Pediatric Bone Disease Research Articles

Severity of acute phase reaction in children receiving the first dose of zoledronic acid and the impact of the underlying condition: a cross-sectional study

IntroductionZoledronic acid (ZA), used for treatment of children with osteoporosis, can cause acute phase reaction (APR) following the first infusion. Many institutions have a policy to admit and monitor all...

Bone health: Quality versus quantity

Healthy bone has the ability to resist deformation and fracture, while adapting to applied mechanical loads. These properties of bone depend on characteristics of its extracellular matrix. This review focuses on the contribution of bone quality and quantity to bone health and highlights current and promising future clinical approaches to measure bone health in the pediatric population. Bone’s unique material properties are derived from its highly organized, hierarchical composite structure, together with its modeling and remodeling dynamics and microdamage mechanisms. Pediatric bone diseases and disorders affect the biological processes that regulate its quality, negatively impacting the extracellular matrix and causing bone fragility. Laboratory bone analysis from human biopsies or animal models of human bone diseases allows high detail examination of the mechanisms contributing to bone fragility. Conversely, clinical measurements of bone fragility are difficult and limited due to the inaccessibility of the material. Because bone quality directly affects fracture resistance, both structure and composition should be used in fracture risk calculation rather than bone mineral density or bone quantity alone. Thus, to advance clinical evaluation of bone fragility, future studies are needed to determine which characteristics of bone quality can be applied to clinical practice to predict bone fragility. New and effective clinical tools are needed to predict fracture risk taking bone quality into consideration. Key Concepts(1)Bone quality and bone quantity are both fundamental for resistance to deformity and fracture.(2)Pediatric bone diseases and disorders alter bone’s composition and structure, compromising bone quality and increasing vulnerability to fracture.(3)Current clinical approaches to assess bone fragility and fracture risk rely mainly on bone quantity measurements from DEXA scans.(4)DEXA bone mineral density poorly correlates with bone’s resistance to fracture, both in adults and children.(5)Future clinical approaches to measure bone health should account for bone quality in order to predict fracture risk.

Vitamin D and pediatric bone health: Important information and considerations for the pediatric orthopaedic surgeon

Vitamin D is an essential fat-soluble vitamin produced in the skin during sun exposure. It plays a considerable role in musculoskeletal health and is largely responsible for the regulation of calcium and phosphate metabolism to maintain a healthy, mineralized skeleton. Optimizing bone mineral density in childhood and adolescence is essential to the foundation of skeletal health; however, the literature lacks consensus on values for normal, deficient, and insufficient serum 25-hydroxyvitamin D levels making supplementation and treatment somewhat challenging.The pediatric orthopaedic surgeon is important to optimizing bone health, particularly in the context of bony pathology/injury. Up to 60% of boys and 40% of girls sustain a fracture in childhood. On top of this baseline incidence, children with low vitamin D levels have been noted to be subject to a higher incidence of fractures from normal activities. While the prevalence of vitamin D deficiency in children in the general population has been determined to be 9%, the prevalence of vitamin D deficiency in the pediatric fracture population can be as high as 75% and 61% of the pediatric population has been determined to have vitamin D insufficiency. The pediatric orthopedist also often is the first to diagnose nutritional rickets as these patients can present solely for complaints of limb deformity. Knowledge of appropriate evaluation, vitamin D supplementation, and indications for pediatric endocrinology referral is vital for the treatment of these patients.In the pediatric population, there is a lack of consensus regarding risk factors that warrant screening for vitamin D deficiency, determining insufficient thresholds, and identifying optimal supplementation recommendations and treatment dosages. More research is needed to clarify the ideal amounts of vitamin D necessary through critical growth periods to prevent rickets and to mitigate fracture risk. Regardless, pediatric Orthopaedic surgeons should promote supplementation to all children and treat diagnosed vitamin D deficiency. Key Concepts(1)Vitamin D plays a vital role in musculoskeletal health and optimizing vitamin D levels in childhood and adolescence is crucial to proper bone development.(2)Vitamin D deficiency and insufficiency in the general population is common; 9% of the pediatric population, representing 7.6 million US children and adolescents, are vitamin D deficient and 61%, representing 50.8 million US children and adolescents, are vitamin D insufficient. The prevalence of vitamin D deficiency in the pediatric fracture population can be as high as 75%.(3)Vitamin D deficiency can lead to nutritional rickets which is the most frequent cause of pediatric bone disease in the world, is entirely preventable, and is characterized by deficient mineralization and subsequent architectural disruption of the physis.(4)Vitamin D supplementation is widely recommended and believed to be beneficial, but there are inconsistent guidelines regarding target levels for optimal vitamin D status.

