Summary
Of the many compounds belonging to the diphosphonate family, clodronate has been widely used in hypercalcemia and osteolysis of malignancy. All published reports indicate that clodronate can normalize plasma calcium in the majority of hypercalcemic, rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux. In these patients, clodronate, given intravenously either as a single infusion or as repeated daily administrations, can normalize serum calcium, usually 3–5 days after the onset of therapy. In these good responders, long-term maintenance treatment should be individually adjusted since relapse appears to depend upon the type of tumor, the extent of malignancy and the administration of anticancer therapy. In a subset of well-rehydrated hypercalcemic patients in whom increased tubular calcium reabsorption represents the prevailing disturbed calcium flux, the acute effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be experimentally reproduced in diphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from lung, kidney and breast carcinomas. This indicates that, in addition to antiosteolytic drugs, such as clodronate, patients with hypercalcemia of malignancy would benefit from the development of agents that can selectively reduce the renal tubular reabsorption of calcium. In patients displaying a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3. This homeostatic reaction probably explains why hypocalcemia rarely occurs in clodronate-treated patients. No serious side effects have been reported in cancer patients receiving oral clodronate, except for the occasional occurrence of mild and transient gastrointestinal upset. A large number of clinical studies indicate that clodronate is a safe and efficacious drug in the treatment of hypercalcemia of malignancy, particularly in cases in which increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium.
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References
Gasser AB, Morgan DB, Fleisch HA, Richelle LJ: The influence of two diphosphonates on calcium metabolism in the rat.Clin Sci 1972;43:31–45
Schenk R, Merz WA, Muhlbauer R, Russell RGG, Fleisch H: Effect of ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats.Calcif Tissue Res 1973;11:196–214
Bonjour JP, Rizzoli R, Jung A: Diphosphonate therapy in hypercalcemia of malignancy and tumoral osteolysis.Trends Pharmacol Sci 1984;5:509–511
Chapuy MC, Meunier PJ, Alexandre CM, Vignon EP: Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases.J Clin Invest 1980;65:1243–1247
Douglas DL, Russell RGG, Preston CJ, Prenton MA, Duckworth T, Kanis JA,et al: Effect of dichloromethylene diphosphonate in Paget's disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease.Lancet 1980;i:1043–1047
Jacobs TP, Siris ES, Bilezikian JP, Baquiran DC, Shane E, Canfield RE: Hypercalcemia of malignancy: treatment with intravenous dichloromethylene diphosphonate.Ann Intern Med 1981;94:3212–3216
Shane E, Jacobs TP, Siris ES, Steinberg SF, Stoddart K, Canfield RE, Bilezikian JP. Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate.Am J Med 1982;72:939–944
Jung A: Comparison of two parenteral diphosphonates in hypercalcemia of malignancy.Am J Med 1982;72:221–227
Paterson AD, Kanis JA, Cameron EC, Douglas DL, Beard DJ, Preston FE,et al: The use of dichloromethylene diphosphonate for the management of hypercalcaemia in multiple myeloma.Br J Haematol 1983;54:121–132
Siris ES, Sherman WH, Baquiran DC, Schlatterer JP, Osserman EF, Canfield RE: Effect of dichloromethylene diphosphonate on skeletal mobilization of calcium in multiple myeloma.N Engl J Med 1980;302:310–315
Delmas PD, Charhon S, Chapuy MC, Vignon E, Briancon D, Edouard C,et al: Long-term effects of dichloromethylene diphosphonate (Cl2MDP) on skeletal lesions in multiple myeloma.Metab Bone Dis Rel Res 1982;4:163–168
Jung A, Chantraine A, Donath A, van Ouwenaller C, Turnill D, Mermillod B,et al: Use of dichloromethylene diphosphonate in metastatic bone disease.N Engl J Med 1983;308:1499–1501
Bonjour JP, Rizzoli R, Hirschel-Scholz S, Caverzasio J: Management of hypercalcemia in relation to pathophysiology.Bone 1987;8(Suppl. 1):S29-S33
Buchs B, Rizzoli R, Bonjour JP: Prevalence of increased tubular reabsorption of calcium (Ca) in the pathogenesis of hypercalcemia [Abstract].J Bone Min Res 1989;4(Suppl. 1):S319
Fleisch H: Bisphosphonates: a new class of drug in diseases of bone and calcium metabolism. In: Brunner KW, Fleisch H, Senn HJ (eds):Recent Results in Cancer Research, Vol 116. Berlin: Springer Verlag, 1989; pp. 1–28
Mundy GR: Bone resorption and turnover in health and disease.Bone (1987);8(Suppl. 1):59-S16
Mundy GR, Roodman GD: Osteoclast ontogeny and function. In: Peck WA (ed.):Bone and Mineral Research/5. Amsterdam: Elsevier, 1987; pp. 209–279
Suva LJ, Winslow GA, Wettenhall REH, Hammonds RG, Moseley JM, Diefenbach-Jagger H,et al: A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression.Science 1987;237:893–896
Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, Leung SC,et al: Parathyroid hormone-like protein from human renal carcinoma cells: structural and functional homology with parathyroid hormone.J Clin Invest 1987;80:1803–1807
