N. A. T. Hamdy

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure

Abstract Objective: To determine whether alfacalcidol—used in management of overt renal bone disease—may safely prevent renal bone disease when used earlier in course of renal failure. Design: Double blind, prospective, randomised, placebo controlled study. Setting: 17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. Subjects: 176 patients aged 18–81 with mild to moderate chronic renal failure (creatinine clearance 15–50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. Interventions: Alfacalcidol 0.25 μg (titrated according to serum calcium concentration) or placebo given for two years. Main outcome measures: Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. Results: 132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P<0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P<0.001). There was no difference in rate of progression of renal failure between the two groups. Conclusion: Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure. Key messages Key messages Treating such patients with alfacalcidol (up to 1 μg/day for two years) significantly improved their osteomalacia and hyperparathyroid disease Treatment had no apparent adverse effect on renal function Hypercalcaemic episodes were uncommon and readily responded to decreases in drug dose Alfacalcidol might be used more widely for patients with moderate renal failure not yet needing dialysis

INTRAVENOUS CLODRONATE IN THE TREATMENT AND RETREATMENT OF PAGET'S DISEASE OF BONE

The effects of short courses (5 days) of intravenous clodronate 300 mg daily were studied in 31 patients with active Pagets disease of bone. The diphosphonate induced a striking reduction in biochemical indices of disease activity, which was sustained for at least 6 months after withdrawal of treatment. Apparent resistance to further treatment in patients previously treated for Pagets disease was an artefact due to incomplete relapse before retreatment. There was no significant difference in the degree of suppression of alkaline phosphatase activity between patients given intravenous clodronate and 45 patients given clodronate 1.6 g daily by mouth for 6 months. Short-term intravenous clodronate provides a useful alternative strategy for the treatment of patients with Pagets disease.

Effects of Intravenous Etidronate Disodium on Skeletal and Calcium Metabolism

The induction of hypercalcemia in malignant disease is almost invariably associated with increased bone resorption. However, tumor-induced changes in bone formation and renal tubular resorption of calcium are also important factors that induce hypercalcemia in some patients. In addition, alterations in calcium fluxes to and from the extracellular fluid secondary to hypercalcemia are important in maintaining or aggravating the hypercalcemic effects of increased bone resorption. These factors significantly affect the responses to treatment of hypercalcemia with inhibitors of bone resorption. This study examined the relative importance of these factors and the effects of intravenous etidronate disodium (etidronate) in neoplastic bone disease with and without hypercalcemia and in Pagets disease of bone. It is concluded that intravenous etidronate is an effective inhibitor of bone resorption, which accounts in large measure for its effects on serum calcium concentrations. These studies of etidronate in hypercalcemia suggest the response is sustained for several weeks.

Effects of amino-butylidene diphosphonate in hypercalcemia due to malignancy

We studied the effect of a single 5 mg intravenous infusion of amino-butylidene diphosphonate (ABDP) in nine patients with hypercalcemia of malignancy, in whom serum calcium values were stable or rising after intravascular volume expansion. Serum calcium fell progressively in all patients and in seven reached the normal reference range by day 6 (p less than 0.001). The decrease in serum calcium was associated with a decrease in the fasting urinary calcium/creatinine ratio (p less than 0.05). Hypercalcemia recurred in seven of the patients by day 12, but two patients remained normocalcemic for 21 days. We conclude that ABDP is a highly potent diphosphonate and that a single intravenous infusion is capable of inhibiting tumour-mediated bone resorption for several days.

Physiology of Bone and Metabolic Approaches to the Treatment of Skeletal Metastases

Advanced breast cancer is commonly associated with bony complications and disturbances in extracellular calcium homeostasis. Bone pain, pathological fracture, and hypercalcemia account collectively for significant morbidity and some of the mortality associated with breast cancer. The aim of this chapter is to review the way in which breast cancer modulates normal bone turnover and extracellular calcium homeostasis, and thereby to provide a rationale for the treatment and possible prophylaxis of the skeletal complications.

Short term high doses of etidronate in Paget's disease of bone.

undoubted, -and we should applaud the white knights progress, especially over the concept ofan essential drug list (24 May, p 1347). Nevertheless, the WHOs advice should not be above criticism, and its suggestions for primary care treatment in epilepsy are highly questionable, specifically its recommendation that phenobarbitone should be the first line anticonvulsant. Phenobarbitone is cheap and efficacious but has several drawbacks which render it peculiarly undesirable in poorly supervised settings in the developing world. Firstly, it is a drug of abuse, and in most countries is subject to special controls. I would not relish encouraging the prospect of a black market in government supplied barbiturate among addicts in the slums of the great Third World cities. Secondly, the safe use of phenobarbitone in epilepsy requires a consistent and reliable supply. The sudden withdrawal ofestablished phenobarbitone therapy in an epileptic is dangerous, with the frequent precipitation of withdrawal seizures and other withdrawal phenomena. The fact that abrupt discontinuation may result in status epilepticus was recognised 75 years ago, within a short time ofthe drugs introduction, and all experienced physicians will treat even its gradual withdrawal with considerable apprehension. Our advisers in Geneva many ofwhom incidentally are not practising clinicians-do not seem to have heeded this lesson. In my experience in developing countries in three continents the availability of phenobarbitone (and indeed other antiepileptic drugs) is notoriously unreliable. In rural hospitals drug supplies are often erratic and intermittent, and in the case of phenobarbitone this may have serious and sometimes fatal consequences. Ironically, the very cheapness of phenobarbitone in some countries exacerbates this problem of availability; because of its low profit margins the manufacturers seldom seem bothered to produce the drug in adequate quantities. These problems ofsupply are widespread in-Africa, Asia, and South America. Thirdly, there are the problems of the interaction of phenobarbitone with alcohol, a potentially serious public health issue. Fourthly, the risks-of death in overdose are greater than with other anticonvulsants. Finally, and very important, are the mental side effects of the -drug. In children drug induced hyperactivity is sometimesprofound, and at all ages depression, sedation, and intellectual slowing may occur. These toxic effects require careful monitoring, and many clinicians in the West no longer recommend this drug for first line treatment, and certaitly not in children. I sense double standards here. If a drug is not receommerkded in the West why should it be acceptable in developing countries? This is to place a hierarchy on mentalfunctioning in the developed and developing world, and it is cynical to pretend that this is anything but an expediency on the grounds ofcost. It is for individual governments to decide on the funding of health, but the WHO should not be party to such medical compronise.