Levels Of Resorption Research Articles

Markers of Bone Formation and Resorption Identify Subgroups of Patients with Clinical Knee Osteoarthritis Who Have Reduced Rates of Cartilage Loss

To determine whether serum markers of bone formation and resorption, used individually or in combination, can be used to identify subgroups who lose cartilage volume at different rates over 2 years within a knee osteoarthritis (OA) population. Changes in cartilage volume over 2 years were measured in 117 subjects with knee OA using magnetic resonance imaging. We examined relationships between change in cartilage volume and baseline serum markers of bone formation [intact N-terminal propeptide of type I procollagen (PINP) and osteocalcin] and resorption [N-telopeptide of type I collagen (NTX-I), C-telopeptide of type I collagen (CTX-I), and C-telopeptide of type I collagen (ICTP). The baseline markers of bone formation, PINP and osteocalcin (p = 0.02, p = 0.01, respectively), and the baseline markers of bone resorption, CTX-I and NTX-I (p = 0.02 for both), were significantly associated with reduced cartilage loss. There were no significant associations between baseline ratios of bone formation to resorption markers and cartilage loss. However, when subjects were divided into subgroups with high or low bone formation markers (based on levels of marker >or= mean or < mean for the population, respectively), in the subgroup with high PINP there was a significant association between increasing bone resorption markers CTX-I and NTX-I and reduced cartilage loss (p = 0.02, p = 0.001, respectively). Similarly, in the subgroup with high osteocalcin, there was a significant association between increasing CTX-I and NTX-I and reduced cartilage loss (p = 0.02, p = 0.003, respectively). In contrast, in subgroups with low bone formation markers, no significant associations were obtained between markers of bone resorption and cartilage loss. Overall, the results suggest that higher bone remodeling (i.e., higher serum levels of bone formation and resorption) is associated with reduced cartilage loss. Considering markers of bone formation and resorption together, it is possible to identify subgroups within the OA population who have reduced rates of cartilage loss.

Effect of IL‐1β, PGE2, and TGF‐β1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts

The RANKL/RANK/OPG pathway is essential for bone remodeling regulation. Many hormones and cytokines are involved in regulating gene expression in most of the pathway components. Moreover, any deregulation of this pathway can alter bone metabolism, resulting in loss or gain of bone mass. Whether osteoblasts from osteoporotic and nonosteoporotic patients respond differently to cytokines is unknown. The aim of this study was to compare the effect of interleukin (IL)-1beta, proftaglandin E(2) (PGE(2)), and transforming growth factor-beta1 (TGF-beta1) treatments on OPG and RANKL gene expression in normal (n = 11) and osteoporotic (n = 8) primary osteoblasts. OPG and RANKL mRNA levels of primary human osteoblastic (hOB) cell cultures were assessed by real-time PCR. In all cultures, OPG mRNA increased significantly in response to IL-1beta treatment and decreased in response to TGF-beta1 whereas PGE(2) treatment had no effect. RANKL mRNA levels were significantly increased by all treatments. Differences in OPG and RANKL responses were observed between osteoporotic and nonosteoporotic hOB: in osteoporotic hOB, the OPG response to IL-1beta treatment was up to three times lower (P = 0.009), whereas that of RANKL response to TGF-beta1 was five times higher (P = 0.002) after 8 h of treatment, as compared with those in nonosteoporotic hOBs. In conclusion, osteoporotic hOB cells showed an anomalous response under cytokine stimulation, consistent with an enhanced osteoclastogenesis resulting in high levels of bone resorption.

