Phase I/II evaluation of effervescent and enteric coated oral pamidronate for bone metastases.

THE DISCOVERY of the action of bisphosphonates on osteoclast activity led to study of their role in the management of tumourinduced osteolysis aad hypercalcaemia [ 11. These encouraging preliminary results have been confirmed by many groups and bisphosphonates are now considered the treatment of choice for hypercalcaemia [2]. Most studies have been performed with intravenous bisphosphonates, as this class of compounds is poorly absorbed from the gut, with an average bioavailability of 1% [3]. Although large doses, relative to those used parenterally, have to be administered, oral pamidronate has been shown to reduce skeletal morbidity in patients with breast cancer and established bone metastases [4] and attention is now turning to the possibility of preventing metastatic bone disease. However, in addition to the problems of absorption, gastrointestinal toxicity secondary to the locally irritant effect of pamidronate on the gut mucosa occurs. For long-term administration, particularly adjuvant use, the level of toxicity with the current non-proprietary formulation of oral pamidronate is considered too high. We have studied the toxicity and efficacy of two new oral formulations: an effervescent tablet and an enteric-coated capsule (Ciba-Geigy, Basle), in patients with bone metastases. 79 patients were treated with oral pamidronate at six hospitals. The median age was $6 years and all but 3 patients had advanced breast cancer. Eligibility required radiographically confirmed bone metastases and during the 1 month trial period patients received no other anticancer drug therapy. The exceptions to this were patients on endocrine treatment, providing this had not been changed in the previous 4 months, who continued with this treatment for the month to exclude the possibility of a withdrawal response. In addition, a raised level of urinary calcium excretion was necessary. This was defined as a urinary calcium/creatinine ratio (UCCR) of more than 0.4 (mmol/mmol) in fasting morning spot urine samples taken on two occasions during the week before trial entry. Patients receiving medication known to affect bone meta-