For many, osteoporosis remains a silent threat — a degenerative condition often unrecognised until a bone breaks from a simple stumble. It is one of the most widespread non-communicable diseases, affecting the integrity of skeletal tissue and compromising the very structure that supports our lives. Yet despite its profound impact, treatment options remain limited, underutilised, and often poorly understood by both patients and providers.
Osteoporosis leads to a progressive decline in bone mineral density (BMD) and the degradation of the internal scaffolding that strengthens bones. Its stealthy nature means that many individuals are unaware of their condition until a fracture exposes the extent of the damage. These injuries — particularly at the hip and spine — often result in long-term disability, loss of independence, and, in some cases, premature death.
The Weight of Numbers: How Common Is Osteoporosis?
The scale of this health challenge is difficult to overstate. One in three women and one in five men over the age of 50 are estimated to develop osteoporosis. In the EU alone, data from 2010 revealed 22 million women and 5.5 million men aged 50 to 84 with the condition. By 2025, that figure is expected to rise to nearly 34 million, driven by ageing populations and increasingly sedentary lifestyles.
In the United States, the issue is equally pressing. Around 54 million people over the age of 50 are affected by low bone mass, and 80 percent of those with diagnosed osteoporosis are women. In China, more than half of women over 50 are thought to have the condition, and in Japan, over a third of women aged 50 to 79 show significant bone loss at the spine. Similar trends appear in Australia, where in 2012, nearly five million people — two-thirds of those over 50 — had osteoporosis or osteopenia.
These figures illustrate the condition’s pervasiveness, but they also underline an urgent need: innovation in treatment.
Breaking the Bank and the Body
The toll of osteoporosis goes well beyond pain and disability. In economic terms, the impact is staggering. Fragility fractures — particularly of the hip — often require hospitalisation, surgery, rehabilitation, and long-term care. In 2017, the combined cost to healthcare systems in the five largest European countries and Sweden reached €37.5 billion. That same year, fall-related injuries in the US amounted to almost $50 billion.
A hip fracture often marks a turning point in a person’s life, particularly for the elderly. It can result in a permanent loss of mobility, reduced quality of life, and, within a year, a significantly increased risk of mortality. The ripple effect on families, carers, and healthcare systems is immense.
Why the Current Treatment Landscape Falls Short
Despite the severity of the disease, osteoporosis remains woefully underdiagnosed and undertreated. Many individuals who suffer an initial fracture — a clear warning sign — receive no follow-up care or preventative treatment. This oversight allows the disease to progress unchecked, heightening the risk of further, more debilitating fractures.
Even when treatment is initiated, options are limited in both scope and duration. Current pharmacological strategies fall into two broad categories:
- Antiresorptives, such as bisphosphonates and denosumab, which work by reducing the rate at which bone is broken down.
- Anabolic agents, like teriparatide and romosozumab, which aim to stimulate new bone formation.
Yet, these medications come with significant limitations. Antiresorptives slow bone loss but do little to rebuild existing damage. Anabolics can boost bone growth but are usually prescribed for only one to two years due to safety concerns. Both approaches often require a follow-up course of antiresorptives to maintain gains — a complicated therapeutic dance with limited success.
There is, therefore, a clear and unmet need for a new class of treatment — one that not only prevents further loss but actively restores skeletal integrity.
A Chance Discovery That Changed Everything
In 2024, a group of researchers from UC Davis Health and UC San Francisco published findings in Nature that could mark a turning point in the fight against bone disease. Their work identified a brain-derived hormone, Cellular Communication Network Factor 3 (CCN3), with extraordinary effects on bone regeneration. Dubbed the Maternal Brain Hormone, CCN3 appears to play a critical role in protecting the maternal skeleton during lactation — a period of extreme physiological stress.
During breastfeeding, a mother’s body must divert large amounts of calcium into breast milk. This results in a temporary loss of up to 10 per cent of bone mineral content in humans and nearly 30 per cent in mouse models. The puzzle for scientists has long been this: how does a woman’s body recover from such intense bone loss without long-term harm, especially given the simultaneous drop in oestrogen levels?
The answer, it seems, lies in CCN3 — a naturally occurring hormone that surges during lactation and acts as a powerful bone-building agent.
How Motherhood Unveiled a Hidden System
Lactation presents a unique scenario. The mother’s skeleton is under pressure to give up calcium, while hormonal changes reduce its natural defences. The fact that this state does not result in permanent bone damage suggested that an alternative protective mechanism was in place. CCN3 now appears to be that mechanism.
The hormone is released from specific neurons in the brain — more precisely, the arcuate nucleus of the hypothalamus — and stimulates bone formation at a systemic level. Its evolutionary purpose seems clear: protect the mother’s skeleton, ensure her survival, and maintain her capacity to care for offspring.
