R. J. Walton

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.

Serum proline imino-peptidase activity in normal adult subjects and in patients with Paget's disease of bone.

The activity of proline imino-peptidase (EC 3.4.1.4) may provide a measure of collagen degradation, and a method for its estimation in human serum is described. The mean value of this enzyme activity in 48 normal adults of 4.7 mU/1 (S.D. 0.9) did not change with sex, age or dietary collagen. In 8 patients with liver disease associated with elevated levels of plasma alkaline phosphatase activity the mean value was normal (4.5 mU/1, S.D. 1.5). However, in 25 patients with untreated Pagets disease of bone, values were significantly increased (mean 7.4 mU/1; S.D. 2.8; p < 0.001) and were positively correlated with plasma alkaline phosphatase activity (r = 0.75; p < 0.001) and with urine total hydroxyproline excretion (r = 0.68; p < 0.001). In patients given disodium ethane-1-hydroxy-1, 1-diphosphonate for 3–6 months, serum proline imino-peptidase activity decreased to normal values.

Comparative effects of 1α-hydroxycholecalciferol in children and adults with renal glomerular osteodystrophy

Summary1α-hydroxycholecalciferol (1α-OH-D3) has been given in daily oral microgram doses for periods of up to 14 months to patients with renal glomerular osteodystrophy. In four non-dialysed children there was radiological and biochemical evidence of healing within 3–6 months, without hypercalcaemia. In three dialysed adults, bone healing was less rapid and recurrent hypercalcaemia occurred. The effects of prolonged treatment with 1α-OH-D3 require further investigation.

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).