Bisphosphonates

(USAN, rINNM)
Bisphosphonates Chemical formula

💊 Chemical information

Bifosfonatos; Biphosphonates; Diphosphonates.
Bisphosphonates are analogues of pyrophosphate, in which the central oxygen atom is replaced by a carbon atom with two further substituents—see Figure 1. Like pyrophosphate they have a strong affinity for bone. The bisphosphonates are used chiefly for their antiresorptive and hypocalcaemic properties (see Uses and Administration, below).

💊 Adverse Effects, Treatment, and Precautions

Bisphosphonates may cause gastrointestinal disturbances including abdominal pain, nausea and vomiting, and diarrhoea or constipation. Peptic ulceration has been reported. Existing gastrointestinal problems may be exacerbated, and oral bisphosphonates should generally be given with care or avoided if acute upper gastrointestinal inflammation is present. Gastrointestinal disturbances may be more frequent with aminobisphosphonates such as alendronate, ibandronate, and risedronate; oesophagitis has also occurred. General precautions to minimise the risk of oesophageal reactions, should be observed. Disturbances in serum electrolytes may occur, most commonly hypocalcaemia and hypophosphataemia. Existing hypocalcaemia or other disturbances of bone and mineral metabolism should be effectively treated before starting bisphosphonate therapy. Adequate intake of calcium and vitamin D is important, and supplementation may be needed if dietary intake is insufficient. Bisphosphonates may cause musculoskeletal pain (which can be severe and incapacitating), osteonecrosis of the jaw (see also Dental Care, below), ocular disturbances, and headache. Hypersensitivity reactions have occurred rarely; angioedema, rashes, urticaria, and pruritus have been reported. Other rare adverse effects include blood disorders such as anaemia, thrombocytopenia, leucopenia and disturbances in liver enzyme values. Transient fever and flu-like symptoms have been reported, usually at the start of treatment, and are common with infusions of ibandronate, pamidronate, and zoledronate. There may be local reactions, including thrombophlebitis, after parenteral doses. Dizziness, vertigo, asthenia, peripheral oedema, paraesthesia, taste disturbances, and joint disorders have also occurred. Impairment of renal function has been reported with bisphosphonates, particularly when given parenterally. As a result their use should generally be avoided in patients with moderate to severe renal impairment and they should be used with care in those with lesser degrees of renal impairment. Etidronate interferes with bone mineralisation, especially at higher doses, which can result in osteomalacia and an increased incidence of fracture. Etidronate should be stopped if a fracture occurs, until healing is complete. It has also been associated with a flare in bone pain in some patients with Paget’s disease. Impaired mineralisation is much less marked at usual doses of other bisphosphonates. Overdosage with bisphosphonates would be likely to result in symptoms of hypocalcaemia; if necessary, parenteral infusion of a calcium salt could be given. Giving milk or antacids, to bind the bisphosphonate and minimise absorption, has been suggested for oral overdosage. There is little clinical experience with bisphosphonates in pregnancy and they are generally contra-indicated; bisphosphonates have been associated with skeletal ab-
normalities in the fetus when given to pregnant animals.
1. Adami S, Zamberlan N. Adverse effects of bisphosphonates: a comparative review. Drug Safety 1996; 14: 158–70
2. Body J-J. Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 2001; 28 (suppl): 49–53
3. Kherani RB, et al. Long-term tolerability of the bisphosphonates in postmenopausal osteoporosis: a comparative review. Drug Safety 2002; 25: 781–90
4. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006; 17: 897–907
5. Bobba RS, et al. Tolerability of different dosing regimens of bisphosphonates for the treatment of osteoporosis and malignant bone disease. Drug Safety 2006; 29: 1133–52
6. Strampel W, et al. Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Safety 2007; 30: 755–63.

Dental care.

