Are you or somebody you love (e.g. a parent or grandparent) experiencing osteoporosis, at risk of osteoporosis, or wanting to prevent it?

As you probably know, osteoporosis is a serious threat to longevity and quality of life.

In a review of multiple studies between 1957 and 2009, women over age 50 had a 5.75-fold increased risk of death from all causes in the first 3 months after a hip fracture, and men over age 50 had a 7.95-fold increased risk of death from all causes in the first 3 months after a hip fracture (R).

A study of 122,808 elderly adults in the US and Europe found that the risk of death increases by 2.78-fold during the first year after a hip fracture (R). And the elevated risk of death remains substantially elevated for many years after a hip fracture, even more so for men than for women.

Many people live in fear of fractures because of what could happen as a result. Clearly, understanding the causes of osteoporosis and how to prevent or overcome it is an important part of healthy aging and greater peace of mind.

Most people are taught that osteoporosis is mainly about estrogen, calcium, and vitamin D. While these are essential for bone health, there are at least 18 other key influences that may not yet be on your radar.

18 Little-Known Influences on Bone Health and Osteoporosis

1. Collagen is an important structural constituent of bones that contributes to bone strength (R), and collagen supplementation has been shown to increase bone mineral density (R, R).
2. Copper is necessary for collagen synthesis in the body, yet it needs to be at a moderate level because both low and overly high levels of copper have been associated with reduced bone mineral density and increased fracture risk (R).
3. Zinc is also involved in collagen synthesis and multiple other aspects of bone metabolism, and higher zinc intake has been associated with lower rates of osteopenia and osteoporosis (R, R, R).
4. Magnesium has important roles in bone metabolism (R), and while low magnesium is often associated with an elevated risk of osteoporosis (R), high magnesium also appears to have harmful effects on bones (R, R).
5. Among boron's surprisingly diverse beneficial roles in human health, boron assists calcium and magnesium metabolism and appears to support bone mineral density (R, R, R).
6. Silicon (R, R) and manganese (R) appear to have roles in maintaining healthy bone mineral density, so deficiencies may play a role in osteoporosis.
7. Selenium intake is associated with higher bone mineral density (R, R), however excessively high selenium may reduce bone mineral density (R).
8. Vitamin K intake is associated with higher bone strength and lower fracture risk (R, R, R, R).
9. Moderate vitamin A intake is associated with the highest bone mineral density, compared to lower and higher vitamin A intake (R).
10. Elevated homocysteine is a recently-recognized risk factor for osteoporosis (R) that is driven by the function of the methylation cycle and therefore influenced by certain genetic polymorphisms (e.g. MTHFR) and the status of nutrients (R, R) such as folate, B12, B6, B2, B3, zinc, iron, serine, and choline.
11. Hyperthyroidism, hypothyroidism, and subclinical hyperthyroidism are associated with decreased bone mineral density (R).
12. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of bone fractures, despite normal to increased bone mineral density (at least during initial stages of T2DM) in some studies, suggesting deterioration of bone quality and increased bone fragility (R), followed by loss of bone mineral density with prolonged T2DM (R).
13. Bones have the 3rd highest mitochondrial metabolic activity behind the brain and heart, and mitochondria play key roles in bone metabolism, with mitochondrial dysfunction appearing to contribute to osteoporosis (R, R, R, R).
14. Chronic oxidative stress (R, R, R) and inflammation (R, R) promote the development of osteoporosis, so inflammatory conditions like mold illness, leak gut syndrome, inflammatory bowel disease, celiac disease, and perhaps mast cell activation syndrome may contribute to osteoporosis.
15. Environmental toxicants, especially heavy metals, are a major contributor to osteoporosis via multiple mechanisms (R).
16. Many prescription and over-the-counter drugs negatively impact bone health (R, R).
17. Elevated cortisol is associated with reduced bone mineral density (R).
18. Estrogen, progesterone, testosterone, pregnenolone, and DHEA have complex relationships with bone metabolism in men and women (R, R) that may not be adequately addressed by pharmaceutical or bioidentical hormone replacement therapy the way they are currently practiced, as discussed later in this article.

