H. A. Ellis

OSTEOMALACIC DIALYSIS OSTEODYSTROPHY: EVIDENCE FOR A WATER-BORNE ÆTIOLOGICAL AGENT, PROBABLY ALUMINIUM

In patients maintained on regular haemodialysis in Newcastle upon Tyne the development of osteomalacia is substantially reduced when water used to prepare dialysate is deionised. After 1--4 years of dialysis, osteomalacia was evident in 15% of patients on deionised water in 70% of patients on softened water from the same source. The close association of dialysis encephalopathy and osteomalacia suggests a common aetiology. Both diseases occur in centres with a high tap-water aluminium content. Serum-aluminium concentrations were raised in patients undergoing regular haemodialysis in the Northern Region of England. Those using softened water had higher concentrations than those using deionised water. Patients on softened water who had encephalopathy or dementia had serum-aluminium concentrations similar to those of patients using the same water-supplies without symptoms of these diseases, but they had been treated for longer. The evidence that aluminium absorption from dialysate causes osteomalacia and encephalopathy is strong enough to justify the expense of treating water by deionisation, reverse osmosis, or both in centres where tap-water aluminium is high.

Azotaemic renal osteodystrophy: a quantitative study on iliac bone.

The histopathology of bone is described in 60 patients with chronic renal failure due to a variety of renal diseases. Changes of azotaemic renal osteodystrophy included osteitis fibrosa, osteomalacia, and osteosclerosis. Quantitative histology using a point-counting technique revealed a significant increase in total bone, mineralized bone, and osteoid in comparison with a control group of 68 individuals. Osteitis fibrosa due to secondary hyperparathyroidism occurred in 93%, osteomalacia in 40%, and osteosclerosis in 30% of patients. Woven bone formation was a characteristic feature and was related to the severity of osteitis fibrosa. There were significant correlations between the weights of parathyroid glands and the number of osteoclasts, amounts of woven bone, and marrow fibrosis in the ilium. Hyperparathyroidism caused degradation of mineralized bone but the loss was balanced or exceeded by the aggradation of woven mineralized bone. Woven bone formation together with excess osteoid gave rise to osteosclerosis. The histological findings indicate that hyperparathyroidism and osteitis fibrosa usually occur early in chronic renal failure and that osteomalacia develops subsequently.

Quantitative observations on mineralized and non-mineralized bone in the iliac crest

The amounts of mineralized bone and osteoid in thin undecalcified sections of iliac crest have been measured in 68 control subjects at necropsy using a point-counting method. The effect of varying the site selected for quantitative study on the value obtained for total bone mass has been investigated in decalcified sections of iliac crest. The total bone mass shows individual variation within a fairly constant range with a mean of 22·7 ± 0·5% up to the age of 50 years and then progressively falls to a mean of 15·5 ± 1·1% for individuals aged > 50 years. Some of the lowest values in the range 5·5 to 16·4 (mean 8·9 ± 1·9%) were observed in elderly women in the seventh to ninth decades. It is concluded that so-called senile osteoporosis is usually a manifestation of a normal aging process. In controls osteoid accounts for only about 0·1% of the area measured and for a maximum of 1·8% of bone with a mean mineralization of 99·5%. Osteoid is patchily distributed and the maximum number of birefringent lamellae in any seam is four. The results of quantitative histology carried out in different parts of the iliac crest indicate that there are variations with the distance of the site from the anterior superior spine and its depth below the crest surface. The importance of this in relation to the site and size of iliac crest biopsies used for quantitative histology is discussed. There is a significant correlation between the values for total bone mass when estimated by the point-counting technique in undecalcified sections and by a volumetric method using blocks of bone.

HISTOPATHOLOGY OF RENAL OSTEODYSTROPHY WITH PARTICULAR REFERENCE TO THE EFFECTS OF lα-HYDROXYVITAMIN D3 IN PATIENTS TREATED BY LONG-TERM HAEMODIALYSIS

(1)The bone histology of 233 non‐dialysed and 276 haemodialysed patients with chronic renal failure is reviewed. In non‐dialysed patients osteitis fibrosa occurred in 83.7% and osteomalacia in 23.6% of patients. Osteomalacia was not found in the absence of osteitis fibrosa. In haemodialysed patients there was a more variable bone histology, sometimes resembling non‐dialysed bone disease, but in general with a greater incidence of osteomalacia, especially with increasing time on dialysis. In some patients there was a predominance of osteomalacia accompanied by no or only mild osteitis fibrosa and the serum alkaline phosphatase was normal. (2) The results of treating twenty‐six haemodialysed patients with lα‐hydroxy vitamin D3 (lα‐OHD3) are described. Patients with osteomalacia and minimal or no osteitis fibrosa and a normal serum alkaline phosphatase (Group I) in general failed to respond and it is suggested that 1,25‐dihydroxyvitamin D3 deficiency is not the sole factor responsible for the osteomalacia in these patients. In contrast, lα‐OHD3 therapy was effective in improving osteitis fibrosa and osteomalacia in some patients with moderate to severe degrees of osteitis fibrosa and osteomalacia (Group IIa) and in improving osteitis fibrosa where this occurred alone (Group IIb).

Effect of renal transplantation on marrow mast cell hyperplasia of chronic renal failure.

Marrow mast cells have been counted in iliac bone from patients with chronic renal failure treated by renal transplantation. Mast cell numbers were initially increased but returned to the normal range in many patients after renal transplantation. Improvement in osteitis fibrosa and osteomalacia after transplant was not clearly related to this diminution in the number of mast cells. The use of prednisone in renal transplant patients may have some effect in reducing the numbers of mast cells. There is no fully acceptable explanation for the increase in marrow mast cells which occurs in chronic renal failure.

THE EFFECT OF lα‐HYDROXYVITAMIN D3 IN PRE‐DIALYSIS RENAL BONE DISEASE

Assessment of 18 azotaemic patients treated with long‐term 1 a‐hydroxyvitamin D, (lα‐OHD3) confirms the generally favourable effect of this analogue of 1,25‐dihydroxyvitamin D3 in azotaemic osteodystrophy. Growing chddren with radiological rickets respond very well as do adults showing mild hyperpara‐thyroidism with or without osteomalacia. However, patients with severe‘pure’hyperparathyroidism and features of autonomy do not respond well and in such patients lα‐OHD3 alone should be avoided. Phosphate restriction and occasionally a sub‐total parathyroidectomy may be indicated in these patients.

1α-Hydroxycholecalciferol in renal osteodystrophy

Early azotaemic renal osteodystrophy is characterised by osteitis fibrosa, due to secondary hyperparathyroidism, and osteomalacia usually appears at a later state (Ellis and Peart, 1973; MaUuche et al. , 1976). In these non-dialysed uraemic patients musculoskeletal symptoms are usually mild. With regular haemodialysis a different pattern evolves. While some patients show progressive hyperparathyroidism associated with excessive phosphate retention, others develop a mainly osteomalacic picture with varying degrees of myopathy and pathological fractures. Haemodialysis osteomalacia was until recently thought to be purely the result of 1,25-dihydroxycholecalciferol (1,25(OH)zD3) deficiency. It is likely that other added factors such as phosphate depletion (Baker et al., 1974; Hill et al., 1975) and the use of hepatic enzyme inducing drugs such as phenobarbitone and phenytoin (Pierides et al. , 1976a), may be responsible for at least some of the more severe forms of haemodialysis osteomalacia. The recent availability of an active vitamin D metabolite, such as la-OHDa, capable of bypassing the renal block, has provided a means of testing the above hypothesis that osteomalacia, in at least some of the haemodialysis patients, is not wholly the result of 1,25-(OH)zD a deficiency.