Osteonecrosis of the jaw has been reported in patients given bisphosphonates (see Effects on the Musculoskeletal System, below). Of the published cases most were associated with intravenous therapy in cancer patients, although some have followed oral therapy in patients with osteoporosis. In many cases the effect followed dental surgery. The Adverse Drug Reactions Advisory Committee in Australia has recommended that all patients scheduled to receive intravenous bisphosphonates should have a dental review,1 and that any dental procedures be completed before beginning the drug.1,2 Furthermore, health professionals should be aware of the presenting clinical features of osteonecrosis.2 In the UK, the Commission on Human Medicines has recommended that a dental review should be considered before bisphosphonate treatment in patients with risk factors such as cancer, chemotherapy, corticosteroid therapy, or poor oral hygiene.3 Licensed information for some bisphosphonates has been amended in a number of countries to include similar warnings.4
1. Adverse Drug Reactions Advisory Committee (ADRAC). Bisphosphonates and osteonecrosis of the jaw. Aust Adverse Drug React Bull 2005; 24: 3. Also available at: http://www.tga.gov.au/ adr/aadrb/aadr0502.pdf (accessed 30/11/06
2. Adverse Drug Reactions Advisory Committee (ADRAC). Osteonecrosis of the jaw (ONJ) with bisphosphonates. Aust Adverse Drug React Bull 2006; 25: 14. Also available at: http:// www.tga.gov.au/adr/aadrb/aadr0608.pdf (accessed 30/11/06
3. Commission on Human Medicines/Medicines and Healthcare products Regulatory Agency. Osteonecrosis of the jaw with bisphosphonates. Current Problems 2006; 31: 4–5. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON2023860&RevisionSelectionMethod= LatestReleased (accessed 23/07/08
4. Tarassoff P, Hei Y-J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353: 101–102. Correction. ibid.; 2728.

Effects on the ears.

For mention of ototoxicity associated with the use of etidronate in 2 patients with pre-existing otosclerosis, and a recommendation that such patients be monitored when given bisphosphonates. For similar effects with pamidronate.

Effects on the eyes.

Ocular effects have been associated with bisphosphonates and although reactions to pamidronate appeared to be rare, the manufacturers were aware of 23 cases up to September 1993 that were possibly associated with the drug.1The reactions included anterior uveitis in 7 patients and unilateral episcleritis or scleritis in 3. In one previously reported case,2 bilateral iritis was associated with risedronate and subsequently pamidronate in a patient who had earlier received etidronate without ill-effect. There have been subsequent reports of unilateral and bilateral scleritis with pamidronate, requiring the drug to be stopped.3 Anterior3,4 and posterior5 uveitis have continued to be reported, and more recently, diplopia with conjunctival swelling and eyelid oedema.6,7 Similarly, alendronate8-11 and zoledronate12 have been associated with scleritis and anterior uveitis. Scleritis,13 episcleritis,14 and uveitis15 have also been reported with risedronate, and bilateral anterior uveitis with clodronate.16 Non-specific conjunctivitis and abnormal or blurred vision have occurred with most of the bisphosphonates, including etidronate.13 Dry eye, sore eye, and conjunctivitis were the most frequently reported ophthalmological events assessed as related to risedronate therapy in a prescription-event monitoring study in England.17 The Australian Adverse Drug Reactions Advisory Committee was aware of 38 reports of serious ocular reactions to bisphosphonates as of April 2004; these were associated with pamidronate or alendronate in 18 cases each, and risedronate or zoledronate in 1 case each.15 Most reports were of inflammatory reactions such as uveitis, iritis, scleritis, episcleritis, or optic neuritis, and occurred a median of 3 weeks after starting therapy. The risk might be higher with intravenous bisphosphonates, but the frequency of reports was thought to relate mostly to usage.15Acute retinal pigment epitheliitis has been reported after an intravenous infusion of zoledronate.18 Patients who have ocular pain or vision loss while taking bisphosphonates should have the drug stopped and be referred to an ophthalmologist.13
1. Macarol V, Fraunfelder FT. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophthalmol 1994; 118: 220–4
2. Siris ES. Bisphosphonates and iritis. Lancet 1993; 341: 436–7
3. Fraunfelder FW, et al. Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 2003; 135: 219–22
4. Rey J, et al. Uveitis, an under-recognized adverse effect of pamidronate: case report and literature review. Joint Bone Spine 2000; 67: 337–40
5. Haverbeke G, et al. Posterior uveitis: an under-recognized adverse effect of pamidronate: 2 case reports. Bull Soc Belge Ophtalmol 2003; 290: 71–6
6. Meaney TPJ, et al. Diplopia following intravenous administration of pamidronate. Eye 2004; 18: 103–4
7. Ryan PJ, Sampath R. Idiopathic orbital inflammation following intravenous pamidronate. Rheumatology (Oxford) 2001; 40: 956–7
8. Mbekeani JN, et al. Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 1999; 117: 837–8
9. Malik AR, et al. Bilateral acute anterior uveitis after alendronate. Br J Ophthalmol 2002; 86: 1443
10. Salmen S, et al. Nongranulomatous anterior uveitis associated with alendronate therapy. Invest Clin 2002; 43: 49–52
11. Asensio Sánchez VM, et al. Bifosfonatos e inflamación intraocular. Arch Soc Esp Oftalmol 2004; 79: 85–8
12. Moore MM, Beith JM. Acute unilateral anterior uveitis and scleritis following a single infusion of zoledronate for metastatic breast cancer. Med J Aust 2008; 188: 370–1
13. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med 2003; 348: 1187–8
14. Viñas G, et al. Epiescleritis secundaria a risedronato. Med Clin (Barc) 2002; 118: 598–9
15. Adverse Drug Reactions Advisory Committee (ADRAC). Bisphosphonates and ocular inflammation. Aust Adverse Drug React Bull 2004; 23: 7–8. Also available at: http:// www.tga.gov.au/adr/aadrb/aadr0404.htm (accessed 22/02/05
16. Fietta P, et al. Clodronate induced uveitis. Ann Rheum Dis 2003; 62: 378
17. Aurich-Barrera B, et al. Ophthalmological events in patients receiving risedronate: summary of information gained through follow-up in a prescription-event monitoring study in England. Drug Safety 2006; 29: 151–60
18. Gilhotra JS, et al. Acute retinal pigment epitheliitis associated with intravenous bisphosphonate. Br J Ophthalmol 2006; 90: 798–9.

