|Abstract / Summary|
Osteomyelitis is a common infectious disease characterized by progressive
inflammation and bone destruction. Although the total number of osteomyelitis cases is
high in that approximately 112,000 and 240 orthopedic device-related infections occur
per year in the US and Denmark respectively, at an approximate hospital cost of $15,000-
70,000 per incident  the infection rates for joint prosthesis and fracture-fixation
devices have been only 0.3-11% and 5-15% of cases respectively over the last decade,
which resulted in a low interest in rigorous prospective clinical studies. Since
osteomyelitis induces osteolysis around the implant, which can lead to fractures and
complicate revision surgery, orthopedists have anecdotally used anti-resorptive
bisphosphonates in these patients to preserve bone stock without knowledge of their
effects on chronic infection. Furthermore, in the recent years there has been an alarming
increase in reports of osteonecrosis of the jaw, a condition that has been associated with
bisphosphonate usage. Although osteomyelitis remains a serious problem in orthopedics,
progress has been limited by the absence of an in vivo model that can quantify the
bacterial load, metabolic activity of the bacteria over time, immunity and osteolysis.
To overcome these obstacles, we developed a murine model of implant-associated
osteomyelitis in which a stainless steel pin is coated with S. aureus and implanted
transcortically through the tibial metaphysis. We analyzed the animals using radiology,
histology as well as serology. Bacterial load and activity was determined by Real-time
quantitative PCR (RTQ-PCR) and in vivo bioluminescence imaging (BLI) of luxA-E
transformed S. aureus (Xen29). Collectively, these studies demonstrate the first
quantitative model of implant-associated osteomyelitis that defines the kinetics of
microbial growth, osteolysis and humoral immunity following infection (paper I).
To better understand the effects of bisphosphonates on osteomyelitis, and shed
light on the mechanism of osteonecrosis of the jaw, we investigated the interaction of
anti-resorptive agents in our established murine model of implant-associated
osteomyelitis. We investigated two distinct classes of anti-resorptive drugs: the most
widely prescribed bisphosphonate alendronate and the biologic antagonist
osteoprotegerin (OPG). Both agents caused an increase in severe infections. This finding
coincided with a significant decrease in osteolysis and draining lymph node volume,
suggesting that anti-resorptive agents decrease efflux of marrow lymph during the
establishment of osteomyelitis that could lead to a dramatic increase in intraosseous
pressure, infarction and bone pain (paper II).
Finally, we evaluated the use of colistin polymethyl methacrylate (PMMA) beads in
treating A. baumannii induced osteomyelitis. This was done by using our established
murine OM model and infecting animals with clinical isolates of multi-drug resistant A.
baumannii. To demonstrate efficacy of colistin prophylaxis in this model, mice were
treated with either parenteral colistin or local colistin using PMMA beads. While
parenteral colistin failed to demonstrate any significant effects vs. placebo, the colistin
PMMA beads significantly reduced the infection rate (paper III).