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To investigate the relationship between fluoride exposure and Osteochondroma (OC) prevalence, a cross-sectional study was conducted in drinking water endemic fluorosis areas of Heilongjiang Province, China. Our study first reported that the prevalence of OC was 2.3% in drinking water endemic fluorosis areas of Heilongjiang Province, China, and no difference in gender. Logistic regression analysis found that compared to 1 st quartile participants, the prevalence of OC was 73% lower in the 2 nd quartile participants of WF (Water fluoride), and 3.4 times higher among the 2 nd quartile UF (Urinary fluoride) participants. Our study suggests that 0.259-0.420 mg/L of WF may be considered an appropriate level for reducing OC prevalence, while UF (≥0.750 mg/L) could slightly increase the prevalence of OC. In summary, the link between fluoride and OC prevalence is complicated and needs to be further investigated in a cohort population.

Objective: It has been suggested that Bisphenol A (BPA), a high-production-volume industrial chemical, can accelerate the development of various type of cancers. However, the effect of BPA on osteosarcoma and the underlying mechanisms are yet to be established. Therefore, in this study we tried to explore the carcinogenic effects of BPA on osteosarcoma and the underlying mechanism., Methods: SaOs-2 cancer cell line was used to treat with BPA at the doses of 0.1, 1, 10 μM DGLAP5 knockdown and overexpression methods were constructed by using adenovirus mediated transfection, and the functional analysis of DGLAP5 was investigated to evaluate the carcinogenic effect of BPA on osteosarcoma through DLGAP5. Xenograft and metastatic mouse model were used to evaluate in vivo experiments., Results: In this study, BPA at 10 μM promoted the proliferation, migration and invasion in vitro, and accelerate the progression and metastasis in vivo. Also, exposure to BPA was associated with poor survival of osteosarcoma in mice. In addition, we observed that BPA at 10 μM significantly increased the expression of DGLAP5 in osteosarcoma. Silencing DGLAP5 could reverse the effect of BPA on proliferation, migration and invasion. Mechanically, BPA promoted IL-6, JAK2, and STAT3 expression and promoted tumor progression in an IL-6-dependent manner through up-regulation of DLGAP5., Conclusion: Our findings demonstrated that BPA could promote the proliferation, migration, invasion of osteosarcoma cells and related to poor survival in a mouse model. DLGAP5 is one of the most critical targets of BPA to act as a carcinogen through IL-6/JAK2/STAT3 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Patients with osteosarcoma (OS) and Ewing sarcoma (ES) are considered to have a high venous thromboembolism (VTE) risk, although the exact incidence and prognostic impact are under-researched in general as well as in relevant age groups., Aims: To study the impact of VTE and major bleeding (MB) in OS and ES patients, subdivided in children, Adolescents Young Adults (AYAs; aged 18-39) and older adults., Methods: Retrospective single-center chart review in 519 OS and 165 ES patients treated between 1980 and 2018. Patients were followed from sarcoma diagnosis until an outcome of interest (VTE, MB) or death occurred. Cumulative incidences were estimated with death as competing risk. Cox models were used to determine prognostic impact., Results: Five-year cumulative incidences of VTE were 12 % (95%CI 9.1-15) for OS and 6.7 % (95%CI 3.5-11) for ES patients, mostly happening in patients ≥18 years; the most frequent VTE presentation was catheter-related upper-extremity thrombosis (OS: 18/65, ES: 7/11). Five-year cumulative incidences for MB were 5.8 % (95%CI 4.0-8.1) in OS and 5.4 % (95%CI 2.5-9.8) in ES patients. 192 OS and 77 ES AYAs were included, who faced similar VTE and MB incidences as older adults. In OS, VTE and MB were both associated with mortality (adjusted HRs 2.0 [95%CI 1.4-2.9] and 2.4 [95%CI 1.4-4.0], respectively), whereas in ES this association was only present for MB (aHR 3.4 [95%CI 1.2-9.6])., Conclusions: VTE is a frequent complication in adult OS and to a lesser extent in ES patients, while the rate of MB was comparably high in both sarcoma types., Competing Interests: Declaration of competing interest F.A.K. has received research support from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all paid to his institution and independent of the current work. M.V.H. reports unrestricted grant support from The Netherlands Organisation for Health Research and Development (ZonMW), and unrestricted grant support and fees for presentations from Boehringer-Ingelheim, Pfizer-BMS, Bayer Health Care, Aspen, Daiichi-Sankyo, all outside the submitted work. The other authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aim: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy., Patients and Methods: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups., Results: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208)., Conclusion: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Adolescents and children worldwide are threatened by osteosarcoma, a tumor that predominantly affects the long bone epiphysis. Osteosarcoma is the most common and highly malignant bone tumor in youngsters. Early tumor detection is the key to effective treatment of this disease. The discovery of biomarkers and the growing understanding of molecules and their complex interactions have improved the outcome of clinical trials in osteosarcoma. This article describes biomarkers of osteosarcoma with the aim of positively influencing the progress of clinical treatment of osteosarcoma. Femoral bone tumor is a typical condition of osteosarcoma. Due to the wide range of femoral stem types, complexities in the distal femur, and tumors in the rotor part of femur, physicians following the traditional clinical approach face difficulties in removing the lesion and fixing the femur with resection of the tumor segment. In this paper, the effect of small doses of different concentrations of lidocaine anesthesia in patients undergoing lumpectomy for osteosarcoma femoral tumor segments is investigated. A computer-based artificial intelligence method for automated determination of different concentration levels of lidocaine anesthesia and amputation of osteosarcoma femoral tumor segment is proposed. Statistical analysis is carried on the empirical data including intraoperative bleeding, intraoperative and postoperative pain scores, surgical operation time, postoperative complications, patient satisfaction, and local anesthetic dose. The results showed that the patients in the study group had low intraoperative bleeding, short operation time, low postoperative hematoma formation rate, high patient satisfaction, higher dosage of anesthetic solution, and low dosage of lidocaine. Results revealed that mean arterial pressure and heart rate in extubating and intubating were significantly lower in the observation group than in the control group, and a significant difference ( P < 0.05) was observed between the two groups. This proves that the proposed algorithm can adequately reduce bleeding, alleviate postoperative pain, shorten operation time, reduce complications, accelerate recovery, and ensure better treatment results., Competing Interests: The authors solemnly declare that there are no conflicts of interest., (Copyright © 2022 Shuqin Ni et al.)