Performance of calcium deficient hydroxyapatite–polyglycolic acid composites: an in vitro study

The strategic incorporation of bioresorbable polymeric additives to calcium-deficient hydroxyapatite cement may provide short-term structural reinforcement and modify the modulus to closer match bone. The longer-term resorption properties may also be improved, creating pathways for bone in-growth. The aim of this study was to investigate the resorption process of a calcium phosphate cement system containing either in polyglycolic acid tri-methylene carbonate particles or polyglycolic acid fibres. This was achieved by in vitro aging in physiological conditions (phosphate buffered solution at 37 degrees C) over 12 weeks. The unreinforced CPC exhibited an increase in compressive strength at 12 weeks, however catastrophic failure was observed above a critical loading. The fracture behaviour of cement was improved by the incorporation of PGA fibres; the cement retained its cohesive structure after critical loading. Gravimetric analysis and scanning electron microscopy showed a large proportion of the fibres had resorbed after 12 weeks allowing for the increased cement porosity, which could facilitate cell infiltration and faster integration of natural bone. Incorporating the particulate additives in the cement did not provide any mechanism for mechanical property augmentation or did not demonstrate any appreciable level of resorption after 12 weeks.

CTX Biochemical Marker of Bone Metabolism. Is It a Reliable Predictor of Bisphosphonate-Associated Osteonecrosis of the Jaws After Surgery? Part II: A Prospective Clinical Study

Biochemical markers of bone metabolism have been used in medicine to evaluate and provide treatment to patients with metabolic bone diseases, such as osteoporosis. Serum cross-linked C-telopeptide of type I collagen (CTX) is a marker of osteoclast activity and is used to assess the level of bone resorption. Recently, in oral and maxillofacial surgery, it was proposed that the levels of serum CTX may predict the subsequent risk of developing osteonecrosis of the jaws (ONJ) after oral surgery procedures for patients taking oral bisphosphonates (BPs). The goal of this study was to determine whether this specific serum marker of bone resorption could preoperatively predict the risk of developing ONJ from oral BPs.We hypothesized that there is no clinical correlation between the observed preoperative serum CTX values and the risk of developing ONJ. The authors examine the scientific basis (validity) of the morning fasting serum CTX test in 163 consecutive patients who underwent various oral surgery procedures in the office. The authors also review the laboratory test results and the recommended protocol based on the test values. One hundred sixty-three patients (mean age, 75.9 years) were divided into 2 groups. Group I was the control group that consisted of 109 patients taking oral BPs who did not take the CTX test preoperatively. Group 2 consisted of 54 patients taking BPs and who elected to have the CTX test performed to assess their level of risk of developing ONJ, preoperatively. Both groups of patients were observed for a period of 8 weeks for signs and symptoms of BP-associated ONJ after surgery. The clinical data at 8 weeks and beyond revealed that there was no evidence of BP-associated ONJ in all participants. We conclude that the serum CTX is not a valid preoperative test to accurately assess the level of risk of developing ONJ and is not indicated in the oral surgery patient.

Rapid and sustained improvement in bone and cartilage turnover markers with the anti–interleukin‐6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from a substudy of the multicenter double‐blind, placebo‐controlled trial of tocilizumab in inadequate responders to methotrexate alone

To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX. Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24. TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders. TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate-to-severe RA.

CTX Biochemical Marker of Bone Metabolism. Is it a Reliable Predictor of Bisphosphonate-Associated Osteonecrosis of the Jaws After Surgery? Part I: Biological Concepts With a Review of the Literature

Biochemical markers of bone metabolism have been used in medicine to evaluate and provide treatment to patients with metabolic bone diseases, such as osteoporosis. Serum cross-linked C-telopeptide of type I collagen is a marker of osteoclast activity and is used to assess the level of bone resorption. Recently, in oral and maxillofacial surgery, it was proposed that the levels of serum cross-linked C-telopeptide of type I collagen may predict the subsequent risk of developing osteonecrosis of the jaws after oral surgery procedures for patients taking oral bisphosphonates. The astute clinician must critically review the scientific literature and must decide if biochemical markers of bone resorption are of benefit in managing the oral surgery patient on bisphosphonates.

