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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e3181dfbb15
Case Report

Risedronate-Induced Arthritis

Yemisci, Oya Umit MD; Yalbuzdag, Seniz Akcay MD; Karatas, Metin MD

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From the Department of Physical Medicine and Rehabilitation, Baskent University, Ankara, Turkey.

Correspondence: Oya Umit Yemisci, MD, Department of Physical Medicine and Rehabilitation, Baskent University, Fevzi Cakmak Cad 5, Sok. No: 48, Bahcelievler 06490, Ankara, Turkey. E-mail: oyaumit@hotmail.com.

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Abstract

In most cases bisphosphonates are the first choice therapy for osteoporosis. We present a case of acute arthritis associated with once-weekly risedronate in a 58-year-old woman with osteoporosis. She developed arthritis 48 hours after the second dose of oral risedronate with elevated serum acute-phase reactants. There was no evidence of rheumatoid arthritis or seronegative arthritis. Her symptoms resolved rapidly with rest, however, recurred after the patient was rechallenged with the same drug 1 week later. Although the mechanism of this potential side effect remains speculative, it is thought to be as a result of the proinflammatory properties of aminobisphosphonates. With the increasing use of bisphosphonates in the treatment and prevention of osteoporosis, physicians should be well aware of this possible side effect of these drugs.

Bisphosphonates are the most frequently prescribed medications for the treatment of osteoporosis. The therapeutic potential of bisphosphonates is the strong inhibition of osteoclast-mediated bone resorption in a variety of ways, including effects on osteoclast recruitment, differentiation, and resorptive activity.1 Although evidence supports a good safety profile for these agents, numerous tolerability issues have been associated with their use. The well-known side effects of bisphosphonates are oesophagitis, influenza-like illness, and very rarely osteonecrosis of the jaw, which has been associated with high-dose intravenous bisphosphonate treatment; however, a small number of patients with cancer and osteoporosis using oral bisphosphonates have also reported this adverse effect.2 Among these side effects, acute arthritis-synovitis development after bisphosphonate treatment is seldom reported in the literature most of which are related to intravenous bisphosphonates3 and oral alendronate treatment.4–6

To our knowledge, this is the first case of acute arthritis induced by oral administration of risedronate during weekly usage.

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CASE REPORT

A 58-year-old woman with a history of Meniere disease was admitted to our hospital for follow-up for osteopenia. Assessment of bone mineral density by dual-energy x-ray absorptiometry revealed reduced mineral density in vertebral site (T-score −3.3 SD). Laboratory investigation showed normal values of blood cell counts, erythrocyte sedimentation rate, C-reactive protein (CRP), renal and liver function tests, bone biochemistry, and serum 25-(OH) vitamin D3. She was diagnosed as postmenopausal osteoporosis and was given once weekly risedronate (35 mg) in addition to oral calcium (1 g daily) and vitamin D3 (800 IU daily).

Twenty-four hours after the first administration of the drug, she developed mild constitutional symptoms such as nausea and myalgia. After 48 hours following the second dose, pain and swelling was observed in the metacarpophalangeal and proximal interphalangeal joints of the ring fingers of both hands. Radiographs of the hands revealed subchondral sclerosis, joint space narrowing, and small subchondral cysts in the proximal interphalangeal and distal interphalangeal joints and in the first carpometacarpal joints of both hands (Fig. 1). In spite of these mild osteoarthritic changes, the patient had never experienced pain or swelling in the hand and finger joints previously. There was no fever or chills. Blood tests revealed elevated CRP at 16.6 mg/dL (normal range 0–10 mg/dL). ESR and white blood cell counts were within normal ranges and rheumatoid factor and antinuclear antibody were negative. She was treated with 15 mg of meloxicam for 1 week and the symptoms resolved dramatically in 2 days. She was rechallenged a week later, with a more severe recurrence of symptoms at the fourth and fifth metacarpophalangeal joints of the left hand, which once again resolved rapidly with rest and nonsteroidal anti-inflammatory drugs.

Figure 1
Figure 1
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Risedronate was discontinued and daily oral raloxifene was initiated for osteoporosis. CRP values returned to normal (0.3 mg/dL) in 1 week and during the 6-month follow-up myalgia and symptoms of arthritis did not reappear.

