Elsevier

Bone

Volume 44, Issue 4, April 2009, Pages 671-677
Bone

Effect of oral erythromycin therapy in patients with aseptic loosening of joint prostheses

https://doi.org/10.1016/j.bone.2008.12.015Get rights and content

Abstract

There is currently no cure for aseptic loosening (AL) of total joint replacement (TJR) except surgical revision. The purpose of this study was to determine whether oral EM could improve the periprosthetic tissue profiles and reduce serum cytokine production in AL patients who are candidates for surgical revision. We recruited 32 AL patients. AL patients were treated with either EM (600 mg/day, n = 18) or placebo (n = 14) daily, started one month before surgery and ending on the day of surgery. Blood samples were obtained before EM treatment and during surgery. Periprosthetic tissues and joint fluids were collected during surgery. Our results demonstrate that oral EM reduces the inflammation of periprosthetic tissues, as manifested by the reduction of the numbers of infiltrating cells, CD68+ macrophages, RANKL+ cells, and TRAP+ cells. Remarkable decreases of TNFα (9.6-fold), IL-1β (21.2-fold), and RANKL (76-fold) gene transcripts were observed in periprosthetic tissues of patients treated with oral EM. Serum levels of both TNFα and (to a lesser extent) IL-1β were significantly reduced following EM treatment (p < 0.05). Our results suggest that EM represents a biological cure or prevention for those patients who might need repeated revision surgeries and/or show the early signs of progressive osteolysis after TJR.

Introduction

Aseptic loosening (AL) is a major complication of total joint replacement (TJR[1], [2], [3]. AL most likely results from an inflammatory response to billions of wear debris particles shed from the prosthesis during normal use, and the loosening periprosthetic tissue represents an inflammatory membrane containing large numbers of macrophages, fibroblasts, giant cells, and osteoclasts [4], [5], [6], [7], [8]. The interaction of macrophages with wear debris is the likely determinant of whether wear debris-induced inflammation will be resolved or progress to irreversible osteolysis [9].

There is currently no cure for AL except surgical revision. A recent approach to limiting osteolysis has focused on understanding and manipulating osteolysis at a molecular level through pharmacological intervention [10], [11]. However, no studies exist to address whether the inflammatory changes of periprosthetic tissues can be improved by drug treatment.

Erythromycin (EM), a 14-member lactone ring macrolide antibiotic, has been used for the treatment of infectious disease for over 50 years [12]. For the last decade, EM has attracted a great deal of attention because of its additional anti-inflammatory effects at sub-antimicrobial doses [13], [14]. EM demonstrates a unique “phagocyte targeted delivery” property, with a tropism for monocytes and macrophages in bone marrow and inflammatory tissues [15], [16]. Oral EM (600 mg/daily) has been reported to significantly improve the 10-year survival rate of diffuse panbronchiolitis (a chronic non-infectious lung inflammation) [17], [18], [19], [20]. Our previous in vitro studies [21] have demonstrated that EM (5 mg/ml) significantly inhibits mRNA expression of IL-1β and TNFα in the wear debris-activated mouse RAW-264.7 macrophage cell line, associated with the reduction of NFkB DNA-binding activity. In addition, EM treatment (0.5 mg/ml) results in a greater than 70% reduction in TRAP+ osteoclast formation [21]. Using a mouse osteolysis model, we demonstrated that EM significantly inhibits wear debris-induced inflammation, osteoclastogenesis, and bone degradation [22]. The objective of this study was to investigate the effects of oral EM on periprosthetic tissue inflammation, cytokine profiles, and osteoclastogenesis in a group of AL patients who were candidates for surgical revision. Our outcome measurements included periprosthetic tissue profiles and cytokine levels in serum and joint fluids.

Section snippets

Human subjects

The Human Subjects Review Board of Wayne State University approved this prospective, double-blinded, clinical study. Informed consents were obtained from all subjects. The subjects included were those who had a total hip prosthesis, thought to be loose without a suspicion of infection. The majority of these had had a cemented-stem, press-fit acetabulum, but a few had had a press-fit femoral stem and a press-fit acetabulum. Thirty-two (32) such AL patients who met the following criteria were

Subject characteristics

The patient demographic data demonstrated a good match of age and gender between patients treated with and without EM. As shown in Table 1, no difference was found between these two groups regarding to their implant type (cement or cementless). All recruited patients tolerated the EM treatment well. One patient was withdrawn from this study due to mild diarrhea, and this patient recovered completely shortly after termination of EM treatment.

Effect of oral EM on UHUMWPE particle-induced cytokine secretion of peripheral mononuclear cells

As shown in Fig. 1, there were no statistical

Discussion

There is currently no cure for AL except surgical revision. A more recent approach has focused on understanding and improving inflammatory osteolysis associated with AL through pharmacological intervention [26], [27]. However, delivering adequate levels of cell-specific therapy to the site of periprosthetic inflammation, without undesirable systemic side effects, presents a considerable challenge. EM represents an appropriate candidate for AL treatment, due to its proven success for the

Acknowledgments

This study was supported by a grant from Orthopaedic Research and Education Foundation (G/F #25NIN) to Dr. Weiping Ren.

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