Bone Metabolic Activity Research Articles

Mechanically induced Ca2+ oscillations in osteocytes release extracellular vesicles and enhance bone formation

The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin (OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We’ve previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca2+) dynamics. Here, by simultaneously monitoring Ca2+ and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca2+ transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles (EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1 (LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca2+ signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle. Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca2+-dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca2+ signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca2+-mediated signaling in bone adaptation.

Markov chain based simulation analysis of bone mineral density and changes in the level of biochemical markers of bone transformation in postmenopausal women

The changes in biochemical marker level of bone turnover of women before and after menopause and the relationship between it and bone mineral density (BMD) are analyzed. At the same time, the level of biochemical markers of bone metabolism of women with decreased BMD at premenopause and postmenopause is discussed. In this paper, the lumbar vertebrae (L1–L4) and femoral neck BMD of 225 female outpatients with osteoporosis were measured by dual-energy X ray bone sonometer. Among them, 185 menopause women at age of 45–65 were selected, and they were divided into normal bone mass group (50), decreased bone mass group (35) and osteoporosis group (100) according to BMD; in addition, 45 menopause women with decreased BMD at age of 51–70 were selected as postmenopause decreased-BMD group, and 25 non-menopause decreased-BMD women at age of 42–50 were selected as premenopause decreased-BMD group. Enzyme-linked immunosorbent assay was carried out to measure the level of serum cathespin K (Cathe K), bone alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase (TRAP) of all patients; and electrochemiluminescence immunoassay is used to detect the level of osteocalcin, β-crosslaps and type-I procollagen N-terminal propeptide(PINP). The Cathe K, PINP, β-crosslaps, osteocalcin and TRAP level of postmenopausal women with osteoporosis are obviously higher than those of normal bone mass group (P 0.05). The Cathe K and TRAP level of serum in postmenopause decreased-BMD group were significantly lower than those in premenopausal women (P 0.05). Osteoporosis of postmenopausal women is high turnover. The changes in the levels of serum osteocalcin, β-crosslaps, PINP, B-ALP, TRAP and Cathe K could reflect the bone metabolism activity. The joint detection of BMD and bone-turnover biochemical marker is beneficial to the prevention, treatment and efficacy observation of the patients with osteoporosis.

Bone metabolism markers and vitamin D in adolescent cyclists.

The purpose of this study was to describe bone metabolic activity in adolescent competitive cyclists compared to age-matched controls. Twenty-two male adolescent cyclists between 14 and 20years (y) and 20 age-matched controls participated in this study. Serum osteocalcin (OC), aminoterminal propeptide of type I procollagen (PINP), and β-isomerized C-telopeptides (β-CTX) were analyzed by electrochemiluminescence immunoassay (ECLIA); plasma 25 hydroxyvitamin D [25(OH)D] was analyzed by enzyme-linked immunosorbent assay (ELISA). Analysis of variance revealed no significant differences in bone metabolism markers and vitamin D between cyclists and controls. Cyclists over 17y had a significantly lower concentration in bone formation and resorption biochemical markers compared to cyclists under 17y (all P < 0.05). Moreover, controls over 17y presented lower concentration for PINP (P < 0.05) compared to their peers under 17y. Comparisons between cyclists and controls under 17y revealed higher concentrations of OC and PINP (P < 0.05) in cyclists. Group interaction by age was found for OC, PINP, and β-CTX (P < 0.01). Cyclists over 17y had higher concentrations of [25(OH)D] (P < 0.05) than age-matched controls. The present results support the idea that cycling during adolescence may be associated to a decrease in bone turnover that may affect bone health later in life.

Clinical Utility of Biochemical Marker of Bone Turnover: Fracture Risk Prediction and Bone Healing.

Bone turnover markers (BTMs) are released during bone remodeling and are thought to reflect the metabolic activity of bone at the cellular level. This review examines BTM as a biological response marker for monitoring future fracture prediction and fracture healing processes. Substantial evidence has been of high value to investigate the use of BTM in fracture risk prediction; nevertheless, the conclusions of some studies are inconsistent due to their large variability. BTM is promising for fracture risk prediction for adopting international reference standards or providing absolute risks, such as 10-year fracture probabilities. There are uncertainties over their clinical use for monitoring osteoporotic fracture healing. More rigorous evidence is needed that can provide more detailed insights for fracture healing and for ascertaining the progression of fracture healing.

Protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulation of IL-6/STAT3 signaling.

The aim of the present study was to assess the effectiveness of Rhizoma Dioscoreae extract (RDE) on preventing rat alveolar bone loss induced by ovariectomy (OVX), and to determine the role of interleukin-6 (IL-6)/signal transducer and activator of transcription3 (STAT3) signaling pathway in this effect. Female Wistar rats were subjected to OVX or sham surgery. The rats that had undergone OVX were treated with RDE (RDE group), vehicle (OVX group) or 17β-estradiol subcutaneous injection (E2group). Subsequently, bone metabolic activity was assessed by analyzing3-D alveolar bone construction, bone mineral density, as well as the plasma biomarkers of bone turnover. The gene expression of alveolar bone in the OVX and RDE groups was evaluated by IL-6/STAT3 signaling pathway polymerase chain reaction(PCR) arrays, and differentially expressed genes were determined through reverse transcription-quantitative PCR. The inhibitory effect of RDE on alveolar bone loss in the OVX group was demonstrated in the study. In comparison with the OVX group, the RDE group exhibited 19downregulated genes and 1upregulated gene associated with the IL-6/STAT3 signaling pathway in alveolar bone. Thus, RDE was shown to relieve OVX-induced alveolar bone loss in rats, an effect which was likely associated with decreased abnormal bone remodeling via regulation of the IL-6/STAT3 signaling pathway.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335-46. ©2017 AACR.

Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study.

ObjectiveThe aim of this study was to evaluate the effect of atorvastatin on the bone formation and resorption markers in ovariectomized rats (experimental study), and to study its effect on the bone mineral density (BMD) in postmenopausal osteoporotic women (clinical study).Materials and methodsThe study involved experimental and clinical aspects. In the experimental aspect, 42 female Wistar rats were divided into five groups: Group I (n=6; sham-operated), Group II (n=6; 1 mL of carboxymethyl cellulose [CMC] was administered orally), Group III (n=6; 20 mg/kg orally of atorvastatin was administered), Group IV (n=12; untreated ovariectomized [OVX] rats and served as a model of osteoporosis [OP]) and Group V (n=12; 20 mg/kg orally of atorvastatin was administered to ovariectomized rats). After 4 weeks, serum acid phosphatase, alkaline phosphatase, osteocalcin, total calcium and inorganic phosphorus were assessed. Then, 3 µm thickness lumbar and femur sections were examined using a light microscope to assess cortical thickness, trabecular area, numbers of osteoblasts and osteoclasts. In the clinical aspect, 85 post-menopausal osteoporotic females with recently detected hyperlipidemia participated in the study. Atorvastatin 40 mg/day, calcium carbonate 500 mg/day and vitamin D 800 international units were given to all patients for a period of 18 months. BMD was measured at the start and at the end of the study by dual-energy X-ray absorptiometry (DEXA).ResultsIn the experiment aspect, the biomarkers of bone remodeling were notably elevated in the OVX group. Administration of atorvastatin produced a significant decrease in the level of these bone metabolic markers. Atorvastatin significantly ameliorates osteoporotic changes induced by ovariectomy. In the clinical aspect, after 18 months the DEXA showed improvement in the T-score for the three measured zones; however, these changes were statistically significant only in the femoral neck area.ConclusionAtorvastatin was able to decrease the rate of bone metabolism and increase osteogenic activity. It has dual mode of action; both anabolic and antiresorptive effect on bone. This lipophilic statin member may act as a double weapon drug.

Osseointegration Pharmacology.

The process of osseointegration around dental implants is similar to the biological events occurring during bone repair and fracture healing. Therefore, bone metabolic activity plays a crucial role on the success of osseointegration, and dysregulation of bone metabolism can have a negative impact on bone healing and implant osseointegration. Accordingly, it could be hypothesized that drugs interfering with healing and bone metabolism could affect osseointegration and implant survival. Looking into the relationship between pharmacology, osseointegration, and dental implants, drugs can open the door for new pharmacological innovations to improve implant success and avoid unnecessary complications, and it is also of special interest because most implant patients are elder adults who are often polymedicated. In this commentary, we discuss the discoveries made by us as well as by other researchers regarding the effect of several drugs on bone, osseointegration, and implant survival. Of particular interest is the growing evidence showing that commonly used drugs such as nonsteroidal anti-inflammatories, serotonin reuptake inhibitors, and proton pump inhibitors could lead to implant failure.

