Alendronate-Associated Rhabdomyolysis in a Patient with Other Risk Factors

Case in Point Alendronate-Associated Rhabdomyolysis in a Patient with Other Risk Factors

Benjamin Basseri, MD and Mary B. White, MD

This elderly patient was taking a statin for hyperlipidemia and regularly consuming moderate quantities of alcohol. Yet the primary cause of his rhabdomyolysis appears to have been initiation of the bisphosphonate alendronate—which has not been associated with the condition previously.

habdomyolysis is a syndrome coenzyme A (HMG-CoA) reductase 3 chronic kidney disease presented that involves muscle necrosis inhibitors (commonly known as to the emergency department (ED) with the release of intracellu- statins). Frequently, the cause is not with muscle pain and weakness. The Rlar muscle contents into the singular but rather a complex inter- patient had begun taking oral alen- circulation. The classic presentation action of factors. dronate 35 mg weekly for osteopo- of rhabdomyolysis includes myal- In this article, we present a case rosis prophylaxis three weeks prior. gia, pigmenturia secondary to myo- of rhabdomyolysis that appears to Two days after his first dose, he began globinuria, and elevations in serum have been attributable primarily to experiencing constant and crampy levels of muscle enzymes.1 Objective use of the oral bisphosphonate alen- muscle pain bilaterally in his biceps muscle weakness also may be pres- dronate—to our knowledge, the first and posterior thighs. Weakness ac- ent—although it is less common and such case to be documented. This el- companied the myalgia and limited usually associated with severe muscle derly patient had a variety of other the patient’s ability to raise his legs to damage. A wide spectrum exists in factors that may have raised his risk cross them or put socks on. He was the severity of disease, ranging from of developing the condition, the most able to ambulate, but with a cautious asymptomatic, mild elevations in notable of which was concurrent use gait. These symptoms intensified after muscle enzyme levels to severe mus- of a statin medication. Nevertheless, the second dose of alendronate, one cle enzyme elevations accompanied the timing of symptom onset and week after the first, and continued to by acute, life threatening renal failure progression implicates alendronate progress until ED presentation eight and electrolyte disturbances. as the chief cause. Following the case days later, with the concomitant de- While the diagnosis of rhabdomy- presentation, we review the known velopment of dark urine. (The patient olysis usually is fairly straightforward, etiologies of rhabdomyolysis, with a skipped his third dose of alendronate pinpointing the precise cause is not focus on drug-induced cases, and dis- due to his worsening symptoms.) always so clear-cut. Common causes cuss possible mechanisms by which The patient’s history included al- of the condition include trauma; mus- bisphosphonates, particularly in com- cohol use—which he described as cle compression; alcohol use; drug bination with statins, could precipi- consumption of a six-pack of beer on interactions; and direct myotoxins, tate the condition. most weekends for many years. He such as 3-hydroxy-3-methylglutaryl reported no recent increase in alco- Initial Exam hol intake and said that he had not Dr. Basseri is a resident physician and Dr. White A 73-year-old, Hispanic man with consumed any alcohol on the previ- is the director of the Transitional Care Unit, both in the department of internal medicine, VA Greater a history of hypertension, hyperlip- ous weekend because of the severity Los Angeles Healthcare System, Los Angeles, CA. idemia, type 2 diabetes, and stage of his symptoms. He had a smoking

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history of 30 pack-years, although he uria. The patient’s urine myoglobin bances, drug interactions, and direct reported quitting smoking 40 years level was 480 ng/mL (reference range, myotoxins have been described. ago. He reported no history of illicit 0 to 5 ng/mL). Vitamin D, thiamine, Multiple mechanisms exist drug intake. and thyroid stimulating hormone through which drugs—both thera- At ED presentation, the patient’s (TSH) levels were not checked dur- peutic and illicit—may precipitate medications included oral simvastatin ing his ED evaluation and subsequent rhabdomyolysis.3,4 Numerous sub- 80 mg at bedtime daily for hyperlip- hospitalization. stances (including heroin, colchicine, idemia and oral rosiglitazone 4 mg alcohol, and statins) are known to twice daily and oral repaglinide 2 mg Hospital course have direct myotoxic effects. Immo- three times daily before meals for type Aggressive intravenous fluid hydra- bilization and ischemic compression 2 diabetes. His simvastatin therapy tion with normal saline was initiated of muscle secondary to coma associ- had been ongoing for several years, immediately and the patient was ad- ated with central nervous system de- with no recent changes in the dos- mitted to the hospital. On the second pressants, such as alcohol or opioids, age, and he was not taking any other day of hospitalization, his CK level may lead to rhabdomyolysis. Drug- cholesterol lowering medications. His improved to 15,781 U/L and his induced seizures, dystonic reactions, last rosiglitazone dosage increase had serum creatinine level dropped to 1.2 agitation states, and hyperthermia been 18 months prior. He reported mg/dL. Given the down-trending CK (for instance, secondary to cocaine no consumption of grapefruit or level and normalization of his renal use) can result in excess muscle in- grapefruit juice and no use of herbal function, the patient was discharged jury and subsequent rhabdomyolysis. remedies or over-the-counter dietary with a plan of one-week follow-up Electrolyte disturbances—such as supplements. with his primary care provider (PCP), hyponatremia, hypernatremia, hyper- Physical examination revealed the with laboratory testing prior to this osmolar states (chiefly, diabetic ke- patient to be afebrile with stable vital appointment. toacidosis), hypokalemia, total body signs. His sclera were anicteric, and At the one-week follow-up visit, potassium depletion, hypocalcemia, cardiovascular, pulmonary, and ab- the patient reported amelioration of and hypophosphatemia—have been dominal examinations yielded benign muscle pain and weakness. Results of associated with rhabdomyolysis.5–9 CK results. There was mild tenderness laboratory testing included a CK level levels peak between two and four days to palpation of the muscles of his of 955 U/L, an ALT level of 253 U/L, after the onset of hyponatremia, and el- upper and lower extremities. Muscle and an aspartate transaminase level of evated CK levels may occur regardless strength could not be assessed accu- 88 U/L. His serum creatinine level of whether the initial hyponatremia is rately because of pain, and range of and electrolytes were normal. He sub corrected. Because there is a release of motion in the hips was decreased bi- sequently resumed oral simvastatin potassium and phosphate from myo- laterally secondary to pain. 80 mg daily, at the discretion of his cytes in rhabdomyolysis, serum levels Results of laboratory testing in- PCP, without any adverse effects. Alen- of these electrolytes may underestimate cluded a serum creatine kinase (CK) dronate was not restarted, as the their actual total body depletion in level of 22,188 U/L, a serum cre- risks of recurrent rhabdomyolysis hypokalemic and hypophosphatemic atinine level of 1.6 mg/dL (patient’s were considered to outweigh the rhabdomyolysis. Rhabdomyolysis sec- baseline range over the prior year, benefits of osteoporosis prophylaxis. ondary to electrolyte abnormalities 1.3 to 1.5 mg/dL), a blood urea ni- often is associated with muscle weak- trogen level of 58 mg/dL (reference About the condition ness and may be associated with pain- range, 5 to 25 mg/dL), and a serum In 1941, the first depiction of rhab- ful hypokalemic myopathy. alanine aminotransferase (ALT) level domyolysis in modern medicine ap- In the case presented here, the pa- of 555 U/L (reference range, less than peared in a report describing bombing tient consumed a significant amount 53 U/L). Serum levels of sodium, po- victims of the Battle of Britain who of alcohol on the weekends, which tassium, chloride, carbon dioxide, developed acute renal failure and died may have contributed to his osteo- calcium, magnesium, and phospho- within one week.2 Thereafter, many penia and placed him at risk for thia- rus were normal. Urinalysis dem- case reports of rhabdomyolysis sec- mine deficiency—which, in turn, can onstrated “large” urine occult blood ondary to trauma, surgical trauma, result in mitochondrial dysfunction. with only 1 red blood cell per high immobility, exertion, metabolic myop- He was also taking a statin when power field, indicative of myoglobin- athies, alcohol use, electrolyte distur- rhabdomyolysis occurred. Given the

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onset of symptoms within two days of initiating alendronate therapy and the HMG-CoA exacerbation of symptoms after the second oral alendronate dose, how- Statin ever, it seems reasonable to pinpoint alendronate as the primary suspect in this case. While alcohol and statin use Mevalonate may have been additional risk factors for rhabdomyolysis, the lack of increased alcohol consumption or an increase in his statin dose make these etiologies less likely to be the primary inciting factor. +gd T cells Isopentenyl PP

