Women in leadership matters: Achieving diversity in radiology residency recruitment.

RATIONALE AND OBJECTIVES: To assess whether academic radiology departments and residency programs with efforts toward supporting and augmenting Diversity, Equity, and Inclusion (DEI) are associated with a higher proportion of residents from diverse backgrounds. MATERIALS AND METHODS: Program Directors within the Radiology Residency Education Research Alliance were surveyed to gather information about program characteristics, incorporation of diversity in resident recruitment, the sponsoring department's commitment to efforts at expanding diversity, and a summary of their current and past residents, staff and faculty members (academic years 2020 and 2023) with respect to a list of diversity characteristics. RESULTS: Survey response rate was 51 %. Sixty-three percent (15/24) of participating programs have departmental committees dedicated to DEI work; 46 % (11/24) of programs' departments have a Vice Chair for DEI. Sixty percent (15/24) of programs use their social media accounts to advertise their DEI programming efforts. Ninety-six percent (23/24) of programs participating in the survey use diversity factors to select candidates for their program. Women Leadership was associated with above-median diversity of residents and faculty. CONCLUSION: This study of radiology residency programs encourages a more prominent role for women in leadership positions within academic radiology departments to drive diversity and inclusion efforts.

Virtual Interviewing for Radiology Residency: Pluses, Minuses, and A Review of the Literature.

This article reviews current medical literature to assess the benefits and drawbacks of virtual interviews for radiology residencies as well as the downstream effects of these changes, best practices, and potential future recruitment methods. Topics covered include the effects of remote recruitment in promoting accessibility and applicant diversity and equality as well as fiscal, environmental, and time savings in combination with technical challenges, the complications of over application, challenges in assessment of program culture and location, impact on morale, and hidden financial and emotional costs. Learnings from other medical specialties are highlighted in addition to the process of signaling, guidelines for conducting and participating in virtual interviews, and matters for future consideration.

Factors Associated With Radioactive Iodine Therapy-Acquired Nasolacrimal Duct Obstruction.

OBJECTIVE: To identify factors associated with radioactive iodine (RAI)-acquired nasolacrimal duct obstruction (NLDO). METHODS: Retrospective chart review and telephone surveys of patients who received RAI therapy for thyroid carcinoma at an academic institution were conducted. Telephone surveys were used to screen for post-RAI NLDO diagnoses. Databases were reviewed for documented NLDO, demographics, RAI dose, total number of RAI treatments, and sialadenitis. Routine post-RAI whole-body scintigraphy (WBS) images were analyzed for the presence or absence of 131I sodium iodide (I-131) in the nasolacrimal duct. Intranasal I-131 activity was graded as none, low, moderate, and high; those with moderate or high activity were considered to have "increased" activity. Logistic and ordinal logistic regression models were used to evaluate the associations with NLDO while adjusting for I-131 dose. RESULTS: Of the 209 patients who completed the survey, 15 (7%) had NLDO diagnoses. Increased intranasal I-131 activity on WBS, presence of nasolacrimal I-131 WBS activity, presence of documented post-RAI sialadenitis, and history of >1 RAI treatment were associated with the development of NLDO from univariate analyses (P ≤ .013). After adjusting for the administered dose of I-131, the presence of sialadenitis and nasolacrimal I-131 activity on WBS were the remaining 2 factors significantly associated with NLDO development (P < .001 and P = .01, respectively). CONCLUSIONS: The presence of sialadenitis and nasolacrimal I-131 activity on WBS are I-131 dose-independent correlative factors for RAI-associated NLDO. Patients with these characteristics should be counseled on their increased risk of NLDO after RAI therapy for thyroid carcinoma.

The Deleterious Effects of Impaired Fibrinolysis on Skeletal Development Are Dependent on Fibrin(ogen), but Independent of Interlukin-6.

