RANK Ligand Inhibitor Research Articles

Medication-Related Osteonecrosis of the Jaws (MRONJ): Etiological Update

Osteonecrosis of the jaws (ONJ) is an uncommon but severe bone disease, can be related to various medicaments (MRONJ) includingbisphosphonates (BRONJ), antiangiogenic and antiresorptive medicaments such as Denosumab (DRONJ), human monoclonalantibody to the receptor activator of nuclear factor-kB ligand. The rise in number in the latest years can be explained with manypatients treated with all these drugs, assumed for osteometabolic (i.e osteoporosis, osteogenesis imperfecta) or neoplastic diseases(multiple myeloma, metastatic breast, prostate and renal cancer). The onset mechanism of MRONJ is not entirely understood,probably different mechanisms are involved, such as inhibition of the osteoclasts differentiation and function, decrease of theangiogenesis and inflammation/infection of the jaw bones. Some pathogenetic mechanisms are different according to the drugs, forexample the cases of the RANK-ligand inhibitor related ONJ may occur without considering the period of medication intake; also therisk of ONJ manifestation after bisphosphonates (BF) is not significantly diminished after interrupting the drug therapy, because BFbind to the bone matrix for many years. Drugs currently implicated in osteonecrosis pathology are various, therefore the term ONJwas currently replaced by MRONJ; it is necessary that the anamnestic phase and management of the patients to be more detailed andcorrect, not only to prevent osteonecrosis but also to plan all necessary treatments before start of the drug therapy.

Effects of antibody to receptor activator of nuclear factor κ-B ligand on inflammation and cartilage degradation in collagen antibody-induced arthritis in mice.

BackgroundRheumatoid arthritis (RA) is an inflammatory disease that leads to destruction of both articular cartilage and bone tissues. In rheumatic joints, synoviocytes and T-lymphocytes as well as bone cells produce the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL), which binds to RANK on the surface of osteoclasts and their precursor cells to induce differentiation and activation of osteoclasts. Hence, inhibition of RANKL may be a promising approach to suppress osteolysis in RA. On the other hand, RANKL production by lymphocytes indicates the possibility that its inhibition would be effective to suppress inflammation in RA. In addition, it has been reported that cathepsin K, a predominant cysteine protease in osteoclasts, is involved in cartilage destruction in RA model mice. Here, we evaluated the effects of an anti-RANKL antibody on inflammation in footpads and degradation of articular cartilage in RA model mice.ResultsWe induced arthritis in mice by injection of anti-type II collagen antibodies and lipopolysaccharide (LPS). Inhibition of RANKL by an anti-RANKL antibody (OYC1, Oriental Yeast, Tokyo, Japan) was confirmed by increased bone volume in the metaphysis of tibias. Swelling in either limb until day 14 was seen in 5 of 6 mice injected with anti-collagen antibodies and LPS without treatment with OYC1, while that was seen in 4 of 5 mice treated with OYC1. The average arthritis scores on day 14 in those groups were 2.17 and 3.00, respectively, indicating that OYC1 did not ameliorate inflammation in the limbs. Histological analyses indicated that OYC1 does not protect articular cartilage from destruction in mice with arthritis.ConclusionsOur present study failed to show the effectiveness of an anti-RANKL antibody to ameliorate inflammation in the limbs or protect articular cartilage from degradation in a collagen antibody-induced arthritis mouse model.Electronic supplementary materialThe online version of this article (doi:10.1186/s12952-014-0018-0) contains supplementary material, which is available to authorized users.

Osteoclasts are dispensable for hematopoietic progenitor mobilization by granulocyte colony-stimulating factor in mice

The contribution of osteoclasts to hematopoietic stem/progenitor cell (HSPC) retention in the bone marrow is controversial. Studies of HSPC trafficking in osteoclast-deficient mice are limited by osteopetrosis. Here, we employed two non-osteopetrotic mouse models to assess the contribution of osteoclasts to basal and granulocyte colony-stimulating factor (G-CSF)-induced HSPC mobilization. We generated Rank(-/-) fetal liver chimeras using Csf3r(-/-) recipients to produce mice lacking G-CSF receptor expression in osteoclasts. Basal and G-CSF-induced HSPC mobilization was normal in these chimeras. We next acutely depleted osteoclasts in wild-type mice using the RANK ligand inhibitor osteoprotegerin. Marked suppression of osteoclasts was observed after a single injection of osteoprotegerin-Fc. Basal and G-CSF-induced HSPC mobilization in osteoprotegerin-Fc-treated mice was comparable to that in control mice. Together, these data indicate that osteoclasts are not required for the efficient retention of HSPCs in the bone marrow and are dispensable for HSPC mobilization by G-CSF.

