Severe hypocalcaemia after being given intravenous bisphosphonate
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《英国医生杂志》
1 Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA
Correspondence to: W D Fraser w.d.fraser@liv.ac.uk
Introduction
Several reports note patients have become hypocalcaemic after receiving bisphosphonates.4-7 Most patients do not become hypocalcaemic because of compensatory mechanisms, the most important of which is increased secretion of parathyroid hormone.1 The ability of the parathyroid gland to start a parathormone response and the degree of increase in parathyroid hormone prevents hypocalcaemia, due to renal reabsorption of calcium, increased vitamin D production, and stimulation of osteoclasts to resorb bone. For patients taking bisphosphonates, the effect of parathyroid hormone on resorption by osteoclasts is blocked, to an extent, depending on the potency of the bisphosphonate.
Each patient showed a different reason for the lack of a parathyroid hormone response to hypocalcaemia. We saw surgical hypoparathyroidism, hypomagnesaemic hypoparathyroidism, and pre-existing secondary hyperparathyroidism; each pathology interfered with the expected physiological response to hypocalcaemia. Lack of increase in parathyroid hormone results in reduced compensatory mechanisms. In addition, low vitamin D in two patients (cases 1 and 3) may have also contributed to hypocalcaemia and decreased synthesis of 1,25-dihydroxy vitamin D. Bone lining cells are present on the surface of bone and retract to expose the bone for osteoclasts. Parathyroid hormone or cytokines may stimulate retraction. Although little evidence shows inhibition of the activity of lining cells by bisphosphonates, such action may affect the normal calcaemic response.
Zoledronic acid is a new potent bisphosphonate with increased effectiveness, and it suppresses the formation and function of osteoclasts more than recommended doses of older bisphosphonates.3 8 Care is needed in patients who are normocalcaemic or hypocalcaemic, with low urinary calcium filtration and excretion, because the normal effect of calcium reabsorption promoted by parathyroid hormone at the renal tubules may not be present to protect against hypocalcaemia. Also, in patients with established renal impairment, care is needed because the kidneys predominantly excrete bisphosphonates.9
Patients given zoledronic acid adjuvantly or for prophylactic treatment for cancer, should also be prescribed a supplement of calcium and vitamin D. This would help prevent hypocalcaemia and secondary hyperparathyroidism. Patients with pre-existing gastrointestinal disease may also experience problems as a result of malabsorption of calcium or magnesium or gastrointestinal loss of these cations and may benefit from dietary supplementation.
The effectiveness of bisphosphonates at treating hypercalcaemia has resulted in their increased use, regardless of cause. Before starting treatment with bisphosphonates or repeating prescriptions, doctors should consider the cause of hypercalcaemia and the calcium and parathyroid status of the patient. Hypercalcaemia is not usually life threatening; immediate rehydration with sodium chloride often lowers serum calcium.10 Rehydration with sodium chloride also improves the effectiveness of bisphosphonates.11 We recommend careful clinical and biochemical evaluation before giving the more potent and longer acting bisphosphonates, such as zoledronic acid.
Severe hypocalcaemia after giving bisphosphonates may be caused by pathology interfering with parathyroid function
Contributors: RP and VM collected information and data on the patients. RP, VM, and WDF were involved in managing the patients and wrote the article. WDF had the idea and is guarantor.
Funding: None.
Competing interests: WDF has given lectures and received funding from Boehringer Ingelheim, MSD, Novartis, Procter & Gamble, Roche, and Sanofi. WDF has acted in a consulting capacity for Boehringer Ingelheim, MSD, and Novartis.
References
Fraser WD, Logue FC, Gallacher SJ, O'Reilly DS, Beastall GH, Ralston SH, et al. Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcemia of malignancy. Bone Miner 1991;12: 113-21.
Vinholes J, Guo CY, Purohit OP, Eastell R, Coleman RE. Metabolic effects of pamidronate in patients with metastatic bone disease. Br J Cancer 1996;73: 1089-95.
Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey JA, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double blind comparative trial. Cancer J 2001;7: 377-87.
Mishra A, Wong L, Jonklaas J. Prolonged symptomatic hypocalcaemia with pamidronate administration and subclinical hypoparathyroidism. Endocrine 2001;14: 159-64.
Sims EC, Rogers PB, Besser GM, Plowman PN. Severe prolonged hypocalcaemia following pamidronate for malignant hypercalcaemia. Clin Oncol (R Coll Radiol) 1998;10: 407-9.
Comlekci A, Biberoglu S, Hekimsoy Z, Okan I, Piskin O, Sekeroglu B, et al. Symptomatic hypocalcaemia in a patient with latent hypoparathyroidism and breast carcinoma with bone metastasis following administration of pamidronate. Intern Med 1998;37: 396-7.
McIntyre E, Bruera E. Symptomatic hypocalcaemia after intravenous pamidronate. J Palliat Care 1996;12: 46-7.
Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcaemia: a pooled analysis of two randomised, controlled clinical trials. J Clin Oncol 2001;19: 558-67.
Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 1996;45: 175-9.
Hosking DJ, Cowley A, Bucknall CA. Rehydration in the treatment of severe hypercalcaemia. Q J Med 1981;50: 473-81.
