Denosumab--a new option in the treatment of osteoporosis

Denosumab is the international name of a human, monoclonal antibody approved for the treatment of osteoporosis. This antibody is associated with RANK ligand (RANKL), inactivating it. In consequence, the formation and survival of osteoclasts are suppressed, leading to their apoptosis. All this results in lower bone resorption, while bone mineral density (BMD) increases. Denosumab also reduces the risk of vertebral and non-vertebral fractures. This agent is similarly effective in various stages of renal function impairment; it does not impair fracture healing processes nor contribute to atherosclerosis progression in patients with high cardiovascular risks. Following an analysis of adverse effects, performed in the FREEDOM study (in which it was demonstrated that the incidence of the majority of adverse effects observed in the course of denosumab use was similar to that in the placebo group), its safety for patients can definitely be confirmed.     

First use of the RANKL antibody denosumab in Osteogenesis Imperfecta Type VI

Osteogenesis imperfecta (OI) is a genetically heterogeneous disease leading to bone fragility. OI-VI is an autosomal-recessive form caused by mutations in SERPINF1. There is experimental evidence suggesting that loss of functional SERPINF1 leads to an activation of osteoclasts via the RANK/RANKL pathway. Patients with OI-VI show a poor response to bisphosphonates. We report on four children with OI-VI who had shown continuously elevated urinary bone resorption markers during a previous treatment with bisphosphonates. We treated these children with the RANKL antibody denosumab to reduce bone resorption. Intervention and results: Denosumab (1 mg/kg body weight) was injected s.c. every 3 months. There were no severe side effects. Markers of bone resorption decreased to the normal range after each injection. N-terminal Propeptide of collagen 1 was measured in the serum during the first treatment cycle and decreased also. Urinary deoxypyridinoline/creatinine was monitored in a total of seven treatment cycles and indicated that bone resorption reached the pre-treatment level after 6-8 weeks. Conclusion: This was the first use of denosumab in children with OI-VI. Denosumab was well tolerated, and laboratory parameters provided evidence that the treatment reversibly reduced bone resorption. Therefore, denosumab may be a new therapeutic option for patients with OI-VI.     

The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction

Denosumab is a fully human monoclonal antibody against RANK ligand (RANKL), an essential cytokine for the formation, function, and survival of osteoclasts. The role of excessive RANKL as a contributor to conditions characterized by bone loss or bone destruction has been well studied. With its novel mechanism of action, denosumab offers a significant advance in the treatment of postmenopausal osteoporosis; bone loss associated with hormone ablation therapy in women with breast cancer and men with prostate cancer; and the prevention of skeletal-related events in patients with bone metastases from solid tumors by offering clinical benefit to these patients in need.     

Erosive arthritis

Inflammation and degradation of bone are two closely linked processes. Chronic inflammatory arthritis not only leads to inflammatory bone loss but it also involves local erosion of articular bone. This osteo-destructive feature of chronic inflammatory arthritis is a major cause of disability in patients with rheumatoid arthritis. Osteoclasts are essential for the resorption of mineralized cartilage and subchondral bone in chronic arthritis. The observed up-regulation of osteoclast differentiation factors (receptor activator of nuclear factor-kappaB ligand [RANKL]) in the synovial membrane of chronically inflamed joints indicates that osteoclasts are abundant in this setting, leading to rapid degradation of mineralized tissue. Blockade of osteoclast formation is thus a key strategy in preventing structural damage in arthritis. Denosumab, a humanized antibody that neutralizes RANKL, is an attractive candidate agent to inhibit inflammatory bone loss.     