Pediatric autoinflammatory bone disorders-a mini review with special focus on pathogenesis and inborn errors of immunity.

Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.

Transition of young adults with metabolic bone diseases to adult care.

As more accurate diagnostic tools and targeted therapies become increasingly available for pediatric metabolic bone diseases, affected children have a better prognosis and significantly longer lifespan. With this potential for fulfilling lives as adults comes the need for dedicated transition and intentional care of these patients as adults. Much work has gone into improving the transitions of medically fragile children into adulthood, encompassing endocrinologic conditions like type 1 diabetes mellitus and congenital adrenal hyperplasia. However, there are gaps in the literature regarding similar guidance concerning metabolic bone conditions. This article intends to provide a brief review of research and guidelines for transitions of care more generally, followed by a more detailed treatment of bone disorders specifically. Considerations for such transitions include final adult height, fertility, fetal risk, heritability, and access to appropriately identified specialists. A nutrient-dense diet, optimal mobility, and adequate vitamin D stores are protective factors for these conditions. Primary bone disorders include hypophosphatasia, X-linked hypophosphatemic rickets, and osteogenesis imperfecta. Metabolic bone disease can also develop secondarily as a sequela of such diverse exposures as hypogonadism, a history of eating disorder, and cancer treatment. This article synthesizes research by experts of these specific disorders to describe what is known in this field of transition medicine for metabolic bone diseases as well as unanswered questions. The long-term objective is to develop and implement strategies for successful transitions for all patients affected by these various conditions.

Bone marrow adiposity inversely correlates with bone turnover in pediatric renal osteodystrophy

Bone marrow adiposity is associated with bone disease in the general population. Although chronic kidney disease (CKD) is associated with increased bone fragility, the correlation between marrow adiposity and bone health in CKD is unknown. We evaluated the relationship between bone marrow adipocytes and bone histomorphometry in 32 pediatric patients. We also evaluated the effects of growth hormone and calcitriol (1,25(OH)2D3)—two therapies commonly prescribed for pediatric bone disease—on marrow adiposity and bone histomorphometry. Finally, the adipogenic potential of primary human osteoblasts from CKD patients was assessed in vitro, both alone and in the presence of 1,25(OH)2D3. In cross-sectional analysis, marrow adipocyte number per tissue area (Adi.N/T.Ar) correlated with bone formation rate/bone surface (BFR/BS) in patients with high bone turnover (r = −0.55, p = 0.01) but not in those with low/normal bone turnover. Changes in bone formation rate correlated with changes Adi.N/T.Ar on repeat bone biopsy(r = −0.48, p = 0.02). In vitro, CKD and control osteoblasts had a similar propensity to transition into an adipocyte-like phenotype; 1,25(OH)2D3 had very little effect on this propensity. In conclusion, marrow adiposity correlates inversely with bone turnover in pediatric patients with high turnover renal osteodystrophy. The range of adiposity observed in pediatric patients with low/normal bone turnover is not explained by intrinsic changes to precursor cells or by therapies but may reflect the effects of circulating factors on bone cell health in this population.

