scholarly journals Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

Blood ◽  
2017 ◽  
Vol 129 (26) ◽  
pp. 3452-3464 ◽  
Author(s):  
Michelle M. McDonald ◽  
Michaela R. Reagan ◽  
Scott E. Youlten ◽  
Sindhu T. Mohanty ◽  
Anja Seckinger ◽  
...  

Key Points Anti-sclerostin treatment increases bone mass and fracture resistance in MM Anti-sclerostin in combination with zoledronic acid is superior to zoledronic acid alone in increasing fracture resistance.

2013 ◽  
Vol 53 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Kent Søe ◽  
Jean-Marie Delaissé ◽  
Erik H. Jakobsen ◽  
Charlotte T. Hansen ◽  
Torben Plesner

2021 ◽  
pp. 107815522199603
Author(s):  
Christina Billias ◽  
Megan Langer ◽  
Sorana Ursu ◽  
Rebecca Schorr

Objective To determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients. Methods This institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw. Results A total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172–1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw. Conclusion Multiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.


2021 ◽  
pp. 153537022110110
Author(s):  
Yu-Ting Cheng ◽  
Jian Liao ◽  
Qian Zhou ◽  
Hua Huo ◽  
Lucas Zellmer ◽  
...  

Bone mass loss (osteoporosis) seen in postmenopausal women is an adverse factor for implant denture. Using an ovariectomized rat model, we studied the mechanism of estrogen-deficiency-caused bone loss and the therapeutic effect of Zoledronic acid. We observed that ovariectomized-caused resorption of bone tissue in the mandible was evident at four weeks and had not fully recovered by 12 weeks post-ovariectomized compared with the sham-operated controls. Further evaluation with a TUNEL assay showed ovariectomized enhanced apoptosis of osteoblasts but inhibited apoptosis of osteoclasts in the mandible. Zoledronic acid given subcutaneously as a single low dose was shown to counteract both of these ovariectomized effects. Immunohistochemical staining showed that ovariectomized induced the protein levels of RANKL and the 65-kD subunit of the NF-κB complex mainly in osteoclasts, as confirmed by staining for TRAP, a marker for osteoclasts, whereas zoledronic acid inhibited these inductions. Western blotting showed that the levels of RANKL, p65, as well as the phosphorylated form of p65, and IκB-α were all higher in the ovariectomized group than in the sham and ovariectomized + zoledronic acid groups at both the 4th- and 12th-week time points in the mandible. These data collectively suggest that ovariectomized causes bone mass loss by enhancing apoptosis of osteoblasts and inhibiting apoptosis of osteoclasts. In osteoclasts, these cellular effects may be achieved by activating RANKL-NF-κB signalling. Moreover, zoledronic acid elicits its therapeutic effects in the mandible by counteracting these cellular and molecular consequences of ovariectomized.


Blood ◽  
2016 ◽  
Vol 127 (13) ◽  
pp. 1676-1686 ◽  
Author(s):  
Zubin Zhang ◽  
Jiefei Tong ◽  
Xiaowen Tang ◽  
Jiaxiang Juan ◽  
Biyin Cao ◽  
...  

Key Points HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation. HERC4 suppresses MM cell proliferation and delays MM tumor growth.


Blood ◽  
2014 ◽  
Vol 123 (16) ◽  
pp. 2504-2512 ◽  
Author(s):  
Jeffrey R. Sawyer ◽  
Erming Tian ◽  
Christoph J. Heuck ◽  
Joshua Epstein ◽  
Donald J. Johann ◽  
...  

Key Points Jumping translocations of 1q12 (JT1q12) provide a mechanism for the deletion of 17p in cytogenetically defined high-risk myeloma. Sequential JT1q12s introduce unexpected copy number gains and losses in receptor chromosomes during subclonal evolution.


Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3765-3777 ◽  
Author(s):  
Elena Tsourdi ◽  
Franziska Lademann ◽  
Michael S Ominsky ◽  
Eddy Rijntjes ◽  
Josef Köhrle ◽  
...  
Keyword(s):  

Blood ◽  
2016 ◽  
Vol 127 (11) ◽  
pp. 1481-1492 ◽  
Author(s):  
Brian M. Dulmovits ◽  
Abena O. Appiah-Kubi ◽  
Julien Papoin ◽  
John Hale ◽  
Mingzhu He ◽  
...  

Key Points Pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis. The mechanism of action of pomalidomide during erythropoiesis is independent of IKZF1 degradation, in contrast to multiple myeloma.


Blood ◽  
2015 ◽  
Vol 126 (17) ◽  
pp. 1996-2004 ◽  
Author(s):  
Rowan Kuiper ◽  
Mark van Duin ◽  
Martin H. van Vliet ◽  
Annemiek Broijl ◽  
Bronno van der Holt ◽  
...  

Key Points Combination of ISS and the EMC92 gene classifier is a novel clinically applicable risk classification for survival in multiple myeloma. ISS has clear independent additive prognostic value in combination with GEP classifiers or FISH markers.


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