Background: Pharmacological inhibition of osteoclast activity is an essential component of oncological therapy for patients with bone metastases. In rare cases, medication-related osteonecrosis of the jaws (MRONJ) is observed. MRONJ can cause bone defects not inferior to primary or metastatic jaw neoplasms. Oral examination of patients on osteoclast-inhibiting medication aims to identify risk factors at an early stage and to initiate therapy. The current focus on osteoclast-inhibiting drugs in the maxillofacial region is MRONJ. Effects of the substances other than MRONJ are rarely reported., Case Report: The female patient with metastatic breast cancer had developed extensive osteolysis of the mandibular ramus at the time of initial diagnosis. The patient was treated with denosumab. Seven months later, a significant reduction in the mandibular osteolytic zone was recorded. However, known bone metastases from other sites had increased in size during multimodal therapy, and further metastases were recorded., Conclusion: Jaw metastasis can shrink under denosumab therapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Adamantinoma-like Ewing sarcoma is a rare variant of Ewing sarcoma with histologic and immunohistochemical evidence of squamous differentiation. This variant most commonly occurs in the head and neck region with a few cases reported in the long bones of the limbs. It may be associated with poorer clinical outcome and could pose a diagnostic challenge, particularly if it occurs in older patients or as a metastatic lesion. We present a case of Ewing sarcoma in the metatarsal of an 11-year-old boy that manifested adamantinoma-like morphology after neoadjuvant chemotherapy. Chemotherapy has been reported to induce neuronal maturation and rhabdoid morphology in cases of Ewing sarcoma, but no reports of treatment-induced squamous differentiation with P40/P63 expression have been demonstrated. This is also the first documented case treated with a pedicled osteocutaneous fibular transfer in a metatarsal malignancy, which is usually treated by either ray or below-knee amputation.

Purpose: During preclinical testing, teriparatide caused a dose-dependent increase in the incidence of osteosarcoma in rats. This study compared the incidence rate of osteosarcoma among patients aged ≥65 years treated with teriparatide vs a matched-comparator cohort., Methods: This population-based comparative-cohort study matched exposure details for each teriparatide user, identified via Medicare Part D prescription claims, and up to four comparators based on age, sex, zip code, date of claim for filled prescription, and number of unique therapeutic classes dispensed. Outcomes were identified via linkage with participating cancer registries. All US state cancer registries were invited to participate., Results: Overall, 153 316 patients in the teriparatide cohort and 613 247 in the comparator cohort were linked to 811 osteosarcoma cases from 26 participating state cancer registries (68% of US patients aged ≥65 years diagnosed 2007-2014). Analysis on a subset of cohorts revealed they were balanced for known osteosarcoma risk factors and Charlson comorbidity index. Mean duration of teriparatide treatment was 10 months. No osteosarcoma cases were observed in the teriparatide cohort; the incidence rate in the comparator cohort was consistent with the background incidence rate among adults aged ≥65 years. The incidence rate ratio was 0.0 (95% confidence interval, 0.0-3.2)., Conclusions: For US patients aged ≥65 years, incidence of osteosarcoma among those treated with teriparatide ranges from 0 to 3.2 times the incidence of osteosarcoma in those treated with other medications. Given low incidence of osteosarcoma, this range of effect is inconsistent with a large absolute increase in osteosarcoma risk., (© 2020 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd..)

Osteosarcoma (OS) is the most common malignant primary bone tumour in humans and dogs. Several studies have established the vital role of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation and remodeling. In addition, these molecules play a role in the progression and metastasis of many human tumour types. This study investigated the expression of PTHR1 and PTHrP in canine OS tissues and assessed their prognostic value. Formalin-fixed, paraffin-embedded tissue samples from 50 dogs diagnosed with primary OS were immunolabeled with antibodies specific for PTHR1 and PTHrP. The immunostaining intensity of tumours from patients with OS was correlated with survival time. Both PTHR1 and PTHrP were detected in all OS samples (n = 50). Dogs with OS tumours showing high immunostaining intensity for PTHR1 (n = 36) had significantly shorter survival times (p = 0.028, Log Rank; p = 0.04, Cox regression) when compared with OS that had low immunostaining intensity for PTHR1 (n = 14).PTHrP immunostaining intensity did not correlate with survival time (p > 0.05). The results of this study indicate that increased expression of PTHR1 antigen in canine OS is associated with poor prognosis. This suggests that PTHR1 may be useful as a prognostic indicator in canine OS.

Osteosarcoma is one of the most malignant tumors in adolescents with severe outcomes while fluoride is one of the most abundant elements in the environment. Epidemiological evidence has elucidated the relationship between fluoride and osteosarcoma, but the molecular mechanisms are extremely complicated. Microarray profiles were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) in the progression of fluoride-affected osteosarcoma. The functional enrichment analysis was performed, a protein-protein interaction network, a microRNA-messenger RNA (mRNA) and a transcription factors-mRNA regulatory network were constructed and performed using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. A total of 171 DEGs were identified. The functions and pathways of the DEGs were enriched in nucleolus, protein ubiquitination, protein binding, RNA transport, and the spliceosome. Eighteen hub genes were identified and functional analysis revealed that these genes are mainly enriched in protein binding, nucleoplasm, and ribosomal RNA processing. Survival analysis showed that the hub genes may be involved in the invasion or recurrence of osteosarcoma. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying fluoride-affected osteosarcoma and provide candidate targets for future research., (© 2019 Wiley Periodicals, Inc.)

