Review
Hematology
Evangelos Terpos, Ioannis Ntanasis-Stathopoulos
Summary: Bone-modifying therapies, including zoledronic acid and denosumab, are essential for patients with multiple myeloma. Denosumab may offer a survival benefit for patients eligible for autologous transplantation and may be safer for those with renal impairment. Prophylactic measures for hypocalcaemia, renal toxicity, and osteonecrosis of the jaw are important considerations for all bone-modifying agents.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Review
Hematology
Munawwar Hussain, Fatima Khan, Samer Al Hadidi
Summary: Multiple myeloma is a blood cancer that causes abnormal plasma cell proliferation in the bone marrow, leading to increased bone pain and skeletal-related events. Myeloma bone disease affects the bone-marrow micro-environment, resulting in decreased bone quality. The treatment for myeloma bone disease includes bone-modifying agents that can reduce bone pain and the risk of fractures, but their impact on overall survival is unknown. This review focuses on different classes of these agents, their mechanisms of action, timing and duration of therapy, and potential survival benefits.
Review
Cell Biology
Zachary S. Bernstein, E. Bridget Kim, Noopur Raje
Summary: Multiple Myeloma is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells in the bone marrow, often leading to bone disease and osteolytic lesions. Treatment options can include osteoclast inhibitory therapies to delay and reduce the risk of skeletal-related events.
Review
Biochemistry & Molecular Biology
Jeng-Shiun Du, Chia-Hung Yen, Chin-Mu Hsu, Hui-Hua Hsiao
Summary: Multiple myeloma is a B-cell neoplasm characterized by clonal plasma-cell proliferation. Treatment with active anti-MM drugs has significantly improved survival and prognosis. Understanding the molecular mechanisms of MM bone disease is crucial in developing effective treatments to prevent skeletal-related events.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Yuh-Ching Gau, Tsung-Jang Yeh, Chin-Mu Hsu, Samuel Yien Hsiao, Hui-Hua Hsiao
Summary: Multiple myeloma-related bone disease (MBD) is caused by an imbalance in the bone-remodeling process and involves various signaling pathways and molecules. Bisphosphonate and denosumab are currently the standard treatments, while novel bone-modifying therapies are being explored.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Fei Fei, Tingting Ma, Xuan Zhou, Meihong Zheng, Bei Cao, Juan Li
Summary: This study identified distinct metabolic features between multiple myeloma patients and healthy volunteers, especially in bone marrow, with disruptions in glutamate metabolism and carnitine synthesis being unique in multiple myeloma patients. Aspartate in plasma was highlighted as a top candidate biomarker for diagnosis, while threonine was identified as a preferential biomarker for risk prediction, showing significant relations with various risk indexes of multiple myeloma in both bone marrow and plasma.
Article
Endocrinology & Metabolism
Jianguo Tao, Venkat Srinivasan, Xiangjiao Yi, Yingchun Zhao, Hengwei Zhang, Xi Lin, Xichao Zhou, Brendan F. Boyce, Peter W. Villalta, Frank H. Ebetino, Koc Kan Ho, Robert K. Boeckman, Lianping Xing
Summary: Limited treatment options exist for cancer within the bone, and new alternative treatments are needed to overcome drug resistance and minimize off-target effects. Bone-targeted conjugates can provide spatiotemporally controlled delivery of drugs, leading to more effective treatment of multiple myeloma. The study demonstrated that the bone-targeted conjugate had better efficacy in overcoming drug resistance and reducing tumor burden and bone destruction.
JOURNAL OF BONE AND MINERAL RESEARCH
(2022)
Article
Oncology
Tina Bech Olesen, Ina Trolle Andersen, Anne Gulbech Ording, Vera Ehrenstein, Anouchka Seesaghur, Carsten Helleberg, Trine Silkjaer, Rohini K. Hernandez, Daniela Niepel, Niels Abildgaard
Summary: The use of bisphosphonates in newly diagnosed multiple myeloma patients in Denmark was influenced by the presence of myeloma bone disease and severity of renal impairment. A proportion of newly diagnosed multiple myeloma patients did not receive bisphosphonate treatment, suggesting a potential unmet need.
