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Denosumab and infections

Su Young Kim, Hwoe Gyeong Ok, Christof Birkenmaier, Kyung Hoon Kim
Osteoblasts, originating from mesenchymal cells, make the receptor activator of the nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in order to control differentiation of activated osteoclasts, originating from hematopoietic stem cells. When the RANKL binds to the RANK of the pre-osteoclasts or mature osteoclasts, bone resorption increases. On the contrary, when OPG binds to the RANK, bone resorption decreases. Denosumab (AMG 162), like OPG (a decoy receptor), binds to the RANKL, and reduces binding between the RANK and the RANKL resulting in inhibition of osteoclastogenesis and reduction of bone resorption...
April 2017: Korean Journal of Pain
Nathan Touati, Konstantinos Tryfonidis, Franco Caramia, Hervé Bonnefoi, David Cameron, Leen Slaets, Belinda S Parker, Sherene Loi
BACKGROUND: Breast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti-tumour immune response. We investigated whether 'severe infection' can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones...
December 24, 2016: European Journal of Cancer
Yahui Grace Chiu, Christopher T Ritchlin
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by focal pathologic bone resorption due to excessive activity of osteoclasts (OC). Receptor activator of nuclear factor kappa B ligand (RANKL) is essential for the proliferation, differentiation, and survival of OC. Denosumab (DMab) is a humanized monoclonal antibody that binds to RANKL with high affinity and blocks its subsequent association with its receptor RANK on the surface of OC precursors. Area covered: The authors review the molecular and cellular mechanisms underlying therapeutic applications of DMab, provide recent highlights on pharmacology, efficacy and safety of DMab, and discuss the potential of DMab as a novel therapeutic option for the treatment of rheumatoid arthritis...
January 2017: Expert Opinion on Biological Therapy
Marco Bonani, Diana Frey, Olivier de Rougemont, Nicolas J Mueller, Thomas F Mueller, Nicole Graf, Rudolf P Wüthrich
BACKGROUND: Infections are a major cause of morbidity and mortality in kidney allograft recipients. In this posthoc analysis of a randomized clinical trial which tested the effect of denosumab on bone mineral density we assessed the impact of this drug on the incidence and severity of infections in the first year after kidney transplantation. METHODS: In this clinical trial we randomized 90 de novo kidney transplant recipients shortly after transplantation to either denosumab on top of standard treatment (calcium and vitamin D) (n=46), or to standard treatment alone (n=44)...
October 28, 2016: Transplantation
Thomas Mücke, Christian R Krestan, David A Mitchell, Jan S Kirschke, Arno Wutzl
For patients with malignant disease taking bisphosphonates and denosumab, the incidence of medication-related osteonecrosis of the jaw (MRONJ) is up to 15% in contrast to 0.01% in patients with osteoporosis. Clinical presentation of MRONJ extends from asymptomatic exposure of bone in 94% of patients to severe cases of mandibular fractures in a minority of 4.5%. The strongest risk factors for MRONJ are invasive dental procedures and dental infections. Advances in imaging provide more preoperation information compared with panoramic radiograph...
July 2016: Seminars in Musculoskeletal Radiology
Nam-Kyong Choi, Daniel H Solomon, Theodore N Tsacogianis, Joan E Landon, Hong Ji Song, Seoyoung C Kim
Limited head-to-head comparative safety and effectiveness data exist between denosumab and zoledronic acid in real-world healthcare. We aimed to examine the safety and effectiveness of denosumab compared to zoledronic acid with regard to risk of serious infection and cardiovascular disease (CVD) and osteoporotic fracture. We conducted a cohort study using claims data (2009-2013) from a US commercial insurance plan database. We included patients aged ≥50 years who were newly initiated on denosumab or zoledronic acid...
March 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
John Acquavella, Vera Ehrenstein, Morten Schiødt, Uffe Heide-Jørgensen, Anders Kjellman, Svein Hansen, Cecilia Larsson Wexell, Bente Brokstad Herlofson, Sven Erik Noerholt, Haijun Ma, Katarina Öhrling, Rohini K Hernandez, Henrik Toft Sørensen
OBJECTIVE: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies. METHODS: As part of a comprehensive pharmacovigilance plan, developed with regulators' input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function)...