Objectives: To study the antinociceptive effect of single and repeated doses of resveratrol in a bone cancer pain model, and whether this effect is prevented by the Silent Information Regulator 1 (SIRT1) inhibitor selisistat., Methods: The femoral intercondylar bone of BALB/c mice was injected with 1 000 000 BJ3Z cancer cells. Bone resorption and tumour mass growth (measured by in vivo X-ray and fluorescence imaging), as well as mechanical nociceptive thresholds (von Frey device) and dynamic functionality (rotarod machine), were evaluated during the following 4 weeks. Acute resveratrol (100 mg/kg i.p.) and/or selisistat (10 mg/kg s.c.) were administered on day 14. Chronic resveratrol (100 mg/kg i.p., daily) and/or selisistat (0.5 μg/h s.c., Alzet pump) were administered between days 14 and 20., Key Findings: Tumour growth gradually incremented until day 31, while mechanical hyperalgesia started on day 3 after cancer cell injection. Acute resveratrol increased the mechanical threshold of pain (peaking at 1.5 h), while the dynamic functionality decreased. Chronic resveratrol produced a sustained antinociceptive effect on mechanical hyperalgesia and improved the loss of dynamic functionality induced by the bone cancer tumour. Selisistat prevented all the effects of resveratrol., Conclusions: Acute and chronic resveratrol induces antinociceptive effect in the model of metastatic osseous oncological pain, an effect that would be mediated by SIRT1 molecular signalling., (© 2018 Royal Pharmaceutical Society.)

The Forteo Patient Registry (FPR) aims to estimate the incidence of osteosarcoma in US patients treated with teriparatide. Enrollment began in 2009 and will continue through 2019, with linkage planned through 2024. To date, no incident cases of osteosarcoma have been identified among patients registered in the FPR., Introduction: The Forteo Patient Registry (FPR) was established in 2009 to estimate the incidence of osteosarcoma in US patients treated with teriparatide. The objective of this paper is to describe study methods, challenges encountered, and progress to date., Methods: The FPR is a prospective US registry designed to link data from participants annually with state cancer registries. Patient enrollment is planned for 10 years (2009-2019) and annual linkage with US state cancer registries for 15 years (2010-2024). All US state cancer registries and DC were invited to participate. Patients are recruited using pre-enrollment materials included in teriparatide device packaging, kits, and brochures distributed by health-care providers; a toll-free number; and a study website. A linkage algorithm is used to match data from enrolled participants with cancer registry data., Results: For the eighth annual linkage in 2017, information necessary for linkage with 63,270 patients in the FPR was submitted to each of the 42 participating registries. These patients contributed approximately 242,782 person-years of follow-up. A total of 5268 adult osteosarcoma cases diagnosed since January 1, 2009, were available for linkage from participating state cancer registries. To date, no incident cases of osteosarcoma have been identified among patients registered in the FPR., Conclusions: Based on the estimated 242,782 person-years of observation as of the eighth annual linkage and projecting current enrollment rate to study end in 2024, it is anticipated that the completed study will be able to detect a fourfold increase in the risk of osteosarcoma if one exists.

Osteosarcoma is the most common bone malignancy that occurs in the young population. After osteosarcoma cells metastasize to the lung, prognosis is very poor owing to difficulties in early diagnosis and effective treatment. Recently, connective tissue growth factor (CTGF) was reported to be a critical contributor to osteosarcoma metastasis. However, the detailed mechanism associated with CTGF-directed migration in bone neoplasms is still mostly unknown. Through the in vivo and in vitro examination of osteosarcoma cells, this study suggests that VCAM-1 up-regulation and increased osteosarcoma cell migration are involved in this process. Antagonizing αvβ3 integrin inhibited cell migration. Moreover, FAK, PI3K, Akt and NF-κB activation were also shown to be involved in CTGF-mediated osteosarcoma metastasis. Taken together, CTGF promotes VCAM-1 production and further induces osteosarcoma metastasis via the αvβ3 integrin/FAK/PI3K/Akt/NF-κB signaling pathway, which could represent a promising clinical target to improve patient outcome., (Copyright © 2018. Published by Elsevier Inc.)

BACKGROUND Epithelial-mesenchymal transition (EMT) is responsible for metastasis of cancers, and NF-κB can promote tumor progression. Ezrin is an important molecule participating in EMT. However, whether Ezrin mediates NF-κB in EGF-induced osteosarcoma is unknown. MATERIAL AND METHODS Ezrin phosphorylation, NF-κB activation, and EGF-induced EMT were studied in MG63 and U20S cells with NF-κB inhibition, silencing, or over-expressing Ezrin. Cell morphology, proliferation, migration, and motility were analyzed. An osteosarcoma model was established in mice by injecting MG63 and U20S and reducing Ezrin. RESULTS With EGF induction in vitro, Ezrin Tyr353 and Thr567 were phosphorylated, and EMT, proliferation, migration, and motility of osteosarcoma cells were promoted. Silencing Ezrin suppressed and over-expressing Ezrin promoted the nuclear translocation of p65 and phosphorylated IκBα (p-IκBα) in EGF-induced osteosarcoma cells. NF-κB inhibitor blocked EGF-induced EMT in both cell types, as well as reserving cell morphology and suppressing proliferation, migration, and motility. In vivo, reducing Ezrin significantly suppressed metastasis of osteosarcoma xenografts, increased liver and lung weights, and activated NF-κB, which were both induced by EGF. CONCLUSIONS Ezrin/NF-κB regulated EGF-induced EMT, as well as progression and metastasis of osteosarcoma in vivo and in vitro. Ezrin/NF-κB may be a new therapeutic target to prevent osteosarcoma from deterioration.