Preparation and Evaluation of 99mTc-labeled Tridentate Chelates for Pre-targeting Using Bioorthogonal Chemistry.

Pre-targeting combined with bioorthogonal chemistry is emerging as an effective way to create new radiopharmaceuticals. Of the methods available, the inverse electron demand Diels-Alder (IEDDA) cycloaddition between a radiolabeled tetrazines and trans-cyclooctene (TCO) linked to a biomolecule has proven to be a highly effective bioorthogonal approach to imaging specific biological targets. Despite the fact that technetium-99m remains the most widely used isotope in diagnostic nuclear medicine, there is a scarcity of methods for preparing 99mTc-labeled tetrazines. Herein we report the preparation of a family of tridentate-chelate-tetrazine derivatives and their Tc(I) complexes. These hitherto unknown compounds were radiolabeled with 99mTc using a microwave-assisted method in 31% to 83% radiochemical yield. The products are stable in saline and PBS and react rapidly with TCO derivatives in vitro. Their in vivo pre-targeting abilities were demonstrated using a TCO-bisphosphonate (TCO-BP) derivative that localizes to regions of active bone metabolism or injury. In murine studies, the 99mTc-tetrazines showed high activity concentrations in knees and shoulder joints, which was not observed when experiments were performed in the absence of TCO-BP. The overall uptake in non-target organs and pharmacokinetics varied greatly depending on the nature of the linker and polarity of the chelate.

Prevalence of Vitamin D deficiency and associated risk factors among children residing at high altitude in Shimla district, Himachal Pradesh, India.

Introduction:Vitamin D is important for bone development in children. A high prevalence of Vitamin D deficiency (VDD) has been documented from different parts of India. However, limited data are available on VDD among children residing at high altitude region of country.Objectives:To assess the prevalence of VDD and associated risk factors among children in the age group of 6–18 years in Shimla, Himachal Pradesh.Methods:A community-based cross-sectional study was conducted in the year 2014–2015. A total of 626 children in the age group of 6–18 years were enrolled from 30 clusters which were identified using population proportionate to size sampling method. A minimum of 20 children in the age group of 6–18 years per cluster were selected using random number tables. The data on socioeconomic status, physical activity, sunlight exposure, and biochemical parameters of bone and mineral metabolism were assessed.Results:Ninety-three percent of school-age children were found Vitamin D deficient as per serum 25(OH) D levels of <20 ng/ml. The prevalence was significantly higher among females.Conclusion:A high prevalence of VDD was found in children residing in high altitude region.

A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives

A convenient strategy to radiolabel a hydrazinonicotonic acid (HYNIC)-derived tetrazine with 99mTc was developed, and its utility for creating probes to image bone metabolism and bacterial infection using both active and pretargeting strategies was demonstrated. The 99mTc-labelled HYNIC-tetrazine was synthesized in 75% yield and exhibited high stability in vitro and in vivo. A trans-cyclooctene (TCO)-labelled bisphosphonate (TCO-BP) that binds to regions of active calcium metabolism was used to evaluate the utility of the labelled tetrazine for bioorthogonal chemistry. The pretargeting approach, with 99mTc-HYNIC-tetrazine administered to mice one hour after TCO-BP, showed significant uptake of radioactivity in regions of active bone metabolism (knees and shoulders) at 6 hours post-injection. For comparison, TCO-BP was reacted with 99mTc-HYNIC-tetrazine before injection and this active targeting also showed high specific uptake in the knees and shoulders, whereas control 99mTc-HYNIC-tetrazine alone did not. A TCO-vancomycin derivative was similarly employed for targeting Staphylococcus aureus infection in vitro and in vivo. Pretargeting and active targeting strategies showed 2.5- and 3-fold uptake, respectively, at the sites of a calf-muscle infection in a murine model, compared to the contralateral control muscle. These results demonstrate the utility of the 99mTc-HYNIC-tetrazine for preparing new technetium radiopharmaceuticals, including those based on small molecule targeting constructs containing TCO, using either active or pretargeting strategies.