Chronic diseases in growing children, such as autoimmune disorders, obesity, and cancer, are hallmarked by musculoskeletal growth disturbances and osteoporosis. Many of the skeletal changes in these children are thought to be secondary to chronic inflammation. Recent studies have likewise suggested that changes in coagulation and fibrinolysis may contribute to musculoskeletal growth disturbances. In prior work, we demonstrated that mice deficient in plasminogen, the principal protease of degrading and clearing fibrin matrices, suffer from inflammation-driven systemic osteoporosis and that elimination of fibrinogen resulted in normalization of IL-6 levels and complete rescue of the skeletal phenotype. Given the intimate link between coagulation, fibrinolysis, and inflammation, here we determined if persistent fibrin deposition, elevated IL-6, or both contribute to early skeletal aging and physeal disruption in chronic inflammatory conditions. Skeletal growth as well as bone quality, physeal development, and vascularity were analyzed in C57BL6/J mice with plasminogen deficiency with and without deficiencies of either fibrinogen or IL-6. Elimination of fibrinogen, but not IL-6, rescued the skeletal phenotype and growth disturbances in this model of chronic disease. Furthermore, the skeletal phenotypes directly correlated with both systemic and local vascular changes in the skeletal environment. In conclusion, these results suggest that fibrinolysis through plasmin is essential for skeletal growth and maintenance, and is multifactorial by limiting inflammation and preserving vasculature.

Severe injury-induced osteoporosis and skeletal muscle mineralization: Are these related complications?

Severely injured patients are beleaguered by complications during convalescence, such as dysregulated biomineralization. Paradoxically, severely injured patients experience the loss of bone (osteoporosis), resulting in diminished skeletal integrity and increased risk of fragility fractures; yet they also accrue mineralization in soft tissues, resulting in complications such as heterotopic ossification (HO). The pathophysiology leading to dysregulated biomineralization in severely injured patients is not well defined. It has been postulated that these pathologies are linked, such that mineralization is "transferred" from the bone to soft tissue compartments. The goal of this study was to determine if severe injury-induced osteoporosis and soft tissue calcification are temporally coincident following injury. Using a murine model of combined burn and skeletal muscle injury to model severe injury, it was determined that mice developed significant progressive bone loss, detectable as early as 3 days post injury, and marked soft tissue mineralization by 7 days after injury. The observed temporal concordance between the development of severe injury-induced osteoporosis and soft tissue mineralization indicates the plausibility that these complications share a common pathophysiology, though further experiments are required.

Modifier Ontologies for frequency, certainty, degree, and coverage phenotype modifier.

Background: When phenotypic characters are described in the literature, they may be constrained or clarified with additional information such as the location or degree of expression, these terms are called "modifiers". With effort underway to convert narrative character descriptions to computable data, ontologies for such modifiers are needed. Such ontologies can also be used to guide term usage in future publications. Spatial and method modifiers are the subjects of ontologies that already have been developed or are under development. In this work, frequency (e.g., rarely, usually), certainty (e.g., probably, definitely), degree (e.g., slightly, extremely), and coverage modifiers (e.g., sparsely, entirely) are collected, reviewed, and used to create two modifier ontologies with different design considerations. The basic goal is to express the sequential relationships within a type of modifiers, for example, usually is more frequent than rarely, in order to allow data annotated with ontology terms to be classified accordingly. Method: Two designs are proposed for the ontology, both using the list pattern: a closed ordered list (i.e., five-bin design) and an open ordered list design. The five-bin design puts the modifier terms into a set of 5 fixed bins with interval object properties, for example, one_level_more/less_frequently_than, where new terms can only be added as synonyms to existing classes. The open list approach starts with 5 bins, but supports the extensibility of the list via ordinal properties, for example, more/less_frequently_than, allowing new terms to be inserted as a new class anywhere in the list. The consequences of the different design decisions are discussed in the paper. CharaParser was used to extract modifiers from plant, ant, and other taxonomic descriptions. After a manual screening, 130 modifier words were selected as the candidate terms for the modifier ontologies. Four curators/experts (three biologists and one information scientist specialized in biosemantics) reviewed and categorized the terms into 20 bins using the Ontology Term Organizer (OTO) (http://biosemantics.arizona.edu/OTO). Inter-curator variations were reviewed and expressed in the final ontologies. Results: Frequency, certainty, degree, and coverage terms with complete agreement among all curators were used as class labels or exact synonyms. Terms with different interpretations were either excluded or included using "broader synonym" or "not recommended" annotation properties. These annotations explicitly allow for the user to be aware of the semantic ambiguity associated with the terms and whether they should be used with caution or avoided. Expert categorization results showed that 16 out of 20 bins contained terms with full agreements, suggesting differentiating the modifiers into 5 levels/bins balances the need to differentiate modifiers and the need for the ontology to reflect user consensus. Two ontologies, developed using the Protege ontology editor, are made available as OWL files and can be downloaded from https://github.com/biosemantics/ontologies. Contribution: We built the first two modifier ontologies following a consensus-based approach with terms commonly used in taxonomic literature. The five-bin ontology has been used in the Explorer of Taxon Concepts web toolkit to compute the similarity between characters extracted from literature to facilitate taxon concepts alignments. The two ontologies will also be used in an ontology-informed authoring tool for taxonomists to facilitate consistency in modifier term usage.