Histological Regression of Giant Cell Tumor of Bone Following RANK Ligand Inhibition.

Lung metastases are a rare complication of giant cell tumors of bone. We herein describe an interesting case of histological regression and size reduction of lung metastases originating from a primary giant cell tumor of bone in response to the RANK ligand inhibitor denosumab.

Effects of Interleukin-17A on Osteogenic Differentiation of Isolated Human Mesenchymal Stem Cells.

Objectives: Rheumatoid arthritis (RA) is characterized by defective bone repair and excessive destruction and ankylosing spondylitis (AS) by increased ectopic bone formation with syndesmophytes. Since TNF-α and IL-17A are involved in both diseases, this study investigated their effects on the osteogenic differentiation of isolated human bone marrow-derived mesenchymal stem cells (hMSCs).Methods: Differentiation of hMSCs into osteoblasts was induced in the presence or absence of IL-17A and/or TNF-α. Matrix mineralization (MM) was evaluated by alizarin red staining and alkaline phosphatase (ALP) activity. mRNA expression was measured by qRT-PCR for bone morphogenetic protein (BMP)-2 and Runx2, genes associated with osteogenesis, DKK-1, a negative regulator of osteogenesis, Schnurri-3 and receptor activator of nuclear factor kappa B ligand (RANKL), associated with the cross talk with osteoclasts, and TNF-α receptor type I and TNF-α receptor type II (TNFRII).Results: TNF-α alone increased both MM and ALP activity. IL-17A alone increased ALP but not MM. Their combination was more potent. TNF-α alone increased BMP2 mRNA expression at 6 and 12 h. These levels decreased in combination with IL-17A at 6 h only. DKK-1 mRNA expression was inhibited by TNF-α and IL-17A either alone or combined. Supporting an imbalance toward osteoblastogenesis, RANKL expression was inhibited by TNF-α and IL-17A. However, TNF-α but not IL-17 alone decreased Runx2 mRNA expression at 6 h. In parallel, TNF-α but not IL-17 alone increased Schnurri-3 expression with a synergistic effect with their combination. This may be related to an increase of TNFRII overexpression.Conclusion: IL-17 increased the effects of TNF-α on bone matrix formation by hMSCs. However, IL-17 decreased the TNF-α-induced BMP2 inhibition. Synergistic interactions between TNF-α and IL-17 were seen for RANKL inhibition and Schnurri-3 induction. Such increase of Schnurri-3 may in turn activate osteoclasts leading to bone destruction as in RA. Conversely, in the absence of osteoclasts, this could promote ectopic bone formation as in AS.

