Improving Bone Health by Optimizing the Anabolic Action of Wnt Inhibitor Multitargeting

Roy B. Choi, Whitney A. Bullock, April M. Hoggatt, Gabriela G. Loots, Damian C. Genetos, Alexander G. Robling

Research output: Contribution to journalArticlepeer-review

Abstract

Sclerostin antibody (romosozumab) was recently approved for clinical use in the United States to treat osteoporosis. We and others have explored Wnt-based combination therapy to disproportionately improve the anabolic effects of sclerostin inhibition, including cotreatment with sclerostin antibody (Scl-mAb) and Dkk1 antibody (Dkk1-mAb). To determine the optimal ratio of Scl-mAb and Dkk1-mAb for producing maximal anabolic action, the proportion of Scl-mAb and Dkk1-mAb were systematically varied while holding the total antibody dose constant. A 3:1 mixture of Scl-mAb to Dkk1-mAb produced two to three times as much cancellous bone mass as an equivalent dose of Scl-mAb alone. Further, a 75% reduction in the dose of the 3:1 mixture was equally efficacious to a full dose of Scl-mAb in the distal femur metaphysis. The Scl-mAb/Dkk1-mAb combination approach was highly efficacious in the cancellous bone mass, but the cortical compartment was much more subtly affected. The osteoanabolic effects of Wnt pathway targeting can be made more efficient if multiple antagonists are simultaneously targeted.

Original languageEnglish (US)
Article numbere10462
JournalJBMR Plus
Volume5
Issue number5
DOIs
StatePublished - May 2021
Externally publishedYes

Keywords

  • BONE ANABOLISM
  • OSTEOPOROSIS
  • SCLEROSTIN Dkk1
  • Wnt

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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