Correlation of Serum Leptin Level with Bone Mineral Density and Bone Turnover Markers in Chinese Adolescent Dancers

To investigate plasma leptin concentrations in adolescent female dancers and to determine whether leptin has some effects on their bone mineral density (BMD) and bone turnover markers. Sixty dancers aged 15-17 years and 77 healthy controls were enrolled in the study. Bone mineral density (BMD) and body composition were detected by dual energy X-ray absorptiometry. Serum leptin concentrations were measured by radioimmunoassay (RIA). Two bone turnover markers, bone-specific alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase(TRACP), were determined by ELISA. The dancers had a lower fat mass and a lower leptin level than the controls, while they had a relatively higher BMD of the total body and legs after adjustment for BMI and age. The levels of bone resorption and formation of markers were higher in the dancers than in the controls. Leptin was positively correlated with BMI, body weight, fat mass, and percentage of body fat. In dancers, Leptin was positively correlated with the BMD of the total body and the left leg. However, after adjustment for BMI, no correlation of serum leptin concentrations with BMD values was found in either dancers or controls. Nor correlation was found between leptin and bone turnover markers after adjustment for BMI. The leptin profile is different between the controls and the dancers with a lower BMI and a lower fat mass. Circulating plasma leptin level depends on BMI and is not a direct determinant of BMD in Chinese adolescent dancers.

Simulation of vertebral trabecular bone loss using voxel finite element analysis

Trabecular bone loss in human vertebral bone is characterised by thinning and eventual perforation of the horizontal trabeculae. Concurrently, vertical trabeculae are completely lost with no histological evidence of significant thinning. Such bone loss results in deterioration in apparent modulus and strength of the trabecular core. In this study, a voxel-based finite element program was used to model bone loss in three specimens of human vertebral trabecular bone. Three sets of analyses were completed. In Set 1, strain adaptive resorption was modelled, whereby elements which were subject to the lowest mechanical stimulus (principal strain) were removed. In Set 2, both strain adaptive and microdamage mechanisms of bone resorption were included. Perforation of vertical trabeculae occurred due to microdamage resorption of elements with strains that exceeded a damage threshold. This resulted in collapse of the trabecular network under compression loading for two of the specimens tested. In Set 3, the damage threshold strain was gradually increased as bone loss progressed, resulting in reduced levels of microdamage resorption. This mechanism resulted in trabecular architectures in which vertical trabeculae had been perforated and which exhibited similar apparent modulus properties compared to experimental values reported in the literature. Our results indicate that strain adaptive remodelling alone does not explain the deterioration in mechanical properties that have been observed experimentally. Our results also support the hypothesis that horizontal trabeculae are lost principally by strain adaptive resorption, while vertical trabeculae may be lost due to perforation from microdamage resorption followed by rapid strain adaptive resorption of the remaining unloaded trabeculae.

Nanoporous TiO2 Thin Film on Titanium Oral Implants for Enhanced Human Soft Tissue Adhesion: A Light and Electron Microscopy Study

Previous experimental studies have demonstrated direct soft tissue attachment for nanoporous titanium dioxide (TiO(2) ) thin film on implants, while implants without TiO(2) thin film have not shown this capability. The aims were to evaluate and compare TiO(2) surface-modified experimental microimplants with unmodified microimplants with respect to tissue interaction of the human oral mucosa evaluated by light microscopy on ground sections and semithin sections and transmission electron microscopy on ultrathin sections, and to characterize the inflammatory response and the level of the marginal bone resorption. The study was a single-center, randomized, comparative, clinical investigation with intrasubject comparison of implants with and without TiO(2) thin film in 15 patients. Two comparator microimplants showed mild erythema and expulsion of fluids. The surrounding tissues around all test implants were clinically healthy. The oral mucosa in contact with the abutment part of the microimplant was 72% for the test implants and 48% for the comparator implants, a statistically significant difference (p =.0268). No statistically significant difference was found in other histological variables. The marginal bone loss in 14 weeks was 0.5 mm for the stable test (n = 11) and 1.7 mm for the stable comparator implants (n = 9; p = .0248). The nanoporous TiO(2) surface modification has potential clinical benefits because of increased adherence of soft tissue and possible reduced bone resorption.

