The Paleo Premise

Autoimmune Disease

2012-05-25T15:33:00.001+10:00

Molecular Mimicry and the Bystander Effect

Infections are strongly associated with autoimmune disease and seem to initiate them either by the process of molecular mimicry or the bystander effect [1].

Molecular mimicry is where the immune system develops antibodies to a particular amino acid sequence expressed by a pathogen, which happens to be structurally similar enough for the antibodies to cross react with self-antigens, our own tissues.

The bystander effect is where an infection leads to inflammation and tissue damage. Then this infected and damaged tissue is considered foreign by the immune system, antibodies are made against it, but these antibodies are cross-reactive with nearby undamaged tissue.

Molecular mimicry and the bystander effect are observed in animal models of autoimmune disease [1]. But these mechanisms are incomplete for two reasons.

1. Why does the immune system continue to attack the body after the pathogen has been destroyed?

2. Why has the incidence of autoimmune disease increased while infectious disease has decreased?

A Dysfunctional Immune System

According to molecular mimicry and the bystander effect, once the autoimmune process is activated it becomes independent of continuous exposure to the environmental trigger, and is therefore self-perpetuating and irreversible [2]. That an adaptive immune system continues to attack the body after the pathogen has been destroyed suggests it’s not so adaptive after all. So I think it’s fair say an immune system that produces autoimmune disease is dysfunctional. For autoimmune disease this dysfunction is primarily a high Th17:Treg ratio [3] [4].

During an extracellular (outside cells) infection CD4+ T cells (the antibody arm of the immune system) differentiate into pro-inflammatory cells such as T-helper 17 (Th17) cells – to coordinate the immune response and clear the pathogen. After the pathogen is cleared the CD4+ T cells differentiate into the anti-inflammatory T-regulatory (Treg) cells to control unwanted immune activation and decrease inflammation. Th17 cells are also up regulated during autoimmune diseases [3].

Under normal circumstances ATP generated from gut bacteria* can be used to produce Th17 cells and beneficial bacteria increase Treg cells to protect themselves from immune attacks [3]

Experimental manipulation of the balance between Th17 and Treg cells can modulate the autoimmune process:

· Germ-free mice have no resident bacteria so they produce very little Th17 cells, which protects them from autoimmune disease. They also have low numbers of Treg cells. If exposed to segmented filamentous bacteria to increase Th17 cells, they develop autoimmune diseases such as RA and experimental autoimmune encephalomyelitis (EAE), an animal model of MS [5] [6].

· Thymectomy (surgically removing the thymus) leads to a deficiency in Treg cells and then autoimmune diseases such as Hashimoto’s thyroiditis and T1D [7]

· Deletion (genetic mutations) or depletion of Treg cells results in widespread autoimmune disease [3] [4]

· Inflammatory responses in autoimmune diseases is promoted by Th17 cells and inhibited by Treg cells [3] [5] [7]

* Microbes reside in many part of the body include skin, mouth and the lower GI tract, which has the greatest density and diversity. There are roughly 100 trillion bacterial cells which combined have 150 times our genetic material. Humans collectively carry roughly 1,000 bacterial species and about 160 in each person [3]. The gut microbiota prevents pathogen colonisation and assist in immune development and homeostasis, T cell differentiation, inflammation, repair and angiogenesis [8]. Bacterial species compete over our GI tract. Beneficial bacteria assist in the immune response against pathogens and some pathogenic bacteria trigger inflammation to kill commensal species [3]

Influencing the Th17:Treg Cell Ratio

Perhaps the major factor behind immune dysfunction is an unhealthy gut bacteria (dysbiosis). Dysbiosis is associated with RA, T1D, IBD (includes Crohn’s disease, ulcerative colitis and others), asthma and allergies [5] [9] [10]. The ‘altered microflora hypothesis’ (similar to the hygiene hypothesis, but more specific and less lazy) suggests that recent environmental changes such as diet and antibiotics negatively alter gut bacteria, which can lead to immune dysfunction and are responsible for the increasing incidence of autoimmune diseases, allergies and asthma [10].

Some factors involved in dysbiosis are difficult to change. Natural birth and breastfeeding provides beneficial bacteria to outcompete any pathogens and are associated with a reduced risk of autoimmune disease. Getting a caesarean or formula deprives the baby of the beneficial bacteria they would ordinarily get [8] [9]. Previous antibiotic use can eliminate bacterial species and provides an opportunity for antibiotic resistant bacteria and fungal infections to gain a foothold [10]. Being raised in an indoor environment surprisingly increases bacterial diversity, but increases pathogenic bacteria at the expense of beneficial bacteria [8].

Dysbiosis may emerge later in life from other factors besides antibiotics:

· Inflammatory substances such as alcohol promote dysbiosis [11], which makes sense as pathogens can use inflammation to kill commensal species.

· Unabsorbed carbohydrates (FODMAPs) give pathogenic bacteria have an easy food source for rapid fermentation and division. The resulting bacterial overgrowth increases inflammation and intestinal permeability [12].

