Analysis Of Bone Resorption Research Articles

Metabolomic analysis of bone resorption in vitro provides new insights into osteoclastic action and reveals novel biomarkers

Metabolomic analysis of bone resorption in vitro provides new insights into osteoclastic action and reveals novel biomarkers

Evaluation of RANK induced periodontitis in rats previously exposed to Cyclosporine A

The aim of this study was to investigate the effect of previous exposure to CsA on the expression of RANK and bone loss in experimental periodontitis induced in rats. Forty rats were divided into four groups as follows: Control (CON); Cyclosporine A (CsA), with daily doses of 10 mg/Kg of CsA; Ligature (LIG), with a ligature around the upper right second molar on day 30; and Ligature + CsA (CsAL). Sixty days later, the animals were sacrificed and samples removed for histomorphometric and immunohistochemical analysis of bone resorption, bone density and RANK expression. There was no significant influence of bone resorption on the application of CsA. LIG Group (735.88 ± 121.82) had significantly higher bone resorption (p = 0.01) than CON Group (569.13 ± 89.76), and CsAL Group (759.38 ± 198.23) also had significantly higher bone resorption (P = 0.001) than CsA Group (410.90 ± 105.95). Bone density in the CsA Group (87.49 ± 4.07) was lower than that of CON Group (92.42 ± 2.27) and similar to that of LIG Group (91.85 ± 3.91). CsAL Group (79.41 ± 3.81) showed the lowest density compared to the other groups. RANK did not differ between the groups. The prior exposure to CsA had no influence on the expression of RANK or bone resorption.

Abstract P3-06-04: 4EVER: The impact of mTOR inhibition on bone health in postmenopausal women with hormone receptor positive (HR+) advanced breast cancer treated with everolimus (EVE) in combination with exemestane (EXE)

Abstract Introduction: The BOLERO-2 study showed significant doubling of PFS benefit with the addition of EVE to EXE in postmenopausal women with hormone receptor–positive advanced breast cancer progressing after non-steroidal aromatase inhibitor (NSAI) therapy. The BOLERO-2 bone sub study indicated an immediate positive influence of EVE on bone health after 6 and 12 weeks of treatment. To further investigate the longer term effect of mTOR inhibition on bone health, we included this exploratory objective in the phase IIIb, multi-center, open label study 4EVER for postmenopausal women with hormone receptor positive advanced breast cancer treated with EVE +EXE. Methods: From May 2012 to November 2012 bone biomarker samples of 247 postmenopausal women with metastatic or locally advanced, hormone receptor positive, HER2 negative breast cancer refractory to NSAI were collected within this phase IIIb study. Here, we report the results of the planned exploratory analysis of biomarkers of bone turnover. The objective of the exploratory biomarker analysis of bone resorption and formation was to assess the effect of EVE on changes of biomarker levels of bone metabolism (CTX, P-I-NP, osteocalcin, vitamin D, testosterone, estradiol, DHEAS, SHBG, PTH,TSH and FSH) from day 1 to weeks 4, 12 and 24 to confirm potential protective effects of EVE on bone via inhibition of bone osteoclast resorption. Descriptive statistics were used to summarize the single bone resorption markers by visit and difference to baseline. Results: Trial data base lock will occur in late June 2014, therefore, the final biomarker analysis of bone resorption and formation and their influence on ORR, PFS and safety will be presented at SABCS 2014. The preliminary analysis on the changes of bone marker levels from baseline to week 24 included 247 patients. The measured changes from baseline to week 24 in biomarker levels revealed increasing levels of testosterone, DHEAS and FSH, while SHBG and PTH were significantly decreased from baseline to week 24. The combination of EVE to EXE resulted in stabilization of bone health as documented by a decrease of absolute P-I-NP levels at week 24 compared to baseline as well as a stabilization of bone resorption as measured by CTX. Conclusion: Our first preliminary results (data cut off 15 Nov 2013) on the changes in bone marker levels supported the hypothesis of EVE having direct impact on bone health, suggesting a decrease of bone turnover and a reversal of the increase in bone resorption associated with aromatase inhibitor therapy. The final analysis of the 4EVER sub study on bone marker levels in correlation with the efficacy data will provide more detailed insights into possible benefits of the combination of EVE plus EXE. Citation Format: Peyman Hadji, Hans Tesch, Oliver Stoetzer, Thomas Decker, Christian M Kurbacher, Romy Neumeister, Frederik Marmé, Andreas Schneeweiss, Christoph Mundhenke, Andrea Distelrath, Peter A Fasching, Micheal P Lux, Diana Lüftner, Wolfgang Janni, Mathias Muth, Julia Kreuzeder, Claudia Weiss, Eva-Maria Grischke. 4EVER: The impact of mTOR inhibition on bone health in postmenopausal women with hormone receptor positive (HR+) advanced breast cancer treated with everolimus (EVE) in combination with exemestane (EXE) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-04.

