The Pathophysiology of Osteoporosis
Pathophysiology—unhealthy bone remodeling—occurs when bone removal outpaces bone formation
Pathophysiology, the medical discipline that describes what happens when normal physiology goes awry, seeks to explain what went wrong and why. In terms of your bones, pathophysiology occurs (#1) when the bone removal process is happening too quickly for the bone replacement process to keep up and/or (#2) when the bone replacement process is inhibited or has ground to a halt.
Virtually anything that promotes chronic inflammation promotes excessive bone removal.
Examples include the many pro-inflammatory factors in the Standard American Diet; environmental exposures to a variety of pollutants, including pesticides, fluoride, heavy metals (lead, mercury, cadmium, arsenic), and endocrine disrupting chemicals, such as bisphenol A and phthalates. (1-14)
The bone replacement process is blocked by anti-resorptive drugs and monoclonal antibody drugs which shut down the bone removal process.
The anti-resorptive drugs poison osteoclasts, the specialized cells that remove damaged or worn out bone, while the monoclonal antibody drugs used to treat osteoporosis prevent osteoclasts from even developing. Both inhibit new bone formation because old or damaged bone must be removed before new bone can be laid down.
Bone renewal is greatly hindered when the nutrients required to build new bone aren’t there in sufficient supply. Just as you can’t make an omelet without eggs, you can’t build bone without calcium, vitamin D, vitamin K2, vitamin C, magnesium, boron and a number of other trace minerals. In addition, a number of other nutrients, including the omega-3 essential fatty acids, vitamin A, vitamin E and the B vitamins play important roles in our ability to maintain healthy bones.
Bone pathophysiology is called osteopenia when the result is bone-thinning (osteo=bone, penia= decrease, deficiency), and osteoporosis, when so much bone has been lost that the bones (osteo) have become brittle and riddled with tiny pore-like holes (porosis). Both diseases indicate that the normal bone remodeling process has become imbalanced so that bone-breakdown (bone-resorption) is outpacing bone formation.
Bone Remodeling Is Essential Throughout Life
Healthy bone remodeling is normal, not pathophysiology — our bones are preprogrammed to constantly rebuild themselves.
Your skeleton is not simply a static framework to which your muscles are attached. Your bones are very much alive and active and are constantly remodeling themselves. In fact, 10% of your skeleton is removed and replaced each year – in 10 years, your entire skeleton will have created itself anew! (15)
This constant bone remodeling is normal physiology. You can’t maintain a healthy skeleton without it for the following reasons:
- First, like all other cells, the cells that make up your bones get old and worn out, and need to be replaced with healthy new cells.
- Secondly, even the normal activities of daily living put stress on our bones and cause tiny areas of damage that require replacement. For example, when you eat, your jawbones take a surprisingly heavy hit with every bite, so continuous removal and replacement of bone damaged by chewing is essential. Exercising and being active is great for our bones and stimulates new bone formation, partly by causing micro-damage to bone. When you dash down or up a flight of stairs, go for a walk, jog, play tennis, take a Zumba, Pilates or barre class, you create super tiny cracks in your bones that must be repaired. This constant repair and renewal is normal human physiology; these processes are supposed to be happening to maintain healthy bones.
The balance between the activities of the osteoclasts, the specialized cells whose job is to break down (resorb) old damaged bone, and the osteoblasts, the specialized cells that form new bone, is the key to bone health. The remodeling actions of both types of cells — the osteoclasts and the osteoblasts — are required for the maintenance of a healthy skeleton. When osteoclast activity is prevented – as it is by the anti-resorptive drugs — old damaged bone accumulates, gradually rendering bones fragile and increasing risk of fracture. When the nutrients that osteoclasts require to lay down new bone are not provided by the diet and supplements — or are not well absorbed due to compromised digestive function or are not well utilized due, for example, to chronic liver or kidney disease — osteoblasts’ ability to create healthy new bone is significantly impaired.
What happens in the bone remodeling process
Remodeling begins when inflammatory cell signaling triggers the development and activity of osteoclasts, which are attracted to areas of microfracture. Once there, the osteoclasts release hydrogen ions, via the activity of an enzyme osteoclasts’ contain called carbonic anhydrase. This acidifies the area, dissolving the mineralized bone matrix. While the bone matrix is dissolving, osteoclasts release several hydrolytic enzymes (e.g., cathepsin and matrix metalloproteases) that effectively break apart (digest) the chemical bonds holding together the organic components of the bone matrix.