2016: Clinical Epidemiology
Hisashi Matsushima
Osteopenia and osteoporosis often become the long term complications in cancer treatment and is defined as cancer treatment-induced bone loss(CTIBL). Hormonal therapy is the main factor for CTIBL in both men and women. Androgen deprivation therapy(ADT)is a mainstay in the systemic therapy for prostate cancer(PC)and often persists for a long term. ADT induces bone loss and increases the risk of osteoporosis and bone fractures, which reduces QOL of the patients, results in the need of nursing care state and a serious adverse event to be connected for shortening of the overall survival...
July 2016: Clinical Calcium
Sven Otto, Oliver Ristow, Christoph Pache, Matthias Troeltzsch, Riham Fliefel, Michael Ehrenfeld, Christoph Pautke
INTRODUCTION: The delineation of the necrotic bone is a crucial step in the surgical treatment of medication-related osteonecrosis of the jaw (MRONJ). Several different approaches have been described including the innovative technique of fluorescence-guided surgery. However, until now there is a lack of data regarding the outcome. Therefore, the aim of the present study is to investigate the long-term success rates of fluorescence-guided surgery in the treatment of MRONJ. PATIENTS AND METHODS: 54 Patients were prospectively assigned for surgical treatment of medication-related osteonecrosis of the jaw using fluorescence-guided surgery...
August 2016: Journal of Cranio-maxillo-facial Surgery
Kenji Yamagata, Hiroki Nagai, Osamu Baba, Fumihiko Uchida, Naomi Kanno, Shogo Hasegawa, Toru Yanagawa, Hiroki Bukawa
Reports of brain abscesses caused by medication-related osteonecrosis of the jaw (MRONJ) are very rare. We here present the case of a 76-year-old man with terminal-stage prostatic carcinoma and a brain abscess caused by MRONJ at the maxilla. The patient had been treated with zoledronic acid and denosumab for bone metastasis. For the brain abscess, an antibiotic regimen based on ceftriaxone and metronidazole and a sequestrectomy contributed to a successful outcome. In the case of maxillary MRONJ extending to the maxillary sinus, active resection of the infected bone should be considered to prevent the spread of the infection beyond the maxillary sinus, into the ethmoid sinus, and into the brain...
2016: Case Reports in Dentistry
Akihiko Matsumoto, Masanori Sasaki, Rainer Schmelzeisen, Yukiko Oyama, Yoshihide Mori, Pit Jacob Voss
OBJECTIVES: Some recent reports have indicated that local infection causes osteonecrosis of the jaw and described that tooth extraction may not be a direct cause of developing medication-related osteonecrosis of the jaw (MRONJ) in patients receiving antiresorptive medications. Tooth extraction and elimination of the source of infection are expected to reduce the risk of developing MRONJ. However, there is no data regarding prevention for developing osteonecrosis of the jaw in patients receiving denosumab...
January 2017: Clinical Oral Investigations
Eugenia Negredo, Amy H Warriner
PURPOSE OF REVIEW: Osteoporosis is a growing concern among people living with HIV (PLWH) because of the recognized risk of fractures, which bring with them morbidity and mortality. New evidence is helping clinicians understand how to prevent and manage osteoporosis in this subpopulation. RECENT FINDINGS: The benefit of calcium and vitamin D is variable in osteoporosis literature in general, but evidence supports the use of these supplements in PLWH to prevent the loss of bone mineral density when initiating antiretroviral therapy and in enhancing the effectiveness of antiosteoporosis treatments...
May 2016: Current Opinion in HIV and AIDS
M Bonani, D Frey, J Brockmann, T Fehr, T F Mueller, L Saleh, A von Eckardstein, N Graf, R P Wüthrich
We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0...