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DISCUSSION

Bisphosphonates are compounds characterized by 2 carbon-phosphate (C-P) bonds and are analogs of inorganic pyrophosphate. Bisphosphonates can be divided into 2 different pharmacologic classes based on the presence or absence of a nitrogen atom on the central carbon atom side chain: non-nitrogen-containing bisphosphonates and nitrogen-containing bisphosphonates, also referred to as nonaminobisphosphonates and aminobisphosphonates, respectively.7 Nitrogen-containing bisphosphonates such as alendronate, risedronate and ibandronate inhibit the metabolic mevalonate pathway leading to enhanced apoptosis by activating caspase-3-like enzymes and inhibiting posttranslational isoprenylation of small guanosine triphosphate-binding proteins.8

The well-recognized side effect of bisphosphonates is “influenza-like illness” and it covers symptoms such as fatigue, fever, chills, myalgia, arthralgia, elevated ESR, and CRP and is often referred to as an “acute-phase reaction.”9 The mechanism of acute-phase reactions associated with nitrogen-containing bisphosphonates seem to be related to the inhibition of the mevalonate pathway, whereby the bisphosphonate induces rapid and copious production of the proinflammatory cytokines like tumor necrosis factor α, interferon-γ, and interleukin-1 and -6 by γδT cells.10–12 In a collagen-induced arthritis model in mice, the aminobisphosphonates showed an exacerbating effect on development of the arthritis13 and similarly, using a mouse model Zysk et al have shown a proinflammatory effect of aminobisphosphonate treatment on synovial microcirculation and exacerbation of joint inflammation with leukocyte adherence.14

Association between aminobisphosphonates and arthritis has been reported in the literature with isolated case reports. Gerster reported a case of severe myalgia and acute polyarthritis related to once-weekly alendronate treatment for postmenopausal osteoporosis.4 Diaz-Borjon et al reported a case of arthritis apparently induced by the administration of intravenous zoledronate and pamidronate in a patient with metastatic breast carcinoma.3 A case of persistent polyarticular synovitis after treatment with alendronate was reported by Frederiksen et al.5 And very recently Gwynne Jones et al described 7 cases of synovitis or arthritis occurring after commencement of alendronate for treatment of osteoporosis.6

In our patient, arthritis developed 48 hours following the second dose of oral risedronate with elevated serum acute-phase reactants. There was no evidence of rheumatoid arthritis or seronegative arthritis. One week later she was rechallenged with a recurrence of symptoms. She recovered without sequelae, and since then she has avoided bisphosphonates and has had no further joint problems. This evidence supports that acute arthritis-synovitis was related to risedronate therapy. To our knowledge, this is the first case related with risedronate.

As mentioned earlier, apart from the well-known adverse events of bisphosphonates, this event is seldom reported in the literature. We believe that this is because the physicians are not familiar with this condition and therefore its prevalence is probably underestimated. The purpose of our report is to emphasize the possibility of this rare side effect of bisphosphonates and that it should be considered in the differential diagnosis of acute arthritis or synovitis in patients treated with these agents.

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REFERENCES

1. Russell G, Graham R. Bisphosphonates: mode of action and pharmacology [review]. Pediatrics. 2007;119(suppl 2):S150–S162.

2. Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of osteoporosis [review]. Drug Saf. 2007;30:755–763.

3. Diaz-Borjon A, Seyler TM, Chen NL, et al. Bisphosphonate-associated arthritis. J Clin Rheumatol. 2006;12:131–133.

4. Gerster JH. Acute polyarthritis related to once-weekly alendronate in a woman with osteoporosis. J Rheumatol. 2004;31:829–830.

5. Frederiksen L, Junker P, Brixen KT. Persistent polyarticular synovitis after treatment with alendronate [English abstract in Reactions Weekly. 2007:7]. Ugeskr Laeger. 2007;169:1583–1584.

6. Gwynne Jones DP, Savage RL, Highton J. Alendronate-induced synovitis. J Rheumatol. 2008;35:537–538.

7. Benford HL, Frith JC, Auriola S, et al. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol. 1999;56:131–140.

8. Luckman SP, Hughes DE, Coxon FP, et al. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including ras. J Bone Miner Res. 1998;13:581–589.

9. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis. 2006;65:654–661.

10. Schweitzer DH, Oostendorp-vande Ruit M, Van der Pluijm G, et al. Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylamino hydroxyproline bisphosphonate. J Bone Miner Res. 1995;10:956–962.

11. Hewitt R, Lissina A, Green A, et al. The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol. 2005;139:101–111.

12. Thompson K, Rogers MJ. Statins prevent bisphosphonate-induced gamma, delta-T-cell proliferation and activation in vitro. J Bone Miner Res. 2004;19:278–288.

13. Nakamura M, Ando T, Abe M, et al. Contrast between effects of aminobisphosphonates and non-aminobisphosphonates on collagen-induced arthritis in mice. Br J Pharmacol. 1996;119:205–212.

14. Zysk SP, Durr HR, Gebhard HH, et al. Effects of ibandronate on inflammation in mouse antigen-induced arthritis. Inflamm Res. 2003;52:221–226.

Keywords:

risedronate; arthritis; side effect; acute-phase reaction

© 2010 Lippincott Williams & Wilkins, Inc.

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