Investigation of Sustained BMP Delivery in the Prevention of Medication‐Related Osteonecrosis of the Jaw (MRONJ) in a Rat Model

Abstract

Medication‐related osteonecrosis of the jaw (MRONJ) poses an ongoing challenge for clinicians and researchers. Currently, there is a lack of preventative measures available for at‐risk patients undergoing tooth extractions, especially those with prior bisphosphonate treatment due to osteoporosis or bone metastasis diagnoses. Here, these issues are addressed using a preventative tissue engineering strategy against MRONJ development. This study evaluates the efficacy of a poly(ethylene glycol)‐heparin hydrogel as a tool for the delivery of arginylglycylaspartic acid (RGD) and recombinant human bone morphogenic protein‐2 (rhBMP‐2). Three groups of skeletally mature rats each receive two doses of intravenous zoledronic acid prior to surgery and undergo extraction of the right first mandibular molar with gingival closure. Experimental groups either have the sockets left empty, filled with hydrogel minus rhBMP‐2, or filled with hydrogel plus rhBMP‐2. Eight weeks postoperatively specimens are analyzed using radiological, histological, and scanning electron microscopy (SEM) techniques. µCT analysis shows increased bone formation with hydrogel/rhBMP‐2 delivery compared to the empty socket. Hydrogel‐treated groups display increased presence of osteocytes and increased osteoclastic action compared to the empty sockets. These results represent the first step toward improved delivery of rhBMP‐2 and a potential MRONJ preventative for patients undergoing bisphosphonate treatment.

BMP-2/β-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model

“…However, the bone regeneration rate promoted by BMP-2/hydrogel was moderate, i.e., the bone volume/total volume in the tooth extraction sockets in the BMP-2/hydrogel group (69.1% ± 13.1%) increased only 1.36 times compared to the non-transplantation group (50.9% ± 8.8%). Moreover, a detailed analysis of necrotic bone with empty lacunae, which is one of the important parameters used to assess the severity of MRONJ, was not performed [ 22 ]. Jung et al have reported a clinical preliminary study showing that only transplantation of BMP-2 absorbed with a collagen sponge (BMP-2/collagen) could not significantly induce bone formation at the MRONJ site, compared with the non-transplantation group, and that PTH administration would be necessary to stimulate the effect of BMP-2 in inducing bone formation [ 32 ].…”

“…Nevertheless, BMP-2 has been considered to have only a moderate effect on the prevention or reconstruction of MRONJ-associated symptoms [ 22 ]. Moreover, Jung et al have shown that the combination of parathyroid hormone (PTH) and BMP-2 helped to significantly improve bone formation compared with BMP-2 alone or a control group [ 23 ].…”

Poly-ε-Caprolactone/Fibrin-Alginate Scaffold: A New Pro-Angiogenic Composite Biomaterial for the Treatment of Bone Defects

“…Immunohistochemistry was carried out on paraffin sections as described previously [ 39 , 40 ]. Briefly, the sections were deparaffinized and rehydrated before they were incubated for 10 min with proteinase K (S302080, Dako, Sydney, Australia) for antigen retrieval.…”

What do we expect to visualize on the radiographs of mronj patients?

“…Although the pathogenesis of MRONJ is not completely understood there are hypothesizes which suggest that MRONJ is related in remodeling and healing of the jaws. Mechanisms that frequently mentioned are inhibition of osteoclast differentiation, inhibition of angiogenesis, induced apoptosis of osteoclasts, reduction of bone turnover (Ristow et al, 2015;Berg et al, 2016;Brierly et al, 2019). Oral malodor, erythema, soft tissue ulceration, which is persisted for more than 8 weeks, neuropathy, jaw pain, mucosal swelling, trismus, exposed bone or a non-healing extraction socket, paresthesia and suppuration are the common clinical signs and symptoms of MRONJ (Brierly et Five different hypotheses were suggested for the pathophysiology of the MRONJ since the first osteonecrosis of the jaws cases were reported; however, the exact pathophysiology is not determined yet (Marx, 2003;Aghaloo et al, 2015).…”