Trabecular bone deterioration in a postmenopausal female suffering multiple spontaneous vertebral fractures due to a delayed denosumab injection – A post-treatment re-initiation bone biopsy-based case study

Drejer, Louise Alstrup; El-Masri, Bilal Mohamad; Ejersted, Charlotte; Andreasen, Christina Møller; Thomsen, Lisbeth Koch; Thomsen, Jesper Skovhus; Andersen, Thomas Levin; Hansen, Stinus

doi:10.1016/j.bonr.2023.101703

Cited by 5 publications

(1 citation statement)

References 49 publications

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“…Discontinuation of ZA results in a gradual declining effect, while discontinuation of Dmab may result in a devastating resorptive rebound phenomenon, probably due to an underlying upregulation of RANKL. Studies including patients with other diseases than MM have shown that terminating treatment with Dmab, or even a brief temporary discontinuation, may result in severe bone resorptive rebound, leading to an increased risk of multiple vertebral fractures [67][68][69][70]. A direct transition from Dmab to ZA has shown to diminish, but not prevent, this rebound phenomenon [71], and this approach may not be viable in patients on Dmab with reduced renal function.…”

Section: Antiresorptive Agents and Duration Of Treatmentmentioning

confidence: 99%

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

Johansen,

Levring,

Stokbro

et al. 2023

Cancers

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Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60–85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.

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Section: Antiresorptive Agents and Duration Of Treatmentmentioning

confidence: 99%

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

Johansen,

Levring,

Stokbro

et al. 2023

Cancers

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Alendronic-acid/denosumab

2024

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Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect

El-Masri,

Andreasen,

Laursen

et al. 2024

Bone Res

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Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1–34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11+ cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

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Trabecular bone deterioration in a postmenopausal female suffering multiple spontaneous vertebral fractures due to a delayed denosumab injection – A post-treatment re-initiation bone biopsy-based case study

Cited by 5 publications

References 49 publications

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

Alendronic-acid/denosumab

Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect

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