Possible mechanisms for nBP bisphosphonate-induced rhabdomyolysis Geranyl PP Bisphosphonates are approved by the FDA for the treatment and preven- nBP tion of osteoporosis. Benefits include increased bone mineral density, a de- crease in the markers of bone resorp- Farnesyl PP tion, and a reduction in the risk of osteoporotic fractures.10 Severe musculoskeletal adverse ef- Squalene Geranylgeranyl PP fects occur in up to 6% of patients taking oral alendronate, ibandronate, or 11,12 risedronate. Musculoskeletal prob- Cholesterol Prenylated proteins lems reported, in order of decreasing frequency, include arthralgia, acute Figure. The mevalonate pathway, which is inhibited by both statins and nitrogen contain- back pain, myalgia, bone pain, and, ing bisphosphonates (nBPs). Statins inhibit the first step in the pathway, the conversion of rarely, chest pain and fever. Higher 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate. nBPs inhibit farnesyl rates of musculoskeletal pain have pyrophosphate (PP) synthase, resulting in accumulation of isopentenyl PP and activation been reported with intravenous infu- of gamma delta (gd) T cells. sions of pamidronate13 and zoledronic acid.14 Reversible erosive esophagitis,15 other upper gastrointestinal adverse after initiation of therapy.19 Discon- With regard to musculoskeletal prob- effects,16 and osteonecrosis of the tinuation usually results in resolution lems in general, nitrogen containing jaws17,18 also have been described. of pain, but recurrence has been re- bisphosphonates (nBPs) inhibit farne- Although musculoskeletal prob- ported when bisphosphonate therapy syl pyrophosphate (FPP) synthase lems are relatively common, an ex- is resumed. Given the frequency and in the mevalonate pathway,20 leading haustive literature review utilizing potential severity of these musculo- to accumulation of isopentenyl py- PubMed and Micromedex databases skeletal problems,19 it is possible that rophosphate (IPP) (Figure). IPP is a did not produce any published cases previous cases of bisphosphonate- potent activator of human peripheral of rhabdomyolysis associated with induced rhabdomyolysis may have blood gamma delta T cells.11 An in bisphosphonate use. Muscle pain been overlooked and attributed to the vitro study has demonstrated the in- associated with this class of drugs, common adverse effect of myalgia. duction of cardiac myocyte apopto- however, has been reported as severe The mechanism by which bisphos- sis by gamma delta T cells,21 and this or debilitating in some cases, appear- phonates, such as alendronate, might mechanism may conceivably produce ing within one day to several months produce rhabdomyolysis is unclear. skeletal myocyte apoptosis.

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Alendronate also has been associ- which may have placed him at addi- Ubiquinone depletion may contrib- ated with hypocalcemia and hypo- tional risk for rhabdomyolysis. ute to the higher ratio of lactate to phosphatemia22,23—both of which are Multiple interactions between pyruvate in patients taking statins, electrolyte disturbances capable of statins and other drugs have been suggesting increased anaerobic me- producing rhabdomyolysis. For this associated with rhabdomyolysis. tabolism and possible mitochondrial reason, it is recommended that cal- Gemfibrozil, macrolide antibiotics, dysfunction.32 The small GTP-bind- cium and vitamin D supplementation cyclosporine, and protease inhibi- ing proteins—such as Ras, Rho, and be given to patients taking alendro- tors used to treat HIV, for instance, Rac—promote cell maintenance and nate. In general, it is wise to correct may interfere with statin clearance. growth and attenuate apoptosis.33–35 any underlying calcium or phospho- Other potentially interacting drugs Inhibition of FPP synthesis by both rus abnormalities before therapy is mentioned in a study of statin-associ- statins and nBPs prevents posttrans- started.24 ated rhabdomyolysis cases reported lational modification (prenylation) For the patient described here, to the FDA between November 1997 of small GTP-binding proteins, thus electrolyte values were not obtained and March 2000 included mibefradil, inhibiting the regulatory actions of before alendronate therapy was fibrates, warfarin, digoxin, and azole these proteins. started. Although his electrolytes, including calcium and phosphorus, were normal at ED presentation (three weeks after initiation of alendronate), it is possible that they had Given the frequency and potential become abnormal after this therapy severity of musculoskeletal problems was started and subsequently normal- ized. It is also possible that his serum associated with bisphosphonate use, phosphorus levels may have appeared previous cases of rhabdomyolysis normal secondary to release of phosphate from damaged myocytes. The may have been overlooked. presence of muscle weakness at presentation supports the hypothesis of an underlying electrolyte disturbance. antifungals.28 Overall, an incidence of in summary A statin-bisphosphonate 0.44 cases of statin-associated rhab- Rhabdomyolysis is a potentially life interaction? domyolysis per 10,000 patient-years threatening condition that may have Statin-induced rhabdomyolysis is has been reported,29 as well as a rate multiple etiologies. In this case re- relatively rare, occurring in less than of 0.15 rhabdomyolysis deaths per 1 port, we have described the first 0.1% of patients taking the drugs.25 million statin prescriptions.30 documented case of rhabdomyoly- Nonetheless, the increasingly wide- Alendronate is not known to sis associated with alendronate use. spread use of statins—over 100 mil- have any interactions with statins, Given the frequency and potential se- lion statin prescriptions were filled nor does it alter their clearance. Re- verity of musculoskeletal problems in 200426—for patients with hyper- cent evidence, however, suggests associated with bisphosphonate use, lipidemia, diabetes, and coronary that statins—like nBPs—may induce previous cases of rhabdomyolysis may artery disease should make clini- skeletal muscle injury through me have been overlooked. cians cognizant of this potentially valonate pathway inhibition.27 Statins It is unclear whether other risk life threatening adverse effect and reduce the production of mevalonic factors must exist for the initiation of the clinical factors that increase its acid from HMG-CoA, the first step in alendronate therapy to result in rhab- likelihood in patients receiving statin the mevalonate pathway. Both statins domyolysis, but such factors as statin therapy. These factors include drug and nBPs, therefore, inhibit the pro- use, alcohol consumption, diabetes, interactions, renal and hepatic dis- duction of FPP, which is required for and renal disease may play a role. Po- ease, diabetes, and hypothyroidism.27 the production of ubiquinone, or co- tential mechanisms may involve elec- Our patient had a history of stage 3 enzyme Q10, and small guanosine tri- trolyte disturbances or downstream chronic kidney disease and diabetes phosphate (GTP)–binding proteins.31 inhibition of the mevalonate pathway,