· A lack of soluble fibre. Fermentation of soluble fibre (prebiotics) into butyric acid supports good bacteria and the butyric acid decreases pro-inflammatory cytokines, increases anti-inflammatory cytokines (such as IL-10, the interleukin of Treg cells) [13], decreases intestinal permeability [14] and supplementation is therapeutic for IBD [15] [16]. Also, probiotic supplementation increases Treg cells [17]

There are other factors involved besides dysbiosis. The development of Treg cells requires TGFβ and retinoic acid (derivative of retinol/vitamin A) [3]. Supplementing retinoic acid increased Treg cells, decreased IL-6 and Th17 cells and halted the progression of an animal model of RA [18]. Sunlight/vitamin D is often associated with a reduced incidence of autoimmune disease [19], perhaps mainly because serum 25-hydroxyvitamin D correlates with Treg cell function [20]. Vitamins A and D also increase CD8+ T cells (cytotoxic T cells), which induces apoptosis in infected or tumour cells and has the effect of better controlling infections and minimising antibody use. This allows them to increase immune function in regards to infection and cancer, while being effective against autoimmunity. People with autoimmune disease tend to have a high CD4+:CD8+ T cell ratio (antibody:cytotoxic) and women have a higher ratio than men [21] [22].

TGFβ and pro-inflammatory cytokines such as IL-1, IL-6 and IL-21 are required for Th17 cell development and IL-17 production (the interleukin of Th17 cells) [3]. Excessive IL-6 from chronic inflammation and other factors can therefore overexcite the immune system, potentially creating an immune profile conducive to autoimmunity.

Women have a higher incidence of autoimmune disease than men [23]. In addition to the CD4+:CD8+ ratio, this is likely because testosterone increasing Treg cells [24] and estrogen promotes immune activity when its high but suppresses immune activity when its low [25]. Cortisone is often used as the drug treatment for autoimmune diseases because it is immunosuppressive. Cortisone is prescribed on the assumption that the immune system of an autoimmune disease patient is overactive, but I think it’s probably more accurate to say that it’s under-regulated.

Intestinal Permeability

Even with a dysregulated immune system it’s unlikely that in real life conditions (as opposed to experimentally depleting Treg cells) one infection will produce lifelong autoimmune disease. A healthy person may only sustain autoimmune damage while infected, whereas a person with a dysregulated immune system may have some autoimmune attacks for some time have the infection has cleared. A lifelong autoimmune disease probably requires a dysregulated immune system and the continuous exposure to the triggering antigen, made possible by intestinal permeability [26].

The intestinal mucosal barrier is made up of structures to connect cells together called tight junctions to separate our body from the outside world (technically the digestive tract is not inside the body) to prevent bacteria, pathogens and toxins from entering the body. There are a number of proteins that make up the tight junctions and keep them closed, but only one that opens them, zonulin [27].

Zonulin is active in the small intestine but no the large intestine. The function of zonulin is to open up the tight junctions to move fluid, macromolecules (proteins, lipids, carbohydrates and anything larger) and leukocytes (white blood cells) between the body and small intestine. In addition bacteria and pathogens inherently stimulate the zonulin pathway so our body is protected against infection in the small intestine (which is usually sterile). When the tight junctions open, water is released into the small intestine and bacteria/pathogens/etc are flushed out of the body, causing diarrhoea* [26].

The prolamines in wheat (gliadin**), rye (secalinin) and barley (hordein) activate the zonulin pathway, increasing intestinal permeability and also are the trigger for coeliac disease [9]. Gliadin also increases pro-inflammatory macrophages, the reactivity of the immune system and promotes dysbiosis [28]. A zonulin inhibitor drug blocks increases in intestinal permeability and GI symptoms when coeliacs have gluten [29]

Other things that can compromise barrier function and increase intestinal permeability include: pro-inflammatory cytokines, glucocorticoids, oxidative stress, low cellular calcium, NSAIDs (by damaging mitochondria and by depleting ATP which is needed for maintaining the tight junctions), psychological stress, acute infections and [27] [30]

Intestinal permeability is related to autoimmune disease:

· People with ankolosing spondylitis, coeliac disease, crohn’s disease, dermatitis herpetiformis, MS, RA and T1D tend to have elevated intestinal permeability or zonulin levels (depending on which was measured) [26] [31] [32]

· An increase in intestinal permeability following elevated zonulin levels precedes the onset of T1D by 2-3 weeks in an animal model. Later a zonulin inhibitor drug blocked autoantibodies [26].

· Intestinal permeability precedes relapse in Crohn’s disease by as much as a year [26]

· Zonulin levels are associated with the severity of symptoms in Crohn’s disease [26]

* With this mechanism in mind the appendix now has a role to play. The appendix stores a culture of beneficial bacteria so when bacteria are flushed out of the body the colon can be repopulated.

** Gluten is made up of gliadin and glutenin

Infection

It’s interesting how one mechanism of disease, such as autoimmunity or mitochondrial dysfunction, can produce so much diversity by way of chronic disease. In autoimmunity this can probably be explained by different infectious agents and other antigens such as gut bacteria in IBD [3] and gliadin in coeliac disease.

In T1D the antigens are probably enteroviruses (especially coxsackievirus B). Enteroviruses can infect the thymus and pancreatic β-cells. This can have a combined effect of altering the balance between Th17:Treg and triggering and autoimmune disease that targets the pancreatic β-cells. T1Ds tend to have enteroviruses and their components in the pancreas and enterovirus RNