Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze-dried onto the cortical surface without losing infectivity. We show that combination rAAV-RANKL-and rAAV-VEGF-coated allografts show marked remodeling and vascularization, which leads to a new bone collar around the graft. In conclusion, we find that RANKL and VEGF are necessary and sufficient for efficient autograft remodeling and can be transferred using rAAV to revitalize structural allografts.In contrast to soft tissue organ transplantation (i.e., heart, liver, kidney), which must be live from a histocompatible donor, structural musculoskeletal grafts (i.e., bone, ligament) are often derived from allogenic cadavers. Although this convenience makes structural allografts readily available, the utility of these transplants is limited by their lack of viability. This is most evident from experimental and clinical studies showing that fresh vascularized autogenous grafts are vastly superior to allograft in terms of healing and remodeling 1,2 . Structural bone grafts used to heal critical defects and bone fusions undergo a repair and remodeling process that closely resembles fracture healing 3 . In live autograft healing, cells from both the graft and the host contribute to mediate bony union 4,5 . In contrast, healing of a diaphyseal defect that has been allografted can only be accomplished by invasion of the graft by host tissue to obtain a cortexCorrespondence should be addressed to E.M.S. (edward_schwarz@urmc.rochester.edu).. COMPETING INTERESTS STATEMENT The authors declare competing financial interests (see the Nature Medicine website for details). to-cortex union 6 . Following union, autografts continue to remodel as a result of osteoclastic resorption of necrotic or disused cortical bone that is followed by osteoblastic formation of new woven bone, which is later remodeled into stronger lamellar bone. In this way, autografts are sustained through normal bone homeostasis. In contrast, once creeping callus from the host calcifies on the cortex of an allograft, healing ceases, leaving a large segment of necrotic bone that is unable to respond to normal mechanical loading. Thus, structural allografts have a limited life span because microfractures that occur in them over time cannot be remodeled and repaired, and negative outcomes include a 25-35% failure rate from infection, nonunion and fracture 7,8 . NIH Public AccessTwo central issues that must be addressed to improve structural allografting are elucidatio...

To further understand the cellular and molecular mechanisms underlying cortical bone graft healing, we have developed a novel mouse femur model that permits quantitative and molecular analysis of structural bone graft healing. A 4 mm mid-diaphyseal femoral segment was removed and replaced by either immediate implantation of a fresh autograft, a frozen, genetically identical isograft or a frozen allograft from a different strain of mouse, which was secured with a 22-gauge metal intramedullary pin. Healing was evaluated by radiology, histomorphometry, and in situ hybridization. Autograft repair occurred by endochondral bone formation at the host-graft junction and by intramembranous bone formation along the length of the graft bed at 2 weeks, with maturation and remodeling apparent by 4 weeks. Bone repair in allografts and isografts completely relied on endochondral bone formation at the host-graft cortical junction, with absence of periosteal bone formation along the length of the graft, suggesting that live periosteal cells from the donor tissue are necessary for this response. This small animal model of structural bone grafting can be used to evaluate tissue-engineered allografts and novel bone graft substitutes using quantitative and molecularly defined outcome measures.

Lead exposure continues to be a significant public health problem. In addition to acute toxicity, Pb has an extremely long half-life in bone. Individuals with past exposure develop increased blood Pb levels during periods of high bone turnover or resorption. Pb is known to affect osteoblasts, osteoclasts, and chondrocytes and has been associated with osteoporosis. However, its effects on skeletal repair have not been studied. We exposed C57/B6 mice to various concentrations of Pb acetate in their drinking water to achieve environmentally relevant blood Pb levels, measured by atomic absorption. After exposure for 6 weeks, each mouse underwent closed tibia fracture. Radiographs were followed and histologic analysis was performed at 7, 14, and 21 days. In mice exposed to low Pb concentrations, fracture healing was characterized by a delay in bridging cartilage formation, decreased collagen type II and type X expression at 7 days, a 5-fold increase in cartilage formation at day 14 associated with delayed maturation and calcification, and a persistence of cartilage at day 21. Fibrous nonunions at 21 days were prevalent in mice receiving very high Pb exposures. Pb significantly inhibited ex vivo bone nodule formation but had no effect on osteoclasts isolated from Pb-exposed animals. No significant effects on osteoclast number or activity were observed. We conclude that Pb delays fracture healing at environmentally relevant doses and induces fibrous nonunions at higher doses by inhibiting the progression of endochondral ossification.

