Correspondence

Liver Damage Due to Alendronate

N Engl J Med 2000; 343:365-366August 3, 2000

Article

To the Editor:

Alendronate is indicated for the treatment of postmenopausal women with osteoporosis and patients with glucocorticoid-induced osteoporosis.1 We report liver dysfunction due to alendronate in a postmenopausal woman given the drug for osteoporosis.

A 71-year-old woman was referred to our clinic for an evaluation of osteoporosis. She had been thought to have primary biliary cirrhosis four years earlier, was receiving ursodeoxycholic acid (ursodiol), and had normal liver function. The diagnosis of primary biliary cirrhosis had been based on high serum alkaline phosphatase and antimitochondrial antibody concentrations, but liver biopsy had not been performed.

Three years later, on evaluation at our clinic, the patient had back pain and severe osteoporosis, with fractures in L4 and L5. The bone mineral density of the lumbar spine was low (T score, –4.21). The T score was –4.66 one year later, at which time she was treated with alendronate (10 mg per day). Two months later, routine biochemical studies revealed high serum liver enzyme concentrations (Table 1Table 1Results of Liver-Function Tests before, during, and after Treatment with Alendronate.). The alendronate was withdrawn but not the ursodiol, and the serum liver enzyme concentrations slowly returned to the normal range.

Serologic tests for hepatitis A, B, and C viruses, Epstein–Barr virus, and cytomegalovirus were negative. Liver biopsy showed lobular inflammation, fatty changes, and portal infiltration of lymphocytes, granulocytes, and eosinophils. Some hepatocytes had necroinflammatory lesions, with piecemeal necrosis. Masson staining revealed no fibrosis. No signs of primary biliary cirrhosis were found.

The main side effects of alendronate are gastric and esophageal inflammation,2 but renal failure, ocular damage, skin reactions, and hypocalcemia have also been reported. A case of hepatitis that developed after treatment with alendronate was recently reported in a 77-year-old woman.3

The mechanism by which alendronate may cause liver damage is not known. Reactivation of the primary biliary cirrhosis might have caused the high serum liver enzyme concentrations in our patient, but there was no evidence of such reactivation. Another possibility is that alendronate, like other aminobisphosphonates, inhibits the synthesis of cholesterol in the liver,4 which may alter liver function, since this pathway is essential in the maturation of Ras-related G proteins.5

Regardless of the mechanism, physicians treating patients with a bisphosphonate should be alert to the possibility of hepatic dysfunction during therapy.

Aaron Halabe, M.D.
Beatriz Mercer Lifschitz, M.D.
Joseph Azuri, M.D.
Edith Wolfson Medical Center, 58100 Holon, Israel

5 References

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   Saag KJ, Emkey R, Schnitzer TJ, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998;337:292-299
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   Graham DY, Malaty HM. Alendronate gastric ulcers. Aliment Pharmacol Ther 1999;13:515-519
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   van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 1999;264:108-111
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   Russell RG, Rogers MJ, Frith JC, et al. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 1999:Suppl 2:53-65.
   

Author/Editor Response

The above letter was referred to Merck & Co., the manufacturer of alendronate, which offers the following reply:

To the Editor: Halabe and colleagues describe a woman who was found to have high serum liver enzyme concentrations and hepatitis while receiving alendronate. The authors attribute the hepatitis to alendronate therapy because it was diagnosed two months after alendronate was started. Yet the patient had had a similar episode of unexplained hepatic dysfunction four years earlier. That episode had been attributed to primary biliary cirrhosis, but the later liver biopsy revealed no evidence of primary biliary cirrhosis. Also, the patient's serum liver enzyme concentrations continued to increase for a month after the discontinuation of alendronate. Therefore, the recurrence of an underlying liver disease seems a likely explanation for the findings in this patient.

