Faculty Bibliography

Bisphosphonates (BPs) are highly effective in treating osteoporosis and reducing hip, vertebral, and other fractures by as much as 50% to 70%. However, since 2006, atypical femur fractures (AFFs) emerged as potential side effects of BPs and other treatments. These fractures have unusual radiologic features and occur with little trauma. Public concern has led to a >50% decrease in BP usage. AFFs are rare: for each AFF, >1200 fractures, including 135 hip fractures, are prevented. Case definition criteria were updated by the American Society of Bone and Mineral Research in 2014. Many epidemiologic studies have been reported, and although methodologically challenging, generally support a BP-AFF association. However, the magnitude of the association between BPs and AFFs is uncertain: estimates of relative risk for AFFs among BP users vs nonusers range from 1 to 65 with a meta-analysis estimate of 1.7. Although mechanistic studies have proposed several hypotheses explaining how BPs might decrease bone strength, AFF pathogenesis remains uncertain and cannot explain the paradox of efficacy of reduction of common fractures while increasing risk for rare fractures at one site. There are several consistent risk factors, including Asian race (in North America), femoral bowing, and glucocorticoid use, whereas others remain unclear. Consensus is emerging about strategies to prevent AFFs in BP users (including drug holidays after 5 years' use in some patients). In conclusion, AFFs can be devastating, but even under the most pessimistic assumptions, the benefit/risk ratio is highly positive for BPs, particularly during 3 to 5 years of use. As understanding of AFFs increases, it is becoming increasingly possible to maximize BP benefits while minimizing AFF risk.

Economic evaluations are increasingly used to assess the value of health interventions, but variable quality and heterogeneity limit the use of these evaluations by decision-makers. These recommendations provide guidance for the design, conduct, and reporting of economic evaluations in osteoporosis to improve their transparency, comparability, and methodologic standards.

Orthobiologics are organic and synthetic materials that are used in and outside of the operating room to augment both bone and soft tissue healing. The orthobiologics portfolio has vastly expanded over the years, and it has become imperative for orthopedic surgeons to understand the role and function of this new class of biologic adjuvants. This review will highlight key components and product groups that may be relevant for the practicing orthopedic surgeon in any subspecialty. This by no means is an extensive list of the available products but provides an important overview of the most highlighted products available in the market today. Those discussed include, bone void fillers, extracelluar matrix (ECM) products, platelet-rich plasma (PRP), bone morphogenetic protein-2 (BMP-2), bone marrow aspirate (BMA), bone marrow aspirate concentrate (BMAC), and mesenchymal stem cells (MSCs). These are further categorized into their uses in several subspecialties including, traumatology, sports medicine, sports surgery, and spine surgery.

Technologies continue to shape the path of medical treatment. Orthopedic surgeons benefit from becoming more aware of how twenty-first century information technology (IT) can benefit patients. The percentage of orthopedic patients utilizing IT resources is increasing, and new IT tools are becoming utilized. These include disease-specific applications. This article highlights the opportunity for developing IT tools applicable to the growing population of patients with osteoarthritis (OA), and presents a potential solution that can facilitate the way OA education and treatment are delivered, and thereby maximize efficiency for the health care system, the physician, and the patient.

OBJECTIVE:Osteoarthritis (OA) is a leading cause of disability in the world. Mesenchymal stem cells (MSCs) have been studied to treat OA. This review was performed to systematically assess the quality of literature and compare the procedural specifics surrounding MSC therapy for osteoarthritis. DESIGN/METHODS:PubMed, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials were searched for studies using MSCs for OA treatment (final search December 2017). Outcomes of interest included study evidence level, patient demographics, MSC protocol, treatment results and adverse events. Level I and II evidence articles were further analyzed. RESULTS:Sixty-one of 3,172 articles were identified. These studies treated 2,390 patients with osteoarthritis. Most used adipose-derived stem cells (ADSCs) (n=29) or bone marrow-derived stem cells (BMSCs) (n=30) though the preparation varied within group. 57% of the sixty-one studies were level IV evidence, leaving five level I and nine level II studies containing 288 patients to be further analyzed. Eight studies used BMSCs, five ADSCs and one peripheral blood stem cells (PBSCs). The risk of bias in these studies showed five level I studies at low risk with seven level II at moderate and two at high risk. CONCLUSION/CONCLUSIONS:While studies support the notion that MSC therapy has a positive effect on OA patients, there is limited high quality evidence and long-term follow-up. The present study summarizes the specifics of high level evidence studies and identifies a lack of consistency, including a diversity of MSC preparations, and thus a lack of reproducibility amongst these articles' methods.

