Impact of Zoledronic Acid and Denosumab Treatment on Growth Factor Concentration in Platelet Rich Fibrin of Patients With Osteolytic Bone Metastases.

BACKGROUND/AIM: Side effects of zolendronic acid (ZA) and RANKL inhibitors (RANKL-I) include impaired wound healing and osteonecrosis of the jaw. Platelet rich fibrin (PRF) enhances wound healing and bone remodelling in vivo and in vitro. However, the topical use PRF in the surgical treatment of patients with medicament-related osteonecrosis of the jaw is relatively new and not thoroughly investigated. Furthermore, the potential attenuation of the PRF effect following antiresorptive treatment remains unclear. Therefore, we investigated the concentration of growth factors within the PRF in healthy volunteers and in patients with antiresorptive treatment. PATIENTS AND METHODS: Blood samples from healthy volunteers and patients were used to produce PRF. The levels of EGF, VEGF, PDGF-BB, TGF-ß1, BMP-2, and CD31 in the PRF was investigated by ELISA. RESULTS: ZA treatment induced a significant decrease in EGF and TGF-ß1 levels, whereas RANKL-I caused lower TGF-ß1 levels. CONCLUSION: Reduced EGF levels in PRF after ZA treatment may explain the delayed wound healing and question the positive effect of PRF in these patients. PRF use in patients undergoing RANKL-I treatment seems to be more justified.

Hypercalcemia and Disseminated Osteolytic Lesions With Normal Blood Counts and Absence of Circulating Blasts: A Rare Presentation of Childhood B-Lymphoblastic Leukemia.

Hypercalcemia and disseminated osteolytic bone lesions are a rare presentation of pediatric acute lymphoblastic leukemia (ALL). The authors report a 3-year-old boy who presented with hypercalcemia and diffuse osteolytic lesions involving axial and appendicular bones. He had normal complete blood count and the absence of blasts in peripheral smear; however, bone marrow aspirate and trephine were consistent with B-cell ALL. A review of the literature highlights the variable clinical outcome of this rare presentation depending on the presence of hypercalcemia and osteolytic lesions with or without chromosomal translocation t(17;19) and coagulation abnormalities. The patient had no coagulopathy and normal karyotype, and showed excellent response to initial treatment in terms of complete remission and negative minimal residual disease after standard-risk induction chemotherapy. Hypercalcemia with diffuse osteolytic lesions warrants bone marrow examination to rule out leukemia even in the absence of any abnormality in complete blood count. The case was reported for awareness of this rare presentation of ALL so that delays can be avoided for this potentially curable but life-threatening disease.

Hypercalcemia caused by humoral effects and bone damage indicate poor outcomes in newly diagnosed multiple myeloma patients.

BACKGROUND: Hypercalcemia of malignancy (HCM) is a serious metabolic complication, and the highest rates are in multiple myeloma (MM). The cause of hypercalcemia in newly diagnosed multiple myeloma (NDMM) remains unknown. We sought to evaluate the prognostic impact and mechanism of hypercalcemia in patients with symptomatic NDMM. METHODS: We studied all consecutive MM patients who were initially diagnosed and followed up at Beijing Jishuitan Hospital between February 2013 and December 2019; 357 patients were included in the retrospective analysis. RESULTS: A total of 16.8% of MM patients presented with hypercalcemia at the time of MM diagnosis. The presence of hypercalcemia was associated with higher serum levels of ß2 microglobulin, creatinine, phosphorus, uric acid, procollagen I N-terminal peptide, ß-carboxy-terminal cross-linking telopeptide of type I collagen and osteocalcin, lower serum levels of hemoglobin, parathyroid hormone (PTH), and advanced ISS and R-ISS stages. Multivariate analysis showed that serum PTH, hemoglobin, creatinine, and uric acid levels were the main factors affecting hypercalcemia. The presence of hypercalcemia was associated with significantly inferior survival (40 months vs 57 months, p < 0.05) based on univariate analysis, and it remained an independent poor prognostic factor (HR: 1.854, 95% CI: 1.006-3.415, adjusted p = 0.048) in a multivariate model that included age and R-ISS stage. CONCLUSION: This study shows that hypercalcemia is associated with poor survival and is caused by manifold factors with humoral effects and local bone destruction.