Denosumab

Denosumab is an anti-receptor activator of nuclear factor (NF)-kappaB (RANK) ligand human monoclonal antibody studied as a treatment for postmenopausal osteoporosis (PMO) and bone destruction due to rheumatoid arthritis (RA) or metastatic cancers. As of February 2009, the candidate was undergoing US Food and Drug Administration review, and might be approved by October 2009. Late phase clinical trials demonstrated that denosumab possesses a similar safety profile to bisphosphonates and that it can be either equally or more effective than bisphosphonates at preventing bone loss due to PMO, RA or cancer treatment and metastases.Key Words: monoclonal antibody, RANKL, bone loss, osteoporosis, breast cancer, rheumatoid arthritis     

Denosumab

Denosumab is an anti-receptor activator of nuclear factor (NF)-kappaB (RANK) ligand human monoclonal antibody studied as a treatment for postmenopausal osteoporosis (PMO) and bone destruction due to rheumatoid arthritis (RA) or metastatic cancers. As of February 2009, the candidate was undergoing US Food and Drug Administration review, and might be approved by October 2009. Late phase clinical trials demonstrated that denosumab possesses a similar safety profile to bisphosphonates, and that it can be either equally or more effective than bisphosphonates at preventing bone loss due to PMO, RA, or cancer treatment and metastases.     

Treatment of osteoporosis with a modified zeolite shows beneficial effects in an osteoporotic rat model and a human clinical trial

The severity of osteoporosis in humans manifests in its high incidence and by its complications that diminish quality of life. A societal consequence of osteoporosis is the substantial burden that it inflicts upon patients and their families. Several bone-modifying drugs have been prescribed to patients with osteoporosis. However, evidence for their anti-fracture efficacy remains inconclusive. To the contrary, long-term use of anti-osteoporotic drugs such as bisphosphonates and Denosumab, an RANKL inhibitor, have resulted in adverse events. We now present an alternative and adjuvant approach for treatment of osteoporosis. The data derive from in vivo studies in an ovariectomized rat model and from a randomized double blind, placebo-controlled human clinical study. Both studies involved treatment with Panaceo Micro Activation (PMA)-zeolite-clinoptilolite, a defined cation exchange clinoptilolite, which clearly improved all bone histomorphometric parameters examined from ovariectomized animals, indicative for increased bone formation. Moreover, intervention with PMA-zeolite-clinoptilolite for one year proved safe in humans. Furthermore, patients treated with PMA-zeolite-clinoptilolite showed an increase in bone mineral density, an elevated level of markers indicative of bone formation, a significant reduction in pain, and significantly improved quality of life compared with patients in the control (placebo) group. These encouraging positive effects of PMA-zeolite-clinoptilolite on bone integrity and on osteoporosis warrant further evaluation of treatment with PMA-zeolite-clinoptilolite as a new alternative adjuvant therapy for osteoporosis.     

地舒单抗联合免疫检查点抑制剂治疗实体瘤骨转移临床疗效及安全性

摘要 目的：探究地舒单抗联合免疫检查点抑制剂治疗实体瘤骨转移临床疗效及安全性。方法：选择2020年7月~2022年11月南通市肿瘤医院收治的60例实体瘤骨转移患者为本次研究对象,分为两组：观察组,n=18,对照组,n=42。对照组开展伊班膦酸+替雷利珠单抗治疗,观察组开展替雷利珠单抗+地舒单抗治疗。比较治疗效果、骨密度水平、骨相关事件、相关指标及安全性。结果：观察组治疗控制率为82.86 %,对照组治疗控制率为54.76 %,观察组更高（P＜0.05）;治疗前,观察组及对照组的右足SOS变化比较无差异（P＞0.05）,治疗后,与治疗前相比,观察组及对照组均升高,且观察组更高（P＜0.05）;观察组骨相关事件发生率为22.22 %,对照组为50.00 %,观察组发生率更低（P＜0.05）;治疗前,匹兹堡睡眠质量指数（PSQI）、焦虑及抑郁自评表（SAS）、（SDS）、日常生活能力评价表（ADL）评分,观察组及对照组比较无差异（P＞0.05）,治疗后,与治疗前比较,观察组及对照组各指标水平均降低,且观察组更低（P＜0.05）;观察组不良反应率为44.44 %,对照组不良反应率为52.38 %,观察组及对照组比较（P＞0.05）。结论：地舒单抗联合免疫检查点抑制剂治疗可有效提升实体瘤骨转移的治疗效果,提升骨密度,降低骨不良事件风险,改善患者心理及生理指标,促进日常生活能力的有效提升,且安全性较高。     