Harinck HI, Bijvoet OL, Plantingh AS, Body JJ, Elte JW, Sleeboom HP, et al. Role of bone and kidney in tumour-induced hypercalcaemia and its treatment with bisphosphonate and sodium chloride. Am J Med 1987;82: 1133-42.(Rajesh Peter, senior hous)
Correspondence to: W D Fraser w.d.fraser@liv.ac.uk
Introduction
Several reports note patients have become hypocalcaemic after receiving bisphosphonates.4-7 Most patients do not become hypocalcaemic because of compensatory mechanisms, the most important of which is increased secretion of parathyroid hormone.1 The ability of the parathyroid gland to start a parathormone response and the degree of increase in parathyroid hormone prevents hypocalcaemia, due to renal reabsorption of calcium, increased vitamin D production, and stimulation of osteoclasts to resorb bone. For patients taking bisphosphonates, the effect of parathyroid hormone on resorption by osteoclasts is blocked, to an extent, depending on the potency of the bisphosphonate.
Each patient showed a different reason for the lack of a parathyroid hormone response to hypocalcaemia. We saw surgical hypoparathyroidism, hypomagnesaemic hypoparathyroidism, and pre-existing secondary hyperparathyroidism; each pathology interfered with the expected physiological response to hypocalcaemia. Lack of increase in parathyroid hormone results in reduced compensatory mechanisms. In addition, low vitamin D in two patients (cases 1 and 3) may have also contributed to hypocalcaemia and decreased synthesis of 1,25-dihydroxy vitamin D. Bone lining cells are present on the surface of bone and retract to expose the bone for osteoclasts. Parathyroid hormone or cytokines may stimulate retraction. Although little evidence shows inhibition of the activity of lining cells by bisphosphonates, such action may affect the normal calcaemic response.
Zoledronic acid is a new potent bisphosphonate with increased effectiveness, and it suppresses the formation and function of osteoclasts more than recommended doses of older bisphosphonates.3 8 Care is needed in patients who are normocalcaemic or hypocalcaemic, with low urinary calcium filtration and excretion, because the normal effect of calcium reabsorption promoted by parathyroid hormone at the renal tubules may not be present to protect against hypocalcaemia. Also, in patients with established renal impairment, care is needed because the kidneys predominantly excrete bisphosphonates.9
Patients given zoledronic acid adjuvantly or for prophylactic treatment for cancer, should also be prescribed a supplement of calcium and vitamin D. This would help prevent hypocalcaemia and secondary hyperparathyroidism. Patients with pre-existing gastrointestinal disease may also experience problems as a result of malabsorption of calcium or magnesium or gastrointestinal loss of these cations and may benefit from dietary supplementation.
The effectiveness of bisphosphonates at treating hypercalcaemia has resulted in their increased use, regardless of cause. Before starting treatment with bisphosphonates or repeating prescriptions, doctors should consider the cause of hypercalcaemia and the calcium and parathyroid status of the patient. Hypercalcaemia is not usually life threatening; immediate rehydration with sodium chloride often lowers serum calcium.10 Rehydration with sodium chloride also improves the effectiveness of bisphosphonates.11 We recommend careful clinical and biochemical evaluation before giving the more potent and longer acting bisphosphonates, such as zoledronic acid.
Severe hypocalcaemia after giving bisphosphonates may be caused by pathology interfering with parathyroid function
Contributors: RP and VM collected information and data on the patients. RP, VM, and WDF were involved in managing the patients and wrote the article. WDF had the idea and is guarantor.
Funding: None.
Competing interests: WDF has given lectures and received funding from Boehringer Ingelheim, MSD, Novartis, Procter & Gamble, Roche, and Sanofi. WDF has acted in a consulting capacity for Boehringer Ingelheim, MSD, and Novartis.
References
Fraser WD, Logue FC, Gallacher SJ, O'Reilly DS, Beastall GH, Ralston SH, et al. Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcemia of malignancy. Bone Miner 1991;12: 113-21.
Vinholes J, Guo CY, Purohit OP, Eastell R, Coleman RE. Metabolic effects of pamidronate in patients with metastatic bone disease. Br J Cancer 1996;73: 1089-95.
Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey JA, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double blind comparative trial. Cancer J 2001;7: 377-87.
Mishra A, Wong L, Jonklaas J. Prolonged symptomatic hypocalcaemia with pamidronate administration and subclinical hypoparathyroidism. Endocrine 2001;14: 159-64.
Sims EC, Rogers PB, Besser GM, Plowman PN. Severe prolonged hypocalcaemia following pamidronate for malignant hypercalcaemia. Clin Oncol (R Coll Radiol) 1998;10: 407-9.
Comlekci A, Biberoglu S, Hekimsoy Z, Okan I, Piskin O, Sekeroglu B, et al. Symptomatic hypocalcaemia in a patient with latent hypoparathyroidism and breast carcinoma with bone metastasis following administration of pamidronate. Intern Med 1998;37: 396-7.
McIntyre E, Bruera E. Symptomatic hypocalcaemia after intravenous pamidronate. J Palliat Care 1996;12: 46-7.
Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcaemia: a pooled analysis of two randomised, controlled clinical trials. J Clin Oncol 2001;19: 558-67.
Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 1996;45: 175-9.
Hosking DJ, Cowley A, Bucknall CA. Rehydration in the treatment of severe hypercalcaemia. Q J Med 1981;50: 473-81.
Harinck HI, Bijvoet OL, Plantingh AS, Body JJ, Elte JW, Sleeboom HP, et al. Role of bone and kidney in tumour-induced hypercalcaemia and its treatment with bisphosphonate and sodium chloride. Am J Med 1987;82: 1133-42.(Rajesh Peter, senior hous)