SUPPORTIVE CARE IN CANCER
(2021)
Review
Biochemistry & Molecular Biology
Oxana Lungu, Denise Toscani, Jessica Burroughs-Garcia, Nicola Giuliani
Summary: The study of osteoblast metabolism has attracted increasing attention recently due to its high energy demand during bone remodeling. In addition to glucose, recent data show that amino acid and fatty acid metabolism plays an important role in providing fuel for osteoblast functioning. Glutamine has been identified as a crucial amino acid for osteoblast differentiation and activity. This review focuses on the metabolic pathways involved in the fate and functions of osteoblasts, particularly in multiple myeloma (MM) bone disease where the presence of malignant plasma cells disrupts osteoblast formation and activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Parinya Samakkarnthai, Dominik Saul, Lei Zhang, Zaira Aversa, Madison L. Doolittle, Jad G. Sfeir, Japneet Kaur, Elizabeth J. Atkinson, James R. Edwards, Graham G. Russell, Robert J. Pignolo, James L. Kirkland, Tamar Tchkonia, Laura J. Niedernhofer, David G. Monroe, Nathan K. Lebrasseur, Joshua N. Farr, Paul D. Robbins, Sudeep Khosla
Summary: In addition to reducing fracture risk, zoledronic acid has been found to extend lifespan and healthspan in animals. The study suggests that the non-skeletal actions of zoledronic acid could be due to its ability to kill senescent cells and inhibit the secretion of harmful substances from these cells. These findings highlight the potential of zoledronic acid in anti-aging therapy.
Article
Oncology
Syed Hassan Mehdi, Carol A. Morris, Jung Ae Lee, Donghoon Yoon
Summary: The research team successfully developed a new multiple myeloma bone disease (MMBD) model, which can better study the biology of MMBD and provide a powerful tool for screening therapeutic candidates.
Review
Hematology
Mehmet Kemal Samur, Raphael Szalat, Nikhil C. Munshi
Summary: Single-cell platforms have become the norm in many research fields, including multiple myeloma, due to the high cellular heterogeneity of the disease. The decreasing cost and increasing accessibility of single-cell platforms, combined with breakthroughs in obtaining multiomics data and analyzing it, have allowed important insights into MM pathogenesis, with further work to be done.
Review
Medicine, General & Internal
Niels W. C. J. van de Donk, Charlotte Pawlyn, Kwee L. Yong
Summary: Multiple myeloma is the second most common haematological malignancy in high-income countries. Current treatment strategies have extended patient survival, but the majority will ultimately die from the disease. Diagnostics and risk stratification are crucial for prognosis and treatment strategies.
Review
Oncology
Raquel Lopes, Bruna Velosa Ferreira, Joana Caetano, Filipa Barahona, Emilie Arnault Carneiro, Cristina Joao
Summary: Multiple myeloma is a hematological malignancy arising from the proliferation of tumor antibody-producing cells in the bone marrow. Immunotherapy is a form of cancer treatment that aims to stimulate the immune system to fight back tumor cells, but has not yet been able to cure multiple myeloma completely.
Article
Pharmacology & Pharmacy
Zhaomeng Hou, Ping Jiang, Shaoting Su, Honghai Zhou
Summary: This study explores the research hotspots and trends of multiple myeloma bone disease in the past 20 years through bibliometric visualization analysis, revealing that the research is mainly focused on oncology and hematology, with recent frontiers in disease diagnosis, prognosis evaluation, pathogenesis, imaging technology, and targeted therapy. Burst keywords like transplantation, progression, activation, lenalidomide, flow cytometry, drug resistance, management, and mesenchymal stem cell reflect the latest research hotspots.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell & Tissue Engineering
Florence Figeac, Michaela Tencerova, Dalia Ali, Thomas L. Andersen, Dan Remi Christiansen Appadoo, Greet Kerckhofs, Nicholas Ditzel, Justyna M. Kowal, Alexander Rauch, Moustapha Kassem
Summary: This study investigated the mechanisms of impaired fracture healing associated with obesity and type 2 diabetes (T2D). The findings showed that both hyperinsulinemia and insulinopenia delayed bone healing. Hyperinsulinemia resulted in reduced newly formed bone, increased accumulation of marrow adipocytes and senescent cells, while insulinopenia had a more pronounced effect on bone healing. Additionally, serum from obese and T2D subjects inhibited osteoblast differentiation and enhanced adipocyte differentiation in human bone marrow stromal cells.