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10. Kamel HK. Update on osteoporosis management 32. De Pinieux G, Chariot P, Ammi-Saïd M, et al. Lipid- which may be partially inhibited al- in long-term care: Focus on bisphosphonates. J Am lowering drugs and mitochondrial function: Effects ready by a statin. In light of this dual Med Dir Assoc. 2007;8(7):434–440. of HMG-CoA reductase inhibitors on serum ubi- 11. Bock O, Boerst H, Thomasius FE, et al. Common quinone and blood lactate/pyruvate ratio. Br J Clin inhibition of the same pathway, as musculoskeletal adverse effects of oral treatment Pharmacol. 1996;42(3):333–337. well as the increasing use of both with once weekly alendronate and risedronate 33. Olson MF, Ashworth A, Hall A. An essential role for in patients with osteoporosis and ways for their Rho, Rac, and Cdc42 GTPases in cell cycle progres- classes of drugs, clinicians should be prevention. J Musculoskelet Neuronal Interact. sion through G1. Science. 1995;269(5228):1270– aware of the potentially increased risk 2007;7(2):144–148. 1272. 12. Boniva tablets [prescribing information]. Nutley, 34. Coleman ML, Olson MF. Rho GTPase signalling of rhabdomyolysis in patients taking NJ: Roche Laboratories, Inc; 2008. pathways in the morphological changes associated concurrent bisphosphonate and statin 13. Aredia [prescribing information]. East Hanover, NJ: with apoptosis. Cell Death Differ. 2002;9(5):493– Novartis Pharmaceuticals Corporation; 2008. 504. therapy. ● 14. Zometa [prescribing information]. East Hanover, 35. Macaluso M, Russo G, Cinti C, Bazan V, Geb- NJ: Novartis Pharmaceuticals Corporation; 2008. bia N, Russo A. Ras family genes: An interesting 15. Graham DY, Malaty HM, Goodgame R. Primary link between cell cycle and cancer. J Cell Physiol. Author disclosures amino-bisphosphonates: A new class of gastrotoxic 2002;192(2):125–130. The authors report no actual or poten- drugs—Comparison of alendronate and aspirin. Am J Gastroenterol. 1997;92(8):1322–1325. tial conflicts of interest with regard to 16. Baker DE. Alendronate and risedronate: What this article. you need to know about their upper gastrointestinal tract toxicity. Rev Gastroenterol Disord. 2002;2(1):20–33. Disclaimer 17. Malden NJ, Pai AY. Oral bisphosphonate associated osteonecrosis of the jaws: Three case reports. Br The opinions expressed herein are those Dent J. 2007;203(2):93–97. of the authors and do not necessarily 18. Heras Rincón I, Zubillaga Rodríguez I, Castrillo Tambay M, Montalvo Moreno JJ. Osteonecrosis of reflect those of Federal Practitioner, the jaws and bisphosphonates. Report of fifteen Quadrant HealthCom Inc., the U.S. cases. Therapeutic recommendations. Med Oral Patol Oral Cir Bucal. 2007;12(4):E267–E271. government, or any of its agencies. 19. Actonel [prescribing information]. Cincinnati, OH: This article may discuss unlabeled or Procter & Gamble Pharmaceuticals, Inc; 2008. 