Risk Factors for Hypocalcemia in Patients with Cancer Receiving Denosumab

ABSTRACT Aim: The potent RANK ligand inhibitor denosumab (Dmab) can cause hypocalcemia (hypoCa). Patients (pts) with inadequate intake of Ca and vitamin D are at increased risk for hypoCa. Additional baseline risk factors for hypoCa in pts with metastatic bone disease (MBD) were evaluated to aid clinical risk assessment for this adverse event. Methods: A post hoc analysis used data from three identically designed, randomized, blinded phase 3 trials comparing monthly dosing of 4 mg zoledronic acid (ZA) to 120 mg Dmab in pts with MBD to identify lab events of grade≥2 hypoCa (CTCAE: Results: The overall incidence of lab grade≥2 hypoCa events in those treated with Dmab was equal to or greater than in those treated with ZA and occurred in 12.4% of Dmab-treated pts. Baseline pt characteristics with the greatest incidence of hypoCa include: male gender (15.4%), prostate cancer (20.5%), small cell lung cancer (18.0%), and CrCl 30 – 2 bone mets and those with higher BSAP or uNTx levels (Table). Osseous lesion type did not significantly increase the risk of developing hypoCa (P ≥ 0.23). Baseline Factor Hazard Ratio 95% CI P-value > 2 bone mets 1.329 (1.044, 1.692) 0.021 BSAP>median (20.77 mg/L) 2.078 (1.579, 2.734) BSAP>median vs≤median > 2 bone mets 4.236 (2.117, 8.479) ≤ 2 bone mets 1.773 (1.312, 2.395) Interaction of baseline BSAP and # of bone mets 0.021 uNTX>50 nmol/mmol 1.316 (1.031, 1.680) 0.027 Interaction of baseline uNTX and # of bone mets 0.21 Conclusions: The risk of hypoCa after Dmab for MBD is associated with the # of bone mets and elevated bone turnover markers, especially high BSAP with>2 mets. BSAP may indicate the potential for deposition of Ca in undermineralized matrix. Pts with high bone turnover may be more susceptible to hypoCa when osteoclasts are rapidly inhibited, particularly when Ca and vitamin D intake is insufficient. Disclosure: J. Body: Consultant for and received research funding from Amgen; received honoraria from Amgen and Novartis; H.G. Bone: Consultant for and received honoraria from Amgen and Novartis; C. van Poznak: Received research funding from Amgen and Novartis; R.H. De Boer: Consultant for and received honoraria from Novartis; received research funding and other remuneration from Amgen and Novartis; A. Stopeck: Consultant for Amgen; honoraria from Amgen and GlaxoSmithKline; research funding from Amgen and Novartis; K. Fizazi: Consultant for Amgen and Novartis; honoraria from Amgen; D.H. Henry: Consultant for and received research funding and honoraria from Amgen, Ortho Biotech, and Watson; T. Ibrahim: Consultant for Amgen; A. Lipton: Honoraria and research funding from Amgen; F. Saad: Consultant for and received research funding and honoraria from Amgen and Novartis; N.D. Shore: Consultant for Amgen, Astellas, Bayer, Dendreon, Janssen, and Medivation; T. Takano: Consultant for and received honoraria from Daiichi-Sankyo; H. Wang: Employee of and owns stock or stock options in Amgen; O.L. Bracco: Employee of and owns stock or stock options in Amgen; A. Balakumaran: Employee of and owns stock or stock options in Amgen; P.J. Kostenuik: Employee of and owns stock or stock options in Amgen. All other authors have declared no conflicts of interest.

Osteoporosis: The connection to urologic health.

Men with prostate cancer are often treated with androgen deprivation therapy (ADT), which is associated with reduced bone mineral density (BMD) and a higher risk for fractures. Maintenance of optimum bone health throughout the natural course of prostate cancer is an important aspect in the management of this patient population. Bone targeted therapies, such as bisphosphonates and the RANK ligand inhibitor denosumab, have been demonstrated to reduce skeletal-related events in patients with metastatic cancer, while denosumab has also been shown to reduce the risk of fracture in men undergoing ADT for prostate cancer.

RANK expression as a prognostic and predictive marker in breast cancer

RANK ligand (RANKL) is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mammary epithelium via its receptor RANK and has a role in expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models. Primary breast carcinoma samples from the neoadjuvant GeparTrio study were analyzed to correlate the expression of human RANK and RANKL with pathological complete response (pCR), disease-free (DFS), and overall (OS) survival. Pre-treatment FFPE core biopsies (n=601) were analyzed for percentage and intensity of immunohistochemical RANK and RANKL expression. Antibodies against human RANK (N-1H8; Amgen) and human RANKL (M366; Amgen) were used. RANK protein was expressed in 160 (27%) patients. Increased RANK expression was observed in 14.5% of patients and correlated with high tumor grade (p<0.023) and negative hormone receptor (HR) status (p<0.001). Patients with high RANK expression showed a higher pCR rate (23.0% vs. 12.6%, p=0.010), shorter DFS (p=0.038), and OS (p=0.011). However, prognostic and predictive information was not an independent parameter. Only 6% of samples expressed RANKL, which was not correlated with any clinical features. Higher RANK expression in the primary tumor is associated with a higher sensitivity to chemotherapy, but also a higher risk of relapse and death. Our study provides a basis for further exploration of the antitumor activity of clinical antibodies against RANKL.