Article
Endocrinology & Metabolism
Morten S. Hansen, Kent Soe, Line L. Christensen, Paula Fernandez-Guerra, Nina W. Hansen, Rachael A. Wyatt, Claire Martin, Rowan S. Hardy, Thomas L. Andersen, Jacob B. Olesen, Bolette Hartmann, Mette M. Rosenkilde, Moustapha Kassem, Alexander Rauch, Caroline M. Gorvin, Morten Frost
Summary: Drugs targeting the GIP receptor have potential as treatments for type-2 diabetes and obesity. GIP can directly act on human bone cells to inhibit bone resorption, increase bone formation, and improve osteoblast survival. Therefore, these drugs may reduce bone resorption while preserving bone formation.
EUROPEAN JOURNAL OF ENDOCRINOLOGY
(2023)
Article
Endocrinology & Metabolism
Marta Diaz-delCastillo, Michael Tveden Gundesen, Christian Walther Andersen, Anne Lerberg Nielsen, Hanne Elisabeth Hojsgaard Moller, Pernille Just Vinholt, Jon Thor Asmussen, Ida Bruun Kristensen, Charlotte Guldborg Nyvold, Niels Abildgaard, Thomas Levin Andersen, Thomas Lund
Summary: Multiple myeloma is an incurable bone marrow cancer that leads to osteolytic lesions. Treatment often involves proteasome inhibitors, but their side effects and administration route limit long-term use. This study investigates the bone effects of ixazomib, a new-generation oral proteasome inhibitor, and suggests that it may promote bone formation by reducing bone resorption and promoting longer bone formation events.
JOURNAL OF BONE AND MINERAL RESEARCH
(2023)
Article
Endocrinology & Metabolism
Thomas Levin Andersen, Pia Rosgaard Jensen, Tanja Tvistholm Sikjaer, Lars Rejnmark, Charlotte Ejersted, Jean-Marie Delaisse
Summary: Proper bone remodeling relies not only on the actions of osteoclasts and osteoblasts, but also on the delivery of osteoblast lineage cells to the remodeling site. A CD271-positive/PDGF beta-R-positive cell layer surrounding the bone marrow provides osteoblastogenic potential on all bone surfaces, including both quiescent and remodeling sites. This cell layer, known as the canopy, plays a critical role in initiating bone remodeling by activating early markers of osteoblastogenesis and supporting cell delivery to the bone surface.
JOURNAL OF BONE AND MINERAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Li Chen, Kaikai Shi, Nicholas Ditzel, Weimin Qiu, Florence Figeac, Louise Himmelstrup Dreyer Nielsen, Michaela Tencerova, Justyna Magdalena Kowal, Ming Ding, Christina Moller Andreasen, Thomas Levin Andersen, Moustapha Kassem
Summary: The levels of KIAA1199, a factor secreted by bone marrow stromal cells, are associated with the risk of osteoporotic fracture. KIAA1199 deficiency enhances bone formation, accelerates bone healing, and protects against ovariectomy-induced bone loss. Transplanted skeletal stem cells generate secreted factors that regulate bone regeneration, and KIAA1199 is identified as one of these factors. Patients with higher plasma levels of KIAA1199 have a higher risk of osteoporotic fracture, while lower expression levels of KIAA1199 in patient bone marrow stromal cells are associated with reduced osteogenic differentiation potential. In vitro and in vivo experiments show that KIAA1199-deficient bone marrow stromal cells exhibit enhanced osteoblast differentiation and ectopic bone formation. KIAA1199 knockout mice have increased bone mass, biomechanical strength, bone formation rate, and accelerated healing of surgically generated bone defects, and are protected from ovariectomy-induced bone loss. Mechanistically, KIAA1199 regulates osteogenesis by inhibiting the production of osteopontin by osteoblasts through integrin-mediated AKT and ERK-MAPK signaling pathways. Therefore, KIAA1199 is a regulator of osteoblast differentiation and bone regeneration, and could be a potential target for treating or managing low bone mass conditions.