Bacillus cereus isolated from a positive bone tissue culture in a patient with osteolysis and high-titer anti-interferon-γ autoantibodies: A case report.

RATIONALE: Bacillus cereus (B cereus) is an aerobic or facultative anaerobic gram-positive, spore-forming bacterium. It can cause fatal disease and generally manifests as 3 distinct syndromes: food intoxication, localized infection, and systemic infection. It is a rare infection that can occur in immunocompetent persons with osteolytic and high-titer anti-IFN-γ autoantibodies. PATIENT CONCERNS: We reported a case of an HIV-negative 24-year old man with an interrupted fever and a 20-day history of progressive ache in the right thigh and high-titer anti-IFN-γ autoantibodies. Magnetic resonance imaging, X-radiography, high-resolution computed tomography, and 3-dimensional reconstruction of the bone showed multiple lucent defects with moth-eaten destruction of the bone and cortical substance of bone in the right femur. Emission CT showed significantly increased uptake in the femur. DIAGNOSIS AND INTERVENTIONS: The patient was originally misdiagnosed with osteosarcoma; acute osteomyelitis was also considered. He received intravenous piperacillin, sulbactam, and levofloxacin during hospitalization; however, he did not respond to the 3-week antibiotic course and his condition worsened. After cultures from incisional biopsy specimens were obtained from the femoral cavity, B cereus-induced osteomyelitis was diagnosed. He received intravenous injections of moxifloxacin 400 mg qd for 4 weeks and oral moxifloxacin 400 mg qd for 8 weeks. OUTCOMES: The patient's symptoms and signs improved. His X-radiography, HRCT, MRI, and 3-dimensional reconstruction of the bone showed absolute absorption in the right femur. However, the anti-IFN-γ autoantibody titer was still high. No recurrence was observed after 24 months of follow-up. He is still undergoing follow-up at this time. LESSONS: This is the first case involving a patient with B cereus infection showing a high titer of anti-IFN-γ autoantibodies. B cereus infection can involve the bone, leading to osteolysis in HIV-negative individuals. Although this patient was HIV-negative and had no other comorbidities, the presence of high titer anti-IFN-γ autoantibodies may be the primary reason for B cereus infection. Clinicians should pay more attention to the identification of osteolytic destruction caused by tumor and infection.

RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease.

Fibrous dysplasia of bone/McCune-Albright syndrome (Polyostotic FD/MAS; OMIM#174800) is a crippling skeletal disease caused by gain-of-function mutations of Gs α. Enhanced bone resorption is a recurrent histological feature of FD and a major cause of fragility of affected bones. Previous work suggests that increased bone resorption in FD is driven by RANKL and some studies have shown that the anti-RANKL monoclonal antibody, denosumab, reduces bone turnover and bone pain in FD patients. However, the effect of RANKL inhibition on the histopathology of FD and its impact on the natural history of the disease remain to be assessed. In this study, we treated the EF1α-Gs αR201C mice, which develop an FD-like phenotype, with an anti-mouse RANKL monoclonal antibody. We found that the treatment induced marked radiographic and microscopic changes at affected skeletal sites in 2-month-old mice. The involved skeletal segments became sclerotic due to the deposition of new, highly mineralized bone within developing FD lesions and showed a higher mechanical resistance compared to affected segments from untreated transgenic mice. Similar changes were also detected in older mice with a full-blown skeletal phenotype. The administration of anti-mouse RANKL antibody arrested the growth of established lesions and, in young mice, prevented the appearance of new ones. However, after drug withdrawal, the newly formed bone was remodelled into FD tissue and the disease progression resumed in young mice. Taken together, our results show that the anti-RANKL antibody significantly affected the bone pathology and natural history of FD in the mouse. Pending further work on the prevention and management of relapse after treatment discontinuation, our preclinical study suggests that RANKL inhibition may be an effective therapeutic option for FD patients. © 2019 American Society for Bone and Mineral Research.

Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.

Bisphosphonates are formidable inhibitors of osteoclast-mediated bone resorption employed for therapy of multiple myeloma (MM) subjects with osteolytic lesions. Osteonecrosis of the jaw (ONJ) is an uncommon drug-induced adverse event of these agents. MicroRNAs (miRNAs) are a group of small, noncoding RNAs nucleotides, which are essential post-transcriptional controllers of gene expression. They have a central role in the normal bone development. The goal of our study was to investigate 18 miRNAs, whose targets were previously validated and described in MM subjects without ONJ, in peripheral lymphocytes of MM subjects with bisphosphonate-induced ONJ. Utilizing reverse transcription quantitative polymerase chain reaction, we evaluated miRNAs in five healthy subjects and in five MM patients with ONJ. Our experimental data revealed that a diverse miRNA signature for ONJ subjects emerged with respect to control subjects. Using the filter for in silico analysis, among the 18 miRNAs, we recognized 14 dysregulated miRNAs. All these miRNAs were significantly over-expressed in patients vs controls (MIR-16-1, MIR-21, MIR-23A, MIR-28, MIR-101-1, MIR-124-1, MIR-129, MIR-139, MIR-145, MIR-149, MIR-202, MIR-221, MIR-424, MIR-520). Among them, six were strongly upregulated (fourfold upregulated and more). These miRNAs target numerous pathways and genes implicated in calcium ion binding, bone resorption, mineralization of bone matrix, and differentiation and maintenance of bone tissue. A modified microRNA expression profile after zoledronate therapy could participate to the onset of ONJ. Targeting these miRNAs could provide a new opportunity for the prevention or treatment of ONJ.

Effects of pulsed electromagnetic fields and platelet rich plasma in preventing osteoclastogenesis in an in vitro model of osteolysis.

Osteolysis is the main limiting cause for the survival of an orthopedic prosthesis and is accompanied by an enhancement in osteoclastogenesis and inflammation, due by wear debris formation. Unfortunately therapeutic treatments, besides revision surgery, are not available. The aim of the present study was to evaluate the effects of Pulsed Electro Magnetic Fields (PEMFs) and platelet rich plasma (PRP), alone or in combination, in an in vitro model of osteolysis. Rats peripheral blood mononuclear cells were cultured on Ultra High Molecular Weight Polyethylene particles and divided into four groups of treatments: (1) PEMF stimulation (12 hr/day, 2.5 mT, 75 Hz, 1.3 ms pulse duration); (2) 10% PRP; (3) combination of PEMFs, and PRP; (4) no treatment. Treatments were performed for 3 days and cell viability, osteoclast number, expression of genes related to osteoclastogenesis and inflammation and production of pro-inflammatory cytokines were assessed up to 14 days. PEMF stimulation exerted best results because it increased cell viability at early time points and counteracted osteoclastogenesis at 14 days. On the contrary, PRP increased osteoclastogenesis and reduced cell viability in comparison to PEMFs alone. The combination of PEMFs and PRP increased cell viability over time and reduced osteoclastogenesis in comparison to PRP alone. However, these positive results did not exceed the level achieved by PEMF alone. At longer time points PEMF could not counteract osteoclastogenesis increased by PRP. Regarding inflammation, all treatments maintained the production of pro-inflammatory cytokines at low level, although PRP increased the level of interleukin 1 beta.

Do cobalt and chromium levels predict osteolysis in metal-on-metal total hip arthroplasty?