The osteoclast demolition crews are normally done with their bone resorption work in just 2 weeks, after which the body begins to switch gears. Just preparing osteoblasts to take over takes about 2 more weeks, following which new bone formation, which takes at least 13 weeks, begins. Just like remodeling a house, it takes a lot longer to rebuild than to break down bone. (For a hilarious visual, watch the demolition crew destroy a house in a matter of hours, then rebuild it over many months in the movie, The Money Pit, starring Tom Hanks and Shelly Long. Warning: If you are in the middle of remodeling your home, you may find this movie too true to life to be funny.)
It’s important to understand that the two aspects of the bone remodeling process, bone resorption and formation are not separate, independent processes. (16)
Osteoclasts and osteoblasts work together inside a unique temporary structure called the basic multicellular unit (BMU). Each BMU contains a team of osteoclasts in the front, a team of osteoblasts in the rear, a central capillary/blood vessel, a nerve supply, and associated connective tissue. In healthy human adults, 3–4 million BMUs are produced each year with ~1 million operating at any moment!
The average lifespan of the BMU osteoclast-osteoblast team is called “the remodeling period.” When all systems are functioning in proper balance, a full cycle of both aspects of the remodeling process is completed in 3–6 months. (17)
Each BMU begins at a particular place and time (origination) and advances toward a target, which is a region of bone in need of replacement, and for a variable distance beyond its target (progression), and eventually comes to rest (termination).
In cortical (also called compact) bone, which is the hard outer shell portion of your bones, the BMU travels through the bone, excavating and replacing a tunnel. In trabecular (also called cancellous) bone, which is the interior, spongy bone, the BMU moves across the surface, excavating and replacing a trench.
If your bones were M&M candies, cortical bone would be the hard outer shell and trabecular bone, the chocolate interior.
Actually, trabecular bone is more like the interior of a Kit Kat Bar. It’s a meshwork of spongy tissue (called trabeculae) that makes up the inside of our vertebrae (the bones of the spine) and the ends of the long bones (e.g., the femur). Trabecular bone’s structure is a honeycomb of interconnecting spaces containing bone marrow, and this bone marrow is the source of the precursor bone cells that can grow up to become osteoblasts and orchestrate the formation and growth of new bone.
In both cortical and trabecular bone, the osteoclasts and osteoblasts in BMUs normally maintain a well-orchestrated spatial and temporal relationship with each other. As noted above, osteoclasts remove damaged bone by secreting acid and proteolytic enzymes that break down the bone matrix. As the BMU team advances, osteoclasts leave the resorption site, and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, an unmineralized, secretion of proteins that eventually gets mineralized into new bone.
The lifespan of each BMU is 6–9 months, which is much longer than the lifespan of either its osteoclasts or osteoblasts. So, a continuous supply of new osteoclasts and osteoblasts is essential for the BMUs to keep making progress on the bone surface. Plus, we want the supply of new osteoclasts to be balanced by the supply of osteoblasts to get the bone-rebuilding work done.
Osteoblasts and osteoclasts are both derived from precursor cells in red bone marrow, which is found in the core of most bones. Osteoblasts are derived from precursor cells called mesenchymal stem cells (MSCs), while osteoclasts develop from precursors called hematopoietic stem cells (HSCs). MSCs can become either osteoblasts or adipocytes (fat cells). HSCs can become osteoclasts, immune cells (macrophages, neutrophils, basophils, eosinophils, T cells, B cells, natural killer cells) or platelets (a component of blood that prevents us from bleeding out by clumping together to form a blood clot).
Production of sufficient osteoclasts is not a problem. Inflammatory signaling triggers osteoclast production, and we certainly don’t have a deficiency of inflammation! Osteoblasts are the cell type modern man (and woman) are at risk of lacking.
What makes MSCs become osteoblasts and not fat cells?
MSCs make the decision to become osteoblasts and build bone for you when you are consuming enough of the (anti-inflammatory) omega-3 essential fatty acids to balance your intake of the (pro-inflammatory) omega-6 fatty acids. Balance here translates to a ratio of omega-6 to omega-3 of no more than 4:1.(18-22)
The omega-3s are alpha linolenic acid [ALA], for which the richest food source is flaxseed, and EPA and DHA, for which the richest dietary source is cold water fish, such as sardines and salmon. EPA and DHA, in addition to causing MSCs to choose to become osteoblasts, are highly-anti-inflammatory.
The omega-6s are linoleic acid [LA], which is found in most vegetable oils (e.g., canola, corn, sunflower and soy oils), and therefore in most processed foods, and arachidonic acid [AA], which is present in significant amounts in meats, in dairy products from non-organic, grain fed cows, and in farm-raised fish.(23)(24)
In contrast to the omega-3s, the omega-6, AA, is highly inflammatory – and anything that promotes chronic inflammation promotes bone loss. Here’s why.