There is so much more to know about bone metabolism than most of us realize until we dig into it. But considering the factors listed above, a reasonably complete approach to preventing, slowing, or even reversing osteoporosis would include at least the following steps:

1. Testing various markers related to bone mineral density and bone metabolism
2. Testing your nutrient status to identify deficiencies you're not aware of and causes of poor nutrient absorption such as inflammatory bowel disease or celiac disease
3. Testing for environmental toxicants that your body has not been effectively excreting
4. Testing markers of inflammation and oxidative stress and identifying their underlying causes (e.g. gastrointestinal inflammation, hidden infections, environmental toxicants)
5. Testing your homocysteine and methylation cycle function
6. Testing thyroid hormone status, if you have symptoms of low or excessive thyroid signaling
7. Testing mitochondrial function, if you have symptoms of mitochondrial dysfunction, such as fatigue, or are above age 40
8. Normalizing bowel function and nutrient absorption
9. Replenishing deficient nutrients
10. Removing the toxicants your body has not been good at eliminating
11. Resolving causes of chronic inflammation and oxidative stress 
12. Normalizing methylation cycle function and homocysteine if not normalized by addressing all of the above, or while addressing all of the above
13. Normalizing thyroid function if not normalized by addressing all of the above, or while addressing all of the above
14. Normalizing mitochondrial function if not normalized by addressing all of the above, or while addressing all of the above
15. Normalizing insulin sensitivity and glucose metabolism if not normalized by addressing all of the above
16. Possibly using new strategies for the use of hormones like estrogen, progesterone, testosterone, and pregnenolone in perimenopause, menopause, and postmenopause

The first logical step in your bone health optimization plan would be to establish a baseline of your bone mineral density, quality, and metabolism.

Testing Bone Mineral Density and Quality

To assess bone mineral density, you would typically get a dual-energy absorptiometry test (DEXA or DXA). However, bone mineral density only accounts for about 60% of bone fragility (R). And DXA can overestimate bone mineral density when bone abnormalities like bone spurs, arthritis, or degenerative scoliosis are present. 

In addition to bone mineral density, another important variable in bone strength is the microarchitecture of the trabeculae, which form the inner, porous part of bone. Loss of bone strength typically first occurs in the trabecular structures in the interior of bones.

Recent research suggests that trabecular bone quality may be more important than bone mineral density as a determinant of bone strength and resistance to fracture. Consequently, software has been developed that uses data from a DXA scan to calculate a trabecular bone score (TBS) as a measure of bone quality. But not all providers of DXA equipment have this software. So when obtaining a DXA scan, ask the provider in advance if they will be able to also provide a trabecular bone score (TBS).

Measuring your bone mineral density (BMD) and obtaining a trabecular bone score (TBS) are the minimum steps for assessing your bone strength and risk of fracture because your bone strength is determined by both bone mineral density and your trabecular bone quality.

In addition to measuring bone strength via BMD and TBS, if budget permits, you might also want to run blood tests that look at several indicators of bone metabolism.

Testing Bone Metabolism

The following tests provide additional insight into what is happening inside your bones:

1. C-telopeptide (serum CTx) test shows whether you are actively losing bone now by assessing the activity level of cells that are breaking down bone.
2. N-telopeptide (urine NTx) looks at the activity level of cells that are breaking down bone.
3. Procollagen type 1 N-terminal peptide (P1NP) looks at bone-building activity.
4. Osteocalcin is a hormone that promotes the movement of calcium out of the blood into bones.
5. Parathyroid hormone promotes the movement of calcium out of bones into blood.
6. Bone-specific alkaline phosphatase is an indicator of bone metabolism that along with other markers like osteocalcin can provide insight into net bone formation versus net bone resorption.
7. 24-hour urinary calcium can be used as an inexpensive measure of active bone loss.

Three of these seven tests (CTx, NTx, P1NP) examine components of bone collagen that is either being broken down or formed, reminding us of how important collagen is as part of the bone matrix.

However, if your budget for osteoporosis-related testing is limited, it might be more important to skip these tests and focus on testing potential causes of osteoporosis.

8 Core Tests for the Causes of Reduced Bone Health

As mentioned previously, bone health is influenced by factors such as the status of certain nutrients, the presence of certain toxic substances, mitochondrial dysfunction, oxidative stress, gut function and inflammation, systemic inflammation, thyroid function, cortisol, and sex hormones. That is why the 7 core tests for the causes of reduced bone health below, or others that accomplish something similar, are important:

1. Micronutrient panel from Vibrant Wellness (for assessing nutrient deficiencies)
2. Total Toxic Burden from Vibrant Wellness (for assessing the presence of toxicants like heavy metals, mold toxins, and environmental pollutants)
3. Metabolomix+ from Genova Diagnostics (for assessing mitochondrial function, oxidative stress, and some markers of gut dysbiosis)
4. Gut Zoomer from Vibrant Wellness (for a detailed assessment of gut function, inflammation, and microbiome)
5. Other tests to assess celiac disease and/or inflammatory bowel disease
6. A group of inflammation-related markers, including homocysteine, hsCRP, erythrocyte sedimentation rate (ESR), TNF, IL-6, and perhaps others
7. A methylation panel from Genova Diagnostics or Doctor's Data
8. A full thyroid panel that includes at least free T3, free T3, reverse T3, and thyroid antibodies (TPOAb and TgAb plus TSI and TRAb if hyperthyroidism is suspected)
9. DUTCH Plus from Precision Analytical (for assessing adrenal and sex hormones)

The DUTCH Plus test in the list above includes testing of estrogens, and most of us have been taught that the reduction in estrogen that occurs in perimenopause, menopause, and postmenopause is what drives osteoporosis in women. But it may not that simple.

Estrogen, Progesterone, Testosterone, Pregnenolone, DHEA, and Cortisol in Osteoporosis

Although estrogen declines in perimenopause and thereafter, progesterone typically declines even more, and the decline in progesterone precedes the decline in estrogen in perimenopause (R). This creates estrogen dominance. So menopause and postmenopause are typically estrogen-dominant states.

Estrogen dominance is even more likely to occur under conditions that promote the conversion of testosterone to estrogen (e.g. inflammation) and/or conditions that reduce progesterone production (e.g. the altered adrenal function and mitochondrial dysfunction that often accompany aging, chronic fatigue, and other conditions). 

One of the effects of estrogen dominance is a reduction in collagen formation, and collagen is a major component of bone. Another potential effect of estrogen dominance can be an increase in inflammation, and inflammation is one of the main drivers of osteoporosis. But estrogen also has anti-inflammatory effects.

Estrogen dominance in menopause and postmenopause might explain why research that showed prevention of osteoporosis in a mouse model did so by using something (pregnenolone) that happens to be antagonistic to estrogen and typically increases progesterone more than estrogen. In this study, pregnenolone prevented LPS-induced inflammatory bone destruction and also prevented ovariectomy-induced osteoporosis (R).

In other words, when mice were given a certain dose of pregnenolone, they did not experience the bone destruction that would normally have occurred when they were subjected to LPS (lipopolysaccharide), also known as endotoxin, the cellular membrane component of gram-negative gut bacteria that causes the body to response with an inflammatory immune response.

And when mice were given a certain dose of pregnenolone, they did not develop the osteoporosis that would normally have occurred as a result of having their ovaries removed (to mimic menopause-induced reduction in sex hormones).

Since pregnenolone is known to have anti-estrogenic effects, partially due to its conversion to progesterone, the results of this study cast some doubt on the importance of estrogen deficiency as the main cause of osteoporosis and perhaps suggest instead that a more appropriate focus might be reducing estrogen dominance (e.g. by raising the ratio of progesterone to estrogen) while perhaps also optimizing the levels of estrogen, progesterone, testosterone and the sex hormone precursors, pregnenolone and DHEA.

In postmenopausal women, androgens (male sex hormones) such as androstenedione, dehydroepiandrosterone (DHEA), and testosterone—especially in the presence of elevated cortisol—appear to be essential to minimizing or avoiding bone loss (R). And as expected, androgens are also essential to maintaining bone mineral density in men, but research suggests that estrogen is even more important than testosterone for preserving bone mineral density in men (R, R, R).

However, the research on men and women seems to under-emphasize the functions of progesterone in bone metabolism, perhaps forgetting that one of estrogen's roles is to potentiate progesterone receptors, which may be at least one reason why hormone therapy that includes progesterone (as progestins in the research) is more effective at preventing osteoporotic fractures than estrogen alone (R).

In fact, it seems that the cycling of estrogen and progesterone that occurs during the menstrual cycle maintains bone mineral density via estrogen's potentiation of progesterone receptors and progesterone's anti-corticosteroid effect, suggesting that "postmenopausal osteoporosis may be, in part, be a progesterone deficiency disease" (R), which is supported by the fact that the inclusion of progesterone improves outcomes in therapies aimed at increasing bone mineral density (R).