INTRODUCTION: Serum metal ions are part of the regular follow-up routine of patients with metal-on-metal total hip arthroplasties (MoM-THA). Increased cobalt levels have been suggested to indicate implant failure and corrosion. QUESTIONS: (1) Is there a correlation between the size of the osteolysis measured on a CT scan and metal ion levels? (2) Can metal ion levels predict the presence of osteolysis in MoM-THA? (3) Are cobalt and chromium serum levels or the cobalt-chromium-ratio diagnostic for osteolysis? MATERIALS AND METHODS: CT scans of patients (n = 75) with a unilateral MoM-THA (Birmingham Hip System, Smith & Nephew, TN, USA) implanted by a single surgeon were reviewed to determine the presence of osteolysis. Statistical analysis was performed to detect its association with metal ion levels at the time of the imaging exam. RESULTS: The incidence of osteolysis was the same in men and women (35.6 vs 35.7 %). The cobalt-chromium-ratio correlates with the size of the osteolysis on the CT scan and the femoral component size in the overall study population (p = 0.050, p = 0.001) and in men (p = 0.002, p = 0.001) but not in women (p = 0.312, p = 0.344). The AUC for the cobalt-chromium-ratio to detect osteolysis was 0.613 (p = 0.112) for the overall population, 0.710 for men (p = 0.021) and 0.453 (p = 0.684) for women. The data suggest that a cut off level of 1.71 for the cobalt-chromium-ratio has a sensitivity of 62.5 % and specificity of 72.4 % to identify male patients with osteolysis. CONCLUSIONS: The disproportional increase of cobalt over chromium, especially in male patients with large component sizes can not be explained by wear alone and suggests that other processes (corrosion) might contribute to metal ion levels and might be more pronounced in patients with larger component sizes.

Circulating sRAGE in the diagnosis of osteolytic bone metastasis.

Despite the clinical importance of metastasis to the skeleton, the diagnostic tools for early detection and monitoring of bone metastasis lack sensitivity and specificity. We evaluated a promising new serum biomarker, the soluble form of the Receptor of Advanced Glycosylated End-products (sRAGE). sRAGE is involved in the Wnt-signaling pathway, and has been reported to reduce the risk of cancer. We investigated the diagnostic potential of sRAGE to improve the detection and monitoring of bone metastasis. We measured sRAGE in the serum of control healthy subjects, patients with primary tumors and patients with bone metastasis. sRAGE was also correlated with the Wnt inhibitors DKK-1 and sclerostin, the bone resorption markers MMP-2, MMP-9 and TRAP5, and the metastatic marker survivin. sRAGE was significantly lower in primary tumor and metastatic patients than in healthy subjects. sRAGE also showed a strong negative correlation with DKK-1, sclerostin, MMP-2, MMP-9, TRAP5b and survivin. These results indicated that sRAGE might play a protective role in bone metastasis progression, and it may diagnostic significance for detecting and monitoring osteolytic metastases.

Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report.

We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-ß and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction.

Osteocytic protein expression response to doxercalciferol therapy in pediatric dialysis patients.

BACKGROUND: Osteocytic protein expression is dysregulated in CKD and is affected by changes in mineral metabolism; however the effects of active vitamin D sterol therapy on osteocyte protein expression in advanced CKD is unknown. METHODS: Eleven pediatric patients with end stage kidney disease underwent bone biopsy, were treated for 8 months with doxercalciferol, and then underwent a second bone biopsy. Bone expression of fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), and sclerostin were determined by immunohistochemistry and quantified by Ariol Scanning. Western blot analysis and qRT-PCR was performed on bone abstracts of a subset of study subjects to determine the nature (i.e. size) of FGF23 and DMP1 in bone before and after therapy. RESULTS: As assessed by immunohistochemistry, bone FGF23, DMP1 and sclerostin protein all increased with therapy. In the case of FGF23, this increase was due to an increase in the full-length molecule without the appearance of FGF23 fragments. DMP1 was present primarily in its full-length form in healthy controls while 57kDa and 37kDa fragments of DMP1 were apparent in bone of dialysis patients at baseline and the 57 kDa appeared to decrease with therapy. CONCLUSION: Marked changes in osteocytic protein expression accompany doxercalciferol therapy, potentially impacting bone mineralization and the skeletal response to PTH. The effects of these bone changes on long-term outcomes remain to be determined.