Physical properties of root cementum: Part 12. The incidence of physiologic root resorption on unerupted third molars and its comparison with orthodontically treated premolars: A microcomputed-tomography study

INTRODUCTION Root resorption can occur as a physiologic or a pathologic process, and it is an unwanted side effect of orthodontic treatment. No baseline studies have assessed this phenomenon in the absence of force variables such as mastication, parafunction, and soft-tissue pressure. In this study, we investigated the incidence and quantitative value of root resorption on unerupted third molars with normal development using microcomputed tomography. Nine unerupted, nonimpacted maxillary third molars were collected from 6 patients (ages, 19.47 plus /minus 1.89 years). The teeth were examined with microcomputed tomography and compared with teeth from other studies. (The other teeth had been treated with buccally directed light [25 g] or heavy [225 g] forces applied for 28 days, or light [25 g] or heavy [225 g] intrusion forces for 28 days.) Imaging and volumetric analyses showed resorption craters in many locations and with various magnitudes. Analysis of variance was completed by position (P = 0.04), surface (P = 0.07), height (P = 0.045), left or right side of the mouth (P = 0.85), and subject (P = 0.70). The midroot region on the mesial surfaces of the third molars, near the root structure of adjacent erupted second molars, had the greatest statistical significance. When compared with crater volumes of fully erupted first premolars, we found that the unerupted third molar sample had a slightly greater cube root volume per tooth than the erupted first premolars not subjected to orthodontic force and a similar cube root volume per tooth as did first premolars subjected to light (25 g) buccal and intrusive orthodontic forces. Root resorption as a consequence of orthodontic treatment might be added to a baseline level of root resorption. The elevated results suggest that resorption might occur as part of hard-tissue remodeling and turnover, eruption, or transmission of masticatory forces through the dentition to the alveolar bone.

Editor's Summary and Q&A: Physical properties of root cementum: Part 12. The incidence of physiologic root resorption on unerupted third molars and its comparison with orthodontically treated premolars: A microcomputed-tomography study

<h3>Introduction</h3> Root resorption can occur as a physiologic or a pathologic process, and it is an unwanted side effect of orthodontic treatment. No baseline studies have assessed this phenomenon in the absence of force variables such as mastication, parafunction, and soft-tissue pressure. In this study, we investigated the incidence and quantitative value of root resorption on unerupted third molars with normal development using microcomputed tomography. <h3>Methods</h3> Nine unerupted, nonimpacted maxillary third molars were collected from 6 patients (ages, 19.47 ± 1.89 years). The teeth were examined with microcomputed tomography and compared with teeth from other studies. (The other teeth had been treated with buccally directed light [25 g] or heavy [225 g] forces applied for 28 days, or light [25 g] or heavy [225 g] intrusion forces for 28 days.) <h3>Results</h3> Imaging and volumetric analyses showed resorption craters in many locations and with various magnitudes. Analysis of variance was completed by position (<i>P</i> = 0.04), surface (<i>P</i> = 0.07), height (<i>P</i> = 0.045), left or right side of the mouth (<i>P</i> = 0.85), and subject (<i>P</i> = 0.70). The midroot region on the mesial surfaces of the third molars, near the root structure of adjacent erupted second molars, had the greatest statistical significance. When compared with crater volumes of fully erupted first premolars, we found that the unerupted third molar sample had a slightly greater cube root volume per tooth than the erupted first premolars not subjected to orthodontic force and a similar cube root volume per tooth as did first premolars subjected to light (25 g) buccal and intrusive orthodontic forces. <h3>Conclusions</h3> Root resorption as a consequence of orthodontic treatment might be added to a baseline level of root resorption. The elevated results suggest that resorption might occur as part of hard-tissue remodeling and turnover, eruption, or transmission of masticatory forces through the dentition to the alveolar bone.

