LOCAL OVER WHOLE-BODY ANTIRESORPTIVE EFFECTS OF A SYSTEMICALLY ADMINISTRATED BISPHOSPHONATE IN THA – RESULTS FROM A RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL

Abstract

Background: Aseptic loosening of implants is commonly associated with periprosthetic bone loss, and several authors aimed to preserve periprosthetic bone mass by treatment with bisphosphonates (BPs) in THA. While local application of BPs was argued to provide higher concentrations of bioactive drug at the component-bone interface, we hypothesized that a systemically administration of BPs will be sufficient for sustained effects on local bone metabolism due to local accumulation of the drug in freshly exposed bone mineral early after reaming during implantation. The high antiresorptive potential of zoldronic acid (ZOL) on osteoclasts will be sustained locally by re-attachment after release by osteoclast resorption during the remodelling cycle. While we were able to demonstrate beneficial effects of ZOL on early implant fixation, its local effects on bone metabolism is best reflected by monitoring the relative changes of biochemical markers during follow-up after THA. This is an important issue to be addressed, since there are no reliable data available but essential for a prove-of-concept.

Methods: Fifty patients with ON-FH were consecutively enrolled to receive randomly either 4mg of ZOL or saline solution (CTR) in a double-blind fashion one day after THA. The biochemical bone turnover markers C-terminal teleopeptides of collagen type I (ICTP), CrossLaps (CL), osteocalcin (OC), osteoprotegerin (OPG), soluble RANKL, as well as 25-hydroxyvitamin D (25OHD3) were measured from fasting blood samples before surgery and at 7 weeks, 6 months, 1 year, and yearly thereafter. One patient was lost and after excluding three patients with deficiency in renal function 22 and 24 patients were analyzed in ZOL and CTR, respectively, during a median follow-up of 2.8 yrs.

Results: Within the placebo group, the bone resorption markers ICTP and CL peaked at 7 wks, but continuously decreased thereafter beyond baseline levels. The bone formation marker OC also increased, but peaked at 6 months and stayed increased during the follow-up. Although there was only a transient effect of ZOL found in ICTP, CL rapidly decreased within 7 wks and remained depressed during the whole follow-up period (~ − 65% at 2 yrs, P< 0.0001). Similarly, OC was also depressed in ZOL but never reached significance compared to baseline levels (~ − 19%, NS). No differences or changes were apparent in 25OHD3 levels.

Discussion and Conclusion: The findings strongly support a predominant local effect of systemically infused ZOL over a whole-body effect. Furthermore, the data demonstrate the sufficiency of a single infusion of a single infusion of ZOL for a pronounced and sustained antiresorptive effect after THA, which is essential to preserve periprosthetic bone mass in an effort to prevent aseptic loosening.