A Bone-Seeking trans-Cyclooctene for Pretargeting and Bioorthogonal Chemistry: A Proof of Concept Study Using 99mTc- and 177Lu-Labeled Tetrazines.

A high yield synthesis of a novel, small molecule, bisphosphonate-modified trans-cyclooctene (TCO-BP, 2) that binds to regions of active bone metabolism and captures functionalized tetrazines in vivo, via the bioorthogonal inverse electron demand Diels-Alder (IEDDA) cycloaddition, was developed. A 99mTc-labeled derivative of 2 demonstrated selective localization to shoulder and knee joints in a biodistribution study in normal mice. Compound 2 reacted rapidly with a 177Lu-labeled tetrazine in vitro, and pretargeting experiments in mice, using 2 and the 177Lu-labeled tetrazine, yielded high activity concentrations in shoulder and knee joints, with minimal uptake in other tissues. Pretargeting experiments with 2 and a novel 99mTc-labeled tetrazine also produced high activity concentrations in the knees and shoulders. Critically, both radiolabeled tetrazines showed negligible uptake in the skeleton and joints when administered in the absence of 2. Compound 2 can be utilized to target functionalized tetrazines to bone and represents a convenient reagent to test novel tetrazines for use with in vivo bioorthogonal pretargeting strategies.

Biochemical bone turnover markers in children and adolescents

Bone is a dynamic tissue that consistently undergoes remodeling. During formation and resorption processes, bone turnover markers are released. They are specific bone-derived molecules that circulate in the blood or are present in the urine reflecting the bone metabolic activity (during childhood and adolescence: bone growth in length, modeling and remodeling). The use of biochemical bone turnover markers provides dynamic indices of bone turnover and complements the static measures of bone, such as measurement of bone mineral density using DEXA or measurement of bone geometry, mass and density using quantitative computed tomography. The assay of bone markers may be repeated at much shorter intervals than remaining measurements so may help in detecting influence of disease or effects of therapy much earlier than changes in bone mass or progression in bone disease can be ascertained. The usefulness of determination of bone turnover markers in children and adolescents requires that the influence of age, sex and pubertal stage be taken into consideration to interpret the results correctly. Bone turnover markers are used in children and adolescents to assess bone metabolic disorders, monitoring disease progression and antiresorptive therapy.

Links Between the Microbiome and Bone.

The human microbiome has been shown to influence a number of chronic conditions associated with impaired bone mass and bone quality, including obesity, diabetes, and inflammatory bowel disease. The connection between the microbiome and bone health, however, has not been well studied. The few studies available demonstrate that the microbiome can have a large effect on bone remodeling and bone mass. The gut microbiome is the largest reservoir of microbial organisms in the body and consists of more than a thousand different species interacting with one another in a stable, dynamic equilibrium. How the microbiome can affect organs distant from the gut is not well understood but is believed to occur through regulation of nutrition, regulation of the immune system, and/or translocation of bacterial products across the gut endothelial barrier. Here we review each of these mechanisms and discuss their potential effect on bone remodeling and bone mass. We discuss how preclinical studies of bone-microbiome interactions are challenging because the microbiome is sensitive to genetic background, housing environment, and vendor source. Additionally, although the microbiome exhibits a robust response to external stimuli, it rapidly returns to its original steady state after a disturbance, making it difficult to sustain controlled changes in the microbiome over time periods required to detect alterations in bone remodeling, mass, or structure. Despite these challenges, an understanding of the mechanisms by which the gut microbiome affects bone has the potential to provide insights into the dissociation between fracture risk and bone mineral density in patients including those with obesity, diabetes, or inflammatory bowel disease. In addition, alteration of the gut microbiome has the potential to serve as a biomarker of bone metabolic activity as well as a target for therapies to improve bone structure and quality using pharmaceutical agents or pre- or probiotics. © 2016 American Society for Bone and Mineral Research.

