Table of Contents
What is Osteoimmunology? | Bone and Immune Diseases | Rheumatoid Arthritis | Gum Disease | Inflammatory Bowel Disease | Osteoporosis | Bone Fracture Repair | Implications for Osteoporosis Treatments | Bone and Immune System Takeaways
A wealth of research points to the key role the immune system plays in bone loss.
In fact, studies have linked conditions like osteoporosis to an imbalance of immune system cells. But how does this imbalance lead to bone loss? And most importantly, what can you do about it?
In this article, you’ll discover:
- How your immune system can trigger bone loss
- The key interactions between your immune and bone cells
- How this ties in with certain chronic conditions like osteoporosis
- And finally, what all this means for practical osteoporosis treatments
What is Osteoimmunology?
Bone and immune cells originate in the same place — the bone marrow. As you can imagine, such close quarters lead to complex interactions between these cells!
But it wasn’t until the early 1970s that the first studies [1, 2] on the relationship between bone and immune cells took place. These studies made the landmark discovery that immune cells could influence bone resorption — the process by which bone is broken down.
Specifically, they found that immune cells produced osteoclast-activating factors. As you may know, osteoclasts are the specialized cells that break down bone. So these studies demonstrated a direct relationship between bone and immune cells!
This relationship was of great interest to the medical community, and ultimately, led to the creation of a whole new field of study: osteoimmunology.
In brief, osteoimmunology is the study of the interactions between the bone and immune systems — sometimes called the “osteo-immune system”.
The term “osteoimmunology” itself was coined in an article published in Nature in 2000. The article explored the dynamic relationship between T-cells — white blood cells (lymphocytes) that are one of the main types of immune cells — and osteoclasts.
More recently, however, new evidence of the interactions between the skeletal and immune systems has been found in humans — through the study of chronic diseases, like osteoporosis.
So in the next section, we’ll cover the basics of osteoimmunology, and give you an overview of the key players involved. Then, we’ll get into the more concrete evidence presented through human studies of bone and immune diseases.
The Key Players in the Bone and Immune System Interplay
Now, it’s well-known that the RANK-RANKL-OPG system connects osteoblasts and osteoclasts and helps regulate bone resorption. So the discovery that immune cells can affect this process too had some far-reaching implications — especially for osteoporosis. (More on this in the next section!)
But first, here’s a brief summary of how these systems interact:
- RANKL binds to RANK and activates osteoclasts.
- Osteoclasts break down bone.
- Your immune system cells can produce RANKL.
- This is how your immune system can cause bone loss.
- Note there are many more molecules that play a role, but this is the basic mechanism that connects these systems!
For a more detailed explanation of the immune and skeletal cells involved in bone regulation, click here.
Bone System Cells
Osteoblasts: The specialized cells that build bone.
Osteoclasts: The specialized cells that break down bone.
Osteoclast precursors: Cells that will become osteoclasts.
Immune System Cells
T-cells: White blood cells that are a key component of the immune system.
B-cells: A small type of white blood cell that’s also key to the immune system.
Receptor activator of nuclear factor kappa-B ligand (RANKL): The main protein that regulates bone loss.
Receptor activator of nuclear factor kappa-B (RANK): The receptor that RANKL binds to, which triggers osteoclast activity.
Osteoprotegerin (OPG): A decoy receptor that can bind with RANKL.
Interferon-ɣ (IFNɣ): A critical immune system cytokine, mainly produced by activated T-cells.
Tumor necrosis factor receptor-associated factor 6 (TRAF6): A protein that aids communication between cells.
RANK/RANKL/OPG System: The main system that regulates osteoclast production and activation.
Here’s a little more information on how the immune and skeletal systems interact:
Inflammation is the product of an immune response. It occurs as a result of an injury, infection, or it can be chronic. (Remember, chronic, low-grade inflammation is one of the top preventable causes of bone loss.) Basically, it’s your immune cells rushing to a site in your body in need of attention and getting to work.
So during inflammation T-cells are activated, and as it happens, one of the cytokines they produce is RANKL. RANKL then binds to RANK on osteoclast precursors, which leads to increased bone resorption. This mechanism is one factor that explains why bone loss is a common side effect of inflammatory conditions. (Again, we’ll go over these next!)