Fluoride, one of the most celebrated ingredients for the prevention of dental caries in the 20th century, has also been controversial for its use in dentifrices and other applications. In the current review, we have concentrated primarily on early-life exposure to fluoride and how it may affect the various organs. The most recent controversial aspects of fluoride are related to toxicity of the developing brain and how it may possibly result in the decrease of intelligence quotient (IQ), autism, and calcification of the pineal gland. In addition, it has been reported to have possible effects on bone and thyroid glands. If nutritional stress is applied during a critical period of growth and development, the organ(s) and/or body will never recover once they pass through the critical period. For example, if animals are force-fed during experiments, they will simply get fat but never reach the normal size. Although early-life fluoride exposure causing fluorosis is well reported in the literature, the dental profession considers it primarily as an esthetic rather than a serious systemic problem. In the current review, we wanted to raise the possibility of future disease as a result of early-life exposure to fluoride. It is not currently known how fluoride will become a cause of future disease. Studies of other nutritional factors have shown that the effects of early nutritional stress are a cause of disease in later life.

Androgen deprivation therapy (ADT) targeting the androgen receptor (AR) is a standard therapeutic regimen for treating prostate cancer. However, most tumors progress to metastatic castration-resistant prostate cancer after ADT. We identified the type 1, 2, and 4 collagen-binding protein transforming growth factor-β (TGFβ)-induced protein (TGFBI) as an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. In prostate cancer cell lines, AR signaling stimulated the activity of the transcription factor SPDEF, which repressed the expression of TGFBI ADT, AR antagonism, or overexpression of TGFBI inhibited the activity of SPDEF and enhanced the proliferation rates of prostate cancer cells. Knockdown of TGFBI suppressed migration and proliferation in cultured cells and reduced prostate tumor growth and brain and bone metastasis in xenograft models, extending the survival of tumor-bearing mice. Analysis of prostate tissue samples collected before and after ADT from the same patients showed that ADT reduced the nuclear abundance of SPDEF and increased the production of TGFBI. Our findings suggest that induction of TGFBI promotes prostate cancer growth and metastasis and can be caused by dysregulation or therapeutic inhibition of AR signaling., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Experimental toxicological studies in laboratory animals and epidemiological human studies have reported a possible association between water fluoridation and osteosarcoma (OSA). To further explore this possibility, a case-control study of individual dogs evaluated by the UC Davis Veterinary Medical Teaching Hospital was conducted using ecologic data on water fluoridation based on the owner's residence. The case group included 161 dogs with OSA diagnosed between 2008-2012. Two cancer control groups included dogs diagnosed with lymphoma (LSA) or hemangiosarcoma (HSA) during the same period (n = 134 and n = 145, respectively). Dogs with OSA were not significantly more likely to live in an area with optimized fluoride in the water than dogs with LSA or HSA. Additional analyses within OSA patients also revealed no significant differences in age, or skeletal distribution of OSA cases relative to fluoride status. Taken together, these analyses do not support the hypothesis that optimal fluoridation of drinking water contributes to naturally occurring OSA in dogs., (© 2016 John Wiley & Sons Ltd.)

Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

This is the first study to demonstrate that benzo(a)-pyrene (BaP) was able to enhance the production of parathyroid hormone‑related protein (PTHrP) by human non‑small cell lung cancer H460 cells. Such effect would further contribute to bone metastasis of lung cancer by increasing osteoclastogenesis. This study is also the first to reveal that tricetin (TCN), a flavonoid derivative found in Myrtaceae pollen and Eucalyptus honey, was able to reverse BaP‑mediated bone resorption activity of lung cancer cells. Human non‑small cell lung cancer H460 cells were treated with BaP to generate conditioned medium. When osteoblasts were cultured with BaP‑H460‑CM, their expression of osteoclastogenesis activator macrophage colony‑stimulating factor (M‑CSF) and receptor activator of nuclear factor κB ligand (RANKL) was increased. BaP‑H460‑CM reduced the production of osteoprotegerin (OPG), an osteoclastogenesis inhibitor, in osteoblasts. Osteoclastogenesis and bone resorption activity of H460 cells were increased by BaP‑H460‑CM. With BaP‑mediated PTHrP upregulation, IL‑8 secretion in H460 cells was increased contributing to human non‑small cell lung cancer‑mediated osteoclast differentiation and bone resorption. Moreover, TCN suppressed BaP‑mediated bone resorption. Therefore, TCN may be a novel agent for treatment of non‑small cell lung cancer patients with bone metastasis.

Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose-response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose-response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0-59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0-47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6-42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5-380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213-5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.

Although estrogen has been clinically available for more than six decades, women have been confused by different opinions regarding the risks and benefits of menopausal hormone therapy (HT), estrogen therapy (ET), and estrogen-progestin therapy (EPT). The publication of randomized controlled trials (RCTs), notably, the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Health Initiative (WHI), has intensified the risk vs. benefit controversy. Millions of women are treated with HT for relief of menopausal symptoms, including vasomotor flushes and sweats, for which estrogen is uniquely and highly effective. Others may continue longer-term treatment in the hope that HT will help to prevent chronic disease. The preservation of bone mass with continuing estrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of estrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrated no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. The absolute incidence of an adverse event is low, and the risk of stroke in an individual woman in a single year is very small, but with long-term use, the risks are cumulative over time. The risk-benefit balance needs to be individualized for each woman.

Objective: To report an unusual case of subungual exostosis in a patient on teriparatide., Methods: We describe the presentation and symptoms of the patient and review of the relevant literature., Results: Teriparatide is used for the treatment of osteoporosis. Rat studies using 3-60x the approved human dose have shown an association between teriparatide and an increased risk of osteosarcoma. Subungual exostosis, to our knowledge, has not been reported. We report the case of a 54-year-old female who presented with a 4-month history of pain and swelling in the medial side of her right thumb with no preceding trauma. The patient had history of severe osteoporosis with multiple fractures and was on teriparatide for 16 months. On examination, the right thumb was swollen and tender with no superficial erythema or signs of an infection. X-ray imaging revealed a trabecular bony overgrowth consistent with subungual exostosis. The patient was treated with subungual excision. Pathology showed endochondral bone formation with reactive atypia, consistent with osteocartilaginous exostosis., Conclusion: To our knowledge, this is the first case hypothesizing an association between teriparatide and subungual exostosis. Subungual exostosis is a benign growth of bone that arises in the distal phalanx, under or adjacent to the nail bed. The pathophysiology is not clearly understood, but the lesion has base of trabecular bone with a proliferating fibrocartilaginous cap. Teriparatide can stimulate the trabecular bone formation. Hence, an association between the use of teriparatide and the development of subungal exostosis cannot be excluded. Further studies delineating this relationship are needed.