June 2016: American Journal of Transplantation
Chien-Liang Chen, Nai-Ching Chen, Huei-Lung Liang, Chih-Yang Hsu, Kang-Ju Chou, Hua-Chang Fang, Po-Tsang Lee
CONTEXT: Secondary hyperparathyroidism (SHPT) may worsen with administration of denosumab in chronic renal failure patients with low bone mass. OBJECTIVE: This study aimed to evaluate the short-term effect of coadministration of calcitriol and denosumab on PTH secretion and parathyroid structure and the incidence of adverse effects in patients with SHPT and low bone mass. DESIGN AND SETTING: This was a 24-week, open-label study at Kaohsiung Veterans General Hospital in Kaohsiung, Taiwan...
July 2015: Journal of Clinical Endocrinology and Metabolism
Chi Chiu Mok, Ling Yin Ho, Kwok Man Ma
OBJECTIVES: To evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users. METHODS: Adult patients who were receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) and oral bisphosphonates (≥2 years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60 mg subcutaneously every 6 months) for 12 months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, β-CTX) were measured...
June 2015: Bone
Luis A Aponte-Tinao, Nicolas S Piuzzi, Pablo Roitman, German L Farfalli
BACKGROUND: A giant cell tumor of bone is a primary benign but locally aggressive neoplasm. Malignant transformation in a histologically typical giant cell tumor of bone, without radiotherapy exposure, is an uncommon event, occurring in less than 1% of giant cell tumors of bone. Although surgery is the standard initial treatment, denosumab, a monoclonal antibody drug that inhibits receptor activator of nuclear factor-κB ligand (RANKL), has shown considerable activity regarding disease and control of symptoms in patients with recurrence, unresectable, and metastatic giant cell tumors of bone...
September 2015: Clinical Orthopaedics and related Research
H Katsarelis, N P Shah, D K Dhariwal, M Pazianas
Medication-related osteonecrosis of the jaw (MRONJ), although initially believed to be exclusively associated with bisphosphonates, has been implicated in recent reports with additional drugs, especially the bone antiresorptive denosumab. The pathophysiology has not been fully elucidated, and no causal association between bone antiresorptive regimens and MRONJ has yet been established. However, reduced bone turnover and infection, an almost universal finding, are thought to be central to the pathogenesis of MRONJ...
April 2015: Journal of Dental Research
Jeffrey R Curtis, Fenglong Xie, Huifeng Yun, Kenneth G Saag, Lang Chen, Elizabeth Delzell
OBJECTIVE: Denosumab is a biologic agent used to treat osteoporosis. Its safety profile given concurrently with biologic drugs for rheumatoid arthritis (RA) has not been well studied. We evaluated hospitalized infections among patients treated with biologic agents for RA who initiated denosumab or zoledronic acid (ZA), a parenteral bisphosphonate without known associations with infection. We hypothesized that the rate of hospitalized infection with denosumab would be noninferior to ZA...
June 2015: Arthritis & Rheumatology
Sarah Zaheer, Meryl LeBoff, E Michael Lewiecki
INTRODUCTION: Low trauma fractures due to osteoporosis are a major health concern worldwide. Despite the availability of many therapeutic compounds to reduce fracture risk, osteoporosis remains undertreated and the burden of osteoporotic fractures remains high. Denosumab is a novel agent that acts to reduce bone turnover, improve bone mineral density, and reduce fracture risk, offering a favorable efficacy and safety profile. AREAS COVERED: This review covers the pharmacology and major clinical trials with extension/post-marketing follow-up, including trials for all FDA-approved indications of denosumab to date...
March 2015: Expert Opinion on Drug Metabolism & Toxicology
Aliya A Khan, Archie Morrison, David A Hanley, Dieter Felsenberg, Laurie K McCauley, Felice O'Ryan, Ian R Reid, Salvatore L Ruggiero, Akira Taguchi, Sotirios Tetradis, Nelson B Watts, Maria Luisa Brandi, Edmund Peters, Teresa Guise, Richard Eastell, Angela M Cheung, Suzanne N Morin, Basel Masri, Cyrus Cooper, Sarah L Morgan, Barbara Obermayer-Pietsch, Bente L Langdahl, Rana Al Dabagh, K Shawn Davison, David L Kendler, George K Sándor, Robert G Josse, Mohit Bhandari, Mohamed El Rabbany, Dominique D Pierroz, Riad Sulimani, Deborah P Saunders, Jacques P Brown, Juliet Compston
This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals...
January 2015: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
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