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The understanding of the pathophysiology and the monitoring of metastatic bone disease remains unsatisfactory. We compared several new markers of bone turnover in normocalcaemic patients with breast cancer-induced osteolysis before and after a single infusion of the bisphosphonate pamidronate. We studied 19 ambulatory patients with advanced breast cancer and extensive bone metastases who did not receive any systemic antineoplastic therapy. Pamidronate was administered at doses of 30, 60, 90 or 120 mg and the patients were followed weekly during a mean of 8 (range 4-10) weeks. Compared with healthy premenopausal women, the percentage of elevated values at baseline was 47% for fasting urinary calcium (uCa), 74% for hydroxyproline, 83% for CrossLaps (a new marker of type I collagen degradation) and 100% for the collagen cross-links (measured by high performance liquid chromatography), namely pyridinoline (Pyr) and deoxyPyr (D-Pyr). Pretreatment levels of uCa did not correlate significantly with any of the four markers of bone matrix resorption, whereas the correlations between these four markers were generally significant (r(s)=0.43-0.71). Alkaline phosphatase correlated significantly with markers of bone matrix resorption (r(s)=0.54-0.74). All parameters, except phosphaturia (uPi) and the bone formation markers (osteocalcin and alkaline phosphatase), fell significantly after pamidronate therapy, up to day 42 for hydroxyproline, D-Pyr and CrossLaps and day 56 for uCa. This longer lasting effect was probably due to the parathyroid hormone (PTH) surge following the decrease in serum calcium, implying that the decrease in uCa can overestimate the effects of bisphophonates on bone resorption. The decrease in bone turnover parameters was most marked for CrossLaps, indicating the potential of this new marker for monitoring therapy. Sequential determinations of markers of bone matrix resorption should be useful in delineating the optimal therapeutic schemes of bisphosphonates and for evaluating treatment effects on bone in cancer patients.

Hypercalcaemia is an important cause of morbidity in malignant disease. We studied the efficacy and safety of intravenous ibandronate (a new, potent bisphosphonate) in a multicentre study of 147 patients with severe cancer-associated hypercalcaemia which had been resistant to treatment with rehydration alone. Of 131 randomized patients who were eligible for evaluation, 45 were allocated to receive 2 mg ibandronate, 44 patients to receive 4 mg and 42 patients to receive 6 mg. Serum calcium values fell progressively in each group from day 2, reaching a nadir at day 5, and in some patients normocalcaemia was maintained for up to 36 days after treatment. The 2-mg dose was significantly less effective than the 4-mg or 6-mg dose in correcting hypercalcaemia, as the number of patients who achieved serum calcium values below 2.7 mM after treatment was 50% in the 2-mg group compared with 75.6% in the 4-mg group and 77.4% in the 6-mg group (P < 0.05; 2 mg vs others). In a logistic regression analysis, three factors were found to predict response; ibandronate dose (higher doses were more effective), severity of presenting hypercalcaemia (severe hypercalcaemia was associated with less complete response) and tumour type (patients with breast carcinoma and haematological tumours responded better than those with other tumours). Ibandronate was generally well tolerated and no serious drug-related adverse events were observed. We conclude that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcaemia, which should prove a useful addition to the current range of therapies available to treat this condition.

Dumon JC, Wantier H, Mathieu F, Mantia M, Body JJ, Technical and clinical validation of a new immunoradiometric assay for human osteocalcin. Eur J Endocrinol 1996;135:231–7. ISSN 0804–4643The measurement of circulating osteocalcin or bone GLA protein (BGP) constitutes a well established and non-invasive means for evaluating preferentially the bone formation rate, but most available commercial assays suffer from several technical constraints, notably a rapid degradation of BGP at room temperature or after thawing and the inability to measure subnormal values. We evaluated, from a technical and a clinical viewpoint, a newly available two-site sandwich immunoradiometric assay (IRMA) using standards of human origin and two different monoclonal antibodies. The theoretical and functional assay detection limit was 0.3 ng/ml. Concentrations of BGP progressively decreased when the serum was left at 4°C or at room temperature (mean apparent loss of 15% after 24 h). Two cycles of freezing–thawing only slightly reduced the BGP concentrations. The mean (± sd) BGP concentration was 19.6 ± 7.9 ng/ml in healthy subjects (NI, N = 61); the normal range was 8.1–35.6 ng/ml. There was a marked difference between pre- and postmenopausal women: 15.1 ±4.4 vs 22.3 ± 8.4 ng/ml, respectively (p<0.05). The mean BGP concentration in patients with tumor-induced hypercalcemia (N = 29) was not significantly different from NI, but nine patients (31%) had subnormal levels and five (17%) had elevated BGP levels. Concentrations of BGP were significantly increased in patients with hyperparathyroidism (N = 14) (45.1 ± 21.0 ng/ml) and significantly lower than NI in patients with hypoparathyroidism (N = 18) (7.3 ± 4.6 ng/ml). Concentrations of BGP were also measured by a classical radioimmunoassay using bovine standards and tracer; the correlations between both sets of measurements were significant in all groups, except in patients with hypoparathyroidism. In summary, this newly available IRMA for measuring circulating human BGP appears to be quite sensitive, reproducible and robust. It should be especially useful for investigating clinical conditions characterized by a low bone formation rate.JJ Body, Institut Jules Bordet, Rue Héger-Bordet 1, 1000 Brussels, Belgium