title: Myelosuppressive therapies significantly increase pro-inflammatory cytokines and directly cause bone loss.
abstract: Skeletal-related events resulting from accelerated bone loss are common complications in patients treated for a range of cancers. However, the mechanisms and rate of bone loss after myelosuppression are unclear. We, therefore, investigated this in mice and humans. We treated mice with different myelosuppressive therapies (chemotherapy or irradiation with or without transplantation) and studied their effects on bone structure. Myelosuppression of mice rapidly caused an increase in bone resorption that was not matched by bone formation. The resultant significant and persistent bone loss early after therapy was associated with increased inflammatory cytokines, in particular, monocyte chemoattractant protein 1 (MCP1). Therapy-induced bone loss was prevented with a single dose of the bisphosphonate zoledronic acid (ZA), administered before myelosuppression. Importantly, ZA treatment of mice did not impair hematopoiesis, including hematopoietic stem cell function. Furthermore, examination of serum from patients before and after autologous or allogeneic stem cell transplantion (SCT) revealed altered levels of bone turnover markers and elevated inflammatory cytokines. MCP1 levels in serum obtained between days 7 and 14 post-SCT positively correlated with bone loss observed at 100 days after allogeneic SCT. Similar to that observed in our studies in mice, the bone loss was long term, persisting at 12 months post-SCT. Furthermore, patients who received chemotherapy less than 100 days before SCT had significantly more bone loss at the hip. In these patients, serum levels of MCP1, but not routine biomarkers of bone turnover, including C-terminal cross-linking telopeptide of type-1 collagen (β-CTx), positively correlated with their bone loss. Hence, myelosuppressive therapies increase inflammation and directly contribute to bone loss. Administration of an osteoclast inhibitor before the initiation of cancer therapy is likely to have the best outcome in preventing bone loss in patients with cancer.
authors.affiliation: Stem Cell Regulation Unit, St Vincent's Institute of Medical Research, Fitzroy, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Quach
authors.forename: Maria
authors.initials: M
authors.lastname: Askmyr
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovic
authors.forename: Emma K
authors.initials: EK
authors.lastname: Baker
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Walsh
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Harrison
authors.forename: Paul
authors.initials: P
authors.lastname: Neeson
authors.forename: David
authors.initials: D
authors.lastname: Ritchie
authors.forename: Peter R
authors.initials: PR
authors.lastname: Ebeling
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000097:blood; D016207:Cytokines / Q000378:metabolism*; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D018836:Inflammation Mediators; D000077211:Zoledronic Acid
keywords: BONE HISTOMORPHOMETRY; BONE µCT; CYTOKINES; OSTEOCLASTS; PRECLINICAL STUDIES