Bisphosphonates

Publication Details

OVERVIEW

Introduction

The bisphosphonates are pyrophosphate analogues that become incorporated into bone matrix and suppress osteoclastic activity, thereby reducing bone turnover and increasing bone mass, which makes them valuable agents for the prevention and therapy of osteoporosis. Therapy with the bisphosphonates has been associated with a low rate of serum enzyme elevations during therapy and has been linked to rare instances of clinically apparent liver injury.

Background

Bisphosphonates are pyrophosphate analogues that have two phosphonate groups attached to a central carbon atom that replaces the oxygen present in pyrophosphate. The bisphosphonates bind calcium and are rapidly taken up in bone matrix where they suppress osteoclastic activity and change the balance between bone resorption and bone formation, thus increasing bone mass. The bisphosphonates have been shown to be effective in treating malignant hypercalcemia and in preventing and treating osteoporosis. Six bisphosphonates have been approved for use in the United States (pronunciation and year of approval given in parentheses) and they differ in formulation, recommended dose regimen, spectrum of activity and clinical indications.

• Alendronate (a len' droe nate) (1995) is available in tablets of 5 and 10 mg for daily use, 35, 40 and 70 mg (with and without vitamin D) for weekly use, and as a suspension for oral use in several generic forms and under the brand name Fosamax. Indications include prevention and treatment of osteoporosis and treatment of Paget disease of bone.

• Etidronate (e" ti droe' nate) (1977) is available in tablets of 200 and 400 mg for daily use in generic forms and under the trade name Didronel. Indications include Paget disease of bone and heterotopic ossification, but it has also been used off label for therapy of osteoporosis.

• Ibandronate (eye" ban droe' nate) (2003) is available in tablets of 2.5 mg for daily and 150 mg for monthly use and as an intravenous formulation under the trade name Boniva. Indications include prevention and treatment of osteoporosis.

• Pamidronate (pam" i droe' nate) (1991) is available as an intravenous formulation generically and under the trade name Aredia. Indications include hypercalcemia of malignancy, multiple myeloma and Paget disease of bone.

• Risedronate (ris" e droe' nate) (1998) is available in tablets of 5 mg for daily use, 30 and 35 mg for weekly use, and 75 and 150 mg for monthly use in generic forms and under the trade name Actonel. Indications include osteoporosis and Paget disease of bone.

• Zoledronic acid (zoe" le droe' nate) (2001) is available as several intravenous formulations generically and under the brand names Zometa and Reclast. Indications and dosage vary by preparation, but include prevention and treatment of osteoporosis, Paget disease of bone, hypercalcemia of malignancy and multiple myeloma.

The side effects of the bisphosphonates vary by route of administration, but are largely class specific. The oral formulations are generally well tolerated, but are recommended to be given on an empty stomach and with care that they enter the stomach (by drinking water and remaining upright) to avoid esophageal irritation and potential ulceration. Common side effects of oral formulations include headache, abdominal discomfort, dyspepsia, nausea and hypocalcemia. The intravenous formulations of the bisphosphonates can be associated with local infusion reactions and in an acute phase reaction in up to 30% of patients. This is characterized by a flu-like syndrome primarily with the initial infusion. Symptoms arise within 10 to 20 hours after the infusion and are accompanied by increases in C reactive protein, decreases in serum zinc and, in some instances, minor elevations in serum enzymes several days later. Severe side effects of the bisphosphanates are rare, but have included esophageal ulcer, gastrointestinal bleeding, atrial fibrillation and, with long-term treatment, osteonecrosis of the jaw and atypical femoral fractures.

Hepatotoxicity

In most large prospective trials, the bisphosphonates were associated with only rare and isolated instances of serum enzyme elevations and no cases of clinically apparent liver injury. Since their general availability and wide scale use, however, there have been occasional publications reporting clinically apparent acute liver injury due to the more commonly used bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), some of which were accompanied by mild jaundice. The time to onset ranged from 2 to 6 months or more, and patients typically presented with abdominal discomfort and nausea, sometimes followed by jaundice. The pattern of serum enzyme elevations was hepatocellular and liver histology showed an acute toxic hepatitis. Immunoallergic features (fever, rash, eosinophilia) and autoantibodies were uncommon. Most cases were mild-to-moderate in severity and most published cases resolved with drug discontinuation, although full recovery was not always prompt.

In addtion, the bisphosphonates given as intravenous infusions (zoledronate, ibandronate, pamidronate) have been associated with rare instances of mild hypersensitivity reactions with rash and fever which may be accompanied by transient and mild serum enzyme elevations without jaundice typically in association with an acute phase reaction occurring with the initial dose. In some cases, infusions can be tolerated using premedication with glucocorticoids or antihistamines. With repeated doses, these reactions become less severe and may disappear. No instances of acute liver failure or chronic liver disease have been convincingly linked to use of the bisphosphonates.

Likelihood scores:

Alendronate: C (probable rare cause of clinically apparent liver injury).

Etidronate: E* (unproven but suspected rare cause of clinically apparent liver injury).

