Summary
The bisphosphonates comprise a new class of drugs, and are increasingly being used to treat bone diseases characterised by increased osteoclastic bone resorption. These compounds are generally well tolerated, but toxicity may vary considerably from one compound to another.
Dosages of etidronic acid above 800 mg/day impair the normal skeletal mineralisation and this may be associated with the appearance of fractures, but at the doses used for the treatment of osteoporosis, none of the bisphosphonates induce clinical or histological signs of impaired mineralisation.
The skeletal half-life of bisphosphonates is of the order of several years, but this appears to be of little clinical consequence since the pharmacological effect is of relatively short duration. The mechanical properties of the skeleton of animals treated over long periods with high doses of various bisphosphonates have been shown to be perfectly preserved. However, in growing individuals, excess inhibition of bone remodelling might induce osteopetrotic-like alterations.
When high doses of amino-bisphosphonates are given to patients who have never received bisphosphonate therapy, the patients may experience fevers up to 39°C for 1 to 3 days, associated with transient haematological changes resembling a typical acute-phase response.
Rapid intravenous injection of bisphosphonates at doses greater than 200 to 300mg may cause severe renal failure; this can be prevented by slowing the rate of infusion (<200 mg/h). Administration of high doses of bisphosphonates to patients with high bone turnover may induce a rapid and transient drop in serum calcium which is seldom symptomatic.
The gastrointestinal absorption of bisphosphonates is low, and they must be taken without food. Oral amino derivatives may induce dose-related serious gastrointestinal lesions, with the sporadic appearance of erosive oesophagitis.
Amino-bisphosphonate administration has been also associated with the sporadic occurrence of uveitis, scleritis and phlebitis and, in single cases, with irritative reactions at the skin, peritoneum and pericardium.
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References
Fleisch H. Bisphosphonates — history and experimental basis. Bone 1987; 8 Suppl. 1: 23–8
Fleisch H. Bisphosphonates: pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs 1991; 42: 919–44
Nixon GA, Buehler EV, Newmann EA. Preliminary safety assessment of disodium etidronate as an additive to experimental oral hygiene products. Toxicol Appl Pharmacol 1972; 22: 661–71
Nolen GA, Buehler EV. The effects of disodium etidronate on the reproductive functions and embryogeny of albino rats and New Zealand rabbits. Toxicol Appl Pharmacol 1971; 18: 548–61
Gertz BJ, Holland SD, Kline WF, et al. Clinical pharmacology of alendronate disodium. Osteoporos Int 1993; 3 Suppl.: 13–6
Halloran BP, De Luca HF. Effect of vitamin D deficiency on fertility and reproductive capacity in the female rat. J Nutr 1980; 110: 1573–80
Francis MD, Slough CL. Acute intravenous infusion of disodium dihydrogen (1-hydroxyethylidene)diphosphonate: mechanism of toxicity. J Pharm Sci 1984; 8: 1097–100
Troehler U, Bonjour JP, Fleisch H. Renal secretion of diphosphonates in rats. Kidney Int 1975; 8: 6–13
Troehler U, Bonjour JP, Fleisch H. Renal transport of bisphosphonates: accumulation by renal cortical slices enhanced by calcium phosphate ions. J Lab Clin Med 1985; 106: 23–9
Lin JH, Chen IW, Deluna FA, et al. Renal handling of alendronate in rats. An uncharacterized renal transport system. Drug Metab Dispos 1992; 20: 608–13
Cal JC, Daley-Yates PT. Disposition and nephrotoxicity of 3-amino-hydroxypropylidene-1,1-bisphosphonate (APD) in rats and mice. Toxicology 1990; 65: 179–97