Of course, there are other factors that limit these bone resorptive effects. Otherwise, bone loss would be a lot more severe during inflammatory conditions like autoimmune diseases, infections, and even, injury.
Namely, OPG can bind with RANKL instead of RANK and block it from activating osteoclasts. IFNɣ, which is mainly produced by activated T-cells, can also prevent bone resorption. It does this by breaking down TRAF6, which is necessary for communication with osteoclast precursors.
For those of you who are more visual, the graphic below illustrates this process:
Not to worry if this all sounds complicated… it is! The main point to understand is that an activated immune response can lead to bone loss.
As for B-cells and osteoblasts, they also play a role in this process. Osteoblasts contribute to the production of B-cells from hematopoietic stem cells (HSCs) in the bone marrow, where they both live. And both osteoblasts and B-cells produce RANKL, which as covered above, is a key instigator of bone resorption.
Now, it may seem counterintuitive that osteoblasts would produce RANKL, but it’s simply part of the natural bone remodeling process. Once osteoblasts are finished their work, they tap in their counterparts, osteoclasts. But when this process becomes unbalanced and osteoclasts are overactivated, bone loss can occur.
Osteoblasts and B-cells are also capable of expressing the decoy receptor OPG, which if you recall, binds with RANKL and blocks its effects. So these cells can both stimulate and slow bone resorption.
As you can see, all these different cells and proteins are connected in some way and work together to regulate the bone resorption process! Like every bodily system, it’s a complicated dance, and there are a lot more partners and steps involved than mentioned here.
And like a complicated dance, it takes a single misstep to throw a partner’s balance out of whack…
The result of such an imbalance can be that a person develops a condition like a chronic inflammatory disease, osteoporosis, or even struggle to recover from a fracture. Next up, a review of these different issues, and how they tie in with the concept of osteoimmunology.
If you’d like more information on the additional cells and processes involved in the osteo-immune system, here’s a selection of high-quality studies:
- 2005 – The role of the immune system in the pathophysiology of osteoporosis
- 2006 – Osteoporosis, inflammation and ageing
- 2011 – The role of the immune system in the development of osteoporosis
- 2012 – Study: bone density may affect immune system
- 2012 – Immune regulation of osteoclast function in postmenopausal osteoporosis
- 2013 – Postmenopausal osteoporosis: the role of immune system cells
- 2013 – Osteoimmunology: a brief introduction
- 2017 – Bone and the immune system
- 2018 – Osteoimmunology
- 2019 – Updates on osteoimmunology
Bone and Immune Diseases
The close relationship between the skeletal and immune systems is further illustrated by a number of chronic conditions. Simply put, many bone diseases are linked to the immune system and vice versa.
Here’s a look at a few of these conditions characterized by bone loss:
Chronic Inflammatory Disease
Bone loss is commonly seen in chronic inflammatory diseases like rheumatoid arthritis, gum disease, and inflammatory bowel disease.
So it may not surprise you to know that most of these conditions involve an imbalance or abnormality of the immune system. That said, many of the medications used to treat these conditions can affect bone health. So researchers have found it challenging to isolate the effects these conditions have on bone.
For example, in a study on inflammatory bowel disease, a researcher might find that a large percentage of patients experience bone loss. But it would be hard to pinpoint how much of that bone loss is due to inflammation versus medication.
That said, there’s still a clear relationship between immune function and bone disease in many of these conditions. The most compelling evidence for this relationship exists for the following:
Rheumatoid arthritis (RA) is a common type of autoimmune arthritis. An autoimmune disease is a condition where your immune system mistakenly attacks your body. In the case of RA, a certain type of T-cell goes rogue and the result is painful inflammation of the joints — especially the small joints of the hands and feet.
One of the leading researchers in osteoimmunology, Hiroshi Takayanagi, provided early insights into the connection between RA and bone loss.
