Anti-resorptive medications have helped millions of patients suffering from bone-wasting conditions.
However, a side effect called medication-related osteonecrosis of the jaw has caused significant anxiety
towards these otherwise useful medications, causing a sharp decline in prescriptions, despite the high benefit
to risk ratio. Unlike other anti-resorptive medications, bisphosphonates (including zoledronate) accumulate in
high concentration in the bone matrix of alveolar bone following the sessation of systemic treatment. Our
preliminary results show that matrix-bound zoledronate contributed to the exclusivity of osteonecrosis to the
jawbone (bisphosphonate-related osteonecrosis of the jaw; BRONJ), but was not the only factor. In human
patients, certain oral bacteria were common in BRONJ lesions (for example, Fusobacterium nucleatum and
Actinomyces israelii), suggesting that these bacteria may also be important for the pathogenesis of BRONJ.
Our central hypothesis is that matrix-bound bisphosphonates render the oral microenvironment favorable to
bacterial colonization of alveolar bone, shifting the balance of the bone regenerative response towards bone
destruction rather than effective regeneration, even after stopping the systemic bisphosphonate treatment. In
this proposal, we will study the interaction between predominant BRONJ-associated oral bacteria (F.
nucleatum and A. israelii) with systemic and matrix-bound bisphosphonates during the pathogenesis of
BRONJ. Specific Aim 1 will test whether matrix-bound ZA enhances attachment of predominant
BRONJ-associated bacteria to mineralized matrix. We will examine the effects of matrix-bound ZA on the
attachment mechanisms of two bacterial strains most commonly identified in necrotic alveolar bone (F.
nucleatum and A. israelii), whether the effects can be reversed by chelating matrix-bound ZA using EDTA, and
the effect of F. nucleatum and A. israelii on osteoclast differentiation, function, and cross-talk with osteoblast
and endothelial cells with and without ZA treatment. Specific aim 2 will test whether BRONJ-associated
bacteria are critical for the development of BRONJ. We will test the hypothesis that matrix-bound
zoledronate render the oral microenvironment favorable to bacterial colonization, even after stopping systemic
bisphosphonate treatment. Such bacterial colonization (F. nucleatum and A. israelii) of zoledronate-treated
animals will induce osteonecrosis following invasive surgical procedures at extra-oral bone sites, an effect that
can be ameliorated by local removal of zoledronate using EDTA. This project is based on the specific aims
accomplished during the first R15 award and is an extension of the same line of research. The award also
provided the sole support for 11 graduate, pre-doctoral, and undergraduate students. Successful renewal will
allow the continuation of student research at the PI’s lab.