Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: Mouse strain disparities and synergic effect with zoledronic acid

Lezot, Frédéric; Chesneau, Julie; Navet, Benjamin; Gobin, Bérengère; Amiaud, Jérôme; Choi, Yongwon; Yagita, Hideo; Castañeda, Beatriz; Berdal, Ariane; Mueller, Christopher G.; Rédini, Françoise; Heymann, Dominique

doi:10.1016/j.bone.2014.12.011

Cited by 32 publications

(55 citation statements)

References 57 publications

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“…Preclinical studies using different animal models have reported specific effects on growing long bones (Battaglia et al, ; Evans, Lau, Oberbauer, & Martin, ; Lézot et al, , ; Zhu, Louis, Brooks, Bouxsein, & Demay, ). Evans et al () using a mouse model of OI type III, evaluated the impact of alendronate on osteoclastic resorption of calcified cartilage septa at the base of the growth plate in the humerus and ulna.…”

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

“…For long term‐treated mice, they observed enlargement of the growth plate hypertrophic zone, characteristic of osteopetrosis, whereas the size of this zone remained unchanged in short term‐treated mice (Lézot et al, ). In a second study in 2015, these authors reported that the effects observed on long bones with the long‐term treatment were gradually reversed by 3 months after the end of the treatment (Lézot et al, ).…”

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

“…They concluded that N‐BP therapy has a potential risk of disturbing maxillofacial growth in young patients (Bradaschia‐Correa et al, ). Lézot et al in the studies previously described (Lézot et al, , ), evaluated the impact of high doses of zoledronate on craniofacial skeleton growth. They found enlargement of the craniofacial sutures in mice (C57BL/6 and CD1 strains) treated with zoledronate, more severe in longer treatments (Lézot et al, , ).…”

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

“…They described a domed skull associated with the suture enlargement. Nevertheless, during the three months following the end of the zoledronate treatment, the suture mineralization defects and dome morphology of the skull gradually normalized (Lézot et al, , ).…”

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

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Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

Vargas-Franco

Castañeda

Rédini

et al. 2018

Journal Cellular Physiology

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Bisphosphonates are considered the most effective drugs for controlling adult and pediatric osteolytic diseases. Although they have been used successfully for many years, several side effects, such as osteonecrosis of the jaw, delayed dental eruption, atypical femoral fracture, and alterations to the bone growth system, have been described. After an overview of nitrogenous bisphosphonate, the purpose of this article is to describe their mechanisms of action and current applications, review the preclinical and clinical evidence of their side effects in the skeleton ("what we know"), and describe current recommendations for preventing and managing these effects ("what we can do"). Finally, promising future directions on how to limit the occurrence of these side effects will be presented.

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Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

Section: Skeletal Side Effects Of Bisphosphonatesmentioning

confidence: 99%

See 2 more Smart Citations

Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

Vargas-Franco

Castañeda

Rédini

et al. 2018

Journal Cellular Physiology

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“…These side effects are more likely to occur with prolonged and/or higher doses of bisphosphonates such as those used for the treatment of skeletal metastasis. In addition, use of bisphosphonates is generally avoided in children as they can delay skeletal growth and tooth eruption [47]. However, using a low-dose bisphosphonate in conjunction with the etoposide chemotherapeutic approach could serve to protect against its deleterious skeletal effects.…”

Section: Discussionmentioning

confidence: 99%

The skeletal impact of the chemotherapeutic agent etoposide

et al. 2017

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Summary Effects of the chemotherapeutic agent etoposide on the skeleton were determined in mice. Numbers of bone marrow cells were reduced and myeloid cells were increased. Bone volume was significantly decreased with signs of inhibition of bone formation. Etoposide after pre-treatment with zoledronic acid still reduced bone but overall bone volume was higher than with etoposide alone. Introduction Chemotherapeutics target rapidly dividing tumor cells yet also impact hematopoietic and immune cells in an off target manner. A wide array of therapies have negative side effects on the skeleton rendering patients osteopenic and prone to fracture. This study focused on the pro-apoptotic chemotherapeutic agent etoposide and its short- and long-term treatment effects in the bone marrow and skeleton. Methods Six- to 16-week-old mice were treated with etoposide (20–25 mg/kg) or vehicle control in short-term (daily for 5–9 days) or long-term (3×/week for 17 days or 6 weeks) regimens. Bone marrow cell populations and their phagocytic/efferocytic functions were analyzed by flow cytometry. Blood cell populations were assessed by CBC analysis. Bone volume and area compartments and osteoclast numbers were measured by microCT, histomorphometry, and TRAP staining. Biomarkers of bone formation (P1NP) and resorption (TRAcP5b) were assayed from serum. Gene expression in bone marrow was assessed using qPCR. Results Flow cytometric analysis of the bone marrow revealed short-term etoposide reduced overall cell numbers and B220+ cells, with increased marrow apoptotic (AnnexinV+PI−) cells, mesenchymal stem-like cells, and CD68+, CD45+, and CD11b+ monocyte/myeloid cells (as a percent of the total marrow). After 6 weeks, the CD68+, Gr1+, CD11b+, and CD45+ cell populations were still relatively increased in etoposide-treated bone marrow. Skeletal phenotyping revealed etoposide decreased bone volume, trabecular thickness, and cortical bone volume. Gene expression in the marrow for the leptin receptor and CXCL12 were reduced with short-term etoposide, and an increased ratio of RANKL/OPG mRNA was observed. In whole bone, Runx2 and osteocalcin gene expressions were reduced, and in serum, P1NP was significantly reduced with etoposide. Treatment with the antiresorptive agent zoledronic acid prior to etoposide increased bone volume and improved the etoposide-induced decrease in skeletal parameters. Conclusions These data suggest that etoposide induces apoptosis in the bone marrow and significantly reduces parameters of bone formation with rapid reduction in bone volume. Pre-treatment with an antiresorptive agent results in a preservation of bone mass. Preventive approaches to preserving the skeleton should be considered in human clinical studies.

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Biology of Bone Sarcomas and New Therapeutic Developments

et al. 2017

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Bone sarcomas are tumours belonging to the family of mesenchymal tumours and constitute a highly heterogeneous tumour group. The three main bone sarcomas are osteosarcoma, Ewing sarcoma and chondrosarcoma each subdivided in diverse histological entities. They are clinically characterised by a relatively high morbidity and mortality, especially in children and adolescents. Although these tumours are histologically, molecularly and genetically heterogeneous, they share a common involvement of the local microenvironment in their pathogenesis. This review gives a brief overview of their specificities and summarises the main therapeutic advances in the field of bone sarcoma.

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Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: Mouse strain disparities and synergic effect with zoledronic acid

Cited by 32 publications

References 57 publications

Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

The skeletal impact of the chemotherapeutic agent etoposide

Biology of Bone Sarcomas and New Therapeutic Developments

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