Ibandronate: D (possible rare cause of clinically apparent liver injury).

Pamidronate: E* (unproven but suspected rare cause of clinically apparent liver injury). Risedronate: D (possible rare cause of clinically apparent liver injury).

Zoledronic acid: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The bisphosphonates are taken up by bone matrix and rapidly cleared from the serum by renal excretion. Hepatic metabolism is minimal, and thus it is somewhat surprising that they can be associated with hepatic injury. The mechanism of injury is likely to be metabolic idiosyncrasy as immunoallergic features are not typical.

Outcome and Management

The clinically apparent acute liver injury attributed to bisphosphonates has been mild-to-moderate in severity without published instances of acute liver failure or chronic liver disease. The possibility of cross reactivity of the hepatic injury among the various bisphosphonates has not been studied, nor is there published experience with rechallenge using the same bisphosphonates. Cross reactivity to such injury should be assumed and switching to another agent done with caution and careful monitoring.

References to the safety and potential hepatotoxicity of all six agents are given at the end of this Overview section.

Drug Class: Osteoporosis Agents, Bone Resorption Inhibitors

CASE REPORTS

Case 1. Asymptomatic rise in serum aminotransferase levels during alendronate therapy.

[Modified from: de La Serna Higuera C, Pérez Villoria A, Rodríguez Gómez S, Martínez Moreno J, Betancourt González A, Martín Arribas M. [Alendronate-induced hepatocellular lesion]. Gastroenterol Hepatol 2001; 24: 244-6. Spanish. PubMed Citation]

A 76 year old woman with osteoporosis was found to have abnormal serum aminotransferase levels on routine testing done 3 months after starting alendronate (10 mg daily). She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. Her other medical conditions included hypertension, but she was not taking any other medications. She denied symptoms of liver disease and physical examination was normal without rash, fever, or hepatic enlargement or tenderness. Serum ALT levels were elevated with ALT 484 U/L, AST 368 U/L, and GGT 118 U/L, but normal alkaline phosphatase, bilirubin and prothrombin time (Table). Tests for hepatitis A, B and C (including HCV RNA) were negative as were routine autoantibodies. Abdominal ultrasound showed no abnormalities of the liver or biliary tree. Alendronate was continued and she was monitored. Two months later, serum aminotransferase levels had risen further and alendronate was stopped. Liver test abnormalities subsequently improved and serum aminotransferase levels were largely normal six weeks later.

Key Points

Laboratory Values

Comment

The absence of any other cause of liver injury combined with worsening abnormalities while alendronate was continued, followed by prompt improvement on stopping, is reasonably good evidence that the bisphosphonate was the cause of the liver test abnormalities. The patient was never jaundiced and was minimally symptomatic.

Case 2. Asymptomatic rise in serum aminotransferase levels after initial dose of zoledronic acid.

[Modified from: Jiang Y, Fu Y, Xing XP, Li M, Wang O, Xia WB, Meng XW. Zoledronic acid-induced hepatotoxicity relieved after subsequent infusions in a Chinese woman with glucocorticoid-induced osteoporosis. Eur J Med Res 2015; 20: 68. PubMed Citation]

A 50 year old woman with glucocorticoid-induced osteoporosis developed fever, myalgia and arthralgia a few hours after an initial infusion of zoledronic acid and 3 days later was found to have abnormal serum aminotransferase levels which had been normal before treatment (Table). She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. She had a history of Behcet disease for which she was treated with corticosteroids in varying doses for the previous 12 years. Her other medical conditions included diabetes for which she was taking metformin. Osteoporosis was diagnosed when she developed back pain and vertebral fractors after a fall. She did not improve with modification of her corticosteroid dose, calcitriol and elemental calcium and zoledronic acid was given. Her flu-like symptroms developed a few hours after the initial infusion, but resolved rapidly. Routine blood tests 3 days later showed serum enzyme elevations without jaundice or symptoms. These resolved within the following two weeks. Serum bilirubin and alkaline phosphatase levels remained normal. She received a second influsion of zoledronic acid one year later and again had mild fever and arthralgia as well as minimal ALT elevations 3 days later. A third infusion of zolendronic acid the following year was well tolerated, without fever or myalgia and will no subsequent rise in serum enzymes.

Key Points

Laboratory Values

Comment

Intravenous formulations of bisphosphanates are associated with an acute phase reaction in approximately one-third of patients. Flu-like symptoms of fever, fatigue, muscle and joint aches, gastrointestinal upset and nausea arise within hours of the infusion, but are generally mild and transient, resolving within 12 to 48 hours. Monitoring of laboratory tests demonstrates rises in acute phase reactants 1-3 days later and this may be accompanied by mild elevations in serum aminotranferase levels, but generally without symptoms or signs of liver disease and little change in alkaline phosphatase or serum bilirubin levels. The syndrome is most prominent with the first infusion and can be ameliorated by use of NSAIDs or, in more severe cases, corticosteroids.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Alendronate – Generic, Fosamax®