Brazy PC, Gullans SR, Mandel L, et al. Metabolic requirement for inorganic phosphate by the rabbit proximal tubule. J Clin Invest 1982; 70: 53–62
Alden CL, Burns JL, Parker RD, et al. Characterization of the early ultrastructural and biochemical events occuring in dichloromethane diphosphonate nephrotoxicity. Toxicol Pathol 1990; 4: 661–6
Gralpel P, Bentley P, Fritz H, et al. Reproduction toxicity studies with pamidronate. Arzneimittel Forschung 1992; 42: 654–67
Minsken DH, Manson JM, Chennekatu PP. Effects of the bisphosphonate, Alendronate, on parturition in the rats. Toxicol Appl Pharmacol 1993; 121: 217–23
Adami S, Zamberlan N, Mian M, et al. Duration of the effects of intravenous alendronate in postmenopausal women and in patients with primary hyperparathyroidism. Bone Miner 1994; 5: 75–82
Netelenbos JC, Van Ginkel FC, Lips P, et al. Effect of a single infusion of aminohydroxypropylidene on calcium and bone metabolism in healthy volunteers monitored during 2 months. J Clin Endocrinol Metab 1991; 72: 223–8
Powell JH, De Mark BR. Clinical pharmacokinetics of diphosphonates. In: Garattini S, editor. Bone resorption metastases and diphosphonates. New York: Raven Press, 1985: 41–9
Fogelman I, Bessent RG, Turner JF, et al. The use of whole-body retention of Tc-99m diphosphonate in the diagnosis of metabolic bone disease. J Nucl Med 1978; 19: 270–5
Sato M, Grasser W, Endo N, et al. Bisphosphonate action: alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991; 88: 2095–105
Balena R, Toolan BC, Shea M, et al. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry and bone strength in ovariectomized non human primates. J Clin Invest 1993; 2577–86
Jowsey J, Holley KE, Linman JW. Effect of sodium etidronate in adult cats. J Lab Clin Med 1970; 76: 126–33
King WR, Francis MD, Michael WR. Effect of disodium ethane-1-hidroxy-1,1-diphosphonate on bone formation. Clin Orthop 1971; 78: 251–70
Schenk R, Merz WA, Muhlbauer R, et al. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (C12MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysys and metaphysys ofrats. Calcif Tissue Res 1973; 11: 196–214
Larsson A. The short-term effects of high doses of ethylene-1-hydroxy-1,1-diphosphonates upon early dentin formation. Calcif Tissue Res 1974; 16: 109–27
Jowsey J, Riggs BL, Kelly PJ, et al. The treatment of osteoporosis with disodium ethane-1-hydroxy-1,1-diphosphonate. J Lab Clin Med 1971; 78: 574–84
de Vries HR, Bijvoet OLM. Results of prolonged treatment of Paget’s disease of bone with disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP). Neth J Med 1974; 17: 281–9
Meunier P, Alexandre C, Khairi MRA, et al. Dose-dependent effects of EHDP on dynamics of bone remodeling in Paget’s disease: studies in involved and non-involved areas. Calcif Tissue Res 1977; 24: 17
Nagant de Deuxchains C, Rombouts-Lindemans C, Heiaux JP, et al. Roentgenologic evaluation of the action of the disphosphonate EHDP and of the combined therapy (EHDP and calcitonin) in Paget’s disease of bone. In: Maclntyre I, Szelka M, editors. Molecular endocrinology. Amsterdam: Elsevier/North-Holland Biomedical Press, 1979: 405–33
Reiner M, Sautter V, Olah A, et al. Disphosphonate treatment in myositis ossificans progressiva. In: Caniggia A, editor. Etidronate. Pisa: Istituto Gentili, 1980: 237
Johnston Jr CC, Altman RD, Canfield RE, et al. Review of fracture experience during treatment of Paget’s disease of bone with etidronate disodium (EHDP). Clin Orthop 1983; 172: 186–94
Boyce BF, Fogelman I, Ralston S, et al. Focal osteomalacia due to low dose diphosphonate therapy in Paget’s disease. Lancet 1984; i: 821–4
Storm T, Steiniche T, Thamsborg G, et al. Changes in bone histomorphometry after long-term treatment with intermittent, cyclic etidronate for postmenopausal osteoporosis. J Bone Miner Res 1993; 8(2): 199–208