Targeting RANKL in metastasis.

Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival. Preclinical data have now firmly established that blockade of tumor-induced osteoclastogenesis by RANKL inhibition will not only protect against bone destruction but will also inhibit the progression of established bone metastases and delay the formation of de novo bone metastases in cancer models. In patients with bone metastases, skeletal complications are driven by increased osteoclastic activity and may result in pathological fractures, spinal cord compression and the need for radiotherapy to the bone or orthopedic surgery (collectively known as skeletal-related events (SREs)). Denosumab, a fully human monoclonal antibody against RANKL, has been demonstrated to prevent or delay SREs in patients with solid tumors that have metastasized to bone. In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts. For example, RANKL also stimulates metastasis via activity on RANK-expressing cancer cells, resulting in increased invasion and migration. Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells. This review describes these distinct but potentially overlapping mechanisms by which RANKL may promote metastases.

RANKL Inhibition Blocks Osteolytic Lesions and Reduces Skeletal Tumor Burden in Models of Non–Small-Cell Lung Cancer Bone Metastases

Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression. We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses. OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts. These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.

Abstract P2-16-12: An exploratory analysis of the role of dasatinib in preventing progression of disease in bone in patients with metastatic breast cancer

Abstract Introduction: The role of dasatinib, an oral SRC inhibitor is being explored for the treatment of metastatic breast cancer. In a phase I study, we previously established that the combination of dasatinib and weekly paclitaxel was feasible. The activity of this combination is currently being explored in an ongoing phase II trial. Since Src kinase has a major role in osteoclast function and dasatinib has established anabolic and anti-resorptive effects in bone in vitro, we hypothesized that patients receiving this combination would have good control of osseous metastases and primarily develop progression of disease in sites other than bone. Patients and methods: Patients were included in this analysis if they participated in the phase I or II metastatic breast cancer studies and received dasatinib at or above the recommended phase II dose of 120mg with paclitaxel (80mg/m2 day 1 and 8 of each 21day cycle). Patients who discontinued therapy for reasons other than progression were excluded. Per protocol, patients were required to discontinue bisphosphonates or other bone modulating agents for the first 8 weeks of study due to the potential for hypocalcaemia. Thereafter, they were permitted to receive these agents at the discretion of their treating physician. Patients provided serum samples for correlative studies. Assessment of N-telopeptide of type 1 collagen (NTX), a product of mature bone collagen that reflects bone specific resorption, is planned. Results: The median age of the 24 patients who met criteria for analysis was 50y (37 - 66y). Of these, 15 (63%) had ER+ disease, and 24 (100%) were negative for human epidermal growth factor receptor (HER2). At study entry, 17 (71%) patients had bone involvement. Following the initial eight week moratorium, 7 (29%) patients received a bisphosphonate or rank ligand inhibitor during treatment with dasatinib + paclitaxel. Patients received a median 2 months (range 1-23) of dasatinib + paclitaxel therapy. To date, 3 (13%) continue on therapy, and 21 (88%) have had progression of disease. Among patients who progressed, 18 (86%) have progressed in visceral sites and only 3 (14%) progressed in bone. Analyses of serum NTX levels are ongoing and will be compared by site of progression. Conclusion: The potential role of serum NTX as a predictive biomarker of benefit from dasatinib and paclitaxel is being explored and updated results will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-12.

Abstract ES09-3: Symptom management and quality of life in metastatic breast cancer