INTRODUCTION: The epidemiology of fracture nonunion has been characterized so it is potentially possible to predict nonunion using patient-related risk factors. However, prediction models are currently too cumbersome to be useful. We test a hypothesis that nonunion can be predicted with /=10 bones, including open fracture, multiple fracture, osteoarthritis, surgical treatment, and use of certain medications, including anticoagulants, anticonvulsants, or analgesics. DISCUSSION: Nonunion can be predicted in 18 fracture locations using parsimonious models with <10 patient demography-related risk factors. The model reduction approach used results in simplified models that have nearly the same AUC as the full model. Reduced algorithms can predict nonunion because risk factors important in the full models remain important in the reduced models. This prognostic inception cohort study provides Level I evidence.

Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.

Introduction: Progranulin (PGRN), is a multifunctional growth factor that directly binds to tumor necrosis factor alpha (TNF-alpha) receptors (TNFR), and inhibits TNF-alpha activity [1]. It is well-accepted that TNF signaling plays an important role in impaired fracture healing as observed in diabetes mellitus. Importantly, we have previously demonstrated that PGRN has a protective and therapeutic effect in bone healing that is mediated, at least partially, through modulation of the TNF-alpha signaling pathway [2]. These previous data promoted us to determine whether PGRN also has therapeutic effects in impaired diabetic fracture healing, and if so what is the molecular mechanism involved. Methods: Murine bone fracture models were established alongside induction of the streptozotocin (STZ)-induced Type 1 diabetes model in wild type mice and in mice deficient for PGRN in order to determine the role of endogenous and recombinant PGRN in diabetic fracture healing. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology, and RT-PCR and western blotting. Results: 1. Deletion of PGRN further delays diabetic bone fracture healing. To investigate the role of PGRN in the course of diabetic bone regeneration, a nonunion segmental radial defect model was employed in the streptozotocin (STZ)-induced, diabetic wild type (WT) and PGRN knockout (KO) mice. Bone healing was impaired in the diabetic mice relative to healthy controls and fracture healing was further delayed in diabetic PGRN deficient mice relative to diabetic WT mice (Fig.1A). Analysis of radiographic evidence of bone healing revealed a significantly larger residual gap size in PGRN KO mice with diabetes (Fig.1B). A unicortical drill-hole model was also established and microCT imaging demonstrated that diabetic PGRN KO mice exhibit markedly less callus formation (Fig. 1C). Statistical analysis of callus mineralized volume fraction (BV/TV) indicates that deficiency of PGRN led to significantly impaired new bone quality (Fig.1D). HE staining of samples revealed that KO mice exhibited dramatically less newly formed bone tissue than the other two groups (Fig. 1E). 2. Recombinant PGRN promotes diabetic bone healing process In order to determine whether the therapeutic effect of PGRN upon bone healing is maintained under diabetic conditions, PGRN was locally delivered to diabetic WT mice via implantation of a collagen sponge containing 10ug of PGRN/PBS into the fracture site coincident with fracture generation. PGRN administration dramatically promoted diabetic bone healing in the nonunion model (Fig.2A). Histological analysis of PGRN-treated mice subjected to the drill-hole model revealed more bone formation and less cortical bone gap (Fig.2B). Western blot and RT-PCR showed expression of NOS-2, IL-1beta, and COX-2 was inhibited by PGRN treatment in the callus of diabetic mice induced under the drill-hole model (Fig.2C-F). Safranin O staining, at day 10, day 16, and day 22 after surgery, revealed the induction of chrondrogenesis following PGRN administration in diabetic mice Einhorn model of impact bone fracture showed chondrogenesis induced by PGRN(Fig.2G). Conclusion: PGRN, a growth factor known to inhibit TNF activity and to induce chondrogenesis, effectively promotes fracture healing in murine diabetic fracture models. (Figure Presented)