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Qihua Tan, Anais Marie Julie Moller, Chuan Qiu, Jonna Skov Madsen, Hui Shen, Troels Bechmann, Jean-Marie Delaisse, Bjarne Winther Kristensen, Hong-Wen Deng, David Karasik, Kent Soe
Summary: Clinical trials have shown that zoledronic acid is effective in preventing bone loss, but its potency varies among patients. Smoking has been reported as a contributing factor to the variation in sensitivity to zoledronic acid. In this study, DNA methylation profiling was performed on blood cells to investigate the molecular basis of smoking-mediated variation in treatment sensitivity. The results revealed significant associations between DNA methylation, smoking, and the half-maximal inhibitory concentration (IC50) of zoledronic acid. Genomic sites associated with bone and body size measures were also found to be enriched near the smoking-associated CpG sites. Furthermore, gene ontology analysis identified several significant functional terms related to ion channel activity and extracellular matrix strength. These findings suggest that smoking affects individual sensitivity to zoledronic acid treatment through epigenetic regulation, highlighting the potential for personalized treatment based on DNA methylation analysis.
CLINICAL EPIGENETICS
(2023)
Article
Endocrinology & Metabolism
Christina Moller Andreasen, Bilal Mohamad El-Masri, Birgit MacDonald, Kaja Sondergaard Laursen, Malene Hykkelbjerg Nielsen, Jesper Skovhus Thomsen, Jean-Marie Delaisse, Thomas Levin Andersen
Summary: This study reveals the association between bone resorption events and vascular development. Analysis of proximal femoral cortical bone showed that vessels were more prevalent in non-quiescent pores compared to quiescent pores. Remodeling of existing pores had a higher density of vessels compared to de novo created pores. Additionally, pores at the eroded-formative remodeling stage had the highest density of vessels. Through 3D reconstruction, it was found that osteoclasts in the cutting cone and preosteoclasts in the lumen expressed VEGFA, while VEGFA-receptors were mainly expressed in endothelial cells in the adjacent vasculature. Therefore, it is proposed that the progression of the vascular network in intracortical remodeling events is driven by osteoclasts expressing VEGFA, and the vasculature is continuously reconfigured according to the demands of the remodeling events at the surrounding bone surfaces.
Article
Endocrinology & Metabolism
Louise Alstrup Drejer, Bilal Mohamad El-Masri, Charlotte Ejersted, Christina Moller Andreasen, Lisbeth Koch Thomsen, Jesper Skovhus Thomsen, Thomas Levin Andersen, Stinus Hansen
Summary: This case report describes a patient with postmenopausal osteoporosis who experienced multiple vertebral fractures after discontinuing denosumab treatment. The study found that reinitiating denosumab treatment led to extensive bone resorption and delayed bone formation. This highlights the importance of developing optimal discontinuation strategies to prevent such complications.
Review
Oncology
Martin Johansen, Mette Boegh Levring, Kasper Stokbro, Marta Diaz-delCastillo, Abdul Ahad Khan, Line Adsboll Wickstroem, Michael Tveden Gundesen, Ida Bruun Kristensen, Charlotte Guldborg Nyvold, Mikkel osterheden Andersen, Thomas Levin Andersen, Niels Abildgaard, Thomas Lund, Efstathios Kastritis, Moshe Gatt
Summary: Multiple myeloma patients often have osteolytic bone disease, causing fractures and reduced quality of life. This paper reviews current and novel treatment modalities, including medication, surgery, and radiation, as well as improvements in managing therapy-related complications. Oral surgery has been successful in managing osteonecrosis of the jaw, while procedures like vertebroplasty and kyphoplasty can provide pain relief and improved mobility for patients with spinal involvement. The first oral proteasome inhibitor, Ixazomib, shows promising results in increasing bone formation activity. Other potential treatment strategies are also discussed.
Article
Endocrinology & Metabolism
Pernille van Dijk Christiansen, Tanja Sikjaer, Christina Moller Andreasen, Jesper Skovhus Thomsen, Annemarie Brueel, Ellen Margrethe Hauge, Jean-Marie Delaisse, Lars Rejnmark, Thomas Levin Andersen
Summary: The study found that the use of rhPTH(1-84) in patients with hypoparathyroidism can promote intracortical remodeling and the transition from erosion to formation. This effect lasts for 30 months and is reversible.
Article
Endocrinology & Metabolism
Pernille van Dijk Christiansen, Christina Moller Andreasen, Bilal Mohamad El-Masri, Kaja Sondergaard Laursen, Jean-Marie Delaisse, Thomas Levin Andersen
Summary: This study investigates the gradual recruitment, proliferation, and differentiation of osteoprogenitors into bone-forming osteoblasts during intracortical remodeling events in healthy adolescent humans. The initiation of bone formation requires a critical density of these osteoprogenitors, which is achieved through proliferation and recruitment of local osteoprogenitors.