Denosumab Use in Adults With Fibrous Dysplasia: Case Reports and Review of the Literature

ObjectiveIn fibrous dysplasia (FD) of the bone, a gain-of-function mutation in the G-nucleotide binding protein alpha subunit results in constitutively active cyclic adenosine monophosphate. Downstream effects include formation of disorganized cortex and bone marrow fibrosis. Patients with FD experience bone pain and are at risk of fracture. Bisphosphonates are traditionally used to manage pain with mixed results. We sought to report denosumab use in patients with FD at our institution and summarized the existing literature on denosumab use in FD.MethodsWe retrospectively identified patients with FD who were treated with denosumab at our institution, describing patient characteristics and outcomes. We reviewed the existing literature on denosumab use in patients with FD.ResultsPatient 1 was diagnosed with FD at the age of 17 years and took bisphosphonates with initial improvement in pain. Pain eventually worsened; therefore, she received 4 doses of denosumab. Patient 2 was diagnosed with FD after a fall and was treated with bisphosphonates, reporting some initial improvement in bone pain. A few years later, the pain recurred, and he received 3 doses of denosumab. Both patients tolerated denosumab well but experienced no improvement in pain. On literature review, although some serious side effects were noted, patients experienced a decline in bone turnover markers, and most reported improvement in bone pain with denosumab.ConclusionDenosumab is a promising therapy for managing symptoms of FD. Further studies are needed to determine the optimal dose and duration of treatment. Its long-term effect on FD lesions remains unclear.     

靶向治疗乳腺癌骨转移的研究进展

本文对双磷酸盐、狄诺塞麦、Sagopilone等特异性靶向药物在乳腺癌骨转移靶向治疗中的作用机制、临床应用、临床疗效等方面的相关研究进展情况进行了简要阐述。双磷酸盐在抑制骨转移和非骨转移中发挥作用,狄诺塞麦可能成为双磷酸盐的合理替代物,尤其在双磷酸盐治疗效果不佳的病人中,而新型抗癌药物Sagopilone、骨唾液酸蛋白抑制剂亦可通过多种机制参与乳腺癌转移过程,具有抑制骨转移的巨大潜力。     

The selection of an adjuvant emulsion for polyclonal antibody production using a low-molecular-weight antigen in rabbits.

Although Freund's adjuvant has been used for decades as an immune enhancer in rabbits, adverse physiologic side effects have prompted the search for more suitable alternatives. We used osteocalcin, a bovine bone protein (M.W. 5,800), as the test antigen to evaluate four adjuvant regimens: a) primary inoculation with complete Freund's adjuvant (CFA) followed by three boosts with incomplete Freund's adjuvant (IFA), b) four serial inoculations with RIBI MPL+TDM+CWS adjuvant, c) four serial inoculations with TiterMax #R-1, and d) primary inoculation (only) with TiterMax #R-1. The antibody yield associated with the CFA/IFA regimen (mean OD = 2.152) was at least sixfold that of either TiterMax (mean OD = 0.358) or RIBI (mean OD = 0.239) multiple injection regimens. No antibody response was observed after the single injection of TiterMax antigen emulsion. Maximal antibody production occurred rapidly in response to Freund's adjuvant (day 31) as compared with TiterMax (day 74) and RIBI (day 66).     

Osteoporosis: the current status of mesenchymal stem cell-based therapy

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.     