PO59 EFFICACY AND SAFETY OF EVEROLIMUS PLUS EXEMESTANE COMBINATION THERAPY VERSUS MONOTHERAPY WITH EVEROLIMUS OR CAPECITABINE IN HR+, HER2− BREAST CANCER: A MULTI-CENTER, OPEN-LABEL, PHASE 2 TRIAL BOLERO-6

benefit in patients who received EVE plus EXE as first-line therapy in the advanced setting. The ongoing BOLERO-4 trial is investigating the efficacy and safety of EVE plus letrozole (LET) in the first-line ER+ advanced BC setting, as well as the potential benefits of continuing EVE plus endocrine therapy beyond initial disease progression. Methods: BOLERO-4 (NCT01698918) is a multicenter, open-label, single-arm, phase 2 trial that is enrolling postmenopausal women with ER+ metastatic or locally advanced unresectable BC who have received no prior therapy for advanced disease. Patients will receive EVE (10 mg/ day) plus LET (2.5 mg/day) until first disease progression. Thereafter, patients will have the option to receive EVE plus EXE (25 mg/day) until further disease progression, or unacceptable toxicity; EVE plus EXE will not be offered to patients who discontinue therapy because of unacceptable toxicity in the first-line metastatic BC setting. The primary endpoint is PFS in the first-line setting. Secondary endpoints include PFS in the second-line setting, response rate, overall survival, and safety. The effectiveness of a dexamethasone oral rinse to reduce the severity and/ or duration of stomatitis will also be evaluated. Exploratory endpoints include biomarker analysis of bone resorption and formation and evaluation of additional biomarkers for further elucidation of disease characteristics. Results: The trial opened for enrollment in Europe, Asia, and the Americas in the first quarter of 2013. The trial plans to enroll a total of 200 patients during the 18-month enrollment period and is estimated to be completed in the fourth quarter of 2015. Conclusions: BOLERO-4 will provide insight regarding the efficacy and safety of first-line EVE plus LET in the metastatic BC setting as well as the efficacy of continuing EVE-based therapy following initial disease progression.

Analysis of bone resorption after secondary alveolar cleft bone grafts before and after canine eruption in connection with orthodontic gap closure or prosthodontic treatment