The role of calcitonin receptor signalling in polyethylene particle-induced osteolysis.

The detection of peptides from the calcitonin (CT) family in the periarticular tissue of loosened implants has raised hopes of opening new regenerative therapies in the process of aseptic loosening, which remains the major cause of early implant failure in endoprosthetic surgery. We have previously shown the roles of α-calcitonin gene-related peptide (α-CGRP) and the CALCA gene which encodes α-CGRP/CT in this process. To uncover the role of direct calcitonin receptor (CTR) mediated signalling, we studied particle-induced osteolysis (PIO) in a murine calvaria model with a global deletion of the CTR (CTR-KO) using µCT analysis and histomorphometry. As expected, CTR-KO mice revealed reduced bone volume compared to wild-type (WT) controls (p<0.05). In CTR-KO mice we found significantly higher RANKL (receptor activator of NF-κB ligand) expression in the particle group than in the control group. The increase in osteoclast numbers by the particles was twice as high as the increase of osteoclasts in the WT mice (400 vs. 200%). Changes in the eroded surface and actual osteolysis due to ultrahigh-molecular-weight polyethylene particles were similar in WTs and CTR-KOs. Taken together, our findings strengthen the relevance of the OPG/RANK/RANKL system in the PIO process. CTR seems to have an effect on osteoclast differentiation in this context. As there were no obvious changes of the amount of PIO in CTR deficiency, regenerative strategies in aseptic loosening of endoprosthetic implants based on peptides arising from the CT family should rather focus on the impact of α-CGRP.

Demographic and clinical features of systemic sclerosis patients with anti-RNA polymerase III antibodies.

Anti-RNA polymerase III antibody (RNAP) is primarily detected in diffuse cutaneous type systemic sclerosis (dcSSc) patients and strongly associated with renal crisis. Additionally, there has been increasing evidence that cancer in SSc patients is associated with RNAP. The aim of this study was to examine the demographic and clinical features of SSc patients with RNAP. Among 246 SSc patients, 5.7% were positive for RNAP, 20.7% were positive for anti-topoisomerase I antibody (Topo I) alone and 39.4% were positive for anticentromere antibody (ACA) alone. The modified Rodnan total skin score (mRTSS) in SSc patients with RNAP (19.1 ± 2.6) was significantly higher than those in SSc patients with Topo I (11.5 ± 1.1) and patients with ACA (4.4 ± 0.4). Furthermore, among SSc patients with RNAP, the levels of RNAP were positively correlated with mRTSS. Renal crisis is also significantly more prevalent in SSc patients with RNAP than patients without RNAP. Male sex, dcSSc subtype, digital vasculopathy, including digital ulcers and acro-osteolysis, interstitial lung disease and rheumatoid arthritis complications were prevalent in SSc patients with RNAP and patients with Topo-I. Primary biliary cirrhosis and Sjögren's syndrome were more in SSc patients with RNAP and patients with ACA compared with patients with Topo 1. No significant difference in the frequency of complications, including Raynaud's phenomenon, pulmonary artery hypertension and malignancy was observed between the three groups. Thus, measurement of RNAP in SSc patients is useful for the diagnosis and risk stratification of severe manifestation, such as renal crisis and severe skin sclerosis.

Wear particles and ions from cemented and uncemented titanium-based hip prostheses-a histological and chemical analysis of retrieval material.