Object. The authors evaluated the effects of pilot hole preparation technique on insertional torque and axial pullout resistance in osteoporotic thoracic and lumbar vertebrae. Methods. Using a probe technique and fluoroscopy, 102 pedicle screws were placed in 51 dual-energy x-ray absorptiometry—proven osteoporotic thoracic and lumbar levels. Screws were inserted using the same-size tapping, one-size-under tapping, or no-tapping technique. Insertional torque and axial pullout resistance were measured. Analysis of variance, Fisher exact test, and regression analysis were performed. Same-size tapping decreased pullout resistance in the lumbar spine. There was no effect on pullout resistance in the thoracic spine. Pullout resistance values were lower for all insertion techniques in the upper thoracic spine. Insertional torque and bone mineral density correlated with pullout resistance in the thoracic and lumbar spine. Conclusions. Tapping decreased pedicle screw pullout resistance in the osteoporotic human lumbar spine, although it did not affect pullout strength in the thoracic spine. Tapping decreased insertional torque in upper thoracic levels. Surgeons should optimize overall construct rigidity when placing thoracic pedicle screws in patients with spinal segment osteoporosis.

Level II.

No abstract

Introduction: A fracture liaison service (FLS) is a coordinated system of care that streamlines osteoporosis management in the orthopaedic setting and can serve as an effective form of secondary preventative care in these patients. The present work reviews the available evidence regarding the impact of fracture liaison services on clinical outcomes. Methods: The literature was reviewed for studies reporting changes in the rates of bone mineral density scanning (DXA), antiresorptive therapy, new minimum trauma fractures, and mortality between cohorts with access to an FLS or not. Studies including intention to treat level data were retained. A Medline search for “fracture liaison” OR “secondary fracture prevention” produced 146 results, 98 were excluded based on the abstract, 38 were excluded based on full-text review. Ten level III studies encompassing 48,045 patients were included, of which 5 studies encompassing 7,086 were analyzed. Odds-ratios for DXA and anti-osteoporosis pharmacotherapy rates were calculated from data. Fixed and random effects analyses were performed using the Mantel-Haenszel method. Results: Four studies reported, on average, a 6-fold improvement in DXA scanning rates (Figure 1). Six studies reported, on average, a 3-fold improvement in antiresorptive therapy rates (Figure 2). Four large studies reported significant reductions in the rate of new fractures using time-dependent Cox proportional hazards models at 12 months (HR = 0.84, 0.95), 24 months (HR = 0.44, 0.65), and 36 months (HR = 0.67). Five large studies reported mortality improvements using time-dependent Cox proportional hazards models at 12 months (HR = 0.88, 0.84, 0.81) and 24 months (HR = 0.65, 0.67). Conclusions: The findings suggest that fracture liaison services improve rates of DXA scanning and antiresorptive therapy as well as reductions in the rates of new fractures and mortality among patients seen following minimum trauma fractures across many time points.

Background: Osteoporosis is often undiagnosed until patients experience fragility fractures. Pelvic fractures are common but underappreciated sentinel fractures. Screening patients with a pelvic fracture for osteoporosis may provide an opportunity to initiate appropriate treatments such as anti-osteoporosis therapy to prevent additional fractures. Methods: This retrospective cohort review examined the management of osteoporosis after pelvic fractures at a large tertiary care center without an established secondary fracture prevention program. Data were extracted from electronic medical records of all new patients with a pelvic fracture who were ≥50 years of age from this center and its affiliated community hospitals from 2008 to 2014. Outcome measures included the initiation of anti-osteoporosis therapy before the fracture, within the year following the fracture, >1 year following the fracture, or never and new osteoporotic fractures within 2 years after a pelvic fracture. Results: From 2008 to 2014, 947 patients presented with pelvic fractures. Of these patients, 27.1% (257 patients) were taking anti-osteoporosis medications before the fracture. Four percent of treatment-naïve patients began anti-osteoporosis therapy within 1 year of fracture, with 1.2% (11 patients) starting after 1 year. Of the treatment-naïve patients, 92.3% (637 patients) were never prescribed anti-osteoporosis therapy. Treatment rates were consistent over time. Within 2 years, 41.0% (388 patients) developed fragility fractures at secondary sites: 12.0% (114 patients) experienced a hip fracture, and 16.4% (155 patients) experienced a vertebral fracture. Conclusions: Osteoporosis screening and initiation of secondary fracture prevention after a pelvic fracture were inadequate in the study population. Of the patients in this study, 909 (96.0%) never underwent a dual x-ray absorptiometry (DXA) scan during the study period. Of the 690 treatment-naïve patients, 637 (92.3%) were never administered anti-osteoporosis medications. Within 2 years, 41.0% of all patients developed additional osteoporotic fractures. This study demonstrates an opportunity to improve bone health by screening for and treating osteoporosis in patients with a pelvic fragility fracture. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.