Alendronate, an inhibitor of osteoclast-mediated bone resorption, rapidly attaches to the bone surface. The drug is not taken up by cells or metabolized, and that which is not deposited in bone is rapidly excreted by the kidneys. Therefore, the potential for systemic toxicity is low.1 Alendronate therapy has been extensively evaluated at high doses (25 to 40 times the 10-mg daily dose) in multiple animal studies without any evidence of hepatotoxicity.2 In randomized, double-blind trials involving a total of more than 17,000 patients treated for up to eight years, with repeated assessments of liver function, there were no increases either in the number of reports of hepatitis or in the mean serum concentrations of aminotransferases, alkaline phosphatase, or bilirubin during treatment with alendronate, as compared with placebo.

The authors speculate that alendronate may affect liver function by inhibiting hepatic synthesis of cholesterol. This seems unlikely. After an oral 10-mg dose, plasma concentrations of alendronate are undetectable (<5 ng per milliliter, or approximately 20 nM)3 and are well below the extracellular concentrations (10 to 30 μM) required to inhibit farnesyl diphosphate synthase in cells that do not actively take up alendronate, as compared with osteoclasts that take up alendronate as bone is resorbed.4,5 In any event, the histologic findings reported by Halabe and colleagues suggest that their patient had inflammatory, rather than toxic, liver injury.

The pharmacologic characteristics of alendronate, extensive data from studies in animals and humans, and five years of experience with the use of the drug in more than 3.5 million patients all support the conclusion that alendronate is very unlikely to be hepatotoxic. We do not believe that the case presented by the authors, with incompletely defined prior liver disease, alters this conclusion or supports their recommendation of periodic measurements of serum aminotransferases in patients receiving a bis-phosphonate.

Anastasia G. Daifotis, M.D.
A. John Yates, M.D.
Merck & Co., Rahway, NJ 07065

5 References

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   Watts N, Freedholm D, Daifotis A. Alendronate: from the laboratory to the patient: the clinical tolerability profile of alendronate. Int J Clin Pract 1999;101:51-61
   

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   Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133-138
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   Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys 2000;373:231-241
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Citing Articles (10)

Citing Articles

1. 1

   Luis Arboleya, Mercedes Alperi, Sara Alonso. (2011) Adverse effects of bisphosphonates. Reumatolog ía Cl ínica (English Edition) 7:3, 189-197
   CrossRef

2. 2

   S. A. Polyzos, J. Kountouras, A. D. Anastasilakis, I. Litsas, M. Kita, G. Arsos, E. Moralidis, E. Terpos. (2011) Zoledronic acid-induced transient hepatotoxicity in a patient effectively treated for Paget’s disease of bone. Osteoporosis International 22:1, 363-367
   CrossRef

3. 3

   Bo Abrahamsen. (2010) Adverse Effects of Bisphosphonates. Calcified Tissue International 86:6, 421-435
   CrossRef

4. 4

   B. Yanık, C. Turkay, H. Atalar. (2007) Hepatotoxicity induced by alendronate therapy. Osteoporosis International 18:6, 829-831
   CrossRef

5. 5

   Michael B. Phillips. (2007) Risedronate-induced Hepatitis. The American Journal of Medicine 120:3, e1-e2
   CrossRef

6. 6

   Claudia O. Zein, Roberta A. Jorgensen, Bart Clarke, Doris E. Wenger, Jill C. Keach, Paul Angulo, Keith D. Lindor. (2005) Alendronate improves bone mineral density in primary biliary cirrhosis: A randomized placebo-controlled trial. Hepatology 42:4, 762-771
   CrossRef

7. 7

   Nuria Guanabens, Albert Pares, Inmaculada Ros, Luisa Alvarez, Francesca Pons, Llorenc Caballeria, Ana Monegal, M. Jesus Martinez Osaba, Merce Roca, Pilar Peris, Juan Rodes. (2003) Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. The American Journal of Gastroenterology 98:10, 2268-2274
   CrossRef

8. 8

   Michael R McClung. (2003) Bisphosphonates. Endocrinology & Metabolism Clinics of North America 32:1, 253-271
   CrossRef

9. 9

   (2000) Current Awareness. Pharmacoepidemiology and Drug Safety 9:7, 615-630
   CrossRef

10. 10

    &NA;. (2000) Alendronic acid. Reactions Weekly &amp;NA;:814, 6
    CrossRef