Abstract Approximately 40,000 women in the US die each year of metastatic breast cancer. Because the disease is incurable at this stage, effective symptom management and preservation of quality of life are paramount for these patients. For those with brain metastases, consideration of cognition, quality of life, and overall survival are extremely important because some subsets of patients with breast cancer metastases to the brain may now enjoy prolonged survival of almost 2 years. For solitary brain metastasis, surgical resection followed by whole brain radiotherapy is known to prolong survival, though the addition of whole brain radiotherapy is associated with significant cognitive impairment and decreased quality of life without clear improvement in overall survival. Stereotactic radiosurgery (SRS) shows promise as a therapeutic option for patients with asymptomatic, smaller brain lesions. SRS, as compared to open surgery, results in improved quality of life. Bone metastasis is another common management dilemma for breast cancer patients. Commonly used bone agents, such as bisphosphonates and RANK ligand inhibitors, are known to decrease bone pain and increase quality of life, as well as reduce skeletal-related events. However, safe and optimal duration of bisphosphonates or RANK ligand inhibitors remains unclear in the metastatic breast cancer population. Finally, we will discuss quality measures for delivering end of life care, trends in the country, and methods for improving end of life care with goals of earlier hospice referrals and less treatments at end of life which lead to hospitalizations or ICU stays. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES09-3.

Abstract P1-08-25: RANK expression is prognostic and predictive in primary breast carcinoma: Analysis of samples from the GeparTrio study

Abstract Purpose: RANK ligand (RANKL), a key factor for bone remodeling and metastasis, is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mouse and human mammary epithelium via its receptor RANK and has a role in ovarian hormone-dependent expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models. Many published expression analyses of RANK and RANKL have been performed using immunohistochemistry (IHC) without documented validation of antibody specificity. This study analyzed primary breast carcinoma samples from the GeparTrio study to correlate the expression of human RANK and RANKL (using specific, monoclonal antibodies validated and optimized for IHC) with pathological complete response (pCR: ypT0 ypN0), disease-free (DFS), and overall (OS) survival after anthracycline-taxane-based neoadjuvant chemotherapy. Methods: Pre-treatment FFPE core biopsies (n = 601) from participants of the neoadjuvant GeparTrio study were analyzed for percentage and intensity (H-score) of immunohistochemical RANK and RANKL expression. Antibodies against human RANK (N-1H8; Amgen) and human RANKL (M366; Amgen) were used for IHC staining. The overall expression measured by IHC was calculated using the H scoring method. The specificity of the antibodies was substantiated by concordant signals observed using multiple independent analyses, including IHC, flow cytometry and Western blots of positive and negative control cells and xenograft samples. Results: RANK protein was expressed within the tumor epithelium in 160 (27%) patients. A cutoff of an H-score of &amp;gt;8.5 was identified as optimal for prediction of pCR, DFS, and OS using an automated cut-off finder (http://molpath.charite.de/cutoff). High RANK expression (&amp;gt;8.5 H-Score) was observed in 14.5% of patients and was strongly correlated with high tumor grade (p&amp;lt;0.001) and negative hormone-receptor status (p&amp;lt;0.001). Patients with high RANK expression showed a higher pCR rate (23.0% vs 12.6%, p = 0.010), shorter DFS (p = 0.038) and OS (p = 0.011) compared to patients with low RANK expression. However, prognostic and predictive information was not independent from other baseline parameters (age, histologic type, stage, grade, and hormone/HER2-receptor) in multivariate analyses. Only 6% of samples expressed RANKL within the tumor epithelium, which was not correlated with any clinical features. Conclusion: Immunohistochemical RANK and RANKL protein expression was observed in the epithelial carcinoma in human primary breast cancers. Higher RANK expression in the primary tumor is associated with a higher sensitivity to chemotherapy, but also a higher risk of relapse and death. However, due to its strong correlation with grade and hormone-receptor status, RANK does not provide independent predictive and prognostic information. Denosumab, a clinically available antibody against RANKL, might have direct anti-tumor activity and should be further explored in this group of patients with high RANK expression. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-25.

