Donor Bisphosphonate Use Affect DBM Quality?

Does demineralized bone matrix (DBM) from donors with a history of bisphosphonate use affect osteogenesis and osseointegration?

This was what a team from Virginia Commonwealth University (VCU) in Richmond and the Otto-von-Guericke University in Magdeburg, Germany, set out to learn. Their study, “Osseointegration and Remodeling of Mineralized Bone Graft Are Negatively Impacted by Prior Treatment with Bisphosphonates,” was published in the August 18, 2022, edition of The Journal of Bone and Joint Surgery.

D. Joshua Cohen, M.D., assistant professor in the Virginia Commonwealth University College of Engineering (Department of Biomedical Engineering) co-author on this work, told OTW, “Previously, we showed that the osteoinductivity of demineralized bone matrix was not affected by the bisphosphonate treatment that the donors had undergone (Schwartz Z et al., J Bone Joint Surg Am 2011 Dec 21;93(24):2278-86). This was likely due to the fact that the demineralization of the bone allograft removes any residual bisphosphonate.”

“The question remained about whether the presence of bisphosphonate in allograft would have an impact on bone formation,” Dr. Cohen continued. “Others have examined what effect allograft soaked in bisphosphonate has on graft integration and reported that added alendronate had a negative impact on osteogenesis (Jakobsen et al., Clin Orthop Relat Res 2007 Oct;463:195-201).”

“To our knowledge, our study is the first one to use mineralized allograft from patient donors who were treated with bisphosphonates compared to aged and sex-matched allografts from patient donors who were never treated with bisphosphonates, and how those grafts integrate with the native bone.”

The team used human block allografts from three bisphosphonate-treated donors and three age and sex-matched control donors (no bisphosphonates); one-half from each donor was demineralized.

In the first of the two rat studies (56 animals) 3 × 2-mm mineralized, and demineralized cylindrical grafts were implanted bilaterally in the femoral metaphysis of 56 rats. For the 24 rats comprising the second study, samples from each group were pooled, prepared as particles, and implanted bilaterally in the femoral marrow canal.

The researchers found that micro-computed tomography revealed greater bone volume in sites treated with demineralized samples compared with the control mineralized and bisphosphonate-exposed mineralized samples.

When compared with mineralized samples, more new bone was generated along the cortical-endosteal interface. When looking at the microarchitecture of the bone, the team found that, “Histology showed significantly less new bone in contact with the mineralized bisphosphonate-exposed allograft (10.4%) compared with mineralized samples that did not receive bisphosphonates (22.8%) and demineralized samples (31.7% and 42.8%). A gap was observed between native bone and allograft in the bisphosphonate-exposed mineralized samples (0.50 mm 2). The gap area was significantly greater compared with mineralized samples that did not receive bisphosphonates (0.16 mm 2) and demineralized samples (0.10 and 0.03 mm 2).”

As Dr. Cohen explained to OTW, “The most important result is that prior bisphosphonate treatment does indeed impact the integration of the fresh frozen allograft with the native bone. Prior bisphosphonate treatment negatively impacts this integration. We hypothesized that this would be the case; however, the space between the graft and the native bone was very clear to see and more pronounced than we expected.”

Co-author Barbara D. Boyan, Ph.D., executive director of the Institute for Engineering and Medicine at VCU, said, “I think this paper resonates with clinicians because it addresses a concern that the successful use of allograft depends on the health of the donor and the donor’s experience with therapeutics that may be incorporated into the bone mineral.”

“This paper assessed the effects of bisphosphonate use, which is fairly common in the older female donor population and is now used in men with osteoporosis as well. What is intriguing is that the allograft remains a perfectly good osteoconductive material BUT the presence of bisphosphonate compromises the effectiveness of the allograft as an agent to support quality integration of an implant in bone. To us, this points to the importance of primary bone remodeling via osteoclasts, which are inhibited by bisphosphonates, in order to achieve stable osseointegration via mature bone formation.”

Exclude Donors With History of Bisphosphonate Use

“Use of fresh frozen allograft is a very common practice in orthopaedic and dental practices,” said Dr. Cohen to OTW. “Our results demonstrate that tissue banks should exclude bone graft from donors with prior bisphosphonate treatment as this tissue may negatively impact the results of bone grafting procedures in patients.”