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Effects of odanacatib on bone-turnover markers in osteoporotic postmenopausal women: a post hoc analysis of the LOFT study

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Abstract

Summary

This post hoc analysis and modeling study examined the mechanism of action of odanacatib using a statistical model to explain sCTx response in ODN-treated patients as a function of other bone-turnover biomarkers that, with other observed biomarker changes, showed that odanacatib persistently inhibited osteoclastic bone removal activity without preventing osteoclastogenesis.

Introduction

Odanacatib (ODN) is an oral selective cathepsin K (CatK) inhibitor, previously in development for osteoporosis treatment. A post hoc analysis examined ODN’s mechanism of action on bone-turnover biomarkers.

Methods

A subset of patients who completed 60 months’ treatment in the Long-Term Odanacatib Fracture Trial (LOFT; NCT00529373) (N = 112 [57 ODN, 55 placebo]) were evaluated. Serum (s) and urine (u) samples were assayed at baseline and months 6–60 for 10 known bone-remodeling biomarkers: sCTx, uαα- and uββCTx/Cr, uNTx/Cr, sNTx, uDPD/Cr, sICTP, sTRAP5b, sPINP, and sBSAP. Because the CrossLaps® CTx assay identifies the CTx peptide as well as larger molecular weight CTx-containing peptides, including ICTP, a best-fit model was developed to explain the transient sCTx reduction in ODN-treated patients.

Results

ODN persistently reduced the bone-resorption markers sNTx, uNTx/Cr, uαα- and uββCTx/Cr, and uDPD/Cr, and gradually increased the target-engagement marker sICTP and osteoclast number (sTRAP5b), versus placebo from baseline to month 60. sCTx was transiently reduced with ODN within 12 months, returning to baseline by month 48. Modeling suggested that sCTx changes in the ODN group were primarily due to increased accumulation of larger CTx species, including sICTP. The bone-formation markers sPINP and sBSAP showed partial reductions, versus placebo, in the first 6 months but approached baseline by months 48–60.

Conclusion

Observed changes in bone-turnover biomarkers support the persistent efficacy of ODN in direct inhibition of osteoclastic bone-resorption activity, without inhibition of osteoclastogenesis. Long-term evaluation also underscores the unique mechanism of ODN on osteoclastic collagen processing and subsequently osteoblastic bone formation.

Trial registration

NCT00529373.

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Data availability

The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

Code availability

Not applicable.

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Acknowledgements

Medical writing assistance, under the direction of the authors, was provided by Gráinne Faherty, MPharm, of CMC AFFINITY, McCann Health Medical Communications, in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. The study sponsor was involved in the study design, collection, analysis and interpretation of data, and writing of the report. Although a clearance review of this manuscript was performed by the sponsor to protect intellectual property or competitive information and prevent inadvertent disclosure, all authors had access to the study data, contributed to the development of this manuscript, approved content, and agreed with the decision to submit for publication.

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Authors and Affiliations

  1. Merck & Co., Inc., Rahway, NJ, USA

    L. T. Duong, S. Clark, M. Pickarski, D. Cohn & S. A. Stoch

  2. MSD Europe Inc., Brussels, Belgium

    H. Giezek & R. Massaad

Authors
  1. L. T. Duong
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  2. S. Clark
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  3. M. Pickarski
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  4. H. Giezek
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  5. D. Cohn
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  6. R. Massaad
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  7. S. A. Stoch
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Corresponding author

Correspondence to S. Clark.

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Not applicable, post hoc analysis.

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Not applicable, post hoc analysis.

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Not applicable, data anonymized.

Conflict of interest

Le T. Duong, Seth Clark, Maureen Pickarski, Hilde Giezek, Dosinda Cohn, Rachid Massaad, and S. Aubrey Stoch are, or were at the time of study conduct, employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or hold stock options in the Company.

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Duong, L.T., Clark, S., Pickarski, M. et al. Effects of odanacatib on bone-turnover markers in osteoporotic postmenopausal women: a post hoc analysis of the LOFT study. Osteoporos Int 33, 2165–2175 (2022). https://doi.org/10.1007/s00198-022-06406-x

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  • DOI: https://doi.org/10.1007/s00198-022-06406-x

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