Effects on the heart.

In a study of once-yearly zoledronate for the treatment of postmenopausal osteoporosis, the number of patients who had arrhythmia in the zoledronate group was significantly higher than that in the placebo group.1 An increased incidence of serious atrial fibrillation was also seen in the zoledronate group. Fifty patients in the zoledronate group had serious atrial fibrillation, compared with 20 patients in the placebo group. Among the 50 patients, the events occurred more than 30 days after infusion in 47 patients, by which time zoledronate would be undetectable in the circulation. The mechanism by which bisphosphonates might cause arrhythmia or atrial fibrillation is unclear; little or no effect on serum calcium concentrations was seen when measured 9 to 11 days after zoledronate infusion. In an analysis2 of a randomised study of alendronate in postmenopausal women with osteoporosis, 47 serious atrial fibrillation adverse events were reported in the alendronate group, compared with 31 events among those receiving placebo. There was no increased risk of all atrial fibrillation adverse events. Although the observed association might have been due to chance,1 it was felt that the possibility of an increased risk of atrial fibrillation with bisphosphonates should be explored.2 Two case-control studies examining the association3,4 came to opposite conclusions as to whether bisphosphonate treatment increased the risk of atrial fibrillation. In the UK, the MHRA stated in July 2008 that any risk appeared low and the balance of risk and benefit for bisphosphonates remained favourable.5 The FDA in the USA, which came to similar preliminary conclusions, was said to be seeking additional data for a more detailed analysis.
1. Black DM, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356: 1809–22
2. Cummings SR, et al. Alendronate and atrial fibrillation. N Engl J Med 2007; 356: 1895–6
3. Heckbert SR, et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008; 168: 826–31
4. Sørensen HT, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008; 336: 813–16
5. MHRA/CHM. Bisphosphonates: atrial fibrillation. Drug Safety Update 2008; 1 (12): 4. Available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON020567&RevisionSelectionMethod= LatestReleased (accessed 16/07/08)
Figure 1. Comparative structures of the bisphosphonates. OPP OO OH OHHO HO Pyrophosphate R 1 R 2 Name C 3 H 6 .NH 2 OH Alendronic Acid Cl Cl Clodronic Acid CH 3 OH Etidronic Acid C 2 H 4 .NCH 3 .C 5 H 11 OH Ibandronic Acid C 7 H 13 .NH H Incadronic Acid H H Medronic Acid CH 2 .C 7 H 5 N 2 OH Minodronic Acid C 5 H 10 .NH 2 OH Neridronic Acid C 2 H 4 .N(CH 3 ) 2 OH Olpadronic Acid H OH Oxidronic Acid C 2 H 4 .NH 2 OH Pamidronic Acid CH 2 .C 5 H 4 N OH Risedronic Acid S.C 6 H 4 Cl H Tiludronic Acid CH 2 .C 3 H 3 N 2 OH Zoledronic Acid CPP OO OH OH HO HO R 1 R 2 Generic structure of a bisphosphonate

Effects on the kidneys.

