Myelosuppressive therapies significantly increase pro-inflammatory cytokines and directly cause bone loss

Julie M Quach, Maria Askmyr, Tanja Jovic, Emma K Baker, Nicole C Walsh, Simon Harrison, Paul Neeson, David Ritchie, Peter Robert Ebeling, Louise E Purton

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

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 prior to 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 7-14 post-SCT positively correlated with bone loss observed at 100 days following 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 prior to 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 (?-CTx), positively correlated with their bone loss. Hence myelosuppressive therapies increase inflammation and directly contribute to bone loss. Administration of an osteoclast inhibitor prior to the initiation of cancer therapy is likely to have the best outcome in preventing bone loss in patients with cancer.
Original languageEnglish
Pages (from-to)886 - 897
Number of pages12
JournalJournal of Bone and Mineral Research
Volume30
Issue number5
DOIs
Publication statusPublished - 2015

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