{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T03:22:28Z","timestamp":1774063348203,"version":"3.50.1"},"reference-count":13,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[1999,9,1]],"date-time":"1999-09-01T00:00:00Z","timestamp":936144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100\u2013850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels \u22652.75 mmol\/l). Based on estimates of potency, the starting dose was 0.002 mg\/kg, and further tested doses were 0.005, 0.01, 0.02, and 0.04 mg\/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol\/l. The two effective dose levels were 0.02 mg\/kg and 0.04 mg\/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate\/kg and 14 out of 15 after 0.04 mg of zoledronate\/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68\u2013100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32\u201339 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg\/kg and 0.04 mg\/kg, i.e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.<\/jats:p>","DOI":"10.1359\/jbmr.1999.14.9.1557","type":"journal-article","created":{"date-parts":[[2006,4,27]],"date-time":"2006-04-27T01:34:54Z","timestamp":1146101694000},"page":"1557-1561","source":"Crossref","is-referenced-by-count":116,"title":["A Dose-Finding Study of Zoledronate in Hypercalcemic Cancer Patients"],"prefix":"10.1093","volume":"14","author":[{"given":"J. J.","family":"Body","sequence":"first","affiliation":[{"name":"Supportive Care Clinic & Bone Diseases Clinic, Institut J. Bordet, Universit\u00e9 Libre de Bruxelles, Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Lortholary","sequence":"additional","affiliation":[{"name":"Centre Paul Papin, Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G.","family":"Romieu","sequence":"additional","affiliation":[{"name":"Centre Val d'Aurelle, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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