Symptomatic Rebound Hypercalcemia After Denosumab Discontinuation in a Pediatric Patient With Cherubism

Background: Pediatric bone diseases due to osteoclast overactivity have limited therapeutic options. Denosumab, a human monoclonal antibody against RANK-ligand, has been used in the treatment of these conditions despite limited pediatric safety data. Rebound hypercalcemia after denosumab cessation is a rare and potentially serious complication in children with an unpredictable course (1). We present the first report of a child with cherubism who experienced acute symptomatic hypercalcemia five months after denosumab cessation. Clinical Case: An 11 year old male presented to our emergency department (ED) with 2 weeks of nausea, vomiting, abdominal pain, and bilateral leg pain. He was diagnosed with cherubism at age 3 years with progressive painless bilateral jaw swelling, teeth crowding, and proptosis. His bilateral maxilla and left mandible were debulked between ages 5-8 years due to tumors causing dyspnea. The resected tumors showed RANK-ligand expression. Thus, he started a 1-year course of denosumab 80 mg monthly subcutaneous injections for additional lesions not amenable to surgery with marked clinical and radiographic improvement. He had mild hypocalcemia during denosumab therapy, for which he received cholecalciferol 2000 IU and calcium citrate total 1500 mg per day. Calcium citrate was stopped with corrected serum calcium (Ca) 10.1 mg/dL (8.8-10.8 mg/dL) three months prior to ED visit. His presentation to ED five months after denosumab revealed marked hypercalcemia (corrected Ca 13.9 mg/dL), iPTH 5.4 pg/mL (7.5-53.5 pg/mL), 25-OH vitamin D 19 ng/mL (30-100 ng/mL), and hypercalciuria (urine Ca/creatinine ratio 0.58 mg/mg, normal <0.2 mg/mg) concerning for rebound hypercalcemia post-denosumab therapy. He received IV hyperhydration, furosemide, calcitonin, and IV pamidronate 0.5 mg/kg. At discharge, corrected Ca was 8.7 mg/dL. One week later he developed acute nausea and vomiting. Laboratory tests again showed hypercalcemia (Ca 13.3 mg/dL) and hypercalciuria. He received one dose of IV zoledronic acid at 0.025 mg/kg with resolution of hypercalcemia. He remains normocalcemic, normocalciuric, and asymptomatic two months after zoledronic acid treatment. Conclusion: This is the first case, to our knowledge, of a pediatric patient with cherubism with acute symptomatic hypercalcemia after denosumab treatment, reinforcing the need for frequent calcium monitoring months after cessation. Zoledronic acid is also shown to effectively treat rebound hypercalcemia after denosumab cessation. Larger studies are needed to further evaluate denosumab use and safety in pediatric bone diseases with osteoclast overactivity. Reference: (1)Upfill-Brown A, Bukata S, Bernthal NM, Felsenfeld AL, Nelson SD, Singh A, Wesseling-Perry K, Eilber FC, Federman NC. Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases. JBMR Plus. 2019 Aug 22;3(10):e10210

Current and Emerging Therapies for Pediatric Bone Diseases

Most pediatric bone diseases result either from mutations of the essential genes for bone development or from abnormalities of mineral homeostasis. With an increase in non-invasive techniques to measure bone mineral density, the number of children with apparent low bone mineral density is rising. Furthermore, a new classification system proposed by the International Society for Clinical Densitometry now considers osteoporosis a valid diagnosis in children. Osteoporosis is a particular problem among children with conditions such as muscular dystrophy, immobilization, and chronic liver diseases and those who received a prolonged course of glucocorticoids. Pharmacologic agents for treatment of osteoporosis were developed primarily to prevent fragility fractures in postmenopausal women, and studies of their efficacy and safety in children are limited. Recent advances have seen new therapies for bone diseases in children; some of these conditions were deemed incurable in the past. This article reviews data regarding mechanism of action, safety, and efficacy of four bone drugs in pediatric patients. These are (1) zoledronic acid, a long-acting bisphosphonate; (2) denosumab, a RANKL inhibitor; (3) asfotase alfa, a synthetic alkaline phosphatase; and (4) burosumab, a monoclonal antibody against FGF23.

Diagnosis and management of pediatric metabolic bone diseases associated with skeletal fragility.