Ott SM, Woodson GC, Huffer WE, et al. Bone histomorphometric changes after cyclic therapy with phosphate and etidronate disodium in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 1994; 78: 968–72
Axelrodt DW, Teitelbaum SL. Results of long-term cyclical etidronate therapy: bone histomorphometry and clinical correlates. J Bone Miner Res 1994; 9 Suppl. 1: 136
Adamson BR, Gallacher SJ, Byars J, et al. Mineralisation defects with pamidronate therapy for Paget’s disease. Lancet 1993; 342: 1459–60
Flora L, Hassing GS, Cloyd GG, et al. The long-term skeletal effects of EHDP in dogs. Metab Bone Dis Relat Res 1981; 4/5: 289–300
Flora L, Hassing GS, Parfitt AM, et al. Comparative skeletal effects of two diphosphonates in dogs. Metab Bone Dis Relat Res 1980; 2: 389–407
Chan MM, Riggins RS, Rucker RB. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dietary fluoride on biomechanical and biochemical changes in chick bone. J Nutr 1977; 107: 1747–54
Lafage MH, Balena R, Battle MA, et al. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. J Clin Invest 1995; 95: 2127–33
Lauritzen DB, Balena R, Shea M, et al. Effects of combined prostaglandin and alendronate treatment on the histomorphometry and biomechanical properties of bone in ovariectomized rats. J Bone Miner Res 1993; 7: 871–9
Motoie H, Nakamura T, O’Uchi N, et al. Effects of the bisphosphonate YM175 on the bone mineral density, strength, structure and turnover in ovariectomized beagles on concomitant dietary calcium restriction. J Bone Miner Res 1995; 6: 910–20
Geusens P, Nijs J, Van der Perre G, et al. Longitudinal effect of tiludronate on bone mineral density, resonant frequency and strength in monkeys. J Bone Miner Res 1992; 6: 599–609
Ferretti JL, Cointry G, Capozza RF, et al. Biomechanical effects of the full range of useful doses of (3-amino-1-hydroxy-propylidene)-1,1-bisphosphonate (APD) on femur diaphyses and cortical bone tissue in rats. Bone Miner 1990; 11: 111–22
Ferretti JL, Mondelo N, Capozza RF, et al. Effects of large doses of olpadronate (dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs. Bone 1995; 27: 285–93
Tarvainen R, Olkkonen H, Nevalainen T, et al. Effect of clodronate on fracture healing in denervated rats. Bone 1994; 15: 701–4
Katsumata T, Nakamura T, Ohnishi H, et al. Intermittent cyclical etidronate treatment maintains the mass, structure and the mechanical property of bone in ovariectomized rats. J Bone Miner Res 1995; 6: 921–31
Hoekman K, Papapoulos SE, Peters ACB, et al. Characteristics and bisphosphonate treatment of a patient with juvenile osteoporosis. J Clin Endocrinol Metab 1985; 61: 952–6
Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int 1987; 41: 326–31
Harink HIJ, Bijvoet OLM, Blanksma HJ, et al. Efficacious management with aminobisphosphonate (APD) in Paget’s disease of bone. Clin Orthop 1987; 217: 79–98
Bijvoet OLM, Frijlink WB, Jie K, et al. APD in Paget’s disease of bone: role of the mononuclear phagocyte system? Arthritis Rheum 1980; 23: 1193–204
Schweitzer DH, Oostendorp-van der Ruit M, van de Pluijm G, et al. Interleukin-6 and the acute-phase response during treatment of patients with Paget’s disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate. J Bone Miner Res 1995; 6: 956–962
O’Doherty DP, Bickestaff DR, McCloskey EV, et al. Treatment of Paget’s disease of bone with aminohydroxybutylidene bisphosphonate. J Bone Miner Res 1990; 5: 480–91
Boonekamp PM, van der Wee-Pals LJA, van Wijk-van Lennep MML, et al. Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1986; 1: 27–40
Reitsma PH, Teitelbaum DL, Bijvoet OLM, et al. Differential action of bisphosphonates (3-amino-1-hydroxy-propylidene)-1,1-bisphosphonate (APD) and disodium dichloromethylidene bisphosphonate (C12MDP) on rat macrophage-mediated bone resorption in vitro. J Clin Invest 1982; 70: 927–33
