Aug. 05, 2026
Traditional approaches to osteoporosis treatment have focused on correcting imbalances in bone remodeling, either by slowing bone breakdown or stimulating bone formation. However, emerging research led by Sundeep Khosla, M.D., an endocrinologist at Mayo Clinic in Rochester, Minnesota, and his colleagues is reframing osteoporosis through an entirely different lens: aging biology itself.
Cellular senescence and the skeleton explained
At the heart of this research lies cellular senescence. In this biological state, cells permanently stop dividing but remain metabolically active. These cells arise in response to stressors such as DNA damage, telomere shortening or metabolic dysfunction and serve a protective role in early life by preventing the propagation of damaged or potentially cancerous cells.
Over time, senescent cells accumulate in otherwise healthy tissues where they actively secrete a variety of inflammatory and tissue-altering substances collectively known as the senescence-associated secretory phenotype (SASP). These factors include cytokines, chemokines and proteases that can disrupt tissue structure and function. Importantly, senescent cells are resistant to apoptosis.
Research from Dr. Khosla and colleagues has demonstrated that senescent cells accumulate within the bone microenvironment, including in osteocytes.
In both animal models and human bone biopsies, markers of senescence, such as p16 and p21, and SASP factors increase with age. This accumulation is associated with impaired bone structure and function, suggesting that senescent cells are not merely markers of aging but also active contributors to skeletal deterioration.
The central hypothesis emerging from this work is compelling: If senescent cells drive age-related bone loss, then removing them might restore healthier bone function. The study results were published in the Aging Cell.
Removing senescent cells improves bone in mice
In genetically engineered mouse models that allowed selective elimination of senescent cells, there were demonstrable improvements in bone mass and microarchitecture in both the spine and femur. This finding indicates that eliminating senescent cells could reverse aspects of skeletal aging.
From genetics to medications: The rise of senolytics
Clearing senescent cells can reduce SASP factors, thereby resulting in increased bone formation, decreased bone resorption, improved osteoblast function and modification of signaling pathways involved in bone metabolism.
Through transcriptomic and bioinformatic approaches, researchers identified that a combination of two existing compounds — dasatinib, a tyrosine kinase inhibitor, and quercetin, a natural flavonoid — could selectively kill senescent cells in vitro.
This combination of dasatinib and quercetin, referred to as D + Q, became the first generation of senolytics. In mouse models, periodic administration of D + Q not only improved overall healthspan but also enhanced bone mass and microarchitecture.
In some studies, senolytic therapy has been associated with reductions in key mediators such as sclerostin, a protein that inhibits bone formation and a therapeutic target of medicines such as romosozumab.
These findings suggest that senolytics may work, at least in part, by shifting the balance toward increased bone formation. This is similar to existing anabolic therapies but happens through a fundamentally different upstream mechanism rooted in aging biology.
Transition to human studies: A first clinical trial
Dr. Khosla and colleagues conducted a randomized controlled trial to evaluate senolytic therapy in humans. The study enrolled women over age 60 and examined whether intermittent administration of D + Q could produce biologically meaningful effects on bone turnover.
Participants received short courses of dasatinib and quercetin every 28 days over a 20-week period, alongside standard calcium and vitamin D supplementation.
The primary outcomes focused on markers of bone turnover. The trial demonstrated that D + Q therapy produced measurable changes in bone turnover markers, particularly an increase in P1NP, reflecting enhanced bone formation.
While these changes were modest when averaged across all participants, a key insight emerged: Not all individuals responded equally.
Toward precision medicine: Identifying who benefits
One of the most important advances from this research is the recognition that the burden of senescent cells varies among individuals and may determine therapeutic response.
Indeed, using the expression of p16 in T cells as a biomarker of systemic senescent cell burden, the investigators found that individuals with higher baseline levels of senescence markers showed greater increases in bone formation with senolytic therapy. For example, participants in the highest tertile of senescence markers exhibited substantially greater increases in P1NP compared with those with lower levels. The study results were published in Nature Medicine.
Conclusion: A shift from treating disease to targeting aging
The work of Dr. Khosla and collaborators represents a paradigm shift in osteoporosis research. Rather than focusing solely on downstream consequences of bone loss, this approach targets one of its root causes: the biological processes of aging itself.
Senolytic therapies offer a novel strategy to rejuvenate the bone microenvironment, improve skeletal outcomes and potentially transform the management of age-related diseases. Equally important, this research underscores the importance of personalization. It recognizes that effective treatment may depend on identifying those individuals in whom senescence is a key driver of disease.
By targeting a shared aging mechanism, senolytic therapies have the potential to address multiple diseases simultaneously, a concept often referred to as geroscience. Finally, while early signals are encouraging, larger and longer-term trials are required to confirm clinical benefits and define the role of senolytics in routine care.
For more information
Farr JN, et al. Characterization of human senescent cell biomarkers for clinical trials. Aging Cell. 2025;24:e14489.
Farr JN, et al. Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: A phase 2 randomized controlled trial. Nature Medicine. 2024;30:2605.
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