Estrogen's potentiation of the progesterone receptor was a central theme of Sex, Lies, and Menopause and the author's recommendation of a biomimetic, bioidentical approach to hormone replacement therapy in which estrogen and progesterone are used in a cyclical pattern very similar to that of a normal menstrual cycle.

Adrenal Gland Health and Function, Chronic Illness, and Osteoporosis

During and after menopause, as sex hormone production by the ovaries declines, the adrenal glands become the source of remaining sex hormone production. This makes it likely that adrenal gland function has a significant influence on bone health via their production of sex hormones in women.

It is commonly observed in clinical practice (but not well-documented in research) that adrenal function typically shifts during long term illness, often decreasing sex hormone production and increasing cortisol production. 

So, almost any long-term illness could promote osteoporosis by reducing adrenal production of both male and female sex hormones (and their precursors, pregnenolone and DHEA, while elevating cortisol production) even more than normal in women who have reached perimenopause or beyond. 

Elevated cortisol has been shown to decrease bone mineral density, even in subclinical hypercortisolism (R), and with the use of glucocorticoid medications (R). Furthermore, cortisol typically increases in the elderly, independently of overt illness, and is associated with reduced bone mineral density in the elderly (R). 

So it appears that managing cortisol and addressing the factors that elevate it (e.g. chronic illness, chronic stress, glucocorticoid medications, and aging) would need to be part of any efforts to prevent or overcome osteoporosis. One of the factors that increases cortisol is the inflammation present in inflammatory disease processes.

Inflammation, Inflammatory Bowel Conditions, Diabetes, Heavy Metals, Mitochondrial Function, and Osteoporosis

Inflammatory diseases such as inflammatory bowel disease, celiac disease, chronic obstructive lung disease, cystic fibrosis, periodontitis, rheumatoid arthritis, fatty liver disease, pancreatitis, cardiovascular disease, and others can promote bone loss and increased risk of bone fracture due to the upregulation of inflammatory cytokines that increase bone degradation via the hyperactivation of osteoclasts and the impairment of osteoblasts (R, R, R, R). 

A key driver of bone loss-promoting inflammation that is present in many inflammatory diseases is gut-derived bacterial LPS / endotoxin (R). Gut permeability tends to increase with age in association with changes in the gut microbiome, allowing more gut-derived LPS / endotoxin into the body (R, R, R). And LPS-generated endotoxemia is also a likely causal factor in diabetes (R, R), which increases fracture risk and reduces bone mineral density (R, R).

Heavy metals and other environmental pollutants also alter the gut microbiome (R) and gut permeability, leading to inflammatory bowel disease (R, R), which can in turn promote osteoporosis via the elevation of inflammatory cytokines.

Heavy metals also promote mitochondrial dysfunction (R), which promotes osteoporosis by altering the balance between osteogenesis (bone-building activity) and osteoclastic (bone-breakdown) activity (R, R). 

One common heavy metal in particular, cadmium, appears to have a uniquely damaging influence on bone health (R). Non-smoking women with higher levels of cadmium had a 347% increased risk of osteoporosis as the femoral neck and a 328% increased risk of osteoporosis at the lumber spine (R). 

Cadmium accumulates in the kidneys where it impairs the conversion of the circulating "storage" form of vitamin D to its most active form, calcitriol, and damages the kidneys' ability to excrete other toxic substances and reabsorb nutrient minerals, including calcium (R). In fact, elevated urinary calcium is an indication of low-level cadmium exposure.

Cadmium also inhibits the action of alkaline phosphatase, which is needed to deposit calcium in bone, and it stimulates osteoclasts to break down bone (R).

Food grown in soils where high-phosphate fertilizers have been used have higher cadmium, and legumes absorb more cadmium than other types of crops, especially soy. So conventional, non-organic soy tends to be one of the foods highest in cadmium. 

Lead damages bone health in ways that are somewhat similar to cadmium (R, R), and pesticides generally promote osteoporosis by increasing oxidative stress and inflammation and damaging kidney function. And anything that damages they kidneys promotes bone loss by reducing the conversion of vitamin D to its most active form, impairing the kidneys' ability to excrete acid substances, and increasing the loss of calcium in urine (R). 

Phthalate plasticizers like BPA are associated with reduced bone mineral density, owing to the following mechanisms.