PET-MR imaging of metabolic bone activity in knee osteoarthritis

PET-MR imaging of metabolic bone activity in knee osteoarthritis

Epigallocatechin-3-gallate Promotes Osteoblastic Activity in Human Osteoblast-like Cells

Purpose: To investigate the effect of epigallocatechin-3-gallate (EGCG) on bone metabolism and osteoblastic activity. Methods: MG-63 human osteoblast-like cells were treated with varied concentrations of EGCG. Alkaline phosphatase (ALP) activity and matrix mineralization assays were carried out on the treated and untreated MG-63 human osteoblast-like cells. Beta-catenin mRNA level was determined by quantitative real-time polymerase chain reaction (q-PCR). Results: The results showed that EGCG treatment significantly increased ALP and mineralization activities at concentrations of 15 and 30 μM, in a dose-dependent manner. Furthermore, EGCG treatment significantly increased beta-catenin mRNA expression by 70.7 ± 11.0 and 126.7 ± 35.1 %, respectively, at EGCG concentration of 15 and 30 μM. In addition, the stimulating effect of EGCG treatment on ALP activity was abolished by co-treatment with ICI 182,780, an antagonist of estrogen receptor (ER). Again, the increase in beta-catenin MRNA, when treated with EGCG, was inhibited by co-treatment with ICI 182,780. Conclusion: EGCG promotes osteoblastic activity in human osteoblast-like cells, by Wnt signaling through estrogen receptor (ER) pathway. Keywords: Epigallocatechin-3-gallate, Osteoporosis, Osteoclast, Proliferation, Estrogen receptor

SPECT/CT demonstrates the osseointegrative response of a stemless shoulder prosthesis

This study evaluates bone remodeling processes in the proximal humerus induced by the implantation of a stemless shoulder prosthesis with regard to time of response and type and extent of bone turnover. Twenty-eight patients with primary osteoarthritis of the shoulder undergoing a stemless shoulder arthroplasty were prospectively evaluated. The local metabolic bone activity in 5 regions of interest (ROIs 1-5) around the implant and in 1 reference region (ROI ref.) in the humeral diaphysis was analyzed after the application of technetium Tc 99m DPD using single-photon emission computed tomography integrated with multidetector computed tomography (SPECT/CT). The study cohort was divided into 4 groups according to the timing of the most recent follow-up appointment to evaluate the primary osseointegrative response after surgery. The bone uptake values were expressed in target (ROIs 1-5) to nontarget (ROI ref.) ratios. No difference within the 4 subgroups with respect to the time of local metabolic bone activity inthe ROIs was found at 90days after surgery. The highest initial metabolic activity and most temporal modifications were found in ROI 1, which was localized in the superior segment of the stem. SPECT/CT data suggest that the primary osseointegration of a stemless shoulder prosthesis is almost completed 3months after implantation. Variations in metabolic activity pattern in the ROIs during follow-up may be caused by different loading conditions of the bone.

Abstract A109: Radium-223 dichloride inhibits tumor growth and tumor-induced bone growth in osteoblastic prostate cancer models

Abstract Radium-223 dichloride (radium-223), an alpha particle-emitting calcium-mimetic, improves overall survival in prostate cancer patients with symptomatic bone metastases. We have defined radium-223 mode-of-action and efficacy in two clinically relevant prostate cancer xenograft models demonstrating PSA expression and osteoblastic growth upon intratibial inoculation of cancer cells. Immunocompromised male mice were inoculated with human LNCaP or patient-derived LuCaP 58 prostate cancer cells in the intratibial compartment and subsequently stratified into treatment groups based on lesion grade and/or serum PSA levels. Radium-223 (300 kBq/kg) or vehicle was administered intravenously, two times at 4-week intervals during the experiment. X-rays and serum samples were obtained biweekly and at sacrifice. Soft tissue tumors were examined macroscopically at sacrifice and tissue samples were collected and processed for γ-counter measurements, micro-CT, autoradiography and histology. Radium-223 treatment inhibited tumor-induced osteoblastic bone growth as indicated by reduced bone volume and surface in LNCaP and LuCaP 58 prostate cancer mouse models. In addition, radium-223 treatment suppressed metabolic activity in bone as evidenced by decreased number of osteoblasts and osteoclasts relative to bone surface and reduced levels of the bone formation marker PINP. Radium-223 resulted in lower PSA values as early as two weeks after the first dose, indicating constrained tumor growth following treatment. This phenomenon was further supported by reduced total bone lesion tissue and tumor area in LNCaP and LuCaP 58 models and increased percentage of necrotic tumor area in the LuCaP 58 model in radium-223-treated mice as compared to vehicle-treated mice. Moreover, DNA double-strand breaks were increased in cancer cells 24 hours post radium-223 treatment in the LuCaP 58 model providing further evidence of anti-tumor effects. Radium-223-treated mice exhibited less visceral metastases in the LuCaP 58 model (not significant). Based on autoradiography, radium-223 was deposited in the intratumoral bone matrix and in conjunction with osteoblasts in osteoblastic metastases. Our results demonstrate that radium-223 dichloride is successfully incorporated into the intratumoral bone matrix and inhibits tumor growth in both cell line- and patient-derived osteoblastic prostate cancer metastasis models. Given the α-particle range of 50-80 μm, potent radiation effects on the tumor microenvironment are evident whereas relevant effects on the more distant bone marrow are not expected. Taken together, radium-223 therapy exhibits a dual mode-of-action that impacts tumor growth and tumor-induced bone reaction, both important players in the destructive vicious cycle of osteoblastic bone metastasis in prostate cancer. Citation Format: Mari I. Suominen, Katja M. Fagerlund, Dominik Mumberg, Karl Ziegelbauer, Sanna-Maria Käkönen, Jussi M. Halleen, Robert L. Vessella, Arne Scholz. Radium-223 dichloride inhibits tumor growth and tumor-induced bone growth in osteoblastic prostate cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A109.

