Can BRONJ be Prevented by Relaxin Administration? A Pilot Study
The pathogenesis of BRONJ appeared related to the potent osteoblast-inhibiting properties of bisphosphonates which act by blocking osteoclast recruitment, decreasing osteoclast activity and promoting osteoclast apoptosis. Moreover, long-term bisphosphonates use leads to the development of abnormal osteoclasts, as well as a direct inhibitory effect on osteogenesis in bone-healing process. Bisphosphonates also show anti-angiogenetic activity; therefore the bones of patients treated with bisphosphonates are poorly vascularized and poorly supplied for wound healing.
Relaxin is a peptide hormone with a two chain structure, similar to that of insulin. This hormone primarly produced in the ovaries and placenta during pregnancy. It was found to promote elongation of the interpubic ligament in estrogen primed mammals, inhibit spontaneous contractions of the uterine and promote cervical softening. Major effects of relaxin include extracellular matrix remodeling, collagen degradation and up-regulation of matrix metalloproteinases. Other than these features it has a potential role in wound healing, angiogenesis and fibrosis. In recent studies, effects of relaxin in bone metabolism; differantiation, activation and stimulation of osteoclasts existance of relaxin receptors on osteoclast have been reported.
We assume that relaxin may be useful to prevent or manage the BRONJ due to the bisphosphanate antagonist effects of relaxin on osteoclastogenesis and angiogenesis.
Materials and Methods: The protocol for this pilot study was approved by the Baskent University Animal Care and Ethics Committee. Four male Sprague-Dawley rats were used as experimental animals in this pilot study. The animals were 10 to 12 weeks old and weighed 350-450 gr. All of the animals were housed in cages with free access to food and water, and were placed in a quiet and temperature/humidity-controlled room. After two weeks of acclimatization, animals were divided into 2 groups randomly: First grou (relaxin group), injected with zoledronate 0,1mg/kg 3 times a week intraperitotoneally and also received recombinant human relaxin (0.17 µg/kg/h) through osmotic minipumps for 12 weeks. Second group (control group) also injected with zoledronate and received saline with osmotic minipumps equal volume of relaxin. At the end of 12 weeks the rats were sacrified. The jaws of each rat were removed and placed in 10% buffered formalin solution. After fixation, the bone samples were decalcified in 25% formic acid.
Methods of Data Analysis: The specimens were processed for paraffin embedding, and sections were cut and stained with HE and histopathologic evaluations were performed. Necrosis was defined as the combined findings of nonviable bone trabeculae that have empty lacunae, inflammatory cells and abscesess.
Results: The histopathological examination revealed severe necrosis in control group, while there was no necrosis occurred in relaxin group. Regarding to inflammation, severe inflammation was observed in control group, while in relaxin group inflammation was mild.
Conclusions: In conclusion, BRONJ may be avoided by combining use of bisphosphonates and recombinant human relaxin.
References:
- Ferlin A, Pepe A, Facciolli A, Gianesello L, Foresta C. Relaxin stimulates osteoclast differentiation and activation. Bone 2010; 46: 504-513
- Senel FC, Kadioglu Duman M, Muci E, Cankaya M, Pampu AA, Ersoz S, Gunhan O. Jaw bone changes in rats after treatment with zoledronate and pamidronate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Mar;109(3):385-91