Renal failure was associated with the intravenous use of etidronate in 2 patients with hypercalcaemia of malignancy.1 One had been given a high dose (1 g) by short intravenous infusion on two successive days and the other had an elevated serum-creatinine concentration before treatment. A third patient given clodronate, who also developed renal failure, also had a slightly raised serum-creatinine concentration beforehand. Others2 commented that with smaller doses of etidronate or clodronate (up to 300 mg daily) by intravenous infusion over 2 to 3 hours, renal impairment had not been seen in more than 40 patients treated. They noted a trend towards raised creatinine concentrations which was reversed when etidronate infusions were stopped. Another group3 found increased serum-creatinine concentrations after the first infusion of etidronate when compared with placebo, but not after subsequent infusions. An overdose of parenteral etidronate led to acute renal failure in one patient.4 Pamidronate has been associated with nephrotoxicity,5proteinuria,6 acute tubular necrosis,7,8 and collapsing focal segmental glomerulosclerosis.9 Over a period of 2 years, 72 cases of renal failure associated with intravenous zoledronate were reported to the FDA.10 Of 7 cases reported over the course of 3.5 years in France, 3 patients recovered completely, and 1 partially, after stopping zoledronate. Two fatalities were reported, but comorbidities prohibited a direct causal link to zoledronate; the outcome in the remaining case was unknown.11 Six cases of acute tubular necrosis have been reported with zoledronate;12 all patients had received pamidronate on previous occasions, and most had mildly raised baseline serum creatinine. While pamidronate may have potentiated the renal toxicity seen with zoledronate, the authors noted that the patterns of nephrotoxicity differ between the 2 drugs. Reports to the Australian Adverse Drug Reactions Advisory Committee have suggested that renal failure or renal impairment may occur more often with zoledronate than with other bisphosphonates. While the deterioration in renal function with zoledronate was acute, in many cases it appeared to be unrelated to the infusion rate; patients may also have been predisposed to renal impairment.13 There has also been a report of acute renal failure with alendronate treatment in a patient with myeloma,14 and with tiludronate in a patient treated for hypercalcaemia of malignancy.15
1. Bounameaux HM, et al. Renal failure associated with intravenous diphosphonates. Lancet 1983; i: 471
2. Kanis JA, et al. Effects of intravenous diphosphonates on renal function. Lancet 1983; i: 1328
3. Hasling C, et al. Etidronate disodium for treating hypercalcaemia of malignancy: a double blind placebo-controlled study. Eur J Clin Invest 1986; 16: 433–7
4. O’Sullivan TL, et al. Acute renal failure associated with the administration of parenteral etidronate. Ren Fail 1994; 16: 767–73
5. Lockridge L, et al. Pamidronate-associated nephrotoxicity in a patient with Langerhans’ histiocytosis. Am J Kidney Dis 2002; 40: E2
6. Desikan R, et al. Nephrotic proteinuria associated with highdose pamidronate in multiple myeloma. Br J Haematol 2002; 119: 496–9
7. Banerjee D, et al. Short-term, high-dose pamidronate-induced acute tubular necrosis: the postulated mechanisms of bisphosphonate nephrotoxicity. Am J Kidney Dis 2003; 41: E18
8. Smetana S, et al. Pamidronate-induced nephrotoxic tubular necrosis—a case report. Clin Nephrol 2004; 61: 63–7
9. Markowitz GS, et al. Nephrotic syndrome after treatment with pamidronate. Am J Kidney Dis 2002; 39: 1118–22
10. Chang JT, et al. Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349: 1676–8
11. Munier A, et al. Zoledronic acid and renal toxicity: data from French Adverse Effect Reporting Database. Ann Pharmacother 2005; 39: 1194–7
12. Markowitz GS, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003; 64: 281–9
13. Adverse Drug Reactions Advisory Committee (ADRAC). Renal impairment with zoledronic acid. Aust Adverse Drug React Bull 2007; 26: 18–19. Also available at: http://www.tga.gov.au/adr/ aadrb/aadr0710.htm (accessed 06/11/07
14. Zazgornik J, et al. Acute renal failure and alendronate. Nephrol Dial Transplant 1997; 12: 2797–8
15. Dumon JC, et al. Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia. Bone Miner 1991; 15: 257–66.

Effects on the musculoskeletal system.