Wear debris-induced inflammation is considered to be the main cause for periprosthetic osteolysis in total hip replacements (THR). The objective of this retrieval study was to examine the tissue reactions and exposure to metal ions and wear particles in periprosthetic tissues and blood samples from patients with titanium (Ti)-based hip prostheses that were revised due to wear, osteolysis, and/or aseptic loosening. Semiquantitative, histological tissue evaluations in 30 THR-patients revealed numerous wear debris-loaded macrophages, inflammatory cells, and necrosis in both groups. Particle load was highest in tissues adjacent to loosened cemented Ti stems that contained mainly submicron zirconium (Zr) dioxide particles. Particles containing pure Ti and Ti alloy elements were most abundant in tissues near retrieved uncemented cups. Polyethylene particles were also detected, but accounted only for a small portion of the total particle number. The blood concentrations of Ti and Zr were highly elevated in cases with high abrasive wear and osteolysis. Our findings indicate that wear particles of different chemical composition induced similar inflammatory responses, which suggests that particle size and load might be more important than the wear particle composition in periprosthetic inflammation and osteolysis.

A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events.

Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.

Advanced lytic lesion is a poor mobilization factor in peripheral blood stem cell collection in patients with multiple myeloma.

This study examined the incidence and predictors of peripheral blood stem cell (PBSC) mobilization failure in patients with multiple myeloma (MM). Retrospective data for 104 patients who received granulocyte colony-stimulating factor (G-CSF) alone or with cyclophosphamide as mobilization regimens were analyzed. The rates of mobilization failure using two definitions of failure (< 2 × 10(6) and < 4 × 10(6) CD34(+) cells/kg) following the first collection attempt were 16.3 and 33.7%, respectively. Predictors of mobilization failure were evaluated using logistic regression analysis which included age, advanced osteolytic lesions, bone marrow cellularity before mobilization, platelet count, body mass index before mobilization, and mobilization method. Lytic bone lesions were assessed using a conventional skeletal survey, and advanced osteolytic lesions were defined as lytic lesions in more than three skeletal sites regardless of the number of lytic lesions. On multivariate analysis, advanced osteolytic lesions [hazard ratio (HR) = 10.95, P = 0.001] and age ≥60 years (HR = 5.45, P = 0.016) were associated with a PBSC yield < 2 × 10(6) CD34(+) cells/kg, and advanced osteolytic lesions (HR = 5.08, P = 0.006), white blood cell count ≤4,000/µL before mobilization (HR = 4.72, P = 0.005), and G-CSF only mobilization (HR 10.52, P < 0.001) were associated with PBSC yield < 4 × 10(6) CD34(+) cells/kg. The data suggest that an advanced osteolytic lesion is a significant predictor of mobilization failure in MM patients.

Particle-induced osteolysis is not accompanied by systemic remodeling but is reflected by systemic bone biomarkers.

Particle-induced osteolysis is caused by an imbalance in bone resorption and formation, often leading to loss of implant fixation. Bone remodeling biomarkers may be useful for identification of osteolysis and studying pathogenesis, but interpretation of biomarker data could be confounded if local osteolysis engenders systemic bone remodeling. Our goal was to determine if remote bone remodeling contributes to biomarker levels. Serum concentrations of eight biomarkers and bone remodeling rates at local (femur), contiguous (tibia), and remote (humerus and lumbar vertebra) sites were evaluated in a rat model of particle-induced osteolysis. Serum CTX-1, cathepsin K, PINP, and OPG were elevated and osteocalcin was suppressed in the osteolytic group, but RANKL, TRAP 5b, and sclerostin were not affected at the termination of the study at 12 weeks. The one marker tested longitudinally (CTX-1) was elevated by 3 weeks. We found increased bone resorption and decreased bone formation locally, subtle differences in contiguous sites, but no differences remotely at 12 weeks. Thus, the skeletal response to local particle challenge was not systemic, implying that the observed differences in serum biomarker levels reflect differences in local remodeling.

Are there biological markers for wear or corrosion? A systematic review.