Posttraumatic Proximal Radioulnar Synostosis after Closed Reduction for a Radial Neck and Olecranon Fracture.

Posttraumatic proximal radioulnar synostosis (PPRUS) is a severe complication of radial head and neck fractures known to occur after severe injury or operative fixation. Cases of PPRUS occurring after minimally displaced, nonoperatively treated radial neck injuries are, by contrast, extremely rare. Here, we present a pediatric case of PPRUS that developed after a nonoperatively treated minimally displaced radial neck fracture with concomitant olecranon fracture. While more cases are needed to establish the association between this pattern of injury and PPRUS, we recommend that when encountering patients with a minimally displaced radial neck fracture and a concomitant elbow injury, the rare possibility of developing proximal radioulnar synostosis should be considered.

Intra-articular Monteggia Fracture: A Case Study of Using the Center of Rotational Angulation to Improve a Functional Outcome.

INTRODUCTION: Elbow fractures are the most common pediatric fracture to require operative fixation and can be associated with significant morbidities such as vascular injury, neurologic injury, and loss of function. Specifically, the chronic Monteggia fracture-dislocation causes devastating losses in range of motion. Presenting as a proximal to midshaft ulna fracture and radiocapitellar joint disruption, the acute injury can be successfully managed with closed reduction, serial casting, and close follow-up. The chronic complications of this injury, however, usually occur from an unrecognized radial head dislocation. Here, we present the first known case of a chronic Monteggia fracture-dislocation in the setting of an intra-articular ulnar fracture. Using the center of rotational angulation (CORA) from injury mechanism and radiographs, an intra-articular osteotomy was performed to correct ulnar length and improve this child's range of motion. CASE REPORT: A 3-year-old Hispanic male was first seen in the emergency department for elbow pain following a fall from a sofa. He was incorrectly diagnosed with an isolated intra-articular ulna fracture. 5 weeks after the initially missed Monteggia fracture-dislocation, he presented to clinic with 90° flexion, 40° extension, and a 20° pronation/supination arc. An opening-wedge osteotomy was performed at the intra-articular CORA to restore ulnar length and allow for reduction of the radial head. The magnitude of the ulnar opening-wedge osteotomy was trialed until the radiocapitellar joint maintained reduction throughout pronosupination. CONCLUSION: 7 months after the surgery, the patient displayed functional improvements with 115° flexion, 15° extension, and a 75° pronation/supination arc. On physical examination, he had no neuropathic symptoms, with intact median, radial, and ulnar nerves. Using the CORA from the perceived injury mechanism and radiographs, an intra-articular osteotomy was performed to correct ulnar length, reduce the radial head, and thereby improve this child's range of motion.

Bone Fracture Acute Phase Response-A Unifying Theory of Fracture Repair: Clinical and Scientific Implications.

Bone fractures create five problems that must be resolved: bleeding, risk of infection, hypoxia, disproportionate strain, and inability to bear weight. There have been enormous advancements in our understanding of the molecular mechanisms that resolve these problems after fractures, and in best clinical practices of repairing fractures. We put forth a modern, comprehensive model of fracture repair that synthesizes the literature on the biology and biomechanics of fracture repair to address the primary problems of fractures. This updated model is a framework for both fracture management and future studies aimed at understanding and treating this complex process. This model is based upon the fracture acute phase response (APR), which encompasses the molecular mechanisms that respond to injury. The APR is divided into sequential stages of "survival" and "repair." Early in convalescence, during "survival," bleeding and infection are resolved by collaborative efforts of the hemostatic and inflammatory pathways. Later, in "repair," avascular and biomechanically insufficient bone is replaced by a variable combination of intramembranous and endochondral ossification. Progression to repair cannot occur until survival has been ensured. A disproportionate APR-either insufficient or exuberant-leads to complications of survival (hemorrhage, thrombosis, systemic inflammatory response syndrome, infection, death) and/or repair (delayed- or non-union). The type of ossification utilized for fracture repair is dependent on the relative amounts of strain and vascularity in the fracture microenvironment, but any failure along this process can disrupt or delay fracture healing and result in a similar non-union. Therefore, incomplete understanding of the principles herein can result in mismanagement of fracture care or application of hardware that interferes with fracture repair. This unifying model of fracture repair not only informs clinicians how their interventions fit within the framework of normal biological healing but also instructs investigators about the critical variables and outputs to assess during a study of fracture repair.

A Subdermal Osteochondroma in a Young Girl.

Osteochondromas are common benign tumors of cartilage and bone. They are usually found as contiguous bone with a cartilage cap at the end of the growth plate of long bones. Similar to structure are extraskeletal osteochondromas. However, unlike typical osteochondromas, extraskeletal osteochondromas are noncontinuous with bone. To our knowledge, all reported extraskeletal osteochondromas have been contained within fascial compartments. Here we present the case of a 5-year-old female who had a slow growing mass of the anterior distal right thigh. Imaging studies revealed an ossified mass extending from dermal layer of the subcutaneous tissue with no connection to the underlying deep fascia. An excisional biopsy was performed and proved to be a subdermal extraskeletal osteochondroma.

Prevalence of Hypertension in Pediatric Tibia Vara and Slipped Capital Femoral Epiphysis.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) and tibia vara (Blount disease) are associated with childhood obesity. However, the majority of obese children do not develop SCFE or tibia vara. Therefore, it is hypothesized that other obesity-related biological changes to the physis, in addition to increased biomechanical stress, potentiate the occurrence of SCFE and tibia vara. Considering that hypertension can impose pathologic changes in the physis similar to those observed in these obesity-related diseases we set out to determine the prevalence of hypertension in patients with SCFE and tibia vara. METHODS: Blood pressure measurements were obtained in 44 patients with tibia vara and 127 patients with SCFE. Body mass index and blood pressure were adjusted for age, sex, and height percentiles utilizing normative distribution data from the CDC. These cohorts were compared with age-matched and sex-matched cohorts derived from an obesity clinic who did not have either bone disease. A multivariable proportional odds model was used to determine association. RESULTS: The prevalence of prehypertension/hypertension was significantly higher in the tibia vara (64%) and SCFE cohort (64%) compared with respective controls (43%). Patients diagnosed with either SCFE or tibia vara had 2.5-fold higher odds of having high blood pressure compared with age-matched and sex-matched obese patients without bone disease. Sex, age, and race did not have a significant effect on a patient's blood pressure. CONCLUSIONS: This is the first study to establish that the obesity-related bone diseases, SCFE and tibia vara, are significantly associated with high blood pressure. These data have immediate clinical impact as they demonstrate that children with obesity-related developmental bone disease have increased prevalence of undiagnosed and untreated hypertension. Furthermore, this prevalence study supports the hypothesis that hypertension in conjunction with increased biomechanical forces together potentiate the occurrence of SCFE and tibia vara. If proven true, it is plausible that hypertension may represent a modifiable risk factor for obesity-related bone disease. LEVEL OF EVIDENCE: Level III-case-control study.

OTO: Ontology Term Organizer.

