Current pharmaceutical therapies can reduce hip fractures by up to 50%, but compliance to treatment is low and therapies take up to 18 months to reduce risk. Thus, alternative or complementary approaches to reduce the risk of hip fracture are needed. The AGN1 local osteo‐enhancement procedure (LOEP) is one such alternative approach, as it is designed to locally replace bone lost due to osteoporosis and provide immediate biomechanical benefit. This in vitro study evaluated the initial biomechanical impact of this treatment on human cadaveric femurs. We obtained 45 pairs of cadaveric femurs from women aged 77.8 ± 8.8 years. One femur of each pair was treated, while the contralateral femur served as an untreated control. Treatment included debridement, irrigation/suction, and injection of a triphasic calcium‐based implant (AGN1). Mechanical testing of the femora was performed in a sideways fall configuration 24 h after treatment. Of the 45 pairs, 4 had normal, 16 osteopenic, and 25 osteoporotic BMD T‐scores. Altogether, treatment increased failure load on average by 20.5% ( p < 0.0001). In the subset of osteoporotic femurs, treatment increased failure load by 26% and work to failure by 45% ( p < 0.01 for both). Treatment did not significantly affect stiffness in any group. These findings provide evidence that local delivery of the triphasic calcium‐based implant in the proximal femur is technically feasible and provides immediate biomechanical benefit. Our results provide strong rationale for additional studies investigating the utility of this approach for reducing the risk of hip fracture. © 2019 The Authors. Journal of Orthopaedic Research ® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.

This first-inhuman study of AGN1 LOEP demonstrated that this minimally-invasive treatment durably increased aBMD in femurs of osteoporotic postmenopausal women. AGN1 resorption was coupled with new bone formation by 12 weeks and that new bone was maintained for at least 5-7 years resulting in substantially increased FEA-estimated femoral strength. Introduction This first-inhuman study evaluated feasibility, safety, and in vivo response to treating proximal femurs of postmenopausal osteoporotic women with a minimally-invasive local osteo-enhancement procedure (LOEP) to inject a resorbable triphasic osteoconductive implant material (AGN1). Methods This prospective cohort study enrolled 12 postmenopausal osteoporotic (femoral neck T-score ≤ − 2.5) women aged 56 to 89 years. AGN1 LOEP was performed on left femurs; right femurs were untreated controls. Subjects were followed-up for 5-7 years. Outcomes included adverse events, proximal femur areal bone mineral density (aBMD), AGN1 resorption, and replacement with bone by X-ray and CT, and finite element analysis (FEA) estimated hip strength. Results Baseline treated and control femoral neck aBMD was equivalent. Treated femoral neck aBMD increased by 68 ± 22%, 59 ± 24%, and 58 ± 27% over control at 12 and 24 weeks and 5-7 years, respectively (p < 0.001, all time points). Using conservative assumptions, FEA-estimated femoral strength increased by 41%, 37%, and 22% at 12 and 24 weeks and 5-7 years, respectively (p < 0.01, all time points). Qualitative analysis of X-ray and CT scans demonstrated that AGN1 resorption and replacement with bone was nearly complete by 24 weeks. By 5-7 years, AGN1 appeared to be fully resorbed and replaced with bone integrated with surrounding trabecular and cortical bone. No procedure-or device-related serious adverse events (SAEs) occurred. Conclusions Treating femurs of postmenopausal osteoporotic women with AGN1 LOEP results in a rapid, durable increase in aBMD and femoral strength. These results support the use and further clinical study of this approach in osteoporotic patients at high risk of hip fracture.

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This study evaluated the effects of AGN1, a triphasic calcium‐based material, and alendronate (A) on distal femoral defect bone repair in ovariectomized (OVX) rats. Of 106 rats, 92 were OVX'ed at 12 weeks old and underwent a 12‐week induction period. Animals were randomized into five groups: OVX Control, OVX Alendronate Control, Normal Control, OVX Implantation, OVX Alendronate + Implantation. OVX Alendronate Control and OVX Alendronate + Implantation groups received alendronate injection twice weekly (0.015 mg/kg) from 6 weeks until sacrifice. Twelve weeks after OVX, 2.5 mm diameter by 4.0 mm long cylindrical, bilateral distal femoral defects were created in experimental animals. One defect was left empty, and one filled with AGN1. Dual‐energy X‐ray absorptiometry, microcomputed tomography, and histomorphometry were performed 0‐, 6‐, 12‐, and 18‐week postdefect/implantation surgery (N = 6–8/group). Results showed OVX induced significant and progressive bone loss which alendronate prevented. Histomorphometry demonstrated rapid AGN1 resorption: AGN1 resorbed from 95.1 ± 0.7% filling of the implant site (week 0) to 1.3 ± 1.0% (18 weeks) with no significant alendronate effect (1.6 ± 1.1%, 18 weeks). Bone formation in empty defects consisted primarily of cortical wall healing, whereas AGN1 implants demonstrated cortical wall healing with new trabecular bone filling the subcortical space. Alendronate dramatically increased bone formation in empty and AGN1 defects. We conclude AGN1 is resorbed and replaced by new cortical and trabecular bone in this OVX model, and alendronate did not compromise these effects.

Oral cancer is the sixth most common cancer worldwide, with approximately 275,000 new cases each year. In some countries, mortality rates reach as high as 70 %. For patients that survive, bodily functions of speaking, swallowing, and chewing are severely compromised. Although there has been improvement in free tissue transfer techniques and virtual planning with implant placement, maxillofacial reconstruction techniques need refinement to allow greater improvement in functional outcomes and quality of life. Regenerative engineering principles provide a potential means of improving maxillofacial tissue regeneration. Maxillofacial reconstruction requires unique insights to maximize clinical impact. Because traditional cancer treatment can include radiation therapy, defect sites may experience hypoxia and experience thrombosis and fibrosis, which complicate restoration [1]. Several cell sources, such as periosteal-derived progenitor cells (PDPCs) and bone marrow-derived mesenchymal stem cells (BMSCs) have been evaluated for use in maxillofacial reconstruction, with variable success. From our comprehensive review of the literature, there is a significant need to further the application of regenerative engineering principles to maxillofacial regeneration following oral cancer treatment. Lay Summary The prevalence of oral cancer and limitations of treatments invites regenerative engineering approaches. While combatting cancer, tissue removal, radiation, and/or chemotherapy often significantly reduce the patient's quality of life. A high-quality Bfunctional outcome^following treatment means the ability to readily perform the seemingly simplest of biological tasks that humans often take for granted-swallowing, breathing, coughing, and speaking intelligibly. Indeed, damage due to clinical treatments may include normal tissues at the cancer site but can also extend to surrounding tissues such as teeth. A regenerative engineering approach, involving tissue enhancement with cellular materials, would allow tissue to be rebuilt following and during potentially harmful clinical treatments.