A review unifies hormones, immune cells, and skeletal stem cells into one model of bone repair, explaining why osteoporosis drugs lose effectiveness over time
A review unifies hormones, immune cells, and skeletal stem cells into one model of bone repair, explaining why osteoporosis drugs lose effectiveness over time
On 17 September 2026, the journal Reviews in Endocrine and Metabolic Disorders published a review from a laboratory at the University of California, Davis. The authors show that bone heals through coordinated action of hormones, immune cells, and the cellular environment surrounding the injury site, and that aging disrupts this coordination at two distinct levels with different degrees of reversibility.
A rigorous definition of skeletal stem cells is recent: in 2018, a Stanford group isolated and functionally validated such a cell in humans by a set of surface markers. That study has been cited over 600 times since and became foundational to the entire field. Before it, the field relied on the vague concept of "mesenchymal stem cells," a mixture of cell types with no reliable link to clinical outcome. One of the authors of that discovery, Thomas Ambrosi, has led a laboratory at Davis since 2024. In 2025, he and co-author Kun Chen showed that the human skeletal stem cell exists in at least four distinct states, and which state activates depends on where the cell sits in the skeleton, that is, on its niche: the specific microenvironment that determines the cell's fate. Bone itself secretes hormones, including osteocalcin and FGF23, that influence the brain, kidneys, and metabolism.
A fracture heals through an active hematoma: within 48 hours, neutrophils build a temporary matrix inside it, and then macrophages pass through four states, from inflammatory to reparative. From day 3 through day 14 after fracture, mice were given pexidartinib, which blocks the CSF1R receptor and prevents macrophages from accumulating excessively at the wound. Scarring decreased and the bone united faster.
Aging of this system operates at two distinct levels with different reversibility. Young blood rejuvenates many processes: parabiosis of old and young mice extended the lifespan of old animals by 10%. Skeletal stem cells, however, are not among them. An earlier study by Ambrosi himself showed that these cells lose their ability to regenerate bone, and neither infusion of young blood nor transplantation of young blood cells corrects it. The niche layer of aging, by contrast, can be reversed from outside: with age, levels of the protein tenascin C drop (this protein is needed to recruit macrophages to the injury site), and administering it to mice restores the bone-regenerating capacity of old animals.
The same niche logic explains osteoporosis, a disease that, according to the International Osteoporosis Foundation, affects one in three women and one in five men over age 50, with fragility fractures occurring up to 37 million times per year. Estrogen deficiency impairs skeletal stem cells directly, while glucocorticoids (anti-inflammatory hormones) disrupt the coupling between bone formation and blood vessel growth through the protein basigin. Blocking basigin with an antibody prevented this bone loss in mice, as the same laboratory showed in 2025.
Chen and Ambrosi argue that the same niche logic explains the limited effectiveness of current osteoporosis drugs:
"We believe that the limited duration and efficacy of anabolic anti-osteoporotic therapies is partly explained by the fact that they do not directly target and reactivate the residual pool of skeletal stem cells, nor do they restore the local niche microenvironment necessary for regeneration"
Rather than suppressing bone resorption or stimulating bone formation broadly, they propose repairing the niche itself in a targeted way, for example through signals like tenascin C.