1. Suppression of osteoblast and osteoclast development, thereby blocking bone renewal (R)
2. Reduces activity of alkaline phosphatase (R)
3. Blocks estrogen related receptor gamma (R)
4. Disruption production and signaling of thyroid, parathyroid, adrenal, and sex hormones (R, R)
5. Reduction circulating vitamin D (R)

Most of the people I have tested had elevated levels of BPA. It is a pervasive and serious toxicant, and its substitutes, BPF, BPS and BPZ, are similarly toxic.

Elevated homocysteine is another osteoporosis-promoting factor that also interfaces with some of the other influences discussed in this section, such as general inflammation, cardiovascular disease, liver disease, and autoimmune disease. The influence of elevated homocysteine on bone health appears to be mediated by increasing oxidative stress, bone breakdown activities of osteoclasts, and reducing blood flow to the bones (R, R).

Vitamins K, A, and D and Calcium

Vitamin K (mostly in the K2 forms and much less so in the K1 forms) is required to activate vitamin K2 dependent bone-building proteins like osteocalcin. So it makes sense that an analysis of the large Nurse's Health Study showed that women consuming less than 109 mcg of vitamin K had lower bone mineral density and increased risk of fracture (R), and that an analysis of the large Framingham Heart Study showed that men and women consuming less than 70.2 mcg daily of vitamin K had significantly lower bone mineral density than those consuming 309 mcg daily (R).

And two reviews of studies on vitamin K supplementation showed that supplementation with vitamin K2 increased bone mineral density and reduced fractures (R, R). 

Vitamin A has a relationship with vitamin D that is both cooperative and antagonistic. So, it is not surprising that moderate vitamin A intake is associated with the highest bone mineral density, compared to lower and higher vitamin A intake. Evidence suggests that both high and low vitamin A intake reduce bone mineral density and increase fracture risk (R).

I would suggest that the best moderate vitamin A intake depends on an individual's intake of vitamin D and that the moderate vitamin A intake shown in studies to be optimal is related to the average vitamin D intake of the participants in those studies. An individual taking higher doses of vitamin D would have a higher optimal "moderate" dose of vitamin A. 

Research on vitamin D and calcium shows less clear relationships between vitamin D and calcium and bone mineral density and fracture risk. And I would suggest that this is because to use calcium in bones, the body requires more than just vitamin D. It must also have vitamins K and A (and other factors as well) to properly orchestrate the deposition of calcium in bones.

Physical Activity, Sedentary Behavior, and Bone Health

Numerous lines of evidence demonstrate a connection between physical activity and bone health, with physical activity probably playing a role in the prevention of osteoporosis (R), and lack of physical activity and time spent in sedentary behavior having negative impacts on bone mineral density (R).

Unfortunately, the fatigue that often accompanies chronic health conditions typically reduces physical activity and exercise. So an important part of anybody's efforts to maintain bone mineral density must involve restoring physical energy to support physical activity and exercise. 

A More Complete Strategy for Preventing or Overcoming Osteoporosis

Many factors contribute to the development of osteoporosis, which is probably why hormone replacement therapy alone or nutrient supplementation alone are often not enough to prevent or overcome osteoporosis. In many cases, a more complete strategy may be needed.

A more complete strategy would include finding out which osteoporosis-promoting factors might be at play and using effective means to resolve them. You would test for nutrient deficiencies, hidden infections and other sources of inflammation, gut health, mitochondrial function, and thyroid, adrenal, and sex hormones. 

And depending on your symptoms and the results of testing, you might need to support adrenal and thyroid function, remove heavy metals and other environmental pollutants, restore gut health, improve mitochondrial function, reverse hormone deficiencies or imbalances, heal dental conditions like periodontitis, reduce autoimmune or other immune system overactivity, normalize blood sugar regulation, and restore healthy function of organs like the liver, pancreas, and kidneys.

The bottom line is that if you want to prevent or overcome osteoporosis, it is important to consider much more than estrogen, calcium, and vitamin D. If you just need to prevent osteoporosis, the sooner you start working to optimize bone health and everything that affects it, the easier it will be to keep bone loss at bay.

If you already have osteoporosis and have implemented the recommendations you have been given thus far without much success, you probably have not yet identified all of the factors causing your osteoporosis, or you have not yet been given effective enough strategies for addressing them.

To get help with creating a more complete and effective bone health strategy that empowers an active life with less fear, connect with us here at Bio-Individual Wellness. You can learn more about our approach by downloading the Bio-Individual Blueprint Roadmap and watching the walkthrough video. If you have already done that, you can schedule a free 15-minute or 45-minute consultation.