The goal of this review is to give an overview of diagnosis and up-to-date management of major pediatric metabolic bone diseases that are associated with bone fragility, including nutritional rickets, hypophosphatemic rickets, osteogenesis imperfecta, Ehlers--Danlos syndrome, Marfan's syndrome, hypophosphatasia, osteopetrosis and skeletal fluorosis. During the past decade, a number of advanced treatment options have been introduced and shown to be an effective treatment in many metabolic bone disorders, such as burosumab for hypophosphatemic rickets and asfotase alfa for hypophosphatasia. On the other hand, other disorders, such as nutritional rickets and skeletal fluorosis continue to be underrecognized in many regions of the world. Genetic disorders of collagen-elastin, such as osteogenesis imperfecta, Ehlers--Danlos syndrome and Marfan's syndrome are also associated with skeletal fragility, which can be misdiagnosed as caused by non-accidental trauma/child abuse. It is essential to provide early and accurate diagnosis and treatment for pediatric patients with metabolic bone disorders in order to maintain growth and development as well as prevent fractures and metabolic complications.

Paediatric Metabolic Bone Disease: A Lifetime Ahead.

Beyond its functions in locomotion, support and protection of vital organs, bone also interacts with other organs to adjust mineral balance in response to physiological requirements. Bone remodelling is a continuous process of bone resorption and formation for the purpose of maintaining healthy bone mass and growth. Any derangement in this process can cause bone disorders with important clinical consequences. The most prominent features of bone diseases in children include early bone fractures, deformities and pain, which can persist and worsen later in life if an accurate and timely diagnosis is not achieved. Biochemical and genetic testing usually help to discriminate the aetiology of the disease, which determines the subsequent management and follow-up. This review focuses on major genetic metabolic bone diseases in children, their pathophysiological mechanisms, the potential therapeutic interventions and the possible consequences in adulthood of the disease and its treatments.

Management of primary and secondary osteoporosis in children.

Osteoporosis in children differs from adults in terms of definition, diagnosis, monitoring and treatment options. Primary osteoporosis comprises primarily of osteogenesis imperfecta (OI), but there are significant other causes of bone fragility in children that require treatment. Secondary osteoporosis can be a result of muscle disuse, iatrogenic causes, such as steroids, chronic inflammation, delayed or arrested puberty and thalassaemia major. Investigations involve bone biochemistry, dual-energy X-ray absorptiometry scan for bone densitometry and vertebral fracture assessment, radiographic assessment of the spine and, in some cases, quantitative computed tomography (QCT) or peripheral QCT. It is important that bone mineral density (BMD) results are adjusted based on age, gender and height, in order to reflect size corrections in children. Genetics are being used increasingly for the diagnosis and classification of various cases of primary osteoporosis. Bone turnover markers are used less frequently in children, but can be helpful in monitoring treatment and transiliac bone biopsy can assist in the diagnosis of atypical cases of osteoporosis. The management of children with osteoporosis requires a multidisciplinary team of health professionals with expertise in paediatric bone disease. The prevention and treatment of fragility fractures and improvement of the quality of life of patients are important aims of a specialised service. The drugs used most commonly in children are bisphosphonates, that, with timely treatment, can give good results in improving BMD and reshaping vertebral fractures. The data regarding their effect on reducing long bone fractures are equivocal. Denosumab is being used increasingly for various conditions with mixed results. There are more drugs trialled in adults, but these are not yet licenced for children. Increasing awareness of risk factors for paediatric osteoporosis, screening and referral to a specialist team for appropriate management can lead to early detection and treatment of asymptomatic fractures and prevention of further bone damage.

Off label uses of pamidronate in rare pediatric bone diseases (Jansen's Metaphyseal Chondrodysplasia and Generalized Arterial Calcification of Infancy): A four year perspective

Off label uses of pamidronate in rare pediatric bone diseases (Jansen's Metaphyseal Chondrodysplasia and Generalized Arterial Calcification of Infancy): A four year perspective

Arab Society for Pediatric Endocrinology and Diabetes (ASPED) Masterclass in Pediatric Bone Disease 2nd November 2018, Dubai, United Arab Emirates

Arab Society for Pediatric Endocrinology and Diabetes (ASPED) Masterclass in Pediatric Bone Disease 2nd November 2018, Dubai, United Arab Emirates

Half-dose versus full-dose macrocyclic gadolinium at 3-T magnetic resonance imaging in paediatric bone and soft-tissue disease.