Osteonecrosis of the jaw has been reported with the use of some bisphosphonates.1-8 The majority of reports have been in cancer patients treated with intravenous bisphosphonates who were also receiving chemotherapy and corticosteroids. However, osteonecrosis has also been reported in patients receiving oral bisphosphonates for osteoporosis or Paget’s disease. Most cases have been associated with dental procedures such as tooth extraction, and many patients had local infection including osteomyelitis.6,7,9,10 Presenting features may include altered local sensation, maxillofacial pain, toothache, denture sore spots, loose teeth, exposed bone or impaired healing, recurrent or persistent soft tissue infection in the oral cavity, and marked oral odour.7 A history of underlying dental problems, such as infection, dental extraction, or maxillofacial surgery may exacerbate the problem.1 Other predisposing factors include oral trauma, periodontitis, and poor dental hygiene.11 For recommendations on dental care in patients prescribed intravenous bisphosphonates see above. Length of exposure was found to correlate with development of osteonecrosis,9,12,13 although some cases have occurred only a few months after bisphosphonate use.9 There is also some evidence for a dose-response relationship.8 Furthermore, the type of bisphosphonate used may affect the risk; intravenous use of bisphosphonates containing an aminoterminal group of a nitrogencontaining side-chain appear to present the highest risk,9 and there is some suggestion that the risk may be higher with zoledronate than with pamidronate.1,12 The incidence appears to be higher in patients with multiple myeloma,1,9,12 and elderly myeloma patients may be at increased risk.9,13 The mechanism by which bisphosphonates induce osteonecrosis has not been fully elucidated. Avascular necrosis of the hip has been reported; it is possible that osteonecrosis may be a systemic bone disease with initial manifestation in the jaw.13 A case of osteonecrosis of the auditory canal has been reported;14 the patient had concurrent osteonecrosis of the jaw. No effective treatment is known and there is no consensus on management. Stopping bisphosphonate therapy does not necessarily promote healing of the necrotic process;8,9,13 recovery of normal osteoclast function and bone turnover may be too gradual for this measure to have clinical significance.10 However, there have been anecdotal reports of healing and complete resolution of lesions several months after cessation of therapy.10 Treatment is directed towards control of pain and infection and careful local debridement of necrotic bone, but not wide excision of lesions.8,10
1. Durie BGM, et al. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353: 99–100
2. Migliorati CA. Bisphosphanates [sic] and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21: 4253–4
3. Ruggiero SL, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62: 527–34
4. Carter G, et al. Bisphosphonates and avascular necrosis of the jaw: a possible association. Med J Aust 2005; 182: 413–15
5. Gibbs SDJ, et al. Bisphosphonate-induced osteonecrosis of the jaw requires early detection and intervention. Med J Aust 2005; 183: 549–50
6. Commission on Human Medicines/Medicines and Healthcare products Regulatory Agency. Osteonecrosis of the jaw with bisphosphonates. Current Problems 2006; 31: 4–5. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON2023860&RevisionSelectionMethod= LatestReleased (accessed 23/07/08
7. Adverse Drug Reactions Advisory Committee (ADRAC). Osteonecrosis of the jaw (ONJ) with bisphosphonates. Aust Adverse Drug React Bull 2006; 25: 14. Also available at: http:// www.tga.gov.au/adr/aadrb/aadr0608.pdf (accessed 28/11/06
8. Krueger CD, et al. Bisphosphonate-induced osteonecrosis of the jaw. Ann Pharmacother 2007; 41: 276–84
9. Migliorati CA, et al. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 2006; 7: 508–14
10. Woo S-B, et al. Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144: 753–61. Correction. ibid.; 145: 235. [title
11. Bilezikian JP. Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med 2006; 355: 2278–81
12. Bamias A, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23: 8580–7
13. Badros A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006; 24: 945–52
14. Polizzotto MN, et al. Bisphosphonate-associated osteonecrosis of the auditory canal. Br J Haematol 2006; 132: 114.

Effects on the respiratory system.

Bronchospasm induced by bisphosphonates has been reported in 2 patients who were aspirin-sensitive asthmatics. The first patient complained of shortness of breath and wheezing 10 minutes after the start of an infusion of clodronate while the second developed similar symptoms 2 days after the start of cyclical therapy with etidronate by mouth. Oral rechallenge in both patients resulted in a fall in the forced expiratory values at 1 second.1 The reaction in these 2 patients was not considered to be immune-mediated. Risedronate reportedly induced bronchiolitis obliterans organising pneumonia in a patient with sarcoidosis.2 For a report of fatal cardiorespiratory failure secondary to acute respiratory distress syndrome caused by etidronate, see Effects on the Skin, under Etidronate.
1. Rolla G, et al. Bisphosphonate-induced bronchoconstriction in aspirin-sensitive asthma. Lancet 1994; 343: 426–7
2. Arai T, et al. Risedronate induced BOOP complicated with sarcoidosis. Thorax 2005; 60: 613–14.

Hypersensitivity.