Pizurki L, Rizzoli R, Moseley J, Martin TJ, Caverzasio J, Bonjour JP: Effect of synthetic tumoral PTH-related peptide on cAMP production and Na-dependent Pi transport.Am J Physiol 1988;255:F957-F961
Rizzoli R, Caverzasio J, Chapuy MC, Martin TJ, Bonjour JP: Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats.J Bone Min Res 1989;4:759–765
Troehler U, Bonjour JP, Fleisch H: Interference of dichloromethylene diphosphonate with parathyroid hormone effects at the bone but not at the kidney level.Min Electrolyte Metab 1982;7:122–126
Bonjour JP, Troehler U, Preston C, Fleisch H: Parathyroid hormone and renal handling of Pi: effect of dietary Pi and diphosphonates.Am J Physiol 1978;234:F497-F505
Cohen AI, Koeller J, Davis TE, Citrin DL: IV dichloromethylene diphosphonate in cancer-associated hypercalcemia: a phase I–II evaluation.Cancer Treatment Rep 1981;65:651–653
Percival RC, Yates AJP, Gray RES, Galloway J, Rogers K, Neal FE,et al: Mechanism of malignant hypercalcaemia in carcinoma of the breast.Br Med J 1985;291:776–779
Bonjour JP, Philippe J, Guelpa G, Bisetti A, Rizzoli R, Jung A,et al: Bone and renal components in hypercalcemia of malignancy and responses to a single infusion of clodronate.Bone 1988;9:123–130
Witte RS, Koeller J, Davis TE, Benson III AB, Durie BG, Lipton A,et al: Clodronate: a randomized study in the treatment of cancer-related hypercalcemia.Arch Intern Med 1987;147:937–939
Ljunghall S, Rastad J, Akerstrom G: Comparative effects of calcitonin and clodronate in hypercalcemia.Bone 1987; 8(Suppl. 1):S79-S83
Urwin GH, Yates AJP, Gray RES, Hamdy NAT, McCloskey EV, Preston FE,et al: Treatment of the hypercalcaemia of malignancy with intravenous clodronate.Bone 1987;8 (Suppl. 1):S43-S51
Adami S, Bolzicco GP, Rizzo A, Salvagno G, Bertoldo F, Rossini M,et al: The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy.Bone and Mineral 1987;2:395–404
Ziegler R, Scharla SH: Treatment of tumor hypercalcemia with clodronate. In: Brunner KW, Fleisch H, Senn HJ (eds.):Recent Results in Cancer Research, Vol 116. Berlin: Springer Verlag, 1989; pp. 46–66
Rizzoli R, Buchs B, Froidevaux P, Bisetti A, Bonjour JP: A randomized study comparing the new diphosphonate aminohydroxybutanediphosphonate (ABDP) to dichloromethylenediphosphonate (Cl2MDP) in hypercalcemia of malignancy (HM).J Bone Min Res (1988;3(Suppl. 1):S128
Bonjour JP, Rizzoli R: Pathophysiological aspects and therapeutic approaches of tumoral osteolysis and hypercalcemia. In: Brunner KW, Fleisch H, Senn HJ (eds.):Recent Results in Cancer Research, Vol 116. Berlin: Springer Verlag, 1989; pp. 29–39
Hugi K, Bonjour JP, Fleisch H: Renal handling of calcium: influence of parathyroid hormone and 1,25-dihydroxyvitamin D3.Am J Physiol 1979;236:F349-F356
Bijvoet OLM, Harinck HIJ: The assessment of renal calcium reabsorption. In: Massry SG, Maschio G, Ritz E (ed.):Advances in Experimental Medicine and Biology, Vol. 78. New York and London: Plenum Press, 1984; pp. 111–126
Yasuda T, Banville D, Rabbani SA, Hendy GN, Goltzman D: Rat parathyroid hormone-like peptide: comparison with the human homologue and expression in malignant and normal tissue.Mol Endocrinol 1989;3:518–525
Rizzoli R, Bonjour JP: High extracellular calcium increases the production of a parathyroid hormone-like activity by cultured Leydig tumor cells associated with humoral hypercalcemia.J Bone Min Res 1989;4:839–844
Hirschel-Scholz S, Jung A, Fischer JA, Trechsel U, Bonjour JP: Suppression of parathyroid secretion after administration of WR-2721 in a patient with parathyroid carcinoma.Clin Endocrinol 1985;23:313–318
Bonjour JP, Freudiger H: Diphosphonates and calciumphosphate homeostasis. In: Donath A, Courvoisier B (eds.):Diphosphonates and Bone. Geneva: Imprimerie Médecine et Hygiène, 1982; pp. 46–73.
Delmas PD, Chapuy MC, Vignon E, Charhon S, Briancon D, Alexandre C,et al: Long-term effects of dichloromethylene diphosphonate in Paget's disease of bone.J Clin Endocrinol Metab 1982;54:837–844
Harris ST, Neer RM, Segre GV, Petkan AJ, Tully III GL, Daly M,et al: Secondary hyperparathyroidism associated with dichloromethylene diphosphonate treatment of Paget's disease.J Clin Endocrinol Metab 1982;55:1100–1107
Papapoulos SE, Harinck HIJ, Bijvoet OLM, Gleed JH, Fraher LJ, O'Riordan JLH: Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcaemic and hypercalcaemic patients treated with APD.Bone and Mineral 1986;1:69–78
Bonjour JP, Trechsel U, Taylor CM, Fleisch H: Parathyroid-hormone-independent regulation of 1,25-dihydroxyvitamin D in response to inhibition of bone resorption.Am J Physiol 1988;254:E260-E264
Hintze KL, D'Amato RA: Comparative toxicology of two diphosphonates.Toxicologist 1980;2:192
Kanis JA, Preston CJ, Yates AJP, Percival RC, Mundy KI, Russell RGG: Effects of intravenous diphosphonates on renal function.Lancet 1983;i:1328
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Bonjour, JP., Rizzoli, R. Clodronate in hypercalcemia of malignancy. Calcif Tissue Int 46 (Suppl 1), S20–S25 (1990). https://doi.org/10.1007/BF02553289
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DOI: https://doi.org/10.1007/BF02553289