This discovery doesn’t just solve a long-standing biological mystery. It opens the door to a completely new therapeutic pathway for conditions like osteoporosis.
A Collaboration Twenty Years in the Making
The identification of CCN3 was not a sudden revelation but the result of decades of research. It began with mouse models lacking progesterone receptors. These animals, studied by researchers at UC Davis, had denser, stronger bones — an unexpected trait that hinted at alternative hormonal pathways influencing bone growth.
Years later, a team at UCSF made a related discovery. Female mice developed significantly higher bone mass when a specific oestrogen receptor (ERα) in the arcuate nucleus was blocked. Interestingly, this effect did not occur in males. The UCSF team partnered with the UC Davis researchers to understand why.
Through a series of experiments, including surgical connections between the circulatory systems of different mice (a technique known as parabiosis), they confirmed the presence of a circulating osteoanabolic factor. When normal mice were paired with the high-bone-mass mutants, they also experienced a bone growth boost.
The question then became: what was this secreted factor?
Diet, Hormones, and Brain Signals Collide
An unexpected breakthrough came via a simple change in diet. When the high-bone-mass female mice were fed a high-fat diet, their bone mass returned to normal levels. This reversal did not happen in males, further suggesting that a brain-specific, female-associated hormone was involved.
Analysis of gene expression in the relevant brain region revealed a significant drop in Ccn3 levels — narrowing the field to a single, likely candidate. Though previously not considered a traditional hormone, CCN3’s patterns of expression and impact on skeletal tissue were compelling. Further investigation confirmed it as the active agent.
The Role of ARCⁱKISS1ⁱ Neurons in Bone Regulation
The specific neurons involved in releasing CCN3 are known as ARCⁱKISS1ⁱ neurons. These neurons have already been recognised for their role in reproduction and metabolism. What is now understood is that they also form part of a direct brain-to-bone communication axis — a link that bypasses traditional hormonal pathways like the pituitary system.
This axis becomes especially active during lactation, where CCN3 levels surge in synchrony with the body’s increased calcium demands. When researchers suppressed CCN3 in these neurons, lactating mice lost more bone and struggled to support their offspring, especially under low-calcium conditions.
The importance of this finding cannot be overstated. It highlights a previously unknown adaptive mechanism, not just for preserving maternal bone but for ensuring reproductive success across generations.
Fun Fact: During lactation, mice can lose nearly a third of their bone mineral content in just a few months, yet recover it fully post-weaning — a process now attributed in part to CCN3.
How CCN3 Rebuilds Bone: From Brain Hormone to Cellular Architect
The discovery of CCN3 as a key player in skeletal regeneration brought with it a deeper understanding of how the body creates strong bone from within. The hormone does not simply enhance the function of existing bone cells — it activates skeletal stem cells (SSCs), the origin point from which all bone-building cells emerge.
By targeting these early-stage progenitor cells, CCN3 prompts the body to not just maintain bone, but regrow it from the ground up.
Awakening the Body’s Own Bone Factory
Skeletal stem cells reside within the bone marrow and serve as the foundation for producing osteoblasts — the cells that synthesise and mineralise new bone. In both mouse and human models, CCN3 has been shown to increase the number and activity of these stem cells, directing them towards bone rather than fat or cartilage formation.
In experiments where SSCs were transplanted into mice with elevated CCN3 levels, researchers observed substantial gains in bone mineralisation and strength. Importantly, these effects were seen across sexes and age groups, highlighting the hormone’s potential for widespread therapeutic use.
Unlike many current osteoporosis drugs, which act only on mature bone cells, CCN3 operates at the source — stimulating the full cascade of bone formation from stem cell to mature tissue.
A Stronger Scaffold, Not Just Denser Bone
Bone density alone is not a guarantee of strength. Poorly structured bone may remain brittle, even if it appears denser on a scan. The new bone formed under the influence of CCN3, however, has proven to be not just more voluminous but also measurably stronger in mechanical testing.
This improved quality is critical for real-world outcomes, particularly in reducing fracture risk. Stronger bone translates into fewer breaks, faster recovery, and greater resilience in older adults or those with compromised bone health.
Preliminary data also suggest that CCN3 may influence marrow fat and microarchitecture, offering a more holistic improvement in skeletal health.
Clarity Amid Complexity: CCN3 and the Role of Osteoclasts
Bone health depends on a balance between creation and destruction. While CCN3 powerfully stimulates new bone formation, it does not appear to radically suppress osteoclasts — the cells responsible for resorption. Instead, it seems to tip the balance in favour of formation, overwhelming normal resorption levels with a surge of new tissue production.
Some previous studies suggested that CCN3 might enhance osteoclast activity in certain disease models, such as bone metastases. However, these effects likely depend on the context, location, and molecular form of the protein. The brain-derived CCN3 released during lactation operates under unique physiological conditions and engages distinct cellular pathways — especially those linked to SSCs.