Bisphosphonates may rarely cause hypersensitivity reactions such as angioedema, urticaria, and pruritus. Reports include a severe allergic reaction to medronate disodium when given as a radiopharmaceutical,1 and mild skin rashes in 2 patients given oral pamidronate.2 There has also been a report of erythroderma with lesions of the mucous membranes associated with use of clodronate in one patient,3 and severe epidermal necrosis may have been associated with tiludronate in another.4A possibly drug-related rash has also been reported in a patient receiving alendronate.5 Other cutaneous reactions reported with alendronate include urticaria,6 erythematous papules and petechiae,7 gyrate erythema,8 and drug-induced lichen planus;9licensed product information states that Stevens-Johnson syndrome has been reported. Two patients with cutaneous reactions to pamidronate or clodronate were able to continue oral clodronate after desensitisation.10 Licensed product information states that zoledronate has been associated with rare reports of hypersensitivity, including angioedema and bronchoconstriction, and very rarely, with anaphylaxis.
1. Elliott AT, et al. Severe reaction to diphosphonate: implications for treatment of Paget’s disease. BMJ 1988; 297: 592–3
2. Mautalen CA, et al. Side effects of disodium aminohydroxypropylidenediphosphonate (APD) during treatment of bone diseases. BMJ 1984; 288: 828–9
3. Pajus I, et al. Erythroderma after clodronate treatment. BMJ 1993; 307: 484
4. Roux C, et al. Long-lasting dermatological lesions after tiludronate therapy. Calcif Tissue Int 1992; 50: 378–80
5. Chesnut CH, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med 1995; 99: 144–52
6. Kontoleon P, et al. Urticaria after administration of alendronate. Acta Derm Venereol 2000; 80: 398
7. Kimura M, et al. Drug eruption due to alendronate sodium hydrate. Contact Dermatitis 2003; 48: 116
8. High WA, et al. Superficial gyrate erythema as a cutaneous reaction to alendronate for osteoporosis. J Am Acad Dermatol 2003; 48: 945–6
9. Lazarov A, et al. Alendronate-induced lichen planus. Isr Med Assoc J 2002; 4: 389–90
10. Phillips EJ, et al. Allergic reactions to bisphosphonates: a report of three cases and an approach to management. J Clin Pharmacol 1998; 38: 842–86.

💊 Interactions

The bisphosphonates are not well absorbed from the gastrointestinal tract, and dosage with food further impairs their absorption. Compounds containing aluminium, calcium, iron, or magnesium, including antacids and mineral supplements and some osmotic laxatives, can also impair the absorption of bisphosphonates given by mouth. It has been suggested that the use of certain bisphosphonates with NSAIDs may result in an increased incidence of gastrointestinal or renal adverse effects. There may be additive hypocalcaemic effects with aminoglycosides.

Aminoglycosides.

Severe hypocalcaemia has been reported after treatment with amikacin,1 or netilmicin2 in patients who had previously received clodronate. In both cases, signs of aminoglycoside toxicity were evident; clodronate had been withdrawn in one patient upon starting the aminoglycoside,1 and in the other several weeks before.2 Bisphosphonates and aminoglycosides can induce hypocalcaemia by different mechanisms and the effects of both drugs may persist for several weeks; care should be taken when giving them together.1,2
1. Mayordomo JI, Rivera F. Severe hypocalcaemia after treatment with oral clodronate and aminoglycoside. Ann Oncol 1993; 4: 432–3
2. Pedersen-Bjergaard U, Myhre J. Severe hypocalcaemia after treatment with diphosphonate and aminoglycoside. BMJ 1991; 302: 295. Correction. ibid.; 791.

💊 Pharmacokinetics

The bisphosphonates are poorly absorbed after oral doses, with bioavailabilities in the fasting state ranging from about 0.7% (alendronate; risedronate) to up to 6% (etidronate; tiludronate). Absorption is reduced by food, especially by products containing calcium or other polyvalent cations. They have a high affinity for bone, with about 50% of an absorbed dose sequestered to ossified tissues and retained in the body for prolonged periods. Excretion is in the urine, as unchanged drug; they do not appear to be metabolised.
1. Cremers SCLM, et al. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 2005; 44: 551–70.