Given the recent concerns about gadolinium-based contrast agent safety, dose reduction strategies are being investigated. To compare half-dose and standard full-dose gadoterate meglumine at 3-tesla (T) MRI in paediatric bone and soft-tissue diseases. We prospectively enrolled 45 children (age range 2.7months to 17.5years, median age 8.7years, 49 total anatomical segments) with bone and soft-tissue diseases (neoplastic, inflammatory/infectious, ischaemic and vascular) imaged at 3-T MRI. Two consecutive half-doses of gadoterate meglumine (0.05mmol/kg body weight) were administered. Two sets of post-contrast T1-weighted images were obtained, one after the first half dose and the other after the second half dose. For qualitative analysis, three radiologists, masked to the gadolinium dose, compared the diagnostic quality of the images. For quantitative analysis, we compared signal-to-noise ratio and contrast-to-noise ratio at half and full doses. Signal-to-noise ratio and contrast-to-noise ratio did not vary significantly between the two groups. Qualitative analysis yielded excellent image quality in both post-contrast image datasets (Cohen κ=0.8). In paediatric bone and soft-tissue 3-T MRI, it is feasible to halve the standard dose of gadoterate meglumine without losing image quality.

Muscle-Bone Interactions in Pediatric Bone Diseases.

Here, we review the skeletal effects of pediatric muscle disorders as well as muscle impairment in pediatric bone disorders. When starting in utero, muscle disorders can lead to congenital multiple contractures. Pediatric-onset muscle weakness such as cerebral palsy, Duchenne muscular dystrophy, spinal muscular atrophy, or spina bifida typically are associated with small diameter of long-bone shafts, low density of metaphyseal bone, and increased fracture incidence in the lower extremities, in particular, the distal femur. Primary bone diseases can affect muscles through generic mechanisms, such as decreased physical activity or in disease-specific ways. For example, the collagen defect underlying the bone fragility of osteogenesis imperfecta may also affect muscle force generation or transmission. Transforming growth factor beta released from bone in Camurati Engelman disease may decrease muscle function. Considering muscle-bone interactions does not only contribute to the understanding of musculoskeletal disorders but also can identify new targets for therapeutic interventions.

Vitamin D Deficiency in Pediatric Critical Care.

Vitamin D deficiency (VDD) is a well-established cause of pediatric bone and muscle disease. In addition, a role has been recognized for vitamin D in the health and stress response of other organs, including the cardiovascular, immune, and respiratory systems. As these organs are central to the development of and recovery from critical illness, VDD has been hypothesized to be a modifiable risk factor for ICU outcome. Over the past 5 years, a growing number of adult and pediatric critical care studies have investigated the prevalence of VDD and its association with illness severity and outcome. The adult studies have recently been synthesized in systematic reviews, with results that convincingly suggest the need for trials to determine whether optimization of vitamin D status improves outcome. In contrast, the pediatric ICU and related literature has not been similarly synthesized. The goal of this review is to describe vitamin D metabolism, known biological mechanisms, potential role in pathophysiology, and summarize the available pediatric intensive care unit (PICU) studies reporting on prevalence of VDD deficiency and its association with outcome. The problems with currently approved supplementation approaches and alternative strategies are discussed, including evidence from available RCTs in adult ICU. Altogether the results suggest that critically ill children are at risk for VDD, and that VDD appears to be associated with a worse clinical course. Clinical trials evaluating novel approaches to testing for and supplementing vitamin D require exploration.

Skeletal scintigraphy with SPECT/CT in benign pediatric bone conditions

Benign bone diseases present an ongoing challenge for pediatricians. Most of them are not life threatening, but may be associated with significant morbidity. Benign space occupying lesions are a source of pain and/or pathological fractures. Their symptoms may raise concern for malignancy and require a complex diagnostic workup. Late or inadequate treatment of bone infections may result in bone and joint destruction and lifelong functional impairment especially in young children. Bone damage due to altered blood supply or due to minor trauma can be difficult to identify. MRI is a cornerstone in modern assessment of pediatric bone disease, but bone scintigraphy remains a useful tool in this clinical field. Unlike MRI, bone scans are widely available, provide whole body rather than focused exploration, are less affected by metallic implants or devices and combined with CT in hybrid SPECT/CT systems, allow visualization of bone morphology and metabolism in a single imaging session. The clinical indication and imaging technique of skeletal SPECT/CT in children are still evolving although the benefit of this technique in evaluation of children with bone pain and/or serendipitously found bone lesions seems ascertained. Improvements in gamma camera technology allow the obtaining of high quality images with either shorter acquisition times and /or reduced radiopharmaceutical administered activities. Sedation is required much less for bone scans than for MRI.