Bone metabolism induced by denture insertion in positron emission tomography

18F-fluoride positron emission tomography (PET) can identify subtle functional variation prior to the major structural change detectable by X-ray. This study aims to investigate the mechanobiological bone reaction around the abutment tooth and in the residual ridge, induced by insertion of removable partial denture (RPD) within two different groups of patients: patients without denture experience (Group 1) and patients with denture experience before (Group 2), using 18F-fluoride PET imaging technique. 18F-fluoride PET/computerised tomography (CT) scan was performed to examine the bone metabolic change in mandible before and after the RPD treatment. Region of interests (ROIs) were placed in alveolar bone around abutment tooth and in residual bone beneath the RPD. Standardised uptake value (SUV), reflecting the accumulation of 18F-fluoride, was measured for each ROI. In all subjects of Group 1, SUVs after insertion were higher than before in both alveolar bone and residual bone, while there was less significant change in SUV in subjects of Group 2. This study demonstrated using longitudinal 18F-fluoride PET scans to effectively examine the bone metabolic change in mandible induced by occlusal loading after RPD insertion. Using this technique, within the six subjects in this study, it was shown that bone metabolism around abutment tooth and residual ridge increased after RPD insertion in case of first-time denture user, while there was no big change in the patient with experience of denture before. This study revealed the effectiveness of applying PET to evaluate bone metabolic activity as mechanobiological reaction.

Normobaric interval hypoxic training in the treatment of fractures of the trochanteric region of the femur

Trochanteric fractures of the femur amount from 2 to 13.5 % of all fractures of bones and 28–37,5 % of femoral fractures, and unsatisfactory outcomes of their treatment — from 16 to 40 %. Negative impact on the outcome of the treatment have osteopo­rosis, immunosuppressive conditions associated with long-term therapy, hormonal therapy, diabetes and thyrotoxicosis. Objec­tive : To improve outcomes of treatment and rehabilitation in patients with fractures of the trochanteric region of the femur by means of the method of normobaric interval hypoxic train­ing (IHT) and to study its effect on bone metabolism. Methods : In the period from 2012 to 2015 at the Clinic of the Chair of general surgery UzhNU we treated trochanteric fractures of the femur in 34 patients. The first group included patients in which we performed IHT with gas mixture of 12 % oxygen; the sec­ond one consisted of patients with thyrotoxicosis who received similar treatment, the control group consisted of 7 patients with these fractures who renounced IHT. Patients were examined by a laboratory and clinical methods. Results : The best physical activity was observed in the patients of the first group. In the second group start physical activity was low but we observed its impetious development. In the control group physical activity comparing to the first two groups increased slowly. On follow-up examination after 1 month it was noted increasing of calcium level in the serum of all groups of patients but it was more in the second one. Phosphorus level decreased in the first and control groups, and it incresed in the second group. Levels of osteocalcin and alkaline phosphatase increased and what is more in the first two groups indeces were significantly higher comparing to the control group. Conclusions : Using of IHT leads to increasing in physical activity and contributes to the process of rehabilitation. After IHT one may observe an improvement of indeces of bone metabolism activity.