The Osteosarcoma Surveillance Study, an ongoing 15-year surveillance study initiated in 2003, is a postmarketing commitment to the United States (US) Food and Drug Administration to evaluate a potential association between teriparatide, rhPTH(1-34), a recombinant human parathyroid hormone analog (self-injectable medication to treat osteoporosis), and development of osteosarcoma in response to a finding from preclinical (animal) studies. Incident cases of primary osteosarcoma diagnosed in adults (aged ≥40 years) on or after January 1, 2003, are identified through population-based state, regional, and comprehensive cancer center registries in the US. Information on possible prior treatment with teriparatide, on demographics, and on risk factors is ascertained by patient or proxy telephone interview after patient consent. Between June 2004 and September 30, 2011, 1448 cases (diagnosed 2003 to 2009) were identified by participating cancer registries (estimated to be 62% of all adult cases in the US for that time period); 549 patients or proxies were interviewed. Interviewed patients were similar to noninterviewed patients with regard to mean age, sex, race, and geographical distribution and tumor type and site of tumor. Mean age of those interviewed was 61 years, 46% were female, 86% were white, and 77% were alive when the case was reported to the study investigators. Data collected in the study provide descriptive information on a large number of adults with osteosarcoma, an uncommon malignant bone tumor. After 7 years of the study, there were no osteosarcoma patients who had a prior history of teriparatide treatment. Thus, approximately halfway through this 15-year study, the study has not detected a pattern indicative of a causal association between teriparatide treatment and osteosarcoma in humans., (Copyright © 2012 American Society for Bone and Mineral Research.)

Background: Rodent models are often suboptimal for translational research on human prostate cancer (PCa). To better fill the gap with human, we refined the previously described orthotopic dog prostate cancer (DPC)-1 model., Methods: Cyclosporine (Cy) A was used for immune suppression at varying doses and time-periods prior and after orthotopic DPC-1 cell implantation in the dog prostate (n = 12). Follow up included digital rectal examination, ultrasound prostate imaging and biopsies of hypoechoic areas. At necropsy, the prostate, iliosacral lymph nodes (LN), lung nodules, and suspicious bone segments were collected for histopathology., Results: 15 mg CyA/kg daily for 10 days was optimal for tumor take. Maintaining these conditions post-implantation resulted in a rapid tumor development within and beyond the prostate and in iliosacral LNs. To minimize tumor burden, 10 times less DPC-1 cells were implanted. A series of dogs was next followed for 3-4 months, under continuous immune suppression (n = 3) or with CyA interruption at 8.5 weeks (n = 2). In all instances, multifocal tumors were found within the prostate. Predominant patterns were micropapillary and cribriform. Metastases were present in iliosacral LNs and lungs. Moreover, pelvic bone metastases producing a mixed osteoblastic/osteolytic reaction were confirmed in two dogs, one per group. Lastly, the release of CyA 1-2 weeks post-implantation (n = 3) did not prevent tumor growth and spreading to LNs., Conclusions: The continuing growth of DPC-1 tumors despite the release of CyA and, for the first time, spreading to bones renders this refined model closer to the spontaneous canine and hormone-refractory phase of human PCa., (Copyright © 2011 Wiley Periodicals, Inc.)

Radium is a naturally occurring radioactive element in the environment that can exist as several isotopes. Little information is available on the acute (short-term) non-cancer effects in humans. Radium exposure has resulted in acute leukopenia, anemia, necrosis of the jaw, and other effects. Cancer is the major effect of concern. Radium, via oral exposure, is known to cause bone, head, and nasal passage tumors in humans. The US Environmental Protection Agency has not classified radium for carcinogenicity.

Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 µg/kg/day. The non-carcinogenic dose level was 4.5 µg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.