Combinatory Effects of Androgen Receptor Deficiency and Hind Limb Unloading on Bone

Male sex hormones play a critical role in regulation of bone metabolism. In male mice lacking androgen receptor (AR), osteopenia and high turnover state in bone remodeling have been reported. However, androgen receptor's role in disuse-induced osteopenia is not known. Therefore, we examined the effects of AR deficiency on unloading-induced bone loss. Wild type or androgen receptor deficient mice (ARKO) were subjected to hind limb unloading (HU) or normal housing (Control). The groups of mice were as follows; wild type control mice (Group WT-Cont), ARKO control mice (Group ARKO-Cont), wild type HU mice (Group WT-HU), and ARKO-HU mice (Group ARKO-HU). HU reduced cancellous bone mass in ARKO (ARKO-HU) by about 70% compared to ARKO-Cont and this reduction rate was over two-fold more than that of wild type (WT-HU) (reduction by less than 30% compared to WT-Cont). Combination of ARKO and HU (ARKO-HU) resulted in the least levels of cortical bone mass and bone mineral density among the four groups. ARKO-HU group indicated the highest levels of systemic bone resorption marker, deoxypyridinoline. Osteoclast development levels in the cultures in ARKO-HU derived bone marrow cells were the highest among the four groups. These data suggest that combination of androgen receptor deficiency and hind limb unloading results in exacerbation of disuse-induced osteopenia due to the enhanced levels of bone resorption.

Intracanal bisphosphonate does not inhibit replacement resorption associated with delayed replantation of monkey incisors

Progressive replacement resorption following delayed replantation of avulsed teeth has proved to be an intractable clinical problem. A wide variety of therapeutic approaches have failed to result in the predictable arrest of resorption, with a good long-term prognosis for tooth survival. Bisphosphonates are used in the medical management of a range of bone disorders and topically applied bisphosphonate has been reported to inhibit root resorption in dogs. This study evaluated the effectiveness of a bisphosphonate (etidronate disodium) as an intracanal medicament in the root canals of avulsed monkey teeth, placed before replantation after 1 h of extraoral dry storage. Incisors of six Macaca fascicularis monkeys were extracted and stored dry for 1 h. Teeth were then replanted after canal contamination with dental plaque (negative control) or after root canal debridement and placement of etidronate sealed in the canal space. A positive control of calcium hydroxide placed 8-9 days after replantation was also included. All monkeys were sacrificed 8 weeks later and block sections were prepared for histomorphometric assessment of root resorption and periodontal ligament status. Untreated teeth showed the greatest extent of root resorption (46% of the root surface), which was predominantly inflammatory in nature. Calcium hydroxide treated teeth showed the lowest overall level of resorption (<30% of the root surface), while the bisphosphonate-treated group was intermediate (39%). Ankylosis, defined as the extent of the root surface demonstrating direct bony union to both intact and resorbed root surface, was the lowest in the untreated control group (15% of the root surface), intermediate in the calcium hydroxide group (27%) and the highest in the bisphosphonate group (41%). Bony attachment to the tooth root was divided approximately equally between attachment to intact cementum and to previously resorbed dentin. Overall, bisphosphonate resulted in a worse outcome than calcium hydroxide in terms of both root resorption and ankylosis.

Targeted Disruption of the CXCL12/CXCR4 Axis Inhibits Osteolysis in a Murine Model of Myeloma-Associated Bone Loss

The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)-mediated skeletal destruction. We have previously shown that elevated plasma levels of PC-derived CXCL12 are associated with presence of X-ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and betaCrossLaps, a marker of bone loss, were measured. A strong correlation between levels of CXCL12 and OC-mediated bone resorption was identified. To confirm the OC-activating potential of MM PC-derived CXCL12 in vivo, we established a model of MM-mediated focal osteolysis, wherein MM PC lines, such as RPMI-8226, were injected into the tibias of nude mice. Implanting RPMI-8226 gave rise to osteolytic lesions proximal to the tumor, resulting in a 5% decrease in bone volume (BV) compared with vehicle control. Importantly, bone loss was significantly inhibited with systemic administration of the CXCL12/CXCR4 antagonist T140. Furthermore, implanting CXCL12-overexpressing RPMI-8226 cells resulted in a 13% decrease in BV and was associated with increased OC recruitment proximal to the tumor, increased serum matrix metalloproteinase activity, and increased levels of collagen I degradation products. These findings confirm our hypothesis that MM PC-derived CXCL12 stimulates the recruitment and activity of OC, thereby contributing to the formation of MM osteolytic lesions.