BACKGROUND: Identification of biomarkers associated with wear and tribocorrosion in joint arthroplasty would be helpful to enhance early detection of aseptic loosening and/or osteolysis and to improve understanding of disease progression. There have been several new reports since the last systematic review (which covered research through mid-2008) justifying a new assessment. QUESTIONS/PURPOSES: We sought to determine which biomarkers have the most promise for early diagnosis and monitoring of aseptic loosening and/or osteolysis related to wear or corrosion in total joint arthroplasty. METHODS: We performed a systematic review using MEDLINE and EMBASE databases, covering the period through December 2013, and identified 1050 articles. We restricted the definition of biomarker to biomolecules and imaging parameters useful for diagnosis and monitoring of disease progression, only including articles in English. We chose 65 articles for full review, including 44 from the original search and 21 from subsequent hand searches. We used the 22 articles in which patients with total joint arthroplasty who had aseptic loosening and/or periimplant osteolysis unrelated to sepsis had been compared with patients with total joint arthroplasty with stable implants. There were 90 comparisons of these two patient populations involving 35 different biomarkers. RESULTS: Diagnostic accuracy was assessed in nine of the 90 comparisons with the highest accuracy found for tartrate-resistant acid phosphatase 5b (0.96), although a separate comparison for this biomarker found a lower accuracy (0.76). Accuracy of > 0.80 was also found for crosslinked n-telopeptide of type I collagen, osteoprotegerin, and deoxypyridinoline. The most studied markers, tumor necrosis factor-α and interleukin-1ß, were found to differ in the affected and control groups in < 30% of the comparisons. Thirty of the 35 biomarkers were studied in four or fewer separate comparisons with nearly half of the biomarkers (17) studied in only one comparison. Many of the comparisons were not able to eliminate a number of confounding variables, and there was only one prospective study. CONCLUSIONS: Currently, there are no validated biomarkers for early diagnosis and monitoring of the biological sequelae of wear or tribocorrosion, although there are some promising leads, including markers of bone turnover.

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.

Elevation of serum tumor necrosis factor α in patients with periprosthetic osteolysis: a case-control study.

BACKGROUND: Periprosthetic osteolysis is the leading reason for THA revision. The relationship of serum biomarkers with severe radiographic periprosthetic osteolysis has not been defined but may be important to direct future research and clinical therapeutics. QUESTIONS/PURPOSES: We determined whether there was an association between measurable inflammatory markers (high-sensitivity C-reactive protein [hsCRP]) or inflammatory mediators (tumor necrosis factor α [TNF-α], IL-1ß, IL-6, receptor activator of nuclear factor κB ligand [RANKL], and osteoprotegerin [OPG]) and periprosthetic osteolysis. METHODS: We identified 15 patients with THAs scheduled for revision surgery because of severe periprosthetic osteolysis. For each study patient, a nonosteolytic, pain-free control patient with THAs was identified and matched for age, sex, time since initial THA, acetabular and femoral component prosthesis material, and prosthesis wear within 1.0 mm/year using a manual wear analysis technique. Overall, the study and control patients had a mean wear rate of 0.25 mm/year since index THA. There were no differences in baseline characteristics between study and control patients in age, sex, BMI, Charlson Comorbidity Index, time since initial THA, UCLA activity score, and acetabular and femoral component type. Serum hsCRP, IL-1ß, IL-6, TNF-α, RANKL, and OPG were measured by ELISA in duplicate assays. Differences in values were assessed using the Wilcoxon rank-sum test. RESULTS: Median TNF-α levels were higher in study patients than in controls (7.1 pg/mL [SD, 11.6 pg/mL] versus 1.5 pg/mL [SD, 1.3 pg/mL]) (p < 0.01). Median IL-6 levels tended to be higher in study patients than in controls (8.9 pg/mL [SD, 13.2 pg/mL] versus 3.5 pg/mL [SD, 0.7 pg/mL]) (p = 0.09). The other serum inflammatory proteins and mediators of bone turnover were not different between groups. CONCLUSIONS: TNF-α is elevated in patients with osteolysis compared to matched controls. The role of TNF-α and its potential as a target of nonsurgical therapy to prevent osteolysis warrant further investigation in larger, prospective studies.