Chronic Inflammation Promotes Bone Loss
Inflammation triggers osteoblasts (yes, your bone-building cells) to produce a protein called the RANK ligand (RANKL). RANKL is an acronym for “receptor activator of nuclear factor-kappa B ligand.” (Fortunately, you don’t have to remember this. Just knowing the acronym RANKL is enough.) Once produced by osteoblasts in response to inflammatory conditions, RANKL zips over to the osteoclast precursor cells in your bone marrow and binds to the RANK receptor on the surface of these cells. This tells these osteoclast-precursors it’s time to start maturing into full blown osteoclasts.(25)
RANKL is expressed in lots of tissues, not just by osteoblasts in your bone marrow. RANKL is expressed by cells in your muscles, thymus, liver, colon, small intestine, adrenal gland, breasts, prostate and pancreas. Why, you might ask – because RANKL to RANK binding also triggers the production of your immune defender T cells. Another name for RANKL is “tumor necrosis factor ligand superfamily member 11” because RANKL’s binding to RANK tells your body to produce immune cells that destroy cancerous tumors and invading viruses, unfriendly bacteria and other pathogens.(26)(27)
How does RANKL-RANK binding send the “get going” message to your osteoclasts and immune cells?
When RANKL binds to its cell surface receptor, RANK (receptor activator of nuclear factor-kappa B, another long name you don’t need to remember), this turns on a seriously pro-inflammatory messenger called NF-kappa B (nuclear factor-kappa B). NF-kappa B moves from the cell membrane into the cell and makes a beeline for its DNA, where it sets off the production of a whole bunch of pro-inflammatory processes—one of which is the activation of osteoclasts. When RANKL activates the RANK receptor on the precursor cells for osteoclasts, these osteoclast-hopefuls get the message that they are to develop into mature osteoclasts and remove worn out, damaged or infected bone.
Too much RANKL secretion, however, promotes bone loss. So, what can you do to prevent it?
If you choose to go the pharmaceutical route, you can take anti-resorptive drugs which prevent bone remodeling by binding to and preventing RANKL from doing its job. Thus preventing osteoclasts (but also your immune cells, specifically your T cells) from maturing and doing theirs.
RANKL can be controlled safely, naturally
A more intelligent way of preventing excessive RANKL secretion is dealing with its cause: chronic inflammation!
In addition to our modern diet, aptly called the SAD (Standard American Diet), which promotes inflammation in numerous ways — including delivering far too much omega-6 and far too little omega-3 (the omega-6: omega-3 ratio of the SAD is 20:1!) — many other environmental and lifestyle factors in our lives promote osteoclast-activating, bone-busting inflammation. (And you can expect to hear more about them, and how to avoid them, in future blogs.) A key factor discussed in this post is that just improving your omega-6: omega-3 ratio can go a long way towards putting out any chronic inflammation smoldering in your body, and the increase in RANKL-RANK binding it promotes.
Another action you can take is to increase your body’s production of RANKL’s natural decoy, another protein produced by osteoblasts called osteoprotegerin. Osteoprotegerin (OPG) also binds to RANKL, effectively preventing RANK-RANKL binding. In contrast to the anti-resorptive drugs I mentioned before, our natural OPG does not completely shut down osteoclast formation and activity, but allows necessary healthy bone remodeling (and immune cell maturation!) to continue.(28)
How can we encourage our natural production of OPG?
By consuming vitamin K and soy foods. Vitamin K, in both its vitamin K1 and vitamin K2 forms, promotes a healthy balance between RANKL and OPG. Vitamin K1 lowers inflammation and RANKL, while K2 (MK-7) increases OPG. Whole soy foods contain a bioactive isoflavone (a phytonutrient compound) called genistein, which lowers inflammation, in part by increasing production of OPG and decreasing that of RANKL.(29-32)
The Bottom Line:
The pathophysiology of osteoporosis /osteopenia is the result of an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Unfortunately, many factors in our modern Western lifestyle can disrupt the healthy balance between these two cell types that is required for lifelong bone renewal. The healthy balance between osteoclast and osteoblast activity can be upset by anything that causes the inflammatory cell signaling that triggers osteoclasts into motion to be chronically activated — or by hampering osteoblasts’ ability to lay down new bone by blocking the bone removal process or by not providing the nutrients needed.
The solution is not to prevent all osteoclast activity (as do the anti-resorptive drugs and monoclonal antibodies), but to restore balanced bone remodeling. This is done by:
- Identifying, in each individual person, the specific inflammatory factors that are promoting excessive osteoclast activation and controlling or eliminating them.
- Ensuring bones’ nutrient needs are met, so osteoblasts are provided with an optimal supply of all the nutrients they require to build new bone.
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