Published online Jul 18, 2020. doi: 10.5312/wjo.v11.i7.328
Peer-review started: January 14, 2020
First decision: April 22, 2020
Revised: May 8, 2020
Accepted: July 1, 2020
Article in press: July 1, 2020
Published online: July 18, 2020
Bone grafting is performed on millions of patients each year, and autologous bone remains the “gold standard” bone graft material. However, autologous bone is limited in supply, is associated with increased surgical risk and donor-site complications and does not ensure optimal bony outcomes. Consequently, there exists an obvious need for implantable bone substitute materials, the creation of which is the focus of bone tissue engineering.
Recently, oxysterols – oxygenated derivatives of cholesterol – have been proposed as a novel class of osteoinductive small molecules for bone tissue engineering. However, there has yet to be a review examining the effect of oxysterols on in vivo bone formation. To address this, here we provide the first systematic review of the effect of oxysterols on in vivo bone formation as a means of evaluating the potential therapeutic utility of oxysterols for bone tissue engineering.
Following PRISMA guidelines, we aimed to systematically review the available literature examining the effect of oxysterols on in vivo bone formation.
Using the PubMed/MEDLINE, Embase, and Web of Science databases, we queried all publications in the English-language literature investigating the effect of oxysterols on in vivo bone formation. Articles were screened for eligibility using PICOS criteria and assessed for potential bias using an expanded version of the SYRCLE Risk of Bias assessment tool. All full-text articles examining the effect of oxysterols on in vivo bone formation were included. Extracted data included: Animal species, surgical/defect model, description of therapeutic and control treatments, and method for assessing bone growth. Primary outcome was fusion rate for spinal fusion models and percent bone regeneration for critical-sized defect models. Data were tabulated and described by both surgical/defect model and oxysterol employed. Additionally, data from all included studies were aggregated to posit the mechanism by which oxysterols may mediate in vivo bone formation.
Thirteen studies (all preclinical) met our inclusion/exclusion criteria. Of the 13 included studies, 5 employed spinal fusion models, 2 employed critical-sized alveolar defect models, and 6 employed critical-sized calvarial defect models. Based upon SYRCLE criteria, the included studies were found to possess an overall “unclear risk of bias”; 54% of studies reported treatment randomization and 38% reported blinding at any level. Overall, seven unique oxysterols were evaluated: 20(S)-hydroxycholesterol, 22(R)-hydroxycholesterol, 22(S)-hydroxycholesterol, Oxy4/Oxy34, Oxy18, Oxy21/Oxy133, and Oxy49. All had statistically significant in vivo osteoinductive properties, with Oxy4/Oxy34, Oxy21/Oxy133, and Oxy49 showing a dose-dependent effect in some cases. In the eight studies that directly compared oxysterols to rhBMP-2-treated animals, similar rates of bone growth occurred in the two groups. Biochemical investigation of these effects suggests that they may be primarily mediated by direct activation of Smoothened in the Hedgehog signaling pathway.
Present preclinical evidence suggests oxysterols significantly augment in vivo bone formation. Based upon prior in vitro work and the observation of dose-dependency, it appears that the observed effects are secondary to oxysterol-mediated upregulation of osteogenic gene products. The present preclinical literature has an unclear risk of bias, but the presence of positive outcomes across multiple animal species and surgical models suggests there is sufficient evidence to explore their application in larger animal models and eventually early phase clinical trials.
Oxysterols appear to be promising osteoinductive small molecules with potential for bone tissue engineering in the fields of orthopaedic surgery, neurosurgery, and oral maxillofacial surgery. Future work is necessary to identify the therapeutically optimal oxysterol and to optimize its pharmacokinetic properties for use in orthopaedic surgery.