In current models, its net result is stronger bones, greater mass, and improved structural integrity—all without the adverse effects commonly seen in other treatments.
Therapeutic Promise: A New Approach for an Old Disease
CCN3, with its unique mechanism and dramatic results, could mark a new chapter in osteoporosis treatment. Unlike drugs that simply slow bone loss, CCN3-based therapies might regenerate bone, potentially reversing the condition rather than just managing it.
In postmenopausal osteoporosis, where low oestrogen leads to declining bone formation and increasing resorption, CCN3 has demonstrated significant efficacy. It has also proven effective in older mice — a key model for age-related bone loss — and in male subjects, who are often underrepresented in bone studies.
By stimulating SSCs directly, this approach could also help in cases of glucocorticoid-induced osteoporosis and other secondary bone diseases where traditional therapies fall short.
Accelerating Fracture Recovery: Healing Beyond the Norm
Beyond osteoporosis, CCN3 shows considerable potential in fracture healing. In elderly mice — whose injuries typically heal slowly — the application of CCN3 via a hydrogel patch accelerated healing and restored bone quality to that of much younger animals.
This raises exciting prospects for:
- Non-union fractures, where healing has failed
- Spinal injuries, where vertebral integrity is critical
- Surgical bone grafts, where integration is essential
- Orthopaedic implants, such as joint replacements or dental work
Rapid and reliable bone healing is one of the most sought-after goals in trauma surgery. CCN3, by directly enhancing the body’s regenerative capacity, could make that goal more attainable.
Building Cartilage, Too?
Cartilage damage, especially in conditions like osteoarthritis — is notoriously difficult to repair due to the tissue’s avascular nature. Yet skeletal stem cells have the capacity to form cartilage as well as bone.
Preliminary investigations are now underway to explore whether CCN3 can be used to guide SSCs toward cartilage regeneration, potentially offering relief to patients with degenerative joint disease.
If successful, this would place CCN3 among a rare group of therapies capable of restoring both bone and cartilage — an achievement with profound clinical implications.
From Bench to Bedside: The Road to Clinical Use
Turning a scientific breakthrough into a viable treatment is a long and complex process. For CCN3, several development paths are being explored:
- Recombinant protein therapies, where the hormone is manufactured and injected
- Peptide analogues, mimicking the active domains of the molecule
- Nanoparticle delivery, enhancing tissue targeting and prolonging activity
- Hydrogel systems, allowing localised, sustained release at fracture sites
Systemic delivery would likely be used for conditions like osteoporosis, while local delivery — for instance, a hydrogel patch — may be better suited for fracture healing or surgical support.
Each route brings its own challenges in terms of stability, immunogenicity, and scalability, but the scientific community is well-equipped to address these through modern bioengineering techniques.
Navigating Regulation: A New Class of Treatment
As a novel hormone-based biologic, CCN3 will undergo strict scrutiny by regulatory agencies like the FDA and EMA. Preclinical trials are already demonstrating safety and efficacy in animal models, but human trials are essential.
These will follow the standard phases:
- Phase 1: Safety and dose tolerance
- Phase 2: Early efficacy in targeted patient groups
- Phase 3: Large-scale trials focused on fracture reduction and quality-of-life improvements
Biomarkers such as P1NP (a marker of bone formation) and changes in bone density will be closely monitored. Longer-term studies will assess the durability of bone gains and any unintended systemic effects.
If successful, CCN3-based treatments could gain accelerated approval for unmet needs, particularly in postmenopausal women and fracture-prone elderly patients.
Anticipated Challenges and Scientific Caution
Despite the enthusiasm, several hurdles remain:
- The pleiotropic nature of CCN3 must be carefully managed. Its effects in non-bone tissues need to be fully characterised.
- The variation between mouse and human biology means translation is not guaranteed. Clinical trials will need to confirm that the ARCⁱKISS1ⁱ-CCN3 pathway operates similarly in people.
- Long-term safety, particularly with systemic administration, must be assessed.
- Public expectation should be tempered. Scientific rigour and patient safety must remain the priority.
Nonetheless, the discovery represents a genuine leap forward — one rooted in robust data and evolutionary logic.
A Paradigm Shift in Bone Science
The identification of brain-derived CCN3 as a master regulator of skeletal stem cell activity may well redefine how we approach bone disease. By targeting the very origin of bone formation, it goes beyond the incremental advances of current treatments and aims for true regeneration.
What sets CCN3 apart is not only its effectiveness, but its evolutionary grounding — a hormone honed by nature to protect the maternal skeleton in one of its most demanding states. This physiological insight offers a blueprint for how medicine might rebuild bone where it has failed, restore strength where it has waned, and perhaps even prevent fractures altogether.