Takayanagi, a professor in the department of immunology at the University of Tokyo, has been studying the interactions between bone and immune cells for over 20 years. He’s participated in hundreds of studies and his research has won numerous awards, including:
- The International Research Prize from the Austrian Society for Bone and Mineral Research (AuSBMR) and the Ludwig Boltzmann Institute of Osteology in 2006
- The JSI Award from the Japanese Society for Immunology in 2016
Takayanagi and his team pointed out the connection between RA and increased osteoclast activity in an early study of cell cultures. Interestingly, he found that even though levels of IFN-γ are high in this condition, osteoclasts are still sent into overdrive. Remember, IFN-γ inhibits osteoclast activation! So why are osteoclasts still highly activated in this condition?
One review of animal studies points to a certain cytokine called interleukin-17 (IL-17). It seems that T-cells activated during RA produce IL-17, and IL-17 stimulates a bunch of cytokines that activate osteoclasts. So the theory is that IL-17 is the main culprit of the bone destruction seen in patients with RA.
Of course, these findings are from cell and animal studies, so they don’t provide definitive proof of how bone loss in RA occurs. But regardless of the underlying mechanisms, results from human studies indicate a relationship between rheumatoid arthritis and bone loss.
In one human study, researchers looked at 121 patients with RA between the ages of 45 and 75. Of these patients, 32.3% had osteoporosis. Now, the sample in this study was small and other factors may have contributed to low bone density like old age, menopause, and low body weight. But the results do suggest that people with RA are at increased risk of osteoporosis.
And there’s additional research that supports this finding…
In an earlier study, researchers looked at 88 patients with RA and 112 controls without RA to determine the prevalence of low bone density in this condition. They found that 45% of patients with RA had osteoporosis at the femoral neck and 25% had osteoporosis at the lumbar spine.
In the end, they concluded that a “significant proportion” of patients with RA had osteoporosis, and that having RA for over 10 years increased the risk of bone loss. Notably, this last finding lines up with what we know about the effects of chronic, low-grade inflammation on bone over time.
Certainly, more research is needed to clarify the connection between RA and bone loss. But it’s important to note that if you suffer from RA, you may be at increased risk of osteoporosis. If you’d like more information on RA and ways to alleviate joint pain, check out our article on “Natural Remedies for Arthritis”.
Gum Disease (Periodontal Disease)
Another condition where immune cells cause bone loss is gum disease, also known as periodontal disease. Gum disease occurs when there’s an infection of the tissues and bones around the teeth, which leads to inflammation. Early on, this can cause the gums to become red and swollen. As the condition progresses, the gums start to recede.
The inflammation in this condition is caused by activated T-cells fighting the infection. And as we covered earlier, activated T-cells also produce RANKL, which stimulates bone resorption.
So there’s an easy explanation for the bone loss commonly seen in patients with gum disease.
And there’s human research to back this explanation…
In a recent study, researchers found that a certain type of T-cell, Th17, was much more prevalent in the gums of patients with gum disease than in the gums of healthy controls. They also found that higher levels of Th17 correlated with more severe gum disease.
From these findings, the researchers deduced that Th17 is the key immune cell that causes bone loss in patients with gum disease. They tested this theory by genetically engineering mice to lack this type of T-cell. And indeed, they found that mice without Th17 didn’t lose as much bone when they had gum disease.
But would this hold true in humans?
To answer this question, the researchers found a group of 35 patients with a gene defect that meant they didn’t have Th17 cells. They reasoned that if Th17 is key for the development of gum disease, then patients without Th17 should be protected from it! Again, the results supported their theory — patients lacking Th17 had “diminished periodontal inflammation and bone loss”.
All this goes to show that T-cells, Th17 cells in particular, are likely the main culprits of inflammation and bone loss seen in gum disease.
It’s worth noting that researchers have also discovered another cytokine, called secreted osteoclastogenic factor of activated T-cells (SOFAT), that may play a role in this condition. What’s remarkable about SOFAT is that it’s able to stimulate osteoclast activity, without the help of RANKL!
And notably, increased expression of SOFAT was found in samples from patients with gum disease. This illustrates another mechanism by which activated immune cells can cause bone loss in this condition.
If you suffer from gum disease, or even if you notice your gums are often red and swollen, you may want to discuss the risk of bone loss with your medical professional. If you find out you have low bone density, here’s some helpful information on increasing bone density naturally. And of course, treat the underlying cause of gum disease by practicing good oral hygiene!