Tartrate-resistant acid phosphatase 5b as a serum marker of bone metastasis in breast cancer patients

Diagnosis and follow-up of bone metastases in breast cancer patients usually rely on symptoms and imaging studies. Tartrate-resistant acid phosphatase 5b (TRACP 5b) is a specific marker of osteoclasts and is herein proposed as a marker of bone metastasis in breast cancer patients. An immunoassay using a monoclonal antibody, 14G6, was used to measure the activity of serum TRACP 5b at pH 6.1 in 30 early breast cancer patients without bone metastasis and in 30 aged-matched breast cancer patients with bone metastasis. Another 60 normal volunteers were recruited as controls. Bone alkaline phosphatase (BAP), a traditional marker of bone turnover, was also measured in selected cases. The overall mean TRACP 5b activity in normal women was 2.83 ± 1.1 U/I, and it increased with age. The mean TRACP 5b activity in early breast cancer patients did not differ from that of the normal group (2.93 ± 0.64 vs. 2.83 ± 1.1 U/I; p=0.66), whereas it was significantly higher in breast cancer patients with bone metastasis (5.42 ± 2.5 vs. 2.83 ± 1.1 U/I; p<0.0001). BAP activity was significantly higher in breast cancer patients with bone metastasis than in early breast cancer patients (p=0.004). Serum TRACP 5b activity correlated well with BAP activity in breast cancer patients with bone metastasis (p<0.0001), but not in normal individuals or in patients without bone metastasis. TRACP 5b activity can be considered a surrogate indicator of bone metastasis in breast cancer patients.     

Stimulant of antibody producers isolated from the supernatants of cell cultures of normal human bone marrow and in various diseases

The biological activity of a stimulant of antibody producers (SAP) isolated from normal human bone marrow was studied and compared with that of a stimulant of antibody producers from the bone marrow of patients with acute myeloblastic leukemia, acute lymphoblastic leukemia, lymphosarcoma, and multiple myeloma. The activity of the SAP from human bone marrow in health was similar to that of analogous transmitters from the bone marrow of other species of the mammals and birds. The activity of the SAP in patients with multiple myeloma was elevated, whereas in patients with acute myeloblastic leukemia, it was lowered.     

Phytoestrogenic effects of black tea extract (Camellia sinensis) in an oophorectomized rat (Rattus norvegicus) model of osteoporosis

The adverse side effects of currently available anti-osteoporotic agents warrant the search for compounds with less toxic effects. In this study, we assessed the phytoestrogenic potentiality of whole aqueous extract of black tea (BTE) in a bilaterally oophorectomized rat model (2.5%, 1 ml/100 g body weight/day for 28 days). Although the supplementation was given for 28 days but, sign of revival of copulation period (estrous stage) from non-receptive diestrous stage was first noticed after 21 days of BTE supplementation in bilaterally oophorectomized rats. This was accompanied by a significant increase in serum estradiol level. To test whether this increase in serum estradiol level could have an influence upon the oophorectomy-induced damage of bone, we assessed marker parameters of bone resorption and osteoclastic activity (tartrate-resistant acid phosphatase), collagen degradation (urinary hydroxyproline), bone loss (bone ash mineral content) and bone breaking strength (bone density). Results indicated that increase in serum estradiol level after BTE supplementation could significantly diminish oophorectomy-induced decaying changes in bone. This study proposes that aqueous BTE may be assessed as a phytoestrogenic compound for prevention against estrogen deficiency-related osteoporotic damages.     

Effects of vitamin D supplementation on the bone specific biomarkers in HIV infected individuals under treatment with efavirenz

ABSTRACT: BACKGROUND: It was reported that antiretroviral drugs such as efavirenz can increase the catabolism of vitamin D in HIV infected individuals. We have not found any study that evaluated effects of vitamin D supplementation on the bone specific biomarkers in HIV positive patients under treatment with antiretroviral regimen containing efavirenz. FINDINGS: Vitamin D deficiency was detected in 88.4 % of included patients. Baseline osteocalcin, but not collagen telopeptidase, serum levels were lower than normal range in all of these individuals. Both bone biomarkers' concentrations increased significantly (p < 0.001 for both of them) after supplementation of vitamin D and it was more predominant for osteocalcin. CONCLUSION: In the HIV-infected patients under treatment with efavirenz, vitamin D deficiency is prevalent. After supplementation with single dose of 300,000 IU vitamin D in this population, the activation of osteoblasts and osteoclasts stimulates bone formation and resorption respectively with favorable bone formation without any adverse event. Significant percent of HIV infected individuals are vitamin d deficient that could benefit from vitamin D supplementation.     

