Treatment of malignant hypercalcaemia with aminohexane bisphosphonate (neridronate)

Abstract

Summary Twenty patients with hypercalcaemia due to malignancy, which persisted following rehydration, were treated with the bisphosphonate, aminohexane bisphosphonate (AHBP), which is structurally similar to pamidronate. The treatment given was a single infusion of 125 mg of AHBP in 500 ml of normal saline infused over 4 h. Serum and urine biochemistry were measured before and after treatment. Acute toxicity was evaluated with particular attention to gastrointestinal symptoms, acute-phase reaction and change in renal function, as judged by serum creatinine. The infusion of AHBP induced a rapid fall apparent by day 3 (P<0.001), with a nadir at day 7. The serum calcium remained lower at days 14 and 28 than at day 0, but the numbers followed up were low (n = 5 and n = 4). In all 20 patients there was a fall in serum calcium after treatment, and in 13 (65%) normocalcaemia was achieved. Failure to respond completely to AHBP appeared to be associated with a renal mechanism of hypercalcaemia. Treatment was associated with a significant decrease in fasting urinary calcium excretion (P<0.05). There was no change in white cell count or renal function following AHBP and only two cases of mild pyrexia after infusion. We conclude that aminohexane bisphosphonate is an effective agent in the treatment of tumour-induced hypercalcaemia, with rapid onset of effect and low toxicity.Hypercalcaemia is a common complication of malignancy, occurring both in patients with solid tumours, particularly carcinoma of the breast and bronchus, and in patients with haematological malignancy. The pathophysiology of the condition varies according to the primary tumour and the presence or absence of focal bone metastases, but in the majority of cases the predominant mechanism is one of increased bone resorption (Bonjour & Rizzoli, 1989). Treatment strategies have therefore focused on the inhibition of bone resorption, and over the past decade the bisphosphonates, specific and potent inhibitors of osteoclastmediated bone resorption, have become the treatment of choice (Coleman & Rubens, 1987;Kanis et al., 1991).The bisphosphonates have in common the central P-C-P structure, but modifications of the side chains alter their biological characteristics, particularly their potency. There are currently three bisphosphonates available for the treatment of tumour-induced hypercalcaemia: 1-hydroxyethylidene-1,1-bisphosphonic acid (HEBP or etidronate), dichloromethylenebisphosphonic acid (Cl2MBP or clodronate) and 3-amino-ihydroxypropylidene-l ,1-bisphosphonic acid (AHPrBP or pamidronate). Pamidronate is the most potent, and research on other experimental compounds suggests that the amino derivatives are particularly active (Shinoda et al., 1983;Rizzoli et al., 1992).However, clinical studies have shown that pamidronate may be associated with a transient acute-phase response which can be manifested as pyrexia or leucopenia Morton et al., 1989). In addition, there are reports of muscle rigors, general malaise, thrombophlebitis and hypocalcaemia, and with the...

Neridronate: From Experimental Data to Clinical Use

“…In 20 patients with cancer-induced hypercalcaemia that persisted following rehydration, a single intravenous infusion of 125 mg of neridronate induced a rapid and significant decrease in adjusted serum calcium levels, and only 2 patients experienced mild hyperpyrexia after the neridronate infusion. 45 …”

Chronic Intravenous Aminobisphosphonate Therapy Increases High-Density Lipoprotein Cholesterol and Decreases Low-Density Lipoprotein Cholesterol

“…On the basis of these new findings on the metabolic activities of aminobisphosphonates we decided to investigate the effect on lipid metabolism during an ongoing phase 2 clinical trial on the skeletal effects of intravenous (iv) Neridronate (Abiogen, Pisa, Italy). This is an aminobisphosphonate that has been used in patients with Paget's disease and malignant hypercalcemia and that is structurally very similar to Pamidronate (Novartis, Switzerland) and Alendronate (MSD, USA), with the hydroxyl‐side chain being represented by aminohexane rather than aminopropane or aminobutane, respectively (7,8) …”

Neridronic acid for the treatment of bone metabolic diseases

“…over 4 h was able to significantly decrease serum calcium with a nadir after 7 days and normalization of serum calcium in 65% of the patients [39].…”