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a term that describes a group of conditions characterized by chronic inflammation of the digestive tract. There are two main types of IBD: Ulcerative colitis and Crohn’s disease. Ulcerative colitis causes inflammation and sores (ulcers) in the lining of the large intestine, while Crohn’s disease is more widespread and causes inflammation all along the digestive tract.
The primary characteristic of IBD is chronic inflammation! And we know that chronic inflammation is one of the underlying causes of bone loss. So it’s no surprise that bone loss is a common side effect of IBD. It doesn’t help that many of the medications used to treat IBD can also be harmful to bone.
As for how the condition itself leads to bone loss, again, there’s a strong connection with the immune system. The inflammation in IBD means that T-cells are highly activated. And as we’ve seen, activated T-cells produce RANKL, which stimulates bone resorption.
In terms of actual clinical proof, the research on this condition is limited to animal and correlational studies. As mentioned earlier, these types of studies don’t always produce reliable results. But one human clinical study worth mentioning found a negative correlation between OPG levels in the blood of IBD patients and bone mineral density (BMD).
Now, correlation shouldn’t be confused with causation. In other words, it’s possible this negative relationship is due to other factors. Nonetheless, the results do suggest a connection between immune system cells and bone loss in this condition.
It’s also worth noting that since IBD is a condition of the digestive tract, it can impair a person’s ability to absorb nutrients. And of course, proper nutrition is key for maintaining bone mass. This suggests another mechanism by which a person with IBD might experience bone loss.
It’s well-recognized that IBD patients are at increased risk of bone loss. If you suffer from IBD, you should discuss bone loss with your medical professional. You should also be extra vigilant to ensure you’re providing your bones with the nutrients they need to stay strong. To read more about nutrition for bone health, visit this page.
You’re no doubt familiar with osteoporosis. It’s a condition where your bone density drops to the point where your bones become fragile and prone to fracture. In recent years, scientists have made important advances in understanding the processes underlying osteoporosis. And their discoveries have implicated immune cells in these processes.
The link between osteoporosis and immune system cells hinges on estrogen deficiency. As you may know, estrogen deficiency is one of the main causes of osteoporosis in post-menopausal women.
This is because estrogen has several important bone protective effects. In short, it both reduces bone resorption and supports bone-building — a powerful dual function. One of the ways it accomplishes these tasks is by suppressing RANKL production not only in osteoblasts, but also in T- and B-cells.
Researchers made this discovery by studying bone marrow cells from three groups of women: Premenopausal, early postmenopausal, and estrogen-treated postmenopausal women. Now, it’s worth noting the sample in this study was small. There were only 12 women in each group, so larger scale studies are needed to draw definitive conclusions.
Nonetheless, this preliminary research found that RANKL concentration was increased on all cells, including T- and B-cells, in postmenopausal women compared to premenopausal and estrogen-treated women. These findings demonstrated how greater RANKL production by T- and B-cells, caused by estrogen deficiency, may contribute to bone loss in humans.
A more recent clinical study supports these findings. Again, the sample in this study was small and included a total of 58 participants. But the conclusions are promising, as they align with previous findings.
This study examined T-cell and RANKL levels in women with postmenopausal osteoporosis compared to postmenopausal controls without osteoporosis. Notably, women with postmenopausal osteoporosis had a “higher T-cell activity than healthy postmenopausal subjects”. Researchers concluded that T-cells contribute to bone loss caused by estrogen deficiency in humans — which directly supports the previous study.
What’s more, another study shows that estrogen deficiency also leads to an increase in B-cells. And as we’ve seen, B-cells can produce RANKL too. This study looked at the immune cells of postmenopausal women with osteoporotic fractures compared to healthy controls. And yes, they found that B-cell levels were higher in the osteoporosis group!
So to recap, the lack of estrogen that occurs as a result of menopause leads to increased production of RANKL by activated T-cells and B-cells. These effects contribute to greater bone loss over time and demonstrate the role of immune cells in the onset of osteoporosis.
Now, this is a simplified version of the role immune cells play in osteoporosis and more research is needed to confirm these mechanisms.
But one thing’s for sure, there are many different types of T-cells and inflammatory cytokines that contribute to bone loss in this condition. In fact, these interactions are so complex that researchers have proposed a dedicated term for their study: immunoporosis.
