Harnessing Chronomodulation to Enhance Osteogenesis

Summary

Chronotherapy is an emerging field in biomedicine that leverages on fine-tuning the timing of drug delivery to obtain a therapeutic effect. Dr. Tamimi and his team have successfully harnessed chronotherapy using NSAIDs to enhance bone healing in a murine fracture model. Unpublished findings revealed that mice receiving carprofen for 3 days post-fracture exclusively during activity hours exhibited superior bone healing outcomes in comparison to specimens that received the same drug during resting hours. This is a 3-arm RCT aimed at evaluating the effect of different chronotherapeutic NSAID regimens on intraoral bone healing in humans using an extraction socket healing model in the context of an early implant placement protocol. The primary aim is to elucidate whether there are differences in osteogenesis and in the characteristics of the newly formed bone between patients following different post-operative NSAID chronotherapeutic protocols. Secondary endpoints of interest include assessment of alveolar bone and soft tissue dimensional changes between pre- and post-extraction, implant insertion torque, serum CRP levels, wound healing index and patient-reported discomfort at different time points. If proven beneficial, the proposed chronotherapeutic approach could be readily implemented in clinical practice as a standalone therapy or as a valuable complement to existing standard-of-care protocols, due to its simplicity, safety and cost-effectiveness.

Timeline

Start

2023-01-01

Primary completion

2023-01-01

Completion

2023-01-01

Publications

• Background Slade GD, Akinkugbe AA, Sanders AE. Projections of U.S. Edentulism prevalence following 5 decades of decline. J Dent Res. 2014 Oct;93(10):959-65. doi: 10.1177/0022034514546165. Epub 2014 Aug 21.
• Background Elani HW, Starr JR, Da Silva JD, Gallucci GO. Trends in Dental Implant Use in the U.S., 1999-2016, and Projections to 2026. J Dent Res. 2018 Dec;97(13):1424-1430. doi: 10.1177/0022034518792567. Epub 2018 Aug 3.
• Background Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Levi FA. The circadian timing system in clinical oncology. Ann Med. 2014 Jun;46(4):191-207. doi: 10.3109/07853890.2014.916990.
• Background Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008 Oct;9(10):764-75. doi: 10.1038/nrg2430.
• Background Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Levi F; European Organisation for Research and Treatment of Cancer Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. doi: 10.1200/JCO.2006.06.1440.
• Background Cutolo M. Glucocorticoids and chronotherapy in rheumatoid arthritis. RMD Open. 2016 Mar 18;2(1):e000203. doi: 10.1136/rmdopen-2015-000203. eCollection 2016.
• Background Okazaki F, Matsunaga N, Hamamura K, Suzuki K, Nakao T, Okazaki H, Kutsukake M, Fukumori S, Tsuji Y, To H. Administering xCT Inhibitors Based on Circadian Clock Improves Antitumor Effects. Cancer Res. 2017 Dec 1;77(23):6603-6613. doi: 10.1158/0008-5472.CAN-17-0720. Epub 2017 Oct 16.
• Background Swanson CM, Kohrt WM, Buxton OM, Everson CA, Wright KP Jr, Orwoll ES, Shea SA. The importance of the circadian system & sleep for bone health. Metabolism. 2018 Jul;84:28-43. doi: 10.1016/j.metabol.2017.12.002. Epub 2017 Dec 9.
• Background Dallmann R, Okyar A, Levi F. Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy. Trends Mol Med. 2016 May;22(5):430-445. doi: 10.1016/j.molmed.2016.03.004. Epub 2016 Apr 5.
• Background Chappuis V, Rahman L, Buser R, Janner SFM, Belser UC, Buser D. Effectiveness of Contour Augmentation with Guided Bone Regeneration: 10-Year Results. J Dent Res. 2018 Mar;97(3):266-274. doi: 10.1177/0022034517737755. Epub 2017 Oct 26.

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