RANK expression on breast cancer cells promotes skeletal metastasis

RANK ligand (RANKL), acting through its cognate receptor RANK, is a key factor for bone remodeling and metastasis by regulating the differentiation, survival and activation of osteoclasts. RANKL is also crucial for the development of mouse mammary glands during pregnancy and has been recently linked to the etiology of breast cancer via its direct activity on RANK-expressing normal or transformed breast epithelial cells, leading to increased mitogenesis, enhanced regenerative potential of mammary stem cells, and increased invasion and migration. We demonstrate that higher RANK expression in MDA-MB-231 breast cancer cells (MDA-231-RANK cells) is sufficient to confer a significantly greater metastatic growth rate in the bone compared with MDA-MB-231 cells which do not express high levels of RANK. Blockade of osteoclastic bone resorption, achieved with treatment by either RANKL inhibition or zoledronic acid, did reduce skeletal tumor progression of MDA-231-RANK cells suggesting that the vicious cycle contributes to metastatic growth. However, RANKL inhibition reduced skeletal growth of MDA-231-RANK tumors to a significantly greater extent than zoledronic acid, indicating that skeletal growth of RANK-positive tumors is also driven by direct RANKL effects. RANKL stimulated the expression of multiple genes associated with cell invasive behavior, including several matrix metalloproteinases and other genes previously defined as part of a bone metastasis gene signature. These data indicate that RANKL provokes breast cancer bone metastases via two distinct, but potentially overlapping mechanisms: stimulation of tumor-associated osteoclastogenesis and stimulation of RANK-expressing tumor cells.

A new antiresorptive approach to the treatment of fragility fractures: long-term efficacy and safety of denosumab

An imbalance of the remodeling process for bone resorption leads to a loss of tissue with consequent microarchitectural damage, evident in conditions such as osteoporosis and related fragility fractures. Currently, pharmacological therapies are able to prevent or slow down bone resorption by inhibiting osteoclast activity. An innovative and targeted anti-resorptive approach is represented by the inhibition of RANK ligand (RANK-L), essential for the proliferation and activity of osteoclastic cells. The human monoclonal antibody against RANK-L (denosumab) has been approved for the treatment of osteoporosis. In clinical trials of patients with osteoporosis, inhibition of RANK-L has reduced bone loss and damage to the microarchitecture and was associated with an increase in mass and resistance at different skeletal sites, with most significant effects than those demonstrated by any other antiresorptive drugs. In addition, after 3 years of treatment, it showed a reduction in vertebral and non-vertebral fracture risk. Denosumab treatment also has not revealed any alteration in the physiological processes of fracture repair, showing no increase in the onset of complications 3 years after the fracture. The data show that denosumab offers an effective alternative therapeutic approach for the treatment of severe osteoporosis, with positive effects on BMD and reduction of fragility fractures risk. So, promising results in terms of therapeutic efficacy and reliability make desirable the wide clinical use of denosumab for the treatment of osteoporotic fractures in the near future.

RANKL Inhibition With Denosumab Does Not Influence 3-Year Progression of Aortic Calcification or Incidence of Adverse Cardiovascular Events in Postmenopausal Women With Osteoporosis and High Cardiovascular Risk

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with bone mineral density (BMD). The osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2363 postmenopausal women with osteoporosis (1142 placebo, 1221 DMAb), selected from 7808 participants in the FREEDOM trial (3906 placebo, 3902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semiquantitative method from lateral spine X-rays. Change in AC score from baseline to 12 (n = 1377), 24 (n = 1231), and 36 months (n = 1045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score >0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60-90), 88% were white, and 77% had AC score >0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.

Successful surgical management of osteonecrosis of the jaw due to RANK-ligand inhibitor treatment using fluorescence guided bone resection

Osteonecrosis of the jaw has recently been described in patients receiving subcutaneous administration of RANKL-inhibitors (denosumab). However, due to promising study results, more patients will receive denosumab in order to avoid skeletal complications due to metastatic bone disease and osteoporosis. Therefore, this has the potential to become a comparable challenge to the bisphosphonate induced jaw necrosis in the area of Oral and Maxillofacial Surgery. Indeed, so far no convincing surgical technique has been described to overcome the non-healing mucosal lesions with exposed bone due to RANKL-inhibitor therapy.In this technical note, we report two successful cases of surgical treatment of jaw-bone necrosis under RANKL-inhibitor treatment using fluorescence guided bone resection.In conclusion, the technique is suggested as treatment option for this entity of osteonecrosis of the jaw.