Hormones and osteoporosis update. Calcitonin, CGRP and bone

Calcitonin is the hormone secreted from parafollicular cells in the thyroid and inhibits osteoclast activity, leading to reduced bone resorption and low levels of serum calcium. Calcitonin is approved to use for osteoporosis and hypercalcemia. However, its effect on the prevention of bone fracture is still controversial, although bone mineral content is apparently improved. The same gene, CALCA, encodes another active peptide, calcitonin gene related peptide (CGRP). CGRP has been reported to promote bone formation based on the high bone mass phenotype of CALCA - deficient mouse.

The effect of tai chi chuan on bone remodeling and cytokines among breast cancer survivors: A feasibility trial

9610 Background: Weight-bearing exercise may slow the rate of bone loss associated with breast cancer treatment. The purpose of this study is to determine the effect of tai chi chuan (TCC) on bone health, as measured by the changes in the levels of bone resorption and bone formation. This study also aimed to investigate whether changes in bone health were correlated with growth and inflammation markers that serve as regulators of bone cell function. Methods: Female patients (N=16) who completed treatment for breast cancer within the past 30 months were randomly assigned to either the TCC group or the psycho-educational support group without exercise (ST) for 60 minutes, three times a week for a period of 12 weeks. Serum levels of bone resorption (N-telopeptides of type I collagen; NTx) and bone formation (bone specific alkaline phosphatase; BAP) were determined by ELISA at baseline and post-intervention. Using validated methods, a bone remodeling index (BRI) was calculated from levels of NTx and BAP. In addition, pre- and post-intervention levels of insulin-like growth factor binding protein 1 (IGFBP-1) and interleukin-2 (IL-2), markers associated with excessive bone resorption, were measured. Lastly, levels of interleukin-6 (IL-6), believed to enhance bone formation, were measured at both pre- and post-intervention. Results: ANCOVA analyses demonstrated that survivors in the TCC group experienced a greater increase in bone remodeling than those in the ST group (Δ BRITCC=1.6 vs Δ BRIST=0.2; p=0.04). All correlations were determined by Pearson's correlation coefficients. IGFBP-1 was negatively correlated with increasing bone remodeling levels (r=-0.43, p=0.14). IL-2 was also negatively correlated with increasing bone remodeling levels (r=-0.35, p=0.24). IL-6 was positively correlated with increasing bone remodeling levels (r=0.69, p=0.01). Conclusions: This pilot study suggests that TCC has positive effects on bone remodeling through changes in growth and inflammation factors that regulate bone cell function. A larger, more definitive trial examining the influence of TCC on bone remodeling is warranted. Funding: Sally Schindel Cone and R25 CA102618 No significant financial relationships to disclose.

Osteoclast Apoptosis in Rheumatic Diseases Characterized by a High Level of Bone Resorption (Osteoporosis, Rheumatoid Arthritis, Myeloma and Pagets Disease of Bone)

Abstract: The resorption and formation of bone are closely linked during bone remodeling. The cessation of bone resorption precedes bone formation, and is characterized by osteoclast apoptosis. The two most common apoptotic pathways consist of the activation of one of the membrane death receptors, including Fas that binds FasL, and the TRAIL receptors that bind TRAIL (TNF-Related Apoptosis-Inducing Ligand), and the mitochondrion-activated pathway involving members of the Bcl-2 family. Apoptosis occurs in osteoclasts, and is an important point of control of bone resorption. M-CSF and RANKL, the two critical factors involved in osteoclast formation and activation, are osteoclast survival factors and down-regulate osteoclast apoptosis. The regulation of this process may be important in controlling bone homeostasis, and could be altered in vivo under conditions characterized by a high level of osteoclast formation. Bone diseases, such as osteoporosis, malignant osteolysis, and Paget’s disease of bone, are characteristically associated with bone hyper-resorption, as rheumatoid arthritis where peri-articular or subchondral bone resorption may occur. There is now increasing evidence suggesting that changes in the regulation of osteoclast death may contribute to these clinically important bone diseases, and that the induction of osteoclast apoptosis is a potential therapeutic tool for treating them.