The main takeaway here is that an imbalance between bone and immune cells contributes to the accelerated bone loss seen in osteoporosis.
Bone Fracture Repair
Your immune cells are like your body’s “first responders”. When a virus attacks or you suffer an injury, your immune cells are first to the scene. And breaking a bone is no exception! So the relationship between fracture repair and the immune system is self-evident.
Immune cells work closely with bone cells to repair fractures. So it makes sense that an imbalance of immune cells can slow down bone healing, and research supports this premise. In fact, in patients with human immunodeficiency virus (HIV) — which is characterized by low levels of immune system cells — fractures take a lot longer to heal.
This holds true for other autoimmune diseases like rheumatoid arthritis (RA). If you recall, RA is characterized by chronic inflammation caused by an overactive immune system. And chronic inflammation impairs fracture healing. So in this instance, too much immune activity is one of the culprits.
All this to say, when it comes to bone fracture repair, both an overactive and an underactive immune system can cause issues. Once again, this highlights the complex relationship between bone and immune system cells.
Any dysregulation of immune cells can have a negative impact on fracture repair! To learn more about fracture healing and how to speed the process, visit our “Bone Fracture Healing Guide”.
Implications for Approaching Osteoporosis
The field of osteoimmunology is fascinating. But research into how the skeletal and immune systems interact has deeper implications too.
As we’ve seen, the RANKL–RANK–OPG system plays a key role in regulating bone loss. The protein RANKL, in particular, sets off a chain of events that stimulates bone resorption. So in theory, by blocking RANKL’s actions, one might slow bone loss…
And indeed, this line of reasoning is what led to the development of a new therapeutic treatment for osteoporosis. This new treatment works by binding with RANKL and blocking its effects. It’s like a “clone” of the decoy receptor OPG. (To learn more about this treatment, click here and scroll down to section 4 on therapeutic strategies of postmenopausal osteoporosis.)
Sounds promising, right?
Unfortunately, this treatment falls prey to the same issue as many other therapeutic treatments for osteoporosis. Yes, by artificially slowing bone resorption, you may increase bone density temporarily. You may even reduce short-term fracture risk. But what about the quality of the bone you’re accumulating? And what are the potential long-term effects of such a treatment?
It’s critical to remember that bone resorption happens for a reason. It’s your body’s way of clearing out old, worn-down bone and making way for new, high-quality bone. So when you block bone loss, you may increase bone density in the short term. But you’re really just accumulating more and more old, brittle bone — you’re not actually building new, strong bone!
And this can lead to increased fracture risk over time, as the quality of your bone deteriorates…
Which, ironically, is the exact opposite of what such a treatment is trying to accomplish.
Not only that, in the case of this new treatment, the potential side effects aren’t well understood. Interfering with how these cells work could have any number of consequences. Again, as we’ve seen, these systems are incredibly complex and exist in a delicate balance.
But there’s an alternative course of action. By taking a natural, multi-nutrient approach to bone health, you can increase your bone density — without worrying about the negative side effects that often accompany conventional treatments.
If you’d like more information on how to approach osteoporosis naturally, visit this page.
Bone and Immune System Takeaways
Scientists used to think of bone as a passive structure — a kind of “scaffolding” for the other organs.
But research has come a long way, and now, we know that bone is extremely dynamic. Not only is it constantly renewing itself through the bone remodeling process, it also interacts with many other bodily systems.
The field of osteoimmunology is a prime example of bone’s dynamic nature. Immune and bone cells are tightly interconnected and involve many players. Notably, the RANKL–RANK–OPG system, which is key for regulating bone resorption, connects these players.
The study of the interaction between bone and immune systems has yielded new insight into how bone loss occurs in chronic conditions like osteoporosis. It’s also led to the development of a new therapeutic treatment for bone loss, but the potential side effects of this treatment are cause for concern.
To break it down simply, here are the main takeaways:
- The bone and immune systems are deeply intertwined and exist in a delicate balance.
- Chronic conditions characterized by bone loss (osteoporosis, rheumatoid arthritis, gum disease, IBD, etc.) often result from an imbalance between these systems.
- If you experience bone loss as a result of any of these conditions, address the underlying cause, and be sure your bones are getting the nutrients they need to stay strong, healthy, and fracture-free!