Institute for Translational Medicine and Pharmacology at Mount Sinai

Founded in 1999 by Mone Zaidi, MD, PhD, FRCP, the Mount Sinai Bone Program has earned international prominence through seminal discoveries in how the vertebrate skeleton is built, maintained, and broken down in health and disease. Its basic and translational research has brought cutting-edge approaches to bear on the full spectrum of bone physiology, from hormonal and enzymatic regulation to the roles of autocoids, second messengers, and transcriptional regulators. By rigorously examining the pathophysiology of bone and mineral disorders, the program has consistently uncovered actionable therapeutic targets with continuous funding by the National Institutes of Health since its inception.

Early Research Contributions

The program's landmark discoveries have repeatedly reshaped the field. Among the first was the discovery of calcium sensing in the osteoclast, the cell responsible for removing old bone, establishing it as a primary physiologic brake on excessive bone resorption. Our research further demonstrated that nitric oxide regulates bone remodeling, an observation that opened the door to testing nitric oxide donors as treatments for human osteoporosis.

In 2003, the program published the first evidence for a pituitary-bone axis. This breakthrough revealed that pituitary hormones, including TSH, ACTH, FSH, oxytocin, and vasopressin, previously believed to act only on their classical target organs, could bypass those organs entirely and act directly on the skeleton. The discovery transformed our understanding of endocrine physiology and implicated these hormones in the pathophysiology of osteoporosis, shifting the field from a one-disease-one-hormone model toward a multifaceted framework with broad therapeutic implications.

Beyond these defining advances, the group has explored the skeletal consequences of genetic diseases including Gaucher disease and congenital adrenal hyperplasia, and has probed the mechanisms underlying osteoporosis arising from aging, menopause, thyroid disease, pregnancy and lactation, hyponatremia, smoking, and organ transplantation. Further research has addressed the roles of the nervous system and muscle in skeletal regulation, the mechanisms governing cartilage homeostasis, connections between anti-cancer and anti-osteoporosis therapies, and the use of stem cells to promote skeletal regeneration.

Recent Research Advances

Building on the foundational discovery of a pituitary-bone axis, the Bone Program has continued to break new ground by revealing the far-reaching consequences of pituitary hormone signaling across multiple organ systems. In groundbreaking papers published in Nature, PNAS, Molecular Psychiatry and JCI, Dr. Zaidi’s team found that inhibiting follicle-stimulating hormone (FSH) not only increased bone mass, but also reduced body fat and neurodegeneration, laying a firm foundation for a single anti-FSH agent to treat osteoporosis, obesity, and Alzheimer's disease simultaneously. This line of research led to the development of a first-in-class humanized monoclonal antibody targeting FSH, which in preclinical models has demonstrated the ability to reduce body fat, increase bone mass, enhance metabolism, and lower cholesterol.

Ongoing research has subsequently confirmed that FSH acts directly on hippocampal and cortical neurons to accelerate the deposition of amyloid-β and tau, hallmarks of Alzheimer's disease, and that blocking FSH action in mouse models abrogates this Alzheimer's-like phenotype. These findings suggest a causal role for rising FSH levels during menopause in the heightened Alzheimer's risk observed in older women, and open a compelling new avenue for treating multiple aging-related conditions with a single therapeutic agent.

Our program has further demonstrated that phosphodiesterase 5 (PDE5) is another promising therapeutic target for bone diseases. We have shown that clinically approved PDE5 inhibitors, including tadalafil and vardenafil, commonly used for pulmonary hypertension and erectile dysfunction, can significantly increase bone mass in mouse models. By inhibiting PDE5 enzymatic activity, these small molecules elevate intracellular cyclic GMP levels, which activates protein kinase G and subsequently upregulates bone-related gene expression. This discovery opens the possibility of repurposing existing Food and Drug Administration-approved medications for osteoporosis treatment. Current investigations using genetically modified mouse models are examining the bone cell-specific mechanisms of PDE5 action, work that may lead to more targeted therapeutic approaches for metabolic bone diseases.

Extending our focus on endocrine regulation of the skeleton, the Bone Program has further redefined the role of glucocorticoids in bone health. While traditionally associated with osteoporosis due to suppression of osteoblast function, our work demonstrates that glucocorticoid effects are highly context-dependent and critically influenced by adrenocorticotropic hormone (ACTH). Preservation of ACTH is linked to enhanced bone formation, whereas its suppression leads to bone loss, identifying ACTH as a key regulator of skeletal integrity. Notably, under specific physiological conditions, glucocorticoids can exert direct anabolic effects on bone, primarily through osteoblast activity and independent of classical hypothalamic–pituitary–adrenal axis suppression.

In parallel, these studies have uncovered a central neuroendocrine mechanism in which glucocorticoid signaling within hypothalamic nuclei modulates sympathetic nervous system output to the skeleton, generating catabolic signals that counterbalance peripheral anabolic effects. This coordinated bone–brain–sympathetic axis integrates hormonal and neural inputs to regulate bone remodeling.

Together, these findings overturn the long-held paradigm of glucocorticoid-induced bone loss and reposition glucocorticoids as nuanced regulators of skeletal homeostasis, opening new opportunities to optimize therapies for patients requiring glucocorticoid treatment while preserving bone health.

Collectively, these advances reflect the Bone Program's overarching vision: that the skeleton is not an isolated organ but a dynamic hub integrating endocrine, metabolic, and neural signals across the body. By dissecting the pathways linking FSH, PDE5, glucocorticoids, and ACTH to bone and beyond, our work is reshaping the conceptual framework of skeletal biology and revealing unexpected therapeutic opportunities at the intersection of osteoporosis, obesity, neurodegeneration, and metabolic disease. As these discoveries move from bench to bedside, through novel biologics, repurposed small molecules, and refined treatment paradigms, the Bone Program continues to define a new era of integrative, multi-system therapeutics aimed at improving health span in an aging population