BACKGROUND: The need to create controlled vocabularies such as ontologies for knowledge organization and access has been widely recognized in various domains. Despite the indispensable need of thorough domain knowledge in ontology construction, most software tools for ontology construction are designed for knowledge engineers and not for domain experts to use. The differences in the opinions of different domain experts and in the terminology usages in source literature are rarely addressed by existing software. METHODS: OTO software was developed based on the Agile principles. Through iterations of software release and user feedback, new features are added and existing features modified to make the tool more intuitive and efficient to use for small and large data sets. The software is open source and built in Java. RESULTS: Ontology Term Organizer (OTO; http://biosemantics.arizona.edu/OTO/ ) is a user-friendly, web-based, consensus-promoting, open source application for organizing domain terms by dragging and dropping terms to appropriate locations. The application is designed for users with specific domain knowledge such as biology but not in-depth ontology construction skills. Specifically OTO can be used to establish is_a, part_of, synonym, and order relationships among terms in any domain that reflects the terminology usage in source literature and based on multiple experts' opinions. The organized terms may be fed into formal ontologies to boost their coverage. All datasets organized on OTO are publicly available. CONCLUSION: OTO has been used to organize the terms extracted from thirty volumes of Flora of North America and Flora of China combined, in addition to some smaller datasets of different taxon groups. User feedback indicates that the tool is efficient and user friendly. Being open source software, the application can be modified to fit varied term organization needs for different domains.

Micro-computed tomography derived anisotropy detects tumor provoked deviations in bone in an orthotopic osteosarcoma murine model.

Radiographic imaging plays a crucial role in the diagnosis of osteosarcoma. Currently, computed-tomography (CT) is used to measure tumor-induced osteolysis as a marker for tumor growth by monitoring the bone fractional volume. As most tumors primarily induce osteolysis, lower bone fractional volume has been found to correlate with tumor aggressiveness. However, osteosarcoma is an exception as it induces osteolysis and produces mineralized osteoid simultaneously. Given that competent bone is highly anisotropic (systematic variance in its architectural order renders its physical properties dependent on direction of load) and that tumor induced osteolysis and osteogenesis are structurally disorganized relative to competent bone, we hypothesized that µCT-derived measures of anisotropy could be used to qualitatively and quantitatively detect osteosarcoma provoked deviations in bone, both osteolysis and osteogenesis, in vivo. We tested this hypothesis in a murine model of osteosarcoma cells orthotopically injected into the tibia. We demonstrate that, in addition to bone fractional volume, µCT-derived measure of anisotropy is a complete and accurate method to monitor osteosarcoma-induced osteolysis. Additionally, we found that unlike bone fractional volume, anisotropy could also detect tumor-induced osteogenesis. These findings suggest that monitoring tumor-induced changes in the structural property isotropy of the invaded bone may represent a novel means of diagnosing primary and metastatic bone tumors.

Autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associates with aggressive osteosarcoma.

UNLABELLED: Osteosarcoma is the most common primary bone malignancy and accounts for more than half of primary skeletal malignancies in children and young adults. Although vascular endothelial growth factor (VEGF) expression in osteosarcoma has been associated with poor outcome, its role in the pathogenesis of osteosarcoma remains controversial. Here, VEGF and VEGFR1 expression in both human and murine osteosarcoma cells associated with increasing malignant potential. Autocrine VEGF/VEGFR1 signaling resulted in constitutive activation of VEGFR1 in highly aggressive osteosarcoma cells. In addition, survival and proliferation of highly aggressive osteosarcoma cells was dependent on autocrine VEGF/R1 signaling in vitro. The effect of VEGFR1 expression on in vivo tumor growth and angiogenesis was evaluated by immunoselecting subpopulations of osteosarcoma cells that express high or low levels of VEGFR1. Cell enriched for high VEGFR1 expression showed increased VEGF production, tumor growth, tumor angiogenesis, and osteolysis in vivo. In addition, it was demonstrated that VEGF and VEGFR1 are coexpressed by a subset of tumor cells in human osteosarcoma, similar to what was observed in the murine osteosarcoma cells. These results suggest that autocrine VEGF/VEGFR1 signaling in a subpopulation of tumor cells plays a pivotal role in osteosarcoma progression. IMPLICATIONS: Aggressive osteosarcoma phenotypes are mediated by autocrine VEGF/VEGFR1 signaling and improved stratification measures and novel anti-angiogenic strategies may benefit this specific tumor type.

Pleiotropic effects of bisphosphonates on osteosarcoma.

Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells.

Fibrin accumulation secondary to loss of plasmin-mediated fibrinolysis drives inflammatory osteoporosis in mice.