💊 Uses and Administration

The bisphosphonates inhibit bone resorption and thus have a hypocalcaemic effect. They are pyrophosphate analogues that have a high affinity for the hydroxyapatite of bone, and that inhibit bone resorption by osteoclasts; because of the coupling of resorption and formation this results in an overall reduction in remodelling and bone turnover. Their antiresorptive potency varies widely. The bisphosphonates also inhibit the formation and dissolution of hydroxyapatite crystals and thus have the potential to interfere with bone mineralisation. The degree to which the bisphosphonates inhibit mineralisation in clinical practice varies; etidronate is the most potent inhibitor of those now in general clinical use. Because bone resorption increases plasma-calcium concentrations, the bisphosphonates are used as adjuncts to the treatment of severe hypercalcaemia, especially when associated with malignancy. They are also used in disorders associated with excessive bone re sorption and turnover, such as Paget’s disease of bone and osteoporosis, as well as in the management of bone metastases. Etidronate has been used in the prevention and treatment of ectopic ossification. The affinity of bisphosphonates for bone allows complexes labelled with radioactive technetium-99m to be used diagnostically as bone scanning agents. Bisphosphonates have been given by intravenous infusion or orally. In the latter case food should be avoided for a suitable period before and after a dose, especially foods with a high calcium content such as milk.
1. Brown DL, Robbins R. Developments in the therapeutic applications of bisphosphonates. J Clin Pharmacol 1999; 39: 651–60
2. Shoemaker LR. Expanding role of bisphosphonate therapy in children. J Pediatr 1999; 134: 264–7
3. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003; 9: 2643–58
4. Cohen SB. An update on bisphosphonates. Curr Rheumatol Rep 2004; 6: 59–65
5. Licata AA. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 2005; 39: 668–77
6. Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics 2007; 119 (suppl 2): S150–S162
7. Kimmel DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res 2007; 86: 1022–33
8. Russell RG, et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 2007; 1117: 209–57.

Complex regional pain syndrome.

Osteoporosis is one of the features of complex regional pain syndrome. Bisphosphonates may be of benefit in controlling associated pain in some patients.

Ectopic ossification.

Bisphosphonates that are potent inhibitors of mineralisation such as etidronate have been advocated for prevention of ectopic ossification, but they do not prevent the formation of the osteoid matrix, and delayed mineralisation may occur once they are withdrawn.

Hypercalcaemia.

In patients with severe symptomatic hypercalcaemia restoration and maintenance of adequate hydration and urine flow is essential, and helps to reduce plasma-calcium concentrations by promoting calcium diuresis. In hypercalcaemia of malignancy therapy with inhibitors of bone resorption such as the bisphosphonates is used. Although sustained, the action of bisphosphonates is not particularly rapid; they may be used with a calcitonin where both rapid and prolonged diminution of plasma-calcium concentration is desired.

Hyperparathyroidism.

Bisphosphonates have been used to inhibit bone resorption in the treatment of hypercalcaemia associated with hyperparathyroidism, but seem to be of little benefit for long-term treatment.

Juvenile idiopathic arthritis.

Bisphosphonates may have a role1 in preventing low bone mineral density and fragility fractures in children with juvenile idiopathic arthritis.
1. Thornton J, et al. Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis. Arch Dis Child 2006; 91: 753–61.

Malignant neoplasms of the bone.

There is good evidence that some bisphosphonates are of benefit in treatment of patients with metastatic bone disease not only to control bone pain1,2 and to manage the attendant hypercalcaemia, but also to reduce skeletal complications such as fractures.2-8 Maximum benefit in terms of skeletal events occurs only after 6 months of treatment.9 It has been suggested that given the strength of the evidence, treatment with bisphosphonates should be begun at first diagnosis of bone metastases, and continued until no longer clinically relevant.2,10 While some continue treatment despite disease progression, others advocate changing to a more potent bisphosphonate, or stopping treatment altogether.9Starting bisphosphonates in women with breast cancer without evidence of bone metastases is not recommended.11 There are concerns over the development of osteonecrosis of the jaw with bisphosphonate treatment (see Effects on the Musculoskeletal System, under Adverse Effects, above), and a possibly increased incidence in patients with multiple myeloma. Some have recommended12,13 that monthly intravenous bisphosphonate therapy continue for 2 years in myeloma patients. After 2 years, therapy can be stopped in those who have achieved a complete response or who are in a stable plateau phase. If disease is still active, frequency of infusion can be decreased to once every 3 months. However, others recommend stopping therapy after 1 year in those with a complete response or very good partial response. For those with a poorer response and ongoing active bone disease, bisphosphonates may be continued for up to 2 years.14 In newly diagnosed patients, pamidronate is favoured over zoledronate as data suggest the risk of osteonecrosis may be higher with the latter.12-14 However, routinely switching patients from zoledronate to pamidronate is not recommended, as no data suggest that this will prevent osteonecrosis. Multiple myeloma patients without evidence of skeletal involvement should not routinely be given bisphosphonates.12 There is also much interest in the use of bisphosphonates to prevent the development of bone metastases;2,4,5,8 however, preliminary evidence of their efficacy is conflicting. Specific references may be found under the individual drugs.
1. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2002 (accessed 30/11/06)
2. Aapro M, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008; 19: 420–32
3. Rule S. Managing cancer-related skeletal events with bisphosphonates. Hosp Med 2004; 65: 355–60
4. Brown JE, et al. The role of bisphosphonates in breast and prostate cancers. Endocr Relat Cancer 2004; 11: 207–24
5. Pavlakis N, et al. Bisphosphonates for breast cancer. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2005 (accessed 30/11/06)
6. Saad F, Schulman CC. Role of bisphosphonates in prostate cancer. Eur Urol 2004; 45: 26–34
7. Djulbegovic B, et al. Bisphosphonates in multiple myeloma. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2002 (accessed 30/11/06)
8. Michaelson MD, Smith MR. Bisphosphonates for treatment and prevention of bone metastases. J Clin Oncol 2005; 23: 8219–24
9. Gainford MC, et al. Recent developments in bisphosphonates for patients with metastatic breast cancer. BMJ 2005; 330: 769–73
10. Ross JR, et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327: 469–72. Correction. ibid. 2004; 328: 384
11. Hillner BE, et al. American Society of Clinical Oncology 2003 Update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042–57. Correction. ibid. 2004; 22: 1351
12. Lacy MQ, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006; 81: 1047–53
13. Kyle RA, et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007; 25: 2464–72
14. Durie BGM, et al.. International Myeloma Working Group. Use of bisphosphonates in multiple myeloma: IMWG response to Mayo Clinic consensus statement. Mayo Clin Proc 2007; 82: 516–7; author reply 517–18.

Osteogenesis imperfecta.

Bisphosphonates have been tried in osteogenesis imperfecta, but orthopaedic treatment and physical activity programmes form the basis of therapy.

Osteoporosis.

Bisphosphonates are used first-line in the prevention and treatment of osteoporosis. Alendronate, risedronate and cyclical etidronate are used orally; clodronate and ibandronate have been used both orally and parenterally, and ibandronate, pamidronate, and zoledronate by intermittent intravenous infusion. Generally, in the management of postmenopausal osteoporosis, bisphosphonates increase bone mineral density (BMD) at both the spine and hip and reduce vertebral fractures; effect on non-vertebral fractures varies.1,2 Treatment in women at highest risk, with prevalent fractures or low BMD, is considered most effective.2 In the UK, NICE3 recommends the use of bisphosphonates for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Alendronate, etidronate, or risedronate may be given to all women aged 75 years and older, to women aged between 65 and 74 years with confirmed osteoporosis, and to postmenopausal women younger than 65 with very low BMD or with confirmed osteoporosis and one or more additional age-independent risk factors. Data also suggest that the more severe the osteoporosis, the greater the benefit, and since bone density continues to decline with age, and vertebral fracture incidence rises after age 75, some consider it more beneficial in older women.4 However, others have expressed concern about a possible increase in brittleness of bones with long-term bisphosphonate treatment.5 Although there is less evidence for the efficacy of bisphosphonates for the treatment of idiopathic osteoporosis in men, some consider them the treatment of choice. A systematic review6 stated that, while further evaluation of bisphosphonate therapy in children with secondary osteoporosis is warranted, evidence does not support their use as standard therapy. Bisphosphonates are also considered effective at prevention and treatment of corticosteroid-induced osteoporosis.7 Fracture risk may also be reduced although a systematic review was inconclusive in this respect.7 A meta-analysis of bisphosphonate use in the early post-transplant period found that they were effective in reducing BMD decline at the lumbar spine; however, prolonged and more intensive treatment may increase the risk of adynamic or low bone turnover disease.8
1. Watts NB. Bisphosphonate treatment of osteoporosis. Clin Geriatr Med 2003; 19: 395–414
2. Masud T, Giannini S. Preventing osteoporotic fractures with bisphosphonates: a review of the efficacy and tolerability. Aging Clin Exp Res 2003; 15: 89–98
3. NICE. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women: Technology Appraisal 87 (issued January 2005). Available at: http://www.nice.org.uk/nicemedia/pdf/TA087guidance.pdf (accessed 23/07/08
4. Dhesi JK, et al. The implications of a growing evidence base for drug use in elderly patients. Part 4: vitamin D and bisphosphonates for fractures and osteoporosis. Br J Clin Pharmacol 2006; 61: 521–8
5. Ott S. New treatments for brittle bones. Ann Intern Med 2004; 141: 406–7
6. Ward L, et al. Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2007 (accessed 18/04/08)
7. Homik J, et al. Bisphosphonates for steroid induced osteoporosis. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 1999 (accessed 22/02/05)
8. Mitterbauer C, et al. Effects of bisphosphonates on bone loss in the first year after renal transplantation—a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2006; 21: 2275–81.

Paget’s disease of bone.

Bisphosphonates may be indicated for patients with Paget’s disease of bone if bone pain is persistent, or to prevent further progression of the disease.
Published October 13, 2018.