Several essential oils contain pulegone and are used for flavoring foods, drinks, and dental products, as fragrance agents, and in herbal medicines. Pulegone was nominated for study by the National Institute of Environmental Health Sciences based on the potential for human exposure and the absence of carcinogenicity data. Male and female F344/N rats and B6C3F1 mice received pulegone (approximately 96% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered 0, 37.5, 75, 150, 300, or 600 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. All male rats and nearly all female rats in the 300 and 600 mg/kg groups died prior to the end of the study. All moribund sacrifices and early deaths were attributed to liver toxicity. Mean body weight gains of males administered 37.5 or 150 mg/kg were significantly less than that of the vehicle controls. Clinical findings in 300 and 600 mg/kg rats included nasal/eye discharge, thinness, lethargy, and ruffled fur. Liver and kidney weights of dosed groups of females were generally significantly greater than those of the vehicle control group. The incidences of necrosis and cytoplasmic vacuolization of the liver in 300 and 600 mg/kg males and females were significantly greater than those in the vehicle control groups. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered 0, 18.75, 37.5, 75, 150, or 300 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. Four females and one male in the 300 mg/kg groups died by study day 5. All early deaths were attributed to liver toxicity. Mean body weights of the dosed groups were similar to those of the vehicle controls. Clinical findings were observed only in 300 mg/kg mice and included thinness, lethargy, and ruffled fur. Liver weights of 300 mg/kg males were significantly greater than those of the vehicle controls. The incidences of cytoplasmic vacuolization and diffuse fatty change in 300 mg/kg females and necrosis in 300 mg/kg males were significantly greater than those in the vehicle controls. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All rats survived until the end of the study except for one female in the 150 mg/kg group that died on day 9. Mean body weights of 75 and 150 mg/kg males and 150 mg/kg females were significantly less than those of the vehicle controls. At the end of the study, there was a small dose-related decrease in the erythron, evidenced by decreases in the hematocrit and hemoglobin values and the erythrocyte counts. An apparent erythroid response to the decreased erythron was evidenced by increased reticulocyte counts. Reduced and oxidized glutathione levels were generally increased in 75 and 150 mg/kg males and in 37.5 mg/kg or greater females. Absolute and relative liver weights of 75 and 150 mg/kg females and relative liver weights of males administered 18.75 mg/kg or greater were significantly greater than those of the vehicle controls. The absolute kidney weight of 150 mg/kg females and the relative kidney weights of all dosed groups, except 9.375 mg/kg males, were significantly greater than those of the vehicle controls. Absolute and relative thymus weights of 150 mg/kg males and females and the absolute thymus weight of 75 mg/kg males were significantly less than those of the vehicle controls. In the kidney, there was hyaline glomerulopathy in 75 mg/kg males and 150 mg/kg males and females. The incidence of renal tubule protein casts was significantly increased in the 150 mg/kg females. In the liver, incidences of bile duct hyperplasia and hepatocyte hypertrophy in 75 and 150 mg/kg males and 150 mg/kg females, hepatocyte focal necrosis in 150 mg/kg males, and oval cell hyperplasia and periportal fibrosis in 150 mg/kg males and females were increased. Incidences of bone marrow hyperplasia in 37.5 mg/kg males and 75 and 150 mg/kg males and females, heart mineralization in 150 mg/kg males, glandular stomach mineralization in 75 and 150 mg/kg females, and cellular histiocytic infiltration in the lung and ovarian cyst in 150 mg/kg females were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of dosed mice were similar to those of the vehicle controls. Reduced and oxidized glutathione levels were generally greater than vehicle control levels in 150 mg/kg males and in 75 and 150 mg/kg females. Liver weights of 150 mg/kg males and 75 and 150 mg/kg females were significantly greater than those of the vehicle controls. No histopathologic lesions were observed that could be attributed to the administration of pulegone. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 18.75 (males only), 37.5, 75, or 150 (females only) mg pulegone/kg body weight in corn oil by gavage, 5 days per week for up to 104 weeks. Due to excessive morbidity and mortality, 75 mg/kg males and 150 mg/kg females were not administered pulegone after week 60 (stop-exposure); these groups were administered the corn oil vehicle until the end of the study. Survival of 37.5 mg/kg males was significantly less than that of the vehicle controls; only two 75 mg/kg stop-exposure males survived, and no 150 mg/kg stop-exposure females survived to the end of the study. Compared to those of the vehicle controls, mean body weights were less in 75 mg/kg stop-exposure males after week 13 and in 75 mg/kg and 150 mg/kg stop-exposure females after weeks 21 and 9, respectively. Clinical findings included thinness, lethargy, and ruffled fur in the 75 mg/kg stop-exposure males and 150 mg/kg stop-exposure females. The incidences of urinary bladder papilloma and of papilloma or carcinoma (combined) were significantly increased in 150 mg/kg stop-exposure females. In the kidney, incidences of hyaline glomerulopathy were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in all dosed groups of females. The severity of chronic progressive nephropathy was increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in 75 mg/kg and 150 mg/kg stop-exposure females; the incidences of nephropathy were significantly increased in 75 mg/kg and 150 mg/kg stop-exposure females. The incidence of renal cyst was significantly increased in 75 mg/kg stop-exposure males. In the liver, incidences of diffuse hepatocyte cellular alteration were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and 75 mg/kg and 150 mg/kg stop-exposure females. There were significant increases in the incidences of other liver lesions including fatty change, bile duct cyst, hepatocyte necrosis, oval cell hyperplasia, bile duct hyperplasia, and portal fibrosis. In the nose, 37.5 mg/kg and 75 mg/kg stop-exposure males and all dosed groups of females had significantly increased incidences of olfactory epithelium degeneration. All dosed groups of females had significantly increased incidences of respiratory metaplasia of the olfactory epithelium and nasal inflammation. In the forestomach, incidences of inflammation and ulcer were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males, and incidences of epithelial hyperplasia and perforation were increased in 75 mg/kg stop-exposure males. In the glandular stomach, the incidence of inflammation was significantly increased in 75 mg/kg stop-exposure males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of 150 mg/kg males and females were less than those of the vehicle controls after weeks 25 and 33, respectively. The incidences of multiple hepatocellular adenoma were significantly increased in all dosed groups of males, and the incidences of hepatocellular adenoma (includes multiple) and hepatoblastoma (includes multiple) were significantly increased in the 75 mg/kg males. The combined incidences of hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma occurred with positive trends and were significantly increased in 75 mg/kg males and 150 mg/kg females. The incidence of hepatocellular adenoma was significantly increased in 150 mg/kg females. The incidences of several nonneoplastic liver lesions were significantly increased, primarily in the 75 and 150 mg/kg groups. These nonneoplastic lesions included clear cell, eosinophilic, and mixed cell foci; focal fatty change; centrilobular hepatocyte hypertrophy; intravascular hepatocyte; necrosis; pigmentation; bile duct cyst and hyperplasia; and oval cell hyperplasia. In the kidney, incidences of hyaline glomerulopathy were significantly increased in all dosed groups of males and 75 and 150 mg/kg females. The incidence of mineralization was significantly increased in 150 mg/kg females, and the incidence of nephropathy in 150 mg/kg females and severity of nephropathy in 150 mg/kg males were increased. Incidences of congestion of the glomerulus were increased in 150 mg/kg males and females. The incidence of osteoma or osteosarcoma (combined) in all organs of 75 mg/kg females exceeded the historical control ranges. One 150 mg/kg male and one 75 mg/kg female had nasal osteoma; no nasal osteomas have been observed in historical control mice. (ABSTRACT TRUNCATED)

