R. G. G. Russell

DIPHOSPHONATES IN PAGET'S DISEASE

Abstract The diphosphonate, sodium etidronate (disodium ethane-1-hydroxy-1,1-diphosphonate) (E.H.D.P.), which inhibits the growth and dissolution of calcium phosphate crystals in vitro, was given at doses of 0, 1, 5, 10, or 20 mg. per kg. per day for up to 6 months to forty-seven patients with Pagets disease of bone. There was a dose-related suppression of the raised alkaline phosphatase in plasma and total hydroxyproline in urine, and at 20 mg. per kg. per day nearly half of the patients had normal values at the end of treatment. A single course of E.H.D.P. could maintain biochemical remission for at least 2 years after stopping treatment. Bone biopsy specimens confirmed the suppression of the Pagets disease. Increases in unmineralised osteoid were only seen in biopsy specimens taken after the higher doses of E.H.D.P. and were usually small. There was also a reversible rise in plasma-phosphate at 20 mg. per kg. per day. It is suggested that E.H.D.P. given for short periods could provide a simple and reliable oral therapy in those cases of Pagets disease in which treatment is regarded as desirable.

1,25-DIHYDROXYCHOLECALCIFEROL AND 1α-HYDROXYCHOLECALCIFEROL IN HYPOPARATHYROIDISM

Abstract Small amounts (0·68-2·7 μg.) of 1,25- dihydroxycholecalciferol (1,25-D.H.C.C.), the hormonally active metabolite of vitamin D 3 , or its synthetic analogue 1α-hydroxycholecalciferol (1α-H.C.C.) rapidly corrected the low plasma-calcium and improved symptoms when given daily to two patients with hypoparathyroidism. The rise in plasma-calcium could be maintained for as long as treatment continued but was readily reversible. The efficacy of minute doses of 1,25-D.H.C.C. and 1α-H.C.C. may indicate that the production of biologically active metabolites of vitamin D is impaired in hypoparathyroidism, and could offer advantages in treatment.

An estimate of the turnover rate of bone-derived plasma alkaline phosphatase in Paget's disease.

A through-knee amputation for suspected osteogenic sarcoma was performed on a patient with Pagets disease of the tibia. Plasma alkaline phosphatase (AP) activity fell to normal values, apparently as a single exponential function of time, with a half-life of 1.7 days. The daily turnover of bone-derived plasma AP was estimated to be approximately 200 I.U. from the Pagetic tibia and 20 I.U. from the rest of the skeleton.

Biochemical measurements in Paget's disease of bone.

Abstract. In a group of eighty‐three patients with untreated Pagets disease of bone, plasma alkaline phosphatase activity (AP), plasma non‐protein‐bound hydroxyproline concentration (PHP) and urinary excretion rate of total hydroxyproline (THP) were closely correlated with each other but not with fasting plasma concentrations of calcium or inorganic phosphate. Probit plots of AP and THP showed log‐normal distributions overlapping the normal ranges.

PHYSIOLOGICAL AND THERAPEUTIC DIFFERENCES BETWEEN VITAMIN D, ITS METABOLITES AND ANALOGUES

Since several metabolites and analogues of vitamin D have become available, their physiological and therapeutic potential have been studied in various disorders of mineral metabolism, particularly those classically termed vitamin D‐resistant. In some instances this resistance appears to be due to defective metabolism of vitamin D or to defective target organ responses. but in others it is not. Although the precise effect of vitamin D or its metabolites on mineralization of bone is still unknown there is some evidence that the metabolites differ in their relative effects on intestine, bone, muscle and parathyroid glands. These differences may eventually have therapeutic value. At present the major advantage of lα‐hydroxylated derivatives of vitamin D over other compounds resides in their more rapid onset and reversal of action which makes them much easier and safer to use.

Effects of a diphosphonate (disodium etidronate: EHDP) on phosphate metabolism in Paget's disease of bone, primary hyperparathyroidism and type I hypophosphataemic rickets.

Disodium etidronate (disodium ethane-l-hydroxy-1,1-diphosphonate; EHDP) is structurally related to inorganic pyrophosphate but contains a P-C-P bond and is therefore resistant to hydrolytic enzymes. Because of its ability to slow bone turnover in experimental animals (9), it is under investigation in man as a treatment for Paget’s disease of bone (1).