OBJECTIVE: Osteoporosis is a skeletal disorder characterized by low bone mass and increased bone fragility associated with aging, menopause, smoking, obesity, or diabetes. Persistent inflammation has been identified as an instigating factor in progressive bone loss. In addition to the role of fibrin in coagulation, inordinate fibrin deposition within a tissue matrix results in increased local inflammation. Given that fibrin accumulation is a hallmark of osteoporosis-related comorbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis. METHODS: Multiple imaging modalities, bone integrity metrics, and histologic analyses were employed to evaluate skeletal derangements in relation to fibrin deposition, circulating fibrinogen levels, and systemic markers of inflammation in mice that were plasminogen deficient and in plasminogen-deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the αM ß2 binding motif. RESULTS: Mice generated with a genetic deficit in the key fibrinolytic protease, plasmin, uniformly developed severe osteoporosis. Furthermore, the development of osteoporosis was fibrin(ogen) dependent, and the derangements in the bone remodeling unit were mechanistically tied to fibrin(ogen)-mediated activation of osteoclasts via activation of the leukocyte integrin receptor αM ß2 on monocytes and secondary stimulation of osteoblasts by RANKL. Notably, the genetic elimination of fibrin(ogen) or the expression of a mutant form of fibrinogen retaining clotting function but lacking the αM ß2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels. CONCLUSION: Taken together, these data reveal for the first time that fibrin promotes inflammation-driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology.

Ethnicity reporting practices for empirical research in three autism-related journals.

This review examines ethnicity reporting in three autism-related journals (Autism, Focus on Autism and Other Developmental Disabilities, and Journal of Autism and Developmental Disorders) over a 6-year period. A comprehensive multistep search of articles is used to identify ethnicity as a demographic variable in these three journals. Articles that identified research participants' ethnicity were further analyzed to determine the impact of ethnicity as a demographic variable on findings of each study. The results indicate that ethnicity has not been adequately reported in these three autism related journals even though previous recommendations have been made to improve inadequacies of descriptive information of research participants in autism research (Kistner and Robbins in J Autism Dev Disord 16:77-82, 1986). Implications for the field of autism spectrum disorders are discussed in addition to further recommendations for future research.

Bisphosphonates inhibit osteosarcoma-mediated osteolysis via attenuation of tumor expression of MCP-1 and RANKL.

Osteosarcoma is the most common primary malignant tumor of bone and accounts for around 50% of all primary skeletal malignancies. In addition to novel chemotherapies, there is a need for adjuvant therapies designed to inhibit osteosarcoma proliferation and tumor-induced osteolysis to attenuate tumor expansion and metastasis. As such, studies on the efficacy of bisphosphonates on human osteosarcoma are planned after feasibility studies determined that the bisphosphonate zoledronic acid (ZOL) can be safely combined with conventional chemotherapy. However, the molecular mechanisms responsible for, and means of inhibiting, osteosarcoma-induced osteolysis are largely unknown. We establish that osteosarcoma growth directly correlates with tumor-induced osteolysis and activation of osteoclasts in vivo. In vitro, tumor cells were determined to expresses surface, but not soluble, receptor activator of NF-κB ligand (RANKL) and stimulated osteoclastogenesis in a manner directly proportional to their malignant potential. In addition, an aggressive osteosarcoma cell line was shown to secrete monocyte chemoattractant protein-1 (MCP-1), resulting in robust monocyte migration. Because MCP-1 is a key cytokine for monocyte recruitment and surface-bound RANKL strongly supports local osteoclastogenesis, we suggest that high levels of these signaling molecules are associated with the aggressive potential of osteosarcoma. Consistent with these findings, abundant expression of RANKL/MCP-1 was observed in tumor in vivo, and MCP-1 plasma levels strongly correlated with tumor progression and osteolysis. ZOL administration directly attenuates osteosarcoma production of RANKL/MCP-1, reducing tumor-induced bone destruction. In vivo, these findings also correlated with significant reduction in osteosarcoma growth. ZOL attenuates tumor-induced osteolysis, not only through direct inhibition of osteoclasts, but also through direct actions on tumor expression of osteoclast activators. These data provide insight regarding the effect of ZOL on osteosarcoma essential for designing the planned upcoming prospective randomized trials to determine the efficacy of bisphosphonates on osteosarcoma in humans.