The ability of parathyroid glandular extracts to stimulate bone acquisition in rodents was established in the 1920s, but interest in this action lay dormant for almost 50 years until application of contemporary laboratory methods permitted the large-scale production of an amino-terminal fragment of PTH, (1-34) hPTH (teriparatide), which was capable of carrying out all known actions of the full-length (1-84) PTH molecule. In the 1970s, largely stimulated by the efforts of a British pharmacologist, Dr. John Parsons, the scientific community began to revisit these anabolic actions and showed that single daily injections of teriparatide dramatically increased bone mass in several mammalian species and restored bone in oöphorectomized rats. Shortly thereafter, human studies confirmed a striking increase in trabecular bone mass and showed also that an important part of teriparatide's action is to increase cortical bone. Eli Lilly and Company conducted a formal registration trial in postmenopausal women with osteoporosis. The unexpected occurrence of osteosarcomas in Fisher 344 rats treated long-term with teriparatide provoked an abrupt cessation of that trial, but ambiguity concerning the relevance of this rat finding to human disease, combined with significant anti-fracture efficacy, led to FDA approval of teriparatide for men and postmenopausal women with osteoporosis "at high risk for fracture" in 2002. Subsequently, teriparatide has been approved also for treatment of patients with glucocorticoid-associated osteoporosis, and papers indicating utility of this agent for dental and orthopedic applications have begun to appear.

The purpose of this case series is to report the unexpected occurrence of four cases of late radiation-induced neurotoxicity with bevacizumab use following radiotherapy to the CNS. We retrospectively reviewed the case records of four patients, three with glioblastoma and one with bone metastases secondary to metastatic breast cancer, who were treated with radiotherapy and developed late radiation-induced neurotoxicity following bevacizumab use. Three cases of optic neuropathy in glioblastoma patients and a single case of Brown-Séquard syndrome in the thoracic spine of a patient with metastatic breast cancer are reported. We hypothesize that bevacizumab use following radiotherapy to the CNS may inhibit vascular endothelial growth factor-dependent repair of normal neural tissue, and thus may increase the risk of late radiation neurotoxicity. Phase III data on the safety and efficacy of bevacizumab use with radiation in the setting of glioblastoma is awaited.

Summary: Since approval by the U.S. Food and Drug Administration (FDA) in December 2002, teriparatide (recombinant 1-34 PTH; Forteo) has been safely used by more than 430,000 patients. Prior to FDA approval, however, there was concern that teriparatide might increase the risk for patients to develop osteosarcoma, as almost 45% of the rats treated with this drug at the highest-tested dose level developed this aggressive form of bone cancer. Balancing the proven benefits of teriparatide shown by clinical trials with the theoretical risk for teriparatide-induced human osteosarcoma, the FDA mandated both a 'black-box' warning of this potential side-effect and a company-sponsored postmarketing surveillance program. As a participating institute of that surveillance program, we report upon the second person with potential teriparatide-induced osteosarcoma, in this case, complicated by a history of pelvic radiation., Introduction: Given the theoretic risk of the drug teriparatide and the known risk of radiation in inducing osteosarcoma, we raise the issue of whether teriparatide magnified the risk of radiation-induced osteosarcoma in our patient and try to determine which factor played the predominant role in the development of his disease., Methods: We analyzed preclinical rat data, human clinical experience with teriparatide, and our patient's clinical history to assess the human risk of teriparatide and radiation exposure., Results: After the first case of suspected osteosarcoma was reported in December 2005, we encountered a second possible teriparatide-induced osteosarcoma less than a year later. Review of the preclinical animal data would suggest that teriparatide is safe for human use when used as recommended by the manufacturer. Given the location of the sarcoma within the field of radiation and the limited exposure to teriparatide before diagnosis, it is unlikely that teriparatide played the predominant role in the emergence of this patient's osteosarcoma. We cannot, however, exclude the possibility that teriparatide magnified the carcinogenic effect of radiation therapy to induce the osteosarcoma., Conclusion: Of more than 430,000 persons who have received teriparatide for treatment of severe osteoporosis, we report the second patient to develop osteosarcoma. Although teriparatide reduces osteoporosis-related fractures in select patient populations, important contraindications, such as prior radiation exposure, should be considered before use.

Background: The osteoblastic bone flare or response is the paradoxical phenomenon of increase in the quantity and/or density of bone lesions in the presence of well-documented disease response to treatment in other tumor sites. It results from the rapid repair and increased osteoblastic activity in bone metastases responding to therapy and therefore represents treatment efficacy. Nevertheless, no reliable markers can differentiate an osteoblastic flare or response from disease progression. In non-small cell lung cancer (NSCLC) osteoblastic bone flare or response has been reported in only a few patients., Methods: Pre- and posttreatment CT scans of NSCLC patients with osteolytic bone lesions and treated with erlotinib as a single treatment modality were reviewed., Results: In 3 cases fulfilling these criteria and responding to erlotinib according to RECIST criteria, an osteoblastic bone response was found. With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitors in patients with NSCLC harboring mutations predicting a good response, the osteoblastic response will likely be increasingly seen. Awareness of this phenomenon with epidermal growth factor receptor tyrosine kinase inhibitors is important for physicians treating patients with NSCLC, so that it is not misinterpreted as progressive disease resulting in premature cessation of effective therapy.

Genomic imprinting, a heritable form of epigenetic information, is thought to play an important role in tumor progression. DNA methylation is a common mechanism of genomic imprinting. To evaluate the genome-wide effects of malignant transformation on osteosarcoma progression, we examined multiple biological properties, including DNA methylation, in human osteoblast hFOB1.19 cells (ATCC Catalog No. CRL-11372) transformed by treatment with carcinogenic agent N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1.0 microg/ml) and carcinogenic promoting agent 12-O-tetradecanoyl phorbol-13-acetate (TPA, 200 ng/ml). We also examined global changes in expression of imprinted genes during transformation using microarray analysis. Ten imprinted genes, including H19, MKRN3, NDN, CDKN1C, PHLDA2, MEST, CD81, GRB10, SLC22A18, and SLC22A3 were aberrantly regulated in transformed cells, suggesting roles in tumorigenesis. Moreover, we analyzed the methylation state of the promoter regions of H19, PHLDA2, and SLC22A18 genes by bisulfite sequencing array and observed a correlation between upregulated expression of H19 and PHLDA2 genes and hypomethylation of their promoter regions, although this was not observed for SLC22A18. Our results suggest that changes in expression of imprinted genes caused by changes in methylation are involved, and are among the earliest events, in neoplastic progression.

