Osseointegration and Remodeling of Mineralized Bone Graft Are Negatively Impacted by Prior Treatment with Bisphosphonates

Abstract

Background:Bisphosphonates limit resorption by inhibiting osteoclast formation and activation. They are removed during preparation of demineralized bone matrix (DBM) particles, but it is not known if osteogenesis and incorporation of mineralized bone allografts from patients treated with oral bisphosphonates are affected in vivo.Methods:Human block allografts from 3 bisphosphonate-treated donors and 3 age and sex-matched control donors who had not received bisphosphonates were obtained (Musculoskeletal Transplant Foundation); one-half from each donor was demineralized. In the first study, 3 × 2-mm mineralized and demineralized cylindrical grafts were implanted bilaterally in the femoral metaphysis of 56 rats. In the second study, samples from each group were pooled, prepared as particles, and implanted bilaterally in the femoral marrow canal of 24 rats. Osseointegration, defined as native bone in contact with allograft, was assessed at 10 weeks by micro-computed tomography (CT) and histomorphometry.Results:Micro-CT showed greater bone volume in sites treated with demineralized samples compared with the control mineralized and bisphosphonate-exposed mineralized samples. More new bone was generated along the cortical-endosteal interface compared with mineralized samples. 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 mm2). The gap area was significantly greater compared with mineralized samples that did not receive bisphosphonates (0.16 mm2) and demineralized samples (0.10 and 0.03 mm2).Conclusions:Mineralized allografts were osseointegrated, but not remodeled or replaced by living bone, preventing full regeneration of the bone defect. Prior treatment of the donor with bisphosphonates affected osteogenesis, preventing osteointegration and remodeling of the allograft into the regenerating bone.Clinical Relevance:Clinical use of mineralized allografts from patients who had received bisphosphonate therapy needs to be evaluated; in this animal model, such grafts were not integrated into the host bone or remodeled, and full regeneration of the bone defects was prevented.

Bone reconstruction of extensive maxillomandibular defects in adults

“…In patients with low‐dose bisphosphonate therapy (e.g., for osteoporosis treatment), the successful healing of autologous grafts is described in a case series 50 . Nevertheless, bisphosphonate treatment is related to negatively affecting osteogenesis, preventing osteointegration and the remodeling of bone grafts 51 . According to some authors, bone grafting should be avoided under high‐dose antiresorptive therapy 52 .…”

“…51 According to some authors, bone grafting should be avoided under high-dose antiresorptive therapy. 52 In conclusion, more evidence-based knowledge is needed on the impact of local and systemic risk factors regarding the reconstruction of significant maxillomandibular bone defects.…”

Are secondary effects of bisphosphonates on the vascular system of bone contributing to increased risk for atypical femoral fractures in osteoporosis?

“…[ 27 ] Interestingly, CYPA1 can be expressed by multiple cell types and is upregulated by hypoxia in human ECs. [ 34,35 ] In addition to specific candidate gene research, it has also been noted that ethnicity also appears to play a role in AFF risk, [ 36 ] but whether this is related to unique genetic associations [ 23 ] or perhaps bone geometry, [ 36–38 ] bone quality [ 39–41 ] or all of these variables is not definitively known. Given the rarity of AFF even in Asian populations, bone geometry may be a risk factor but cannot explain the mechanism alone and thus may be a secondary risk factor.…”

“…[32] The potential role of the indicated genes and others in AFF [33] has recently been reviewed by Serra-Vinardell et al [27] Interestingly, CYPA1 can be expressed by multiple cell types and is upregulated by hypoxia in human ECs. [34,35] In addition to specific candidate gene research, it has also been noted that ethnicity also appears to play a role in AFF risk, [36] but whether this is related to unique genetic associations [23] or perhaps bone geometry, [36][37][38] bone quality [39][40][41] or all of these variables is not definitively known.…”

“…Thus, the number of affected patients that have been assessed for microdamage is not yet large and it is not clear if this is a common finding in most AFF patients. BP treatment is also reported to influence the properties of bone, [ 41 ] and some genetic polymorphisms have also been implicated in the bone response to BP. [ 49 ] It is also not certain presently if such findings are directly or indirectly involved in the outcomes leading to AFF risk, but a generalized effect of BP on bone quality must be entertained as potentially playing a role in the risk as it also appears to affect surgical outcomes in the treatment of patients with an AFF.…”