Enamel matrix derivative is a potent inhibitor of breast cancer cell attachment to bone

This study examined whether enamel matrix derivative (EMD) inhibits the adhesion of cancer cells to bone. A typical breast cancer cell line, MCF-7, was used. Conditioned human osteosarcoma cell (Saos-2) medium was used as extracellular bone matrix (ECBM) to measure cell attachment. MCF-7 cells were incubated on ECBM-coated culture plates with or without soluble EMD, Arg-Gly-Asp (RGD) sequence blocking peptides, recombinant bone sialoprotein (rBSP), or specific integrin antibodies, and the attached cells were quantified using toluidine blue staining. EMD markedly reduced the attachment of MCF-7 cells to ECBM in a dose-dependent manner. An RGD peptide (GRGDSP) and recombinant BSP inhibited cell attachment to the same degree as EMD. Similarly, anti-alphavbeta3 integrin antibody strongly reduced cell attachment, whereas anti-alphavbeta5 and anti-beta1 integrin antibodies had less marked effects on cell attachment. These results show that EMD inhibits MCF-7 cell attachment to a bone matrix and that it might be useful as an anti-adhesive agent for breast cancer cells to bone in vivo.     

Safety of rituximab in the treatment of B cell malignancies: implications for rheumatoid arthritis

The chimeric anti-CD20 monoclonal antibody rituximab has been used extensively in the treatment of B cell malignancies, and more recently it has emerged as a potential treatment for rheumatoid arthritis (RA), via selective B lymphocyte depletion. Experience in oncology shows that rituximab is well tolerated in a variety of settings, with mild-to-moderate infusion related reactions following the first infusion being the most common adverse event. Current data suggest that the safety profile of rituximab in patients with RA is similar to that in oncology, but that the adverse events are less frequent and less severe in patients with RA.     

In vitro stoichiometry of complexes between the soluble RANK ligand and the monoclonal antibody denosumab

The in vitro binding stoichiometry of denosumab, an IgG2 fully human monoclonal therapeutic antibody, to RANK ligand was determined by multiple complementary size separation techniques with mass measuring detectors, including two solution-based techniques (size-exclusion chromatography with static light scattering detection and sedimentation velocity analytical ultracentrifugation) and a gas-phase analysis by electrospray ionization time-of-flight mass spectrometry from aqueous nondenaturing solutions. The stoichiometry was determined under defined conditions ranging from small excess RANK ligand to large excess denosumab (up to 40:1). High concentrations of denosumab relative to RANK ligand were studied because of their physiological relevance; a large excess of denosumab is anticipated in circulation for extended periods relative to much lower concentrations of free soluble RANKL. The studies revealed that an assembly including 3 denosumab antibody molecules bound to 2 RANKL trimers (3D2R) is the most stable complex in DPBS at 37 °C. This differs from the 1:1 binding stoichiometry reported for RANKL and osteoprotegerin (OPG), a soluble homodimeric decoy receptor which binds RANKL with high affinity. Denosumab and RANKL also formed smaller assemblies including 1 denosumab and 2 RANKL trimer molecules (1D2R) under conditions of excess RANKL, 3 denosumab molecules and 1 RANKL trimer (3D1R) under conditions of excess denosumab, and larger assemblies, but these intermediate species were only present at lower temperatures (4 °C), shortly after mixing denosumab and RANKL, and converted over time to the more stable 3D2R assembly.