Hypocalcaemia after intravenous bisphosphonate
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《英国医生杂志》
EDITOR—The word limit for lessons of the week can result in removal of discussion points during editing. We considered several of Breay's and Fergus's comments in early versions of our article. Their points are valid, and doctors prescribing bisphosphonates must read the product information and understand what can happen if the prescribing guidelines are not followed.
Our cases highlighted severe hypocalcaemia after bisphosphonate treatment, and, although mild hypocalcaemia is a well documented side effect, we are sure that Breay would agree that such dangerously low serum calcium values are not seen in 1-10% of patients treated with bisphosphonates. Experienced doctors treating hypercalcaemia of malignancy commonly use doses of 60-90 mg pamidronate for a calcium concentration around 3.0 mmol/l, and the Novartis sponsored study comparing zoledronic acid and pamidronate in patients with values 3.0 mmol/l used 90 mg pamidronate.1 Although failure to comply with prescribing recommendations may have contributed to the effects seen in our cases, the inability to mount a normal physiological response as described played a large part in the severe hypocalcaemia.
Palmieri et al misquote and wrongly interpret us. At no point did we advocate that "bisphosphonates can be used as prophylaxis against metastatic bone cancer." We wrote: "Bisphosphonates are increasingly used to treat metabolic bone disease and as prophylaxis against metastatic cancer."
Reviews and meta-analyses of bisphosphonates in cancer have shown clear advantages in terms of reduced skeletal morbidity.2 Guidelines outline the accepted use of these drugs.3 Recent studies have further defined the value of bisphosphonates such as zoledronic acid in several clinical settings and show treatment advantage in reducing skeletal related events in some cancers.4 The study by Saarto et al seems to contradict these findings, but the methodological problems, including a randomisation schedule that resulted in a significant imbalance of hormone receptor positive breast cancers in the two treatment groups,5 are greatly discussed at international meetings. The adverse effect of clodronate on overall survival lost significance in multivariate analysis. Further trials should clarify the position of adjuvant bisphosphonates in treating and preventing cancer related bone disease.
Rajesh Peter, senior house officer
Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
Vinita Mishra, specialist registrar
Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
William D Fraser, professor
w.d.fraser@liverpool.ac.uk, Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
Competing interests: WDF has given lectures and received funding from Boehringer Ingelheim, MSD, Novartis, Procter and Gamble, Roche, and Sanofi. WDF has acted in a consulting capacity for Boehringer Ingelheim, MSD, and Novartis.
References
Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19: 558-67.
Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al. A systematic review of the role of bisphosphonates in metastatic disease. Health Technol Assess 2004;8: 1-176.
British Association of Surgical Oncology Guidelines. The management of metastatic bone disease in the United Kingdom. Eur J Surg Oncol 1999;25: 3-23.
Brown JE, Neville-Webbe H, Coleman RE. The role of bisphosphonates in breast and prostate cancers. Endocr Relat Cancer 2004;11: 207-24.
Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19: 10-7.
Our cases highlighted severe hypocalcaemia after bisphosphonate treatment, and, although mild hypocalcaemia is a well documented side effect, we are sure that Breay would agree that such dangerously low serum calcium values are not seen in 1-10% of patients treated with bisphosphonates. Experienced doctors treating hypercalcaemia of malignancy commonly use doses of 60-90 mg pamidronate for a calcium concentration around 3.0 mmol/l, and the Novartis sponsored study comparing zoledronic acid and pamidronate in patients with values 3.0 mmol/l used 90 mg pamidronate.1 Although failure to comply with prescribing recommendations may have contributed to the effects seen in our cases, the inability to mount a normal physiological response as described played a large part in the severe hypocalcaemia.
Palmieri et al misquote and wrongly interpret us. At no point did we advocate that "bisphosphonates can be used as prophylaxis against metastatic bone cancer." We wrote: "Bisphosphonates are increasingly used to treat metabolic bone disease and as prophylaxis against metastatic cancer."
Reviews and meta-analyses of bisphosphonates in cancer have shown clear advantages in terms of reduced skeletal morbidity.2 Guidelines outline the accepted use of these drugs.3 Recent studies have further defined the value of bisphosphonates such as zoledronic acid in several clinical settings and show treatment advantage in reducing skeletal related events in some cancers.4 The study by Saarto et al seems to contradict these findings, but the methodological problems, including a randomisation schedule that resulted in a significant imbalance of hormone receptor positive breast cancers in the two treatment groups,5 are greatly discussed at international meetings. The adverse effect of clodronate on overall survival lost significance in multivariate analysis. Further trials should clarify the position of adjuvant bisphosphonates in treating and preventing cancer related bone disease.
Rajesh Peter, senior house officer
Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
Vinita Mishra, specialist registrar
Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
William D Fraser, professor
w.d.fraser@liverpool.ac.uk, Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
Competing interests: WDF has given lectures and received funding from Boehringer Ingelheim, MSD, Novartis, Procter and Gamble, Roche, and Sanofi. WDF has acted in a consulting capacity for Boehringer Ingelheim, MSD, and Novartis.
References
Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19: 558-67.
Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al. A systematic review of the role of bisphosphonates in metastatic disease. Health Technol Assess 2004;8: 1-176.
British Association of Surgical Oncology Guidelines. The management of metastatic bone disease in the United Kingdom. Eur J Surg Oncol 1999;25: 3-23.
Brown JE, Neville-Webbe H, Coleman RE. The role of bisphosphonates in breast and prostate cancers. Endocr Relat Cancer 2004;11: 207-24.
Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19: 10-7.