Purpose: We sought to analyze the success rate of secondary alveolar cleft bone grafts before and after canine eruption in connection with orthodontic gap closure or gap opening. Patients and Methods: Sixty-eight secondary alveolar cleft bone grafts with iliac crest spongiosa were carried out in 57 patients (mean age, 9 years; age range, 8 to 11 years) with 11 bilateral and 46 unilateral clefts of the lip, alveolus, or palate. Gap closures were carried out after 53 bone grafts (78%), and gap openings with subsequent dental implants were carried out with 15 bone grafts (22%). The parameters acquired radiologically (orthopantomograms) at the time of the surgery and the follow-up examination (mean age, 3 years; age range, 7 months to 9 years) were 1) bone resorption in relation to the interdental height of the alveolar process in the vicinity of the cleft and 2) root growth of the teeth in the vicinity of the cleft. The statistically significant differences ( P < .05) were monitored with a software program. Resorption grades I and II (>50% of the interalveolar bone height) were considered to be a success. Results: Resorption was grade I in 69%, grade II in 19%, grade III in 10%, and grade IV in 1% of cases. Thus, the overall success rate was 88%. At the time of the osteoplasty, the root growth of the tooth in the immediate vicinity of the cleft was fully completed in 27 teeth (39%), three-quarters completed in 23 teeth (26.5%), and semicompleted in 18 teeth (33.8%). Twelve teeth (18%) in the vicinity of the cleft (lateral incisors/canine) remained unerupted and displaced after the surgery. It was necessary to expose unerupted teeth surgically to reposition them orthodontically. The resorption losses were significantly lower with gap closures than with gap openings ( P < .001). However, bone grafts performed before canine eruption were largely carried out with the objective of orthodontic gap closure, in contrast to the bone grafts that were carried out after canine eruption ( P < .02). Conclusion: Gap closures provide more favorable results than do gap openings in regard to resorption. Controlled dental eruptions or orthodontic gap closures reduce the graft resorption. The exact timing of surgery proved to be only a secondary consideration.

ウシ骨基質由来骨吸収因子の部分精製とその性質に関する研究

The mechanism of bone remodeling has been investigated by many researchers. However, little is known about the role of the local factors which exist in the bone matrix. In this study, the author attempted to purify the bone-resorbing factor from the bovine bone matrix and to find its role in bone remodeling. The demineralized bovine bone matrix was extracted with 4M Gdn-HCl and the bone-resorbing factor was purified by means of heparin affinity and gel filtration chromatography. The analysis of bone resorption was carried out by the measurement of the released 45Ca from the pre-labeled mouse calvariae. The results of this study were that the bone-resorbing factor in the bone matrix was suggested to be a heat-stable glycoprotein having a molecular size higher than 150,000, which stimulated osteoclastic bone resorption via a prostaglandin-mediated mechanism.

口腔へん平上皮癌細胞の産生する骨吸収促進因子に関する研究

In order to study the mechanisms of bone resorption induced by squamous cell carcinoma (SCC), the author analyzed bone resorbing substances released into the medium by an established SCC cell line Ca 9-22 PF. This cell line was derived from human gingival SCC and cultured in a protein-free medium. The analysis of bone resorption was carried out by the measurement of released 45Ca from pre-labeled mouse calvariae.The results were as follows:1) A dose dependent stimulation of bone resorbing activity was found by adding the cultured supernatant of Ca 9-22 PF cells.2) The bone resorption was due to the formation and activation of osteoclasts, because the stimulation was found only in live calvariae and was reduced by calcitonin treatment.3) About half of the 45Ca release stimulating effect was inhibited by indomethacin, an inhibitor of prostaglandin production.4) When the conditioned medium was fractionated by gel chromatography, the bone resorbing activity was found in multiple fractions. The molecular size in each fraction having a bone resorbing activity was 12000-16000, 16000-20000, 35000 and larger than 50000, respectively.5) The bone resorbing substance having the MW 12000-16000 was identified as IL-la by a specific radioimmunoassay and neutralization by antibody.6) The substance having the MW 16000-20000 was identified as PTHrP by stimulation of cAMP production in ROS 17/2 cells and by the Northern blot hybridization.7) The substance having the MW 35000 was identified as PDGF-AA by stimulation of proliferation in BALB 3 T 3 fibroblasts and neutralization by antibody.8) In addition to IL-1α, IL-1 β, PTHrP and PDGF-AA, the substances responsible for the stimulated bone resorption were identified as TGFα and TGFβ by the Northern blot analysis.9) The conditioned media of other SCC cell lines, HSC-2 PF, HSC-3 PF, HSC-4 PF, A 431 PF and ZAPF, also showed bone resorbing activity similar to Ca 9-22 PF. Bone resorbing factors were also identified to be about the same as those produced in Ca 9-22 PF by the Northern blot hybridization.In conclusion, it was speculated that the synergistic action of these substances produced by SCC are responsible for a marked increase in osteoclastic bone resorption and malignancy associated hypercalcemia.