Physiological doses of calcium regulatory hormones do not normalize bone cells in uraemic rats

• Published in: European journal of clinical investigation 1999-06, Vol.29 (6), p.529-535
• Main Authors: Szabó, A., Freesmeyer, M. G., Abendroth, K., Stein, G., Rosivall, L., El-Shakmak, A., Ritz, E.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - pathology; Calcitriol; Calcitriol - blood; Calcitriol - pharmacology; Calcium - physiology; Hormones. Endocrine system; Kidney Failure, Chronic - pathology; Kidney Failure, Chronic - physiopathology; Lumbar Vertebrae; Male; Medical sciences; Nephrectomy; Osteoblasts - drug effects; Osteoblasts - pathology; Osteoclasts - drug effects; Osteoclasts - pathology; parathyroid hormone; Parathyroid Hormone - blood; Parathyroid Hormone - pharmacology; Parathyroid Hormone - physiology; parathyroid hormone resistance; Parathyroidectomy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; secondary hyperparathyroidism; uraemia; Uremia - pathology; Uremia - physiopathology
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1046/j.1365-2362.1999.00499.x

Background Low bone turnover despite normal parathyroid hormone (PTH) concentrations has been found in many patients with end‐stage renal failure. Hyporesponsiveness to the calcaemic action is also a known feature of uraemia. Hyporesponsiveness of bone surface cells involved in bone modelling has not been demonstrated to date. It was the purpose of this study using a rat model of moderate renal failure to investigate whether doses of PTH and calcitriol that reverse the effect of parathyroidectomy on calcaemia also normalize bone surface cell activity. Materials and methods Sham‐operated pair‐fed male Spraque–Dawley rats were compared with subtotally nephrectomized (SNX), parathyroidectomized (PTX) rats that received either solvent or calcitriol (5 pmol kg −1 h−1) + 1,34 rat PTH (100 ng kg −1 h−1) by osmotic mini‐pump. Histomorphometric measurements were carried out in the vertebral body (L5). Results In SNX/PTX animals, calcitriol + 1,34 rat PTH caused a modest increase in serum calcium (S‐Ca) within the normal range. Osteoclast surface per cent was significantly lower in solvent‐treated SNX/PTX rats than in sham‐operated controls [3.7 ± 2.8 osteoclast surface/bone surface (OcS/BS%) vs. 6.3 ± 3.9], and this was not normalized by PTH + calcitriol (3.3 ± 3). In contrast, osteoblast surface per cent and osteoid surface per cent were increased over values in sham‐operated rats; as a result, co‐administration of calcitriol and 1,34 rat PTH caused a highly significant increase in fractional bone volume (BV/TV). Conclusions The results show that administration of PTH and calcitriol in doses that raise serum calcium fails to normalize the percentage of osteoclast surface, but was effective in raising osteoblast number and osteoblast volume in experimental renal failure. The results argue for abnormal response of bone cells to calcium‐regulating hormones and/or the action of factors other than calcium regulatory hormones in the genesis of skeletal abnormalities of renal failure.