The Journal of Bone and Joint Surgery (American). 2010;92:129-137.
doi:10.2106/JBJS.H.01561
© 2010 The Journal of Bone and Joint Surgery, Inc.
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In Vitro Cytotoxic Effects of Benzalkonium Chloride in Corticosteroid Injection Suspension

Daniel Davis, MSc1, Mathew Cyriac, MBA, BSc2, Dongxia Ge, MD3, Zongbing You, MD, PhD1 and Felix H. Savoie, MD1

1 Tulane Institute of Sports Medicine, Department of Orthopaedic Surgery (D.D., Z.Y., and F.H.S.), and Department of Structural and Cellular Biology, Tulane Cancer Center, LCRC, Tulane Center for Aging (D.G. and Z.Y.), Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. E-mail address for Z. You: zyou{at}tulane.edu
2 Albany Medical College, 43 New Scotland Avenue, Albany, NY 12208
3 Institute of Biomedical Engineering, West China Medical Center, Sichuan University, No. 3-17 Ren Min Nan Lu Road, Chengdu, Sichuan, China 610041

Investigation performed at Tulane University School of Medicine, New Orleans, Louisiana

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Background Some deleterious effects on cartilage and even severe arthropathy have been reported after intra-articular corticosteroid injections. The objective of the present in vitro study was to determine if an injectable corticosteroid suspension is toxic to articular chondrocytes and synovial cells.

Methods Human and bovine articular chondrocytes, bovine synovial cells, mouse C3H10T1/2 cells, and human osteosarcoma MG-63 cells were treated for thirty minutes in monolayer or suspension culture with an injectable corticosteroid suspension or its chemical components, including betamethasone sodium phosphate, betamethasone acetate, and benzalkonium chloride (as preservative). Cell viability was determined by means of microscopy or flow cytometry analysis.

Results In monolayer culture, the betamethasone corticosteroids per se did not cause cell death, whereas benzalkonium chloride caused death of articular chondrocytes. In suspension culture, betamethasone sodium phosphate at dosages of as high as 6 mg/mL did not cause significant death of human or bovine articular chondrocytes (p > 0.05). In contrast, benzalkonium chloride caused a death rate of 10.6% in human articular chondrocytes at a dosage of 10 µg/mL (p < 0.01), 21.0% at a dosage of 13.3 µg/mL (p < 0.01), and 99.3% and 99.4% at dosages of 20 and 200 µg/mL, respectively (p < 0.001 for both). Similarly, benzalkonium chloride caused death of bovine articular chondrocytes, bovine synovial cells, C3H10T1/2 cells, and MG-63 cells in a dose-dependent manner. When treated with a combination of betamethasone sodium phosphate and 200 µg/mL benzalkonium chloride, >99% of human or bovine articular chondrocytes were dead (p < 0.001).

Conclusions The injectable corticosteroid suspension caused death in in vitro culture of human and bovine articular chondrocytes as well as bovine synovial cells because of its preservative benzalkonium chloride. The betamethasone corticosteroids per se did not cause significant chondrocyte death under the conditions tested.

Clinical Relevance These findings should stimulate an in vivo animal study to test the degree to which the changes seen in vitro also occur in vivo.


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