20. van Beek E, Pieterman E, Cohen L, Löwik C, Pa- investigational use of certain drugs. papoulos S. Nitrogen-containing bisphosphonates Please review complete prescribing in- inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative formation for specific drugs or drug potencies corresponding to their antiresorptive po- combinations—including indications, tencies in vitro and in vivo. Biochem Biophys Res Commun. 1999;255(2):491–494. contraindications, warnings, and ad- 21. Huber SA. T cells expressing the gamma delta T verse effects—before administering cell receptor induce apoptosis in cardiac myocytes. Cardiovasc Res. 2000;45(3):579–587. pharmacologic therapy to patients. 22. Schussheim DH, Jacobs TP, Silverberg SJ. Hypocal- cemia associated with alendronate. Ann Intern Med. 1999;130(4 pt 1):329. References 23. Staley CA. Oral bisphosphonates: Alendronate 1. Knochel JP. Rhabdomyolysis and myoglobinuria. and risedronate. Womens Health Primary Care. Annu Rev Med. 1982;33:435–443. 2000;3(9):662–663. 2. Bywaters EG, Beall D. Crush injuries with impair- 24. Bauer DC, Black D, Ensrud K, et al. Upper gas- ment of renal function. 1941. J Am Soc Nephrol. trointestinal tract safety profile of alendronate: 1998;9(2):322–332. The Fracture Interventional Trial. Arch Intern Med. 3. Curry SC, Chang D, Connor D. Drug- and 2000;160(4):517–525. toxin-induced rhabdomyolysis. Ann Emerg Med. 25. Evans M, Rees A. Effects of HMG-CoA reductase 1989;18(10):1068–1084. inhibitors on skeletal muscle: Are all statins the 4. Prendergast BD, George CF. Drug-induced rhabdo- same? Drug Saf. 2002;25(9):649–663. myolysis—Mechanisms and management. Postgrad 26. Dirks AJ, Jones KM. Statin-induced apoptosis Med J. 1993;69(811):333–336. and skeletal myopathy. Am J Physiol Cell Physiol. 5. Akmal M. Rhabdomyolysis in a patient with hypo- 2006;291(6):C1208–C1212. calcemia due to hypoparathyroidism. Am J Nephrol. 27. Thompson PD, Clarkson P, Karas RH. Statin- 1993;13(1):61–63. associated myopathy. JAMA. 2003;289(13): 6. Dominic JA, Koch M, Guthrie GP, Galla JH. Primary 1681–1690. aldosteronism presenting as myoglobinuric acute 28. Omar MA, Wilson JP. FDA adverse event reports on renal failure. Arch Intern Med. 1978;138(9):1433– statin-associated rhabdomyolysis. Ann Pharmaco- 1434. ther. 2002;36(2):288–295. 7. Putterman C, Levy L, Rubinger D. Transient exer- 29. Graham DJ, Staffa JA, Shatin, et al. Incidence of cise-induced water intoxication and rhabdomyoly- hospitalized rhabdomyolysis in patients treated with sis. Am J Kidney Dis. 1993;21(2):206–209. lipid-lowering drugs. JAMA. 2004;292(21):2585– 8. Shintani S, Shiigai T, Tsukagoshi H. Marked hypo- 2590. kalemic rhabdomyolysis with myoglobinuria due 30. Staffa JA, Chang J, Green L. Cerivastatin and re- to diuretic treatment. Eur Neurol. 1991;31(6):396– ports of fatal rhabdomyolysis. N Engl J Med. 398. 2002;346(7):539–540. 9. Singhal PC, Kumar A, Desroches L, Gibbons N, 31. Flint OP, Masters BA, Gregg RE, Durham SK. Inhi- Mattana J. Prevalence and predictors of rhabdo- bition of cholesterol synthesis by squalene synthase myolysis in patients with hypophosphatemia. Am J inhibitors does not induce myotoxicity in vitro. Med. 1992;92(5):458–464. Toxicol Appl Pharmacol. 1997;145(1):91–98.

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