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Apatone®: The Benefits In Joint Replacement

Written by Mark Kovacik, Research Associate, Walter A. Hoyt Jr. Musculoskeletal Research Laboratory, Department of Orthopaedics, Orthopaedic Focus Winter 2010

Since the inception of total joint replacement in the late 1950s, the most common clinical cause of long-term failure is a non-infectious condition known as aseptic osteolysis (bone loss). at first, this osteolytic problem was thought to be a reaction to the cement (termed “cement disease”) used to hold the artificial implant in place.  Today, this condition is better understood as an inflammatory reaction to the microscopic metal and plastic particulates – known as wear debris – that are released within the joint by the implant during normal activity.

These wear particulates can stimulate complex biological interactions between cells of the fibroblast,
macrophage/osteoclast and the mesenchymal cell lineage, which can, in turn, lead to the activation of the inflammatory cascade, the inhibition of new bone formation and, ultimately, bone destruction.

While the focus of this problem has shifted to such fine wear particulates, little is still known of the triggering mechanism.  During the past decades, many have speculated that an inherent metal sensitivity to nickel may predispose some patients to failure.

Aseptic osteolysis has been a primary focus at the Walter A. Hoyt Jr. Musculoskeletal Research Laboratory. Under the direction of Ivan A. Gradisar Jr., M.D., and Thomas F. Bear, M.D., culture studies have been

performed in which cells extracted from human knee joints are exposed to various micron-sized metallic alloy particulates to better understand the bioreactive and cytotoxic effects they can instigate.

In conjunction, recent collaborative efforts with The University of Akron have allowed the Hoyt Lab to further examine the elemental composition at the surface (first several nanometers) of both cobalt-chromium and titanium alloy particulates using a quantitative technique known as X-ray photoelectron spectroscopy.

The results demonstrated that, irrespective of each material’s bulk elemental composition, the elemental
enrichment/depletion at the surface (a region of constant cellular contact) demonstrated the greatest bioreactive and cytotoxic effect on the cells, with high levels of surface cobalt having the greatest deleterious effect.

This phenomenon, known as surface elemental segregation, is commonly attributed to the thermal cycling that can occur during the manufacturing process (casting and sterilization) and wearing of the implant.  Because these elemental surface compositions were shown to vary between orthopaedic vendors and different batches from the same vendor, it becomes increasingly more challenging to determine the potential bioreactivity to any one patient. Thus the need to develop a potential prophylactic adjuvant that can mitigate the initial inflammatory reaction and potential for bone loss is warranted.

Recognizing the similarities in the biological response of a foreign-body induced inflammatory reaction to that of cancer, the Hoyt Lab began collaborative research in 2007 with the Urology Research Laboratory (known now as the Apatone Development Center) at Summa to investigate the potential orthopaedic application of a chemotherapeutic adjuvant (Apatone®) already under clinical evaluation for prostate cancer.

Owned by Summa and licensed to IC-MedTech (El Cajon, CA), this amalgam of Vitamin C and Vitamin K3 has been shown to be an effective antioxidant and anti-inflammatory agent, with virtually no demonstrated side effects. By structurally mimicking the glucose molecule and exploiting its increased uptake by inflamed cells, Apatone can selectively target and treat only these cells. Once retained within the cell, Apatone uses a double-barrel attack: The reduced form of Vitamin C acts to reduce reactive oxygen species (free radicals) while its oxidized form (dehydroascorbic acid) acts to prevent the activation of Nuclear-Factor-kappa-Beta (NFκB) – a prominent inflammatory transcription factor linked to osteolysis. 

Following renewed cellular exposure studies using the same deleterious metallic particulates previously described, the addition of a single dose of Apatone resulted in a 27 percent decrease in NFκB levels, a 44 percent decrease in the proinflammatory cytokine release of interleukin-6, a 47 percent decrease in the pro-inflammatory chemokine release of interleukin-8 and yielded an 18 percent increase in cellular proliferation.

Based on these experimental findings, an international orthopaedic patent application for Apatone®B was filed with a second international patent filed for more indications based on further research.

Most importantly, following approvals by the Summa IRB-2 and the FDA for an approved Investigational New Drug status (IND #108,383), enrollment for a double-blinded 13-week phase-IIb clinical trial using Apatone-B has commenced in October 2010 for symptomatic total joint patients.