of vascular pathologies and dysfunction in CKD, our group has shown that cortical bone tissue perfusion is higher in a rat model of high-turnover CKD. The goal of the present study was to test the hypothesis that parathyroid hormone (PTH) suppressive interventions would normalize cortical bone vascular perfusion in the setting of CKD. METHODS: In two separate experiments, 35-week-old CKD animals and their normal littermates underwent intra-cardiac fluorescent microsphere injection to assess the effect of 10 weeks of PTH suppression (Experiment 1: calcium supplementation, Experiment 2: calcimimetic treatment) on alterations in bone tissue perfusion. RESULTS: In Experiment 1, CKD animals had serum blood urea nitrogen (BUN) and PTH levels significantly higher than NL (+ 182% and + 958%; p < 0.05). CKD+Ca animals had BUN levels that were similar to CKD, while PTH levels were significantly lower and comparable to NL. Both femoral cortex (+ 220%, p = 0.003) and tibial cortex (+ 336, p = 0.005) tissue perfusion were significantly higher in CKD animals when compared to NL; perfusion was normalized to those of NL in CKD+Ca animals. MicroCT analysis of the proximal tibia cortical porosity showed a trend toward higher values in CKD (+ 401%; p = 0.017) but not CKD+Ca (+ 111%; p = 0.38) compared to NL. Experiment 2, using an alternative method of PTH suppression, showed similar results as those of Experiment 1. CONCLUSIONS: These data demonstrate that PTH suppression-based interventions normalize cortical bone perfusion in the setting of CKD.
Subject(s)
Chronic Kidney Disease-Mineral and Bone Disorder/physiopathology , Cortical Bone/blood supply , Parathyroid Hormone/antagonists & inhibitors , Renal Insufficiency, Chronic/physiopathology , Animals , Blood Urea Nitrogen , Calcium/pharmacology , Calcium/therapeutic use , Chronic Kidney Disease-Mineral and Bone Disorder/blood , Chronic Kidney Disease-Mineral and Bone Disorder/drug therapy , Dietary Supplements , Disease Models, Animal , Drug Evaluation, Preclinical/methods , Male , Parathyroid Hormone/blood , Peptides/pharmacology , Peptides/therapeutic use , Pilot Projects , Porosity , Rats , Regional Blood Flow/drug effects , Regional Blood Flow/physiology , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/drug therapy , X-Ray MicrotomographyABSTRACT
This work examines the skeletal accumulation of fluorescently tagged zoledronate in an animal model of chronic kidney disease. The results show higher accumulation in 24-h post-dose animals with lower kidney function due to greater amounts of binding at individual surfaces. INTRODUCTION: Chronic kidney disease (CKD) patients suffer from increased rates of skeletal-related mortality from changes driven by biochemical abnormalities. Bisphosphonates are commonly used in reducing fracture risk in a variety of diseases, yet their use is not recommended in advanced stages of CKD. This study aimed to characterize the accumulation of a single dose of fluorescently tagged zoledronate (FAM-ZOL) in the setting of reduced kidney function. METHODS: At 25 weeks of age, FAM-ZOL was administered to normal and CKD rats. Twenty-four hours later, multiple bones were collected and assessed using bulk fluorescence imaging, two-photon imaging, and dynamic histomorphometry. RESULTS: CKD animals had significantly higher levels of FAM-ZOL accumulation in the proximal tibia, radius, and ulna, but not in lumbar vertebral body or mandible, based on multiple measurement modalities. Although a majority of trabecular bone surfaces were covered with FAM-ZOL in both normal and CKD animals, the latter had significantly higher levels of fluorescence per unit bone surface in the proximal tibia. CONCLUSIONS: These results provide new data regarding how reduced kidney function affects drug accumulation in rat bone.
Subject(s)
Bone Density Conservation Agents/pharmacokinetics , Bone and Bones/metabolism , Renal Insufficiency, Chronic/metabolism , Zoledronic Acid/pharmacokinetics , Animals , Bone and Bones/diagnostic imaging , Disease Models, Animal , Male , Optical Imaging/methods , Rats, Inbred Strains , Tibia/diagnostic imaging , Tibia/metabolismABSTRACT
In a double-blind study involving 24 patients, treatment with lidoflazine in comparison with placebo was associated with a significant improvement in exercise tolerance; the median increase in work performed was 62 percent. This increase was significant at the 6th week of assessment. Ten patients were followed up for a further 2 years. Lidoflazine therapy was associated with a significant improvement in work done over that period. Lidoflazine was well tolerated and apparent adverse effects were minor.
