# Wnt16: a new potential therapeutic target for osteoporotic non-vertebral fracture treatment

## TL;DR

This paper reviews how Wnt16, a protein involved in bone regulation, could be a new treatment target for preventing non-vertebral fractures in osteoporosis.

## Contribution

The paper introduces Wnt16 as a novel therapeutic target for osteoporotic non-vertebral fractures.

## Key findings

- Wnt16 regulates bone mineral density through genetic associations with GWAS-identified loci.
- Wnt16 reduces cortical bone porosity and increases thickness.
- Notum inhibitors are proposed as potential therapeutic agents for targeting Wnt16.

## Abstract

Osteoporotic non-vertebral fractures are a major clinical burden, with cortical bone impairment being a key pathogenic factor often overlooked in traditional treatments. This review aims to synthesize current evidence on the role of Wnt16 (a non-canonical Wnt ligand) in regulating cortical bone and its potential as a therapeutic target for osteoporotic non-vertebral fractures. We systematically review literature on Wnt16 in senile, postmenopausal, and glucocorticoid-induced osteoporosis, focusing on its mechanisms of action: (1) regulating bone mineral density via genetic associations with GWAS-identified loci; (2) reducing cortical bone porosity and increasing thickness; (3) dual regulation of osteoblasts (via JNK/β-catenin pathways) and osteoclasts (via OPG-dependent/independent NF-κB pathways). Wnt16 has been shown to improve bone density and reduce non-vertebral fracture risk in preclinical models, though conflicting findings exist regarding its full compensation for glucocorticoid-induced bone loss. We conclude that Wnt16 is a promising target for non-vertebral fracture prevention, with Notum inhibitors emerging as potential therapeutic agents. This review provides a comprehensive framework for future clinical and translational research.