Serum bone turnover markers may be involved in the metastatic potential of lung cancer patients

The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.

Bovine dentine organic matrix down-regulates osteoclast activity

Physiological root resorption is a phenomenon that normally takes place in deciduous teeth; root resorption of permanent teeth occurs only under pathological conditions. The molecular mechanisms underlying these processes are still unclear. Our previous study showed that osteoclasts cultured on deciduous dentine exhibited a higher degree of resorption and higher levels of cathepsin K and MMP-9 mRNA than osteoclasts cultured on permanent dentine. These results could be because of different susceptibilities to acid and the different organic matrices between deciduous and permanent dentine. Thus, the purpose of this study was to investigate the effect of dentine extracts from bovine deciduous and permanent dentine on osteoclast activity. Osteoclasts, obtained from mouse bone marrow cells co-cultured with an osteoblast-rich fraction in the presence of 1,25-(OH)(2)-vitamin D3 and PGE2, were incubated with or without 0.6 M HCl extracts from bovine deciduous or permanent dentine for 48 h. TRAP positive cell number, TRAP activity, the areas of resorption pits, and mRNA levels of TRAP, v-ATPase, calcitonin receptor, cathepsin K, and MMP-9 were examined. The results illustrated that TRAP activity, the resorbed area, and the mRNA levels of osteoclast marker genes seemed to be suppressed by both deciduous and permanent dentine extracts. These findings indicate that some factors that suppress osteoclast activity are contained in both deciduous and permanent dentine extracts. Although there was no significant difference in osteoclast activity between deciduous and permanent dentine extracts, osteoclasts incubated with permanent dentine extracts tend to exhibit less resorption activity than those incubated with deciduous dentine extracts. However, we could not clearly explain the causes of this.

Effects of denosumab treatment in breast cancer patients with bone metastases and elevated bone resorption levels after therapy with intravenous bisphosphonates: results of a phase 2 randomized trial.

Abstract Abstract #1155 Background: Patients with breast cancer-induced bone disease and elevated urine-N-telopeptide (uNTx), a marker of bone resorption, are at increased risk for skeletal complications, disease progression, and death. Receptor activator of NF-kB ligand (RANKL) mediates osteoclastic bone resorption. Denosumab, a fully human monoclonal antibody, inhibits bone destruction by binding and neutralizing RANKL. Denosumab efficacy and safety were assessed in a phase 2, randomized, open-label, active-controlled trial in patients with bone metastases and elevated levels of uNTx after at least 8 weeks of intravenous (IV) bisphosphonate (BP) therapy. We report results in a subset of patients with breast cancer.&amp;#x2028; Methods: Cancer patients with bone metastases and uNTx &amp;gt;50 nM/mM creatinine [Cr] following at least 8 weeks of IV BP therapy were randomized to continue IV BP therapy every 4 weeks (Q4W) or switch to subcutaneous (SC) denosumab injection (180 mg) Q4W or every 12 weeks (Q12W). The primary endpoint was the proportion of patients who achieved uNTx &amp;lt;50 nM/mM at week 13. Safety was also assessed.&amp;#x2028; Results: The study population (N = 111) included 46 patients (41%) with breast cancer; the median time since diagnosis of bone metastases was approximately 1 year in both groups. At week 13, 76% of denosumab-treated patients and 33% of IV BP-treated patients had uNTx &amp;lt; 50 nM/mM. Denosumab-induced suppression of uNTx was rapid (as early as 2 weeks after initial treatment), sustained through week 25, and unaffected by baseline uNTx (Table). In the total study population, adverse events of grade 3, 4, or 5 were reported in 25 (71%) IV BP-treated patients and 40 (55%) denosumab-treated patients.&amp;#x2028; &amp;#x2028; Discussion: Denosumab reduced bone turnover in breast cancer patients with bone metastases and elevated uNTx despite prior IV BP therapy. Phase 3 trials of denosumab in cancer patients with bone metastases are in progress. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1155.