Etidronate – Generic, Didronel®

Ibandronate – Generic, Boniva®

Pamidronate – Generic, Aredia®

Risedronate – Generic, Actonel®

Zoledronic Acid – Reclast®, Zometa®

DRUG CLASS

Osteoporosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

ANNOTATED BIBLIOGRAPHY

References updated: 14 June 2018

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    (81 year old woman with osteoporosis developed rise in ALT after 3 years of risedronate therapy, resolving slowing upon stopping; few details given).
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    (47 year old woman developed abdominal pain 2 months after starting alendronate [bilirubin not given, ALT 46 rising to 114 U/L, GGT 30 rising to 84 U/L], resolving within 3 months of stopping).
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    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to a bisphosphonate).
  • Papapetrou PD. Bisphosphonate-associated adverse events. Hormones (Athens) 2009; 8: 96-110. [PubMed: 19570737]
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    (53 year old woman with Paget disease developed mild flu-like symptoms and serum enzyme elevations within a day of zoledronic acid infusion [bilirubin 0.4 mg/dL ALT rising from 19 to 127 U/L, GGT from 11 to 74 U/L], falling to normal within two weeks).
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    (61 year old woman with lupus erythematosus developed fatigue 4 months after starting monthly injections of ibandronate and 12 months after starting atorvastatin [bilirubin 8.0 mg/dL, ALT 1684 U/L, Alk P 208 U/L, ANA 1:640, SMA 1:160, IgG 2,850 mg/dL], responding to prednisone, but relapsing when they were stopped, ultimately resolving after ursodiol therapy).
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  • Tadrous M, Wong L, Mamdani MM, Juurlink DN, Krahn MD, Lévesque LE, Cadarette SM. Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis. Osteoporos Int 2014; 25: 1225-35. [PubMed: 24287510]
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  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Among 176 published reports of drug induced liver injury between 1996 and 2012, none were attributed to a drug for osteoporosis).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, only 1 case was attributed to a bisphosphate, a self limited case of acute hepatitis with jaundice that was considered "possibly" due to zoledronic acid).
  • Jiang Y, Fu Y, Xing XP, Li M, Wang O, Xia WB, Meng XW. Zoledronic acid-induced hepatotoxicity relieved after subsequent infusions in a Chinese woman with glucocorticoid-induced osteoporosis. Eur J Med Res 2015; 20: 68. [PMC free article: PMC4546306] [PubMed: 26297149]
    (52 year old Chinese woman with corticosteroid induced osteoporosis developed fever after a first infusion of zoldedronate and had transient serum enzyme elevations [biliurbin 0.5 mg/dL, ALT 254 U/L, Alk P 118 U/L], resolving within 1 week and not recurring with subsequent yearly infusions).
  • Lu Y, Pei Y, Shao Y, Yan S, Ma L, Fang F, Jin M, et al. Hepatotoxicity induced by zoledronic acid in an aged woman with primary osteoporosis. EXCLI J 2013; 12: 115-7. [PMC free article: PMC4803018] [PubMed: 27034632]
    (73 year old woman developed flu like symptoms and had abnormal serum enzymes 3 days after an initial infusion of zoledronic acid [bilirubin not provided, ALT rising from 17 to 169 U/L, GGT from 41 to 85 U/L], falling into the normal range within 2 weeks).
  • Reid IR. Short-term and long-term effects of osteoporosis therapies. Nat Rev Endocrinol 2015; 11: 418-28. [PubMed: 25963272]
    (Review of osteoporosis, its management and treatment, mentions that intravenous bisphonosphates produce an acute phase response in one-third of patients).
  • Mukaiyama K, Kamimura M, Uchiyama S, Ikegami S, Nakamura Y, Kato H. Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover. Aging Clin Exp Res 2015; 27: 413-8. [PubMed: 25534961]
    (Among 626 postmenopausal women with osteoporosis, serum Alk P levels were elevated in 14%, largely due to bone rather than hepatic sources; treatment with alendronate and risedronate led to decreases in levels into the normal range in 65 of 84 subjects).
  • Rossini M, Adami G, Adami S, Viapiana O, Gatti D. Safety issues and adverse reactions with osteoporosis management. Expert Opin Drug Saf 2016; 15: 321-32. [PubMed: 26699669]
    (Review of the safety of drugs for osteoporosis mentions that intravenous nitrogen-containing bisphosphonates cause an acute phase response in about 30% of patients, marked by transient flu-like symptoms within a day of administration that resolves within 3 days and decreases in severity with subsequent infusions).
  • Schneider JS, Montani M, Stickel F. Drug-Induced Autoimmune Hepatitis following Treatment with Zoledronic Acid. Case Rep Gastroenterol 2017; 11: 440-5. [PMC free article: PMC5624238] [PubMed: 29033761]
    (73 year old woman developed fever, fatigue and pruritus and elevations in serum enzymes shortly after an initial infusion of zoledronic acid for osteoporosis [bilirubin not provided, ALT 183 U/L, GGT 639 U/L], ultimately treated with prednisone after enzymes remained elevated for 4 weeks, with an initial response and relapse when withdrawn 10 weeks later requiring reinitiation of immunosuppressive therapy).