Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice

Sandra Freitas-Rodríguez, Alejandra Valle-Cao, Carmen Fiuza-Luces, Alejandro Lucia, Carlos López-Otín, Alejandro López-Soto, Alicia R. Folgueras

1. 01

   Osteocyte-specific RANKL deletion reversed bone loss in long bones and vertebrae in Zmpste24-null mice

2. 02

   RANKL-deleted progeroid mice showed increased grip strength and improved endurance capacity

3. 03

   Osteocyte-specific RANKL deletion increased survival in the progeroid model

4. 04

   A neutralizing anti-RANKL antibody reproduced the bone benefit, reduced muscle fibrosis and extended lifespan

5. 05

   Supports RANKL as having extra-osseous roles in aging, consistent with prior signals in muscle aging

6. 06

   Provides a mechanistic rationale for exploring denosumab, an approved anti-RANKL antibody, in geroscience contexts

Study Design

Preclinical Study

Sample Size

Not reported

Study Duration

Lifespan follow-up in progeroid mice

Methodology

Genetic approach using osteocyte-specific RANKL deletion crossed into the Zmpste24-null HGPS mouse model, with bone densitometry and histomorphometry of long bones and vertebrae, grip strength and endurance testing, muscle fibrosis histology and survival analysis; parallel translational arm administering a neutralizing anti-RANKL antibody with matched endpoints.

Limitations

Conducted in a progeroid (Zmpste24-null) model of accelerated aging, not in naturally aged mice — lifespan extension in progeroid models frequently fails to translate to normal aging. No naturally aged cohort has been reported. No human aging-indication data exist. Clinically, denosumab carries a well-characterised rebound bone-loss and vertebral fracture risk on discontinuation, plus hypocalcaemia and osteonecrosis-of-the-jaw considerations, which constrain any speculative geroprotective use.