Cecchini MG, Fleisch H. Bisphosphonates in vitro specifically inhibits, among the hematopoietic series, the development of the mouse mononuclear phagocyte lineage. J Bone Miner Res 1990; 10: 1019–27
Labat ML, Florentini I, Davigny M, et al. Dichloromethylene disphosphonate (Cl2MDP) reduces natural killer (NK) cell activity in mice. Metab Bone Dis Relat Res 1984; 5: 281–7
Labat ML, Tzehoval E, Moricard Y, et al. Lack of a T-cell dependent subpopulation of macrophages in (dichloromethylene) disphosphonate-treated mice. Biomed Pharm 1983; 37: 270–6
Menkin C, Shapiro IM. Osteoclasts, mononuclear phagocytes, and physiological bone resorption. Calcif Tissue Int 1986; 39: 357–9
Data on file, Procter & Gamble
Mian M, Beghè F, Caprio A, et al. Tolerability and safety of clodronate therapy in bone diseases. Int J Clin Pharmacol Res 1991; 11: 107–14
Borgström GH, Elomaa I, Blomqvist C, et al. Cytogenetic investigations of patients on clodronate therapy for Paget’s disease of bone. Bone 1987; 8 Suppl. 1: 85–6
Bounameaux HM, Sheifferli J, Montani JP, et al. Renal failure associated with intravenous diphosphonates. Lancet 1983; i: 471
Adami S, Bolzicco GP, Rizzo A, et al. The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcaemia of malignancy. Bone Miner 1987; 2: 395–404
Conte N, Di Virgilio R, Rolter I, et al. Hypercalcemia in malignancies: treatment with dichloromethylene diphosphonate (C12MDP). Tumori 1985; 71: 51–4
Conte N, Di Virgilio R, Bettiol V. The use of dichloromethylene diphosphonate for the management of hypercalcemia of malignancies. Curr Ther Res 1986; 39: 421
Scharia SH, Minne HW, Sattar P, et al. Therapie der Tumorhypercalciamie mit Clodronat-einfluss auf Parathormon und Calcitriol. Deutsch Med Wochenschr 1987; 112: 1121–5
Kanis JA, Preston CJ, Yates AJP, et al. Effects of intravenous diphosphonates on renal function [letter]. Lancet 1983; i: 1328
Bonjour JP, Philippe J, Guelpa G, et al. Bone and renal components in hypercalcemia of malignancy and responses to a single infusion of clodronate. Bone 1988; 9: 123–30
Ralston SH, Alzaid AA, Gallacher SJ, et al. Clinical experience with minohydroxypropylidene bisphosphonate (APD) in the management of cancer-associated hypercalcemia. Q J Med 1988; 258: 825–34
Canfield RE, Sins ES, Jacobs TP. Dichlorometylene diphosphonate action in hematologic and other malignancies: Bone 1987; Suppl.: 57–62
Delmas PD, Charhon S, Chapuy MC, et al. Long-term effects of dichloromethylene diphosphonate (C12MDP) on skeletal lesions in multiple myeloma. Metab Bone Dis Relat Res 1982; 3: 163–8
Douglas DL, Kanis JA, Paterson AD, et al. Drug treatment of primary hyperparathyroidism: use of clodronate disodium. BMJ 1983; 286: 587–90
Douglas DL, Duckworth T, Kanis JA, et al. Biochemical and clinical responses to dichloromethylene diphosphonate (C12MDP) in Paget’s disease of bone. Arthritis Rheum 1980; 23: 1185–92
Dodwell DJ, Howell A, Ford J. Reduction in calcium excretion in women with breast cancer and bone metastasis using the oral biphosphonate pamidronate. Br J Cancer 1990; 61: 123–5
Harink HIJ, Papapoulos SE, Blanskma HJ, et al. Paget’s disease of bone: early and late response to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). BMJ 1987; 295: 1301–5
Tubiana-Hulin M, de Vernejoul MC, Brier M, et al. Traitement des hypercalcemies des metastases osteolytiques par l’amino-hydroxypropylidene-diphosphonate par voie orale. Presse Med 1984; 8: 483–6
Van Breukelen FJM, Bijvoet OLM, Frijlink WB, et al. Efficacy of amino-hydroxy-propylidene bisphosphonate in hypercalcemia: observations on regulation of serum calcium. Calcif Tissue Int 1982; 34: 321–7
Lufkin EG, Argueta R, Whitaker MD, et al. Pamidronate: an unrecognized problem in gastrointestinal tolerability. Osteoporos Int 1994; 4: 320–2