An update on childhood bone health: mineral accrual, assessment and treatment.

To update the reader's knowledge about the factors that influence bone mineral accrual and to review the advances in the assessment of bone health and treatment of bone disorders. Maternal vitamin D status influences neonatal calcium levels, bone mineral density (BMD) and bone size. In turn, BMD z-score tends to track in childhood. These factors highlight the importance of bone health as early as fetal life. Dual-energy x-ray absorptiometry is the mainstay of clinical bone health assessment in this population because of the availability of appropriate reference data. Recently, more information has become available about the assessment and treatment of bone disease in chronically ill pediatric patients. Bone health must become a health focus starting prenatally in order to maximize peak bone mass and to prevent osteoporosis-related bone disease in adulthood. Vitamin D, calcium and weight-bearing activity are the factors of key importance throughout childhood in achieving optimal bone health as BMD z-score tracks through childhood and into adulthood. Recent updates of the International Society for Clinical Densitometry focus on the appropriate use of dual-energy x-ray absorptiometry in children of all ages, including children with chronic disease, and on the treatment of pediatric bone disease.

Does low vitamin D have a role in pediatric morbidity and mortality? An observational study of vitamin D in a cohort of 52 postmortem examinations.

Vitamin D is required for calcium absorption and normal bone mineralization; it has a key role in immune regulation against infections and is believed to be involved in immunomodulation in asthma. We did a retrospective analysis of 52 postmortem cases (aged 2 days to 10 years). Seventeen children had vitamin D deficiency (<25 nmol/L); 24 children had vitamin D insufficiency (25-49 nmol/L); 10 children had suboptimal vitamin D levels (50-79 nmol/L); and only 1 child had adequate levels (≥80 nmol/L). Three infants had fractures. Growth plate histology was abnormal in 10 cases with vitamin D deficiency (59%), but radiology was abnormal in only 3 of those cases. Eight infants (33%) with vitamin D insufficiency had abnormal histology, but radiology was normal in all cases. In 3 children hypocalcemia due to vitamin D deficiency was considered accountable for death; they all showed radiological and histological rickets: 2 babies had cardiomyopathy and a 3-year-old had hypocalcemic seizures. Children from all ethnic groups had a high proportion of low vitamin D levels. Vitamin D deficiency (the most common form of pediatric metabolic bone disease) is preventable and treatable. Profound hypocalcemia due to severe vitamin D deficiency can cause unexpected death in babies and young children. Measuring serum vitamin D levels postmortem may provide invaluable information on sudden unexplained death in 'at-risk' children. Vitamin D deficiency may be relevant in childhood asthma and in children with multiple infections and babies with bone fractures. Postmortem vitamin D levels are stable and easy to measure.

Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors.

Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination. We previously showed that CYR61/CCN1 expression in osteosarcoma cells is correlated to aggressiveness both in vitro and in vivo in mouse models, as well as in patients. In this study, we found that CYR61 is a critical contributor to the vascularization of primary tumor. We demonstrate that silencing CYR61, using lentiviral transduction, leads to a significant reduction in expression level of pro-angiogenic markers such as VEGF, FGF2, PECAM and angiopoietins concomitantly to an increased expression of major anti-angiogenic markers such as thrombospondin-1 and SPARC. Matrix metalloproteinase-2 family member expression, a key pathway in osteosarcoma metastatic capacity was also downregulated when CYR61 was downregulated in osteosarcoma cells. Using a metastatic murine model, we show that CYR61 silencing in osteosarcoma cells results in reduced tumor vasculature and slows tumor growth compared with control. We also find that microvessel density correlates with lung metastasis occurrence and that CYR61 silencing in osteosarcoma cells limits the number of metastases. Taken together, our data indicate that CYR61 silencing can blunt the malignant behavior of osteosarcoma tumor cells by limiting primary tumor growth and dissemination process.