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Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg

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Abstract

Summary

Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms.

Introduction

Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen.

Methods

In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion.

Results

The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen.

Conclusion

Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

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Acknowledgments

The authors would like to thank all the patients who participated in the study and the following study investigators—Australia: Philip Clifton-Bligh, Michael Hooper, Bronwyn Stuckey, Peter Nash, Stephen Stranks; Canada: Jeannette Janzen, Jack Kooy, Richard Kremer, Jean-Pascal Ouellet, Brian Zidel, Ben Lasko; Russia: Sergey Mazurenko, Svetlana Rodionova, Valentina Soroskaya, Lidia Benovolenskaya; South Africa: Graham Ellis, Stanley Lipschitz, SL Brown; USA: James Dreyfus, Susan Nattrass, Theodore Rooney, Suzanne Trupin, Thomas Klein

Conflicts of interest

JD Wark is employed by the University of Melbourne. He has received consultancy fees, speaker’s bureau, contract research, and investigator-initiated research grants from Novartis. He has received industry support from Novartis, Servier, Amgen, Sanofi-Aventis/Procter & Gamble, Eli Lilly, UCB Pharma, Government support from Australian NHMRC, Australian Research Council, and other support from the Gardiner Foundation, Arthritis Australia, Scoliosis Research Society, Cancer Council of Victoria, Curtin University of Technology.

W Bensen is a clinical professor of medicine at St. Joseph’s Hospital and McMaster University. He has received consultancy fees, speaker bureau fees, contract research and advisory board fees from Amgen/Wyeth, BMS, Roche, Abbott, UCB, Schering-Plough, Pfizer, Merck, Procter & Gamble, Sanofi-Aventis, Eli Lilly, Servier and Novartis.

C Recknor is employed by United Osteoporosis Centers. He has received speaker’s fees from Novartis, Zelos, Roche, GlaxoSmithKline, Amgen, NEGA Medical Center, Embryon, Liposcience, and consulting or advisory fees from Novartis, Takeda, Eli Lilly, Procter & Gamble.

O Ryabitseva is employed by the Russian State Institution of Healthcare. She has received clinical research grants and consulting fees from Novartis. She has also received clinical research grants from Schering-Plough and Roche.

J Chiodo III is an employee of Otsuka America Pharmaceuticals Inc

P Mesenbrink is an employee of Novartis Pharmaceutical Corporation who owns full ADRs, restricted ADRs and tradeable options of Novartis stock.

TJ De Villiers is self-employed in private practice. He has served on advisory boards for Novartis, Servier and Wyeth, has received speaker’s honoraria from Novartis, Wyeth, Novo Nordisk and MSD, and has been an investigator in clinical trials sponsored by Novartis, Pfizer, Wyeth, MSD, Eli Lilly and Roche.

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Correspondence to J. D. Wark.

Appendix—List of study centers and institutional review board

Appendix—List of study centers and institutional review board

The following institutional review boards or ethics committees reviewed and approved the study protocol:

Australia: Royal North Shore Hospital, St Leonards, New South Wales; HREC, Sir Charles Gairdner Hospital, Nedlands, Western Australia; Melbourne Health Research Directorate, Melbourne Hospital Parkville Victoria; Royal Brisbane Hospital & Royal Women’s Hospital & Health Service District HREC, Herston, Queensland; Research and Ethics Committee, Repatriation General Hospital, Daws Park, South Australia.

Canada: McGill University Health Center; Institutional Review Board Services, Kells Medical Research Group; The Medical Arts Health Research Group, Penticton, British Columbia; Royal Victoria Hospital, Montreal, Quebec; Q&T Research, Sherbrooke, Quebec; Malten Medical Centre, Mississauga, Ontario; Manna Research, Toronto, Ontario.

Russia: Local ethics committee affiliated with Kazan State Medical University, Kazan; Local ethics committee affiliated with Reumatology Center at Regional Hospital #1, Ekaterinburg; Local ethics committee at Medical and Sanitary Unit #122, St. Petersburg; Local ethics committee affiliated with N.N. Priorov Central Research Institute of Traumatology and Orthopedics, Moscow; Independent ethics committee at Tula Regional hospital, Tula; Local ethics committee affiliated with Institute of Rheumatology at Russian Academy of Medical Science, Moscow; Research Center ethics committee at Medical Center of the President of Russian Federation, Moscow.

South Africa: SAMA Research Ethics Committee, Pretoria; Research Ethics Committee, University of Cape International Academic Programmes Office (IAPO), Rondebosch; University of the Witwatersrand Human Research Ethics Committee, Johannesburg;

USA: Quorum Central IRB, Seattle, WA; Mercy Medical

Center—Des Moines Institutional Review Committee, Des Moines, IA.

The following is a list of study centers:

Australia: Northern Metabolic Bone Centre, St Leonards, New South Wales; Gordon Private Rooms, Gordon, New South Wales; Keogh Institute for Medical Research, Nedlands, Western Australia; Royal Melbourne Hospital, Parkville, Victoria; Sixth Avenue Specialist Centre, Cotton Tree, Queenslands; Repatriation General Hospital, Daw Park, South Australia.

Canada: Wynn Tech Inc, Hamilton, Ontario; Kells Medical Research Group, Pointe Claire, Quebec; PCT Networks Inc, Penticton, British Columbia; Royal Victoria Hospital, Montreal, Quebec; Q&T Research, Sherbrooke, Quebec; Malten Medical Centre, Mississauga, Ontario; Manna Research, Toronto, Ontario.

Russia: Regional Hospital no 1, Ekaterinburg; Centre of Osteoporosis and Skeleton Metabolic Diseases, St Petersburg; N.N. Priorov Central Research, Institute of Traumatology and Orthopedics, Moscow; Tula Regional Hospital, Tula; Institute of Rheumatology, Russian Academy of Medical Science, Moscow; Outpatient department with the Medical Center of Administration of the President of the Russian Federation, Moscow

South Africa: Medi-Clinic, Cape Town; Helderbery Osteoporosis Clinic, Cape Town; Osteoporosis Clinic, Johannesburg; Donald Gordon Medical Centre, Johannesburg.

USA: Medical Specialists Clinical Research Center, Munster, IN; Puget Sound Osteoporosis Center, Seattle, WA; United Osteoporosis Center, Gainesville, GA; Mercy Arthritic and Osteoporosis Center, Des Moines IA; Women’s Health Center, Champaign, IL; Heartland Research, Whichata, KS.

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Wark, J.D., Bensen, W., Recknor, C. et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 23, 503–512 (2012). https://doi.org/10.1007/s00198-011-1563-8

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