Maconi G, Bianchi Porro G. Multiple ulcerative esophagitis caused by alendronate. Am J Gastroenterol 1995; 90: 1889–90
Adami S, Mian M, Gatti D, et al. Effects of two oral doses of alendronate in the treatment of Paget’s disease of bone. Bone 1994; 4: 415–7
Adami S, Passeri M, Ortolani S, et al. Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone 1995; 17: 383–90
Evans KT, Roberts GN. Where do all the tablets go? Lancet 1976; ii: 1237–9
Papapoulos SE, Harink HIJ, Bijvoet OLM, et al. Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcemic and hypercalcemic patients treated with APD. Bone Miner 1986; 1: 69–78
Adami S, Frijlink WB, Bijvoet OLM, et al. Regulation of calcium absorption by 1,25-dihydroxy-vitamin D. Studies of the effects of a bisphosphonate treatment. Cacif Tissue Int 1982; 34: 317–20
Pederson-Bjergaard O, Myhre J. Severe hypocalcaemia after treatment with disphosphonate and aminoglycoside. BMJ 1991; 302: 295
Mayordomo JI, Rivera F. Severe hypocalcemia after treatment with oral clodronate and aminoglycoside. Ann Oncol 1993; 4: 432–3
Walton RJ, Russell RGG, Smith R. Changes in the renal and extrarenal handling of phosphate induced by disodium etidronate (EHDP) in man. Clin Sci Mol Med 1979; 49: 45–56
Gallacher SJ, Boyle IT, Capell HA. Pseudogout associated with the use of cyclical etidronate therapy. Scott Med J 1991; 36: 49
Recker RR, Hassig GS, Lau JR, et al. The hyperphosphatemic effect of disodium ethane-1-hydroxy-l,1-disphosphonates (EHDP TM). Renal handling of phosphorus and the renal response to parathyroid hormone. J Lab Clin Med 1973; 81: 258–66
Russel RGG, Smith R, Preston C, et al. Diphosphonates in Paget’s disease. Lancet 1974; i: 894–8
Challa A, Noorwali AA, Bevington A, et al. Cellular phosphate metabolism in patients receiving biphosphonate therapy. Bone 1986; 7: 255–9
Vasikaran SD, O’Doherty DP, McCloskey EV, et al. The effect of alendronate on renal tubular reabsorption of phosphate. Bone Miner 1994; 27: 51–6
Macarol V, Fraunfelder F. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophthalmol 1994; 118: 220–4
Siris ES. Bisphosphonates and iritis. Lancet 1993; 341: 436
Ghose K, Waterworth R, Trolove P, et al. Uveitis associated with pamidronate. Aust NZ J Med 1994; 24: 320
Reid IR, Mills DAJ, Wattie DJ. Ototoxicity associated with intravenous bisphosphonate administration. Calcif Tissue Int 1995; 56: 584–5
Calligeros D, Douglas P, Abeygunasekera S, et al. Aseptic peritonitis in association with the use of pamidronate. Med J Aust 1993; 159: 144
Foley-Nolan D, Daly MJ, Williams D, et al. Pamidronate associated hallucinations. Ann Rheum Dis 1992; 51: 927–8
Schweitzer DH, Zwinderman AH, Vermeil P, et al. Improved treatment of Paget’s disease with dimethylaminohydroxy-propylidene bisphosphonate. J Bone Miner Res 1993; 2: 175–82
Ralston SH, Gardner MD, Drybury FJ, et al. Comparison of aminohydroxypropylidene bisphosphonate, mithramycin and corticosteroids/calcitonin in treatment of cancer associated hypercalcaemia. Lancet 1985; ii: 907–10
Pajus I, Lestang P, Liote F, et al. Erythroderma after clodronate treatment. BMJ 1993; 307: 84
Mautalen CA, Casco CA, Gonzalez D, et al. Side effects of disodium aminohydroxypropylidene-disphosphonate (APD) during treatment of bone diseases. BMJ 1984; 288: 828–9
Elliot AT, Murray T, Mackie RM, et al. Severe reaction to diphosphonate: implications for treatment of Paget’s disease. BMJ 1988; 297: 592–3
Roux C, Listrat V, Villette B, et al. Long-lasting dermatological lesions after tiludronate therapy. Calcif Tissue Int 1992; 50: 378–80
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Adami, S., Zamberlan, N. Adverse Effects of Bisphosphonates. Drug-Safety 14, 158–170 (1996). https://doi.org/10.2165/00002018-199614030-00003
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DOI: https://doi.org/10.2165/00002018-199614030-00003