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 tissue engineering is an area of continued interest within orthopaedic surgery, as it promises to create implantable bone substitute materials that obviate the need for autologous bone graft. Recently, oxysterols – oxygenated derivatives of cholesterol – have been proposed as a novel class of osteoinductive small molecules for bone tissue engineering. Here, we present the first systematic review of the in vivo evidence describing the potential therapeutic utility of oxysterols for bone tissue engineering.
To systematically review the available literature examining the effect of oxysterols on in vivo bone formation.
We conducted a systematic review of the literature following PRISMA guidelines. 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.
Our search identified 267 unique articles, of which 27 underwent full-text review. 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. However, clinical trials are necessary to determine which have the greatest therapeutic potential for orthopaedic surgery patients.
Core tip: Here we present the first systematic review evaluating the utility of oxysterols for bone tissue engineering. Thirteen preclinical studies examining seven unique oxysterols were evaluated; all examined compounds were found to have statistically significant in vivo osteoinductive properties, with some showing dose-dependent effects. Importantly, eight studies found oxysterols to have similar osteoinductive properties to rhBMP-2 in treated animals. These effects are thought to occur through direct activation of Smoothened in the Hedgehog signaling pathway. Future clinical work is necessary to determine the exact therapeutic utility of these molecules in orthopaedic surgery patients.