Patterns of treatment (tx) with bone-modifying agents (BMA) in patients with bone metastases (mets).

e20690 Background: Bone mets can lead to serious and debilitating skeletal-related events (SREs: fracture, spinal cord compression, and surgery or radiation to bone). Three BMAs are approved in the US for prevention of SREs in cancer patients (pts) with bone mets: 2 intravenous bisphosphonates (IV BP) with recommended dosing every 3-4 weeks (pamidronate [PAM] and zoledronic acid [ZA]), and 1 RANK ligand inhibitor with subcutaneous injection every 4 weeks (denosumab). Monitoring real-world tx trends is important, particularly as low persistence has been linked to higher rates of SREs (Hatoum et al 2008). Methods: A retrospective cohort was defined from the Oncology Services Comprehensive Electronic Records (OSCER) database, which includes medical records from &gt;500K pts treated at 76 US oncology practices. Adult solid tumor pts with bone mets who initiated tx with a BMA between Jan 2011 and Oct 2011 were included and followed for 12 mos after tx initiation. Pts were either naïve (no BMA in previous 6 mos) or transition (different BMA received in previous 6 mos). Results: The cohort was composed of 1445 denosumab pts (62% naïve) and 1807 IV BP pts (99% naïve). Pt characteristics were similar, although denosumab pts were somewhat more likely to have prostate cancer than IV BP pts (30% vs 25%). Denosumab pts were more likely to receive regular tx during follow-up and less likely to switch tx than IV BP pts (Table). Trends were consistent across tumor types and for naïve vs transition pts. Conclusions: This descriptive analysis reports on tx patterns for pts with bone mets since the availability of denosumab in Dec 2010. Denosumab represented almost half (44%) of pts initiating a BMA and one-third of pts naïve to tx. Uninterrupted tx was more common for denosumab pts than IV BP pts, regardless of tumor type. Trends, including reasons for and consequences of tx interruption, should be monitored as the pt experience develops. [Table: see text]

Reducing the burden of bone metastases

Bone metastases occur frequently in patients with solid tumours such as those of the prostate, breast and lung, and are associated with an increased risk of skeletal-related events (SREs). This article reviews the personal, social and economic burdens of bone metastases and SREs, and approaches to treatment. PubMed searches were conducted using a broad range of search terms. Articles identified were refined by author review of abstracts. Additional material was identified by searching recent relevant congress abstracts. Bone metastases often decrease quality of life, but quantitative data on the extent of this effect are limited. Data from the USA demonstrate a significant financial burden associated with bone metastases; similar trends are now being uncovered in Europe as the number of assessments of health economics and healthcare resource utilisation in the region increases. The bisphosphonate zoledronic acid reduces the incidence of SREs compared with placebo. Recent phase 3 studies have shown that therapy with the RANK ligand inhibitor denosumab is superior to zoledronic acid for preventing or delaying SREs in patients with bone metastases from solid tumours. Denosumab also has a comparable safety profile to bisphosphonates, with reduced risk of renal toxicity and acute phase reactions. Data from Europe suggest that denosumab is cost-effective for the prevention of SREs compared with zoledronic acid. Additionally, several new experimental bone-targeted agents show promise. Recent progress may help to reshape evidence-based guidelines to improve patient care and reduce the economic burden of bone metastases.

Skeletal-Related Events in Metastatic Prostate Cancer and the Number Needed to Treat: A Critical Consideration

Purpose: With stage migration induced by early diagnosis of prostate-specific antigen, the course of disease for prostate cancer (PCa) patients has changed. Increasingly, patients undergo long-term androgen ablation with consecutive risks including osteoporosis and pathologic fractures. A recent randomized trial found that the RANK ligand inhibitor denosumab was more effective preventing skeletal-related events in patients with metastatic PCa as compared to treatment with the bisphosphonate zoledronic acid. This improved efficacy was linked to an increase of side effects. Methods: The present analysis compares results reported for both substances using a number needed to treat analysis approach. Based upon these findings, risk-benefit calculations were performed. Results: The results demonstrate that for patients with bone metastatic castration-resistant PCa, decision for or against treatment with either denosumab or zoledronic acid must not only consider efficacy but needs to balance the desired effects versus potential side effects. This is of specific relevance since life expectancy is limited in this patient cohort with end-stage disease. Conclusions: Further scientific efforts are necessary to identify optimal dosing and application intervals for denosumab and zoledronic acid as well as to answer the question of optimal duration of treatment. These findings will directly impact the risk versus benefit relations for both therapeutic options.