For centuries, we've known muscles move bones. Now, science has discovered they're having a chemical love affair.
When you lift a weight, you witness a simple mechanical relationship: your muscle contracts, pulling on your bone to create movement. This mechanical partnership has long been understood. But beneath this visible interaction, an intricate chemical conversation is occurring—a constant stream of messages being passed between your bones and muscles that science is only beginning to decipher. This hidden dialogue, conducted through hormones and signaling molecules, reveals that our bones are far more than passive scaffolding and our muscles more than mere engines. Understanding this conversation is crucial, as it holds the key to combating the twin age-related conditions of osteoporosis and sarcopenia that affect over 1.7 billion people worldwide 1 2 .
The traditional view of the muscle-bone relationship was purely mechanical. As one article explains, "Bone serves as an attachment site for skeletal muscle, while muscle exerts force on the bone to facilitate movement" 1 . This mechanical coupling is undeniably essential; our skeletons adapt their strength to the loads placed upon them by our muscles, following principles like Wolff's law, where bone architecture reorganizes in response to force lines 5 .
However, a paradigm shift has occurred over the last decade. Researchers now understand that bone and muscle function as endocrine organs, releasing signaling factors into the bloodstream that can influence distant tissues, including each other 1 4 . This means that even when you're at rest, your bones and muscles are in constant biochemical crosstalk, regulating each other's health and metabolism through a complex language of soluble molecules.
The vocabulary of this hidden conversation consists of secreted factors:
Biochemical signals released by bone cells (osteoblasts, osteocytes, osteoclasts) that can travel to muscle tissue to influence its function 4 .
Factors secreted by muscle cells, especially during contraction, that can affect bone metabolism 4 .
This review will focus on the often-overlooked voice in this dialogue: the bone-derived factors, or osteokines, that actively regulate muscle health.
Bone is a vibrant, metabolically active tissue that secretes a cocktail of factors with diverse effects on skeletal muscle. The table below summarizes some of the most significant bone-derived factors identified to date 1 2 .
| Bone-Derived Factor | Primary Effect on Skeletal Muscle |
|---|---|
| Osteocalcin | Enhances muscle function, exercise capacity, and energy metabolism 1 |
| FGF23 | Associated with muscle atrophy in chronic kidney disease 2 |
| IGF1 | Promotes muscle cell proliferation, differentiation, and hypertrophy 2 |
| Sclerostin | Can inhibit muscle differentiation; its blockade may improve function 2 |
| Prostaglandin E2 (PGE2) | Stimulates myoblast proliferation and differentiation 2 |
| Wnt3a | Accelerates myogenic differentiation and improves muscle contractile force 2 |
| TGF-β | In excess, can promote muscle weakness and fibrosis 2 |
| FGF9 | Inhibits myogenic differentiation; a potential biomarker for sarcopenia 2 |
Osteocalcin is perhaps the most fascinating osteokine. Once considered merely a marker for bone formation, it is now recognized as a powerful bone-derived hormone 1 .
It exists in two main forms: carboxylated (Gla-Ocn), which is stored in the bone matrix, and uncarboxylated (Glu-Ocn or ucOC), which acts as a hormone. During bone resorption, the acidic environment converts Gla-Ocn into bioactive Glu-Ocn, which then enters the circulation 1 2 .
Once in the bloodstream, Glu-Ocn travels to muscle cells and binds to its receptor, Gprc6a. This binding sets off a cascade of events that:
This discovery was groundbreaking because it proved for the first time that a bone-derived hormone could directly influence muscle physiology and performance, independent of mechanical loading.
Visualization of osteocalcin's journey from bone to muscle and its effects.
To truly appreciate how science uncovers these hidden connections, let's examine a pivotal experiment that highlights osteocalcin's role in muscle function.
A key study, as summarized in recent literature, took a multi-pronged approach to test the hypothesis that osteocalcin signaling is essential for muscle adaptation to exercise 1 2 .
Researchers used genetically engineered mouse models lacking the osteocalcin gene (Ocn−/−) and mice lacking its receptor, Gprc6a, specifically in muscle fibers.
They administered injections of bioactive uncarboxylated osteocalcin (Glu-Ocn) to wild-type mice.
The exercise capacity of these different mouse models was evaluated and compared.
Muscle tissue was analyzed to measure the expression of genes and proteins involved in energy metabolism and the production of other myokines, like interleukin-6 (IL-6).
The results were clear and compelling, as summarized below.
| Experimental Group | Observed Effect on Muscle | Scientific Implication |
|---|---|---|
| Ocn−/− mice | Reduced exercise capacity | Osteocalcin is necessary for normal muscle function during exertion 1 . |
| Mice with Gprc6a receptor knockout in muscle | Impaired response to exercise | Osteocalcin's effect is specifically mediated through this receptor on muscle fibers 1 . |
| Wild-type mice injected with Glu-Ocn | Enhanced exercise capacity | Supplementing osteocalcin is sufficient to improve muscle performance 1 . |
| All groups | Glu-Ocn increased muscle fuel (glucose & fatty acid) catabolism for ATP production | The hormone works by boosting the energy supply available to working muscles 1 . |
This experiment demonstrated that bone, via osteocalcin, is not just a passive partner but an active regulator of muscle function during exercise. It provides a biochemical explanation for why bone and muscle health are so closely linked: they are parts of an integrated system that communicates through hormones. When this communication breaks down, both tissues suffer.
The discovery of bone-muscle biochemical crosstalk is not just an academic curiosity; it has profound implications for human health, particularly in aging.
A condition characterized by bone fragility and increased fracture risk.
Age-related loss of muscle mass, strength, and function.
Osteoporosis (bone fragility) and sarcopenia (muscle wasting) are two debilitating conditions that frequently occur together in the elderly, dramatically increasing the risk of falls, fractures, and loss of independence 1 6 . The mechanical explanation—weaker muscles lead to less force on bones, causing bone loss—is only part of the story. We now know that a breakdown in biochemical communication is also to blame.
As we age, the secretion and effectiveness of key osteokines and myokines can change. For example, levels of bioactive osteocalcin may decline, potentially contributing to reduced muscle function. Similarly, elevated levels of other factors like TGF-β or FGF23 can promote muscle wasting 2 . This creates a vicious cycle: bone loss leads to worse muscle quality, which in turn exacerbates bone loss.
This new molecular understanding opens up exciting possibilities for treatment. Researchers are now exploring:
Could osteocalcin or molecules that mimic its action be used as a therapy to treat both sarcopenia and osteoporosis simultaneously?
Developing drugs to inhibit the effects of harmful factors like TGF-β or sclerostin could help preserve muscle and bone mass 2 .
Understanding these pathways can help design specific exercises that optimally stimulate the beneficial biochemical dialogue between bone and muscle.
The once-clear line between the functions of our bones and muscles has blurred. We now see them as an integrated, dynamic system—a "bone-muscle unit"—constantly engaged in a silent, chemical conversation that is as vital to our movement and metabolism as their mechanical coupling . The next time you move, remember that there's more happening beneath the surface than just levers and pulleys. A complex molecular dance is underway, and each step you take helps keep this essential conversation flowing, ensuring a stronger, healthier you.