Teriparatide (recombinant human 1-34 parathyroid hormone) has been registered for the treatment of postmenopausal osteoporosis and osteoporosis in men for more than 5 years, whereas 1-84 parathyroid hormone has just recently been registered in Europe for osteoporosis management. Therefore, more data are available regarding the long-term safety of teriparatide. The issues to be considered are the effects of the registered dose of teriparatide (20 microg/day) on the incidence of hypercalcemia, hypercalciuria, and hyperuricemia, and the US Food and Drug Administration's "black-box" warning regarding osteogenic sarcoma in the rat model. This review discusses these issues and provides the author's extensive clinical experience and advice on the use of teriparatide in clinical practice.

Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

Objective: We explored age-specific and gender-specific effects of fluoride level in drinking water and the incidence of osteosarcoma., Methods: We used data from a matched case-control study conducted through 11 hospitals in the United States that included a complete residential history for each patient and type of drinking water (public, private well, bottled) used at each address. Our analysis was limited to cases less than 20 years old. We standardized fluoride exposure estimates based on CDC-recommended target levels that take climate into account. We categorized exposure into three groups (<30%, 30-99%, >99% of target) and used conditional logistic regression to estimate odds ratios., Results: Analysis is based on 103 cases under the age of 20 and 215 matched controls. For males, the unadjusted odds ratios for higher exposures were greater than 1.0 at each exposure age, reaching a peak of 4.07 (95% CI 1.43, 11.56) at age 7 years for the highest exposure. Adjusting for potential confounders produced similar results with an adjusted odds ratio for males of 5.46 (95% CI 1.50, 19.90) at age 7 years. This association was not apparent among females., Conclusions: Our exploratory analysis found an association between fluoride exposure in drinking water during childhood and the incidence of osteosarcoma among males but not consistently among females. Further research is required to confirm or refute this observation.

Osteosarcoma is a rare malignancy of largely unknown etiology. Although there is no consistent evidence for an association between fluoridation and cancer, some concerns remain about osteosarcoma. As part of the design of a collaborative study, bone samples were collected to allow for an evaluation of the association between osteosarcoma risk and individual fluoride exposure measured by levels of fluoride in bone. In this report, we provide the results of pilot experiments to consider issues that arose during the study design and to assess the reliability of the bone assays. Correlations of fluoride levels between normal bone near the affected area and iliac crest bone were strong and positive. The day-to-day laboratory analysis of fluoride in human and deer jaw bone yielded acceptable average coefficients of variation below 10% and an overall estimate of 5%. The intraclass correlation (ICC) is of particular importance to epidemiologists because it indicates the effect of measurement error on study results. Here, the estimated ICC is 0.86, and the estimated downward bias is only 14%. Hence, the ICC is strong enough so that the estimates of the relative risk will suffer little attenuation from lab measurements.

For over 40 years, the metal-on-polyethylene bearing has dominated the field of total hip replacement. Problems of wear, osteolysis (dissolution of bone), and ultimately failure of prostheses have led to the development of alternative bearing surfaces. Metal-on-metal hip resurfacing has taken current orthopaedic surgery almost by storm. However, metal ion release following metal-on-metal hip resurfacing remains a major cause for concern. This article looks into the development and examines problems and issues surrounding metal-on-metal resurfacing arthroplasty.

Metal-on-metal (MOM) bearings offer extremely low wear and the avoidance of polyethylene but generate metallic wear particles. Although their total volume is dramatically smaller than polyethylene debris, these particles are in the nanometre size range and are many times more numerous. Metallic particles are ingested by macrophages or may be disseminated via lymphatics to the reticuloendothelial system. They corrode, and metal ions are present in the circulation and concentrated in erythrocytes. Excretion of metal ions via the kidneys seems to balance their generation in patients with MOM implants. However, highly sensitive detection methods can be used to show that levels of circulating cobalt and chromium ions are several times the normal level. These concentrations are well within the limits identified as dangerous to health in workers exposed to industrial chemicals, and also considerably lower than the levels found to cause cell toxicity in vitro. The local concentrations of particles and metal ions in the synovial tissue may occasionally exceed these limits and cause tissue necrosis. Clinical experience of lysis is rare in association with MOM bearings, as are hypersensitivity reactions and MOM bearings have had an excellent record over four decades and have a favourable benefit to risk ratio. Further reduction in risk will be achieved by improvement of materials, engineering, and accuracy of insertion.

The advantages seen by patients receiving total hip arthroplasties and the implications of the release of both metal particles and soluble metal ions are discussed. This paper describes some of the early changes that have been observed in metal-on-metal hip arthroplasties, in terms of both changes in metal levels in blood and chromosome changes.

The carcinogenic potential of human parathyroid hormone 1-84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 microg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density. In the mid-and high-dose groups, proliferative changes in bone increased with dose. Osteosarcoma was the most common change, followed by focal osteoblast hyperplasia, osteoblastoma, osteoma and skeletal fibrosarcoma. The incidence of bone neoplasms was comparable in control and low-dose groups providing a noncarcinogenic dose for PTH of 10 microg/kg/day at a systemic exposure to PTH that is 4.6-fold higher than for a 100 microg dose in humans. The ability of PTH to interact with and balance the effects of both the PTH-1 receptor and the putative C-terminal PTH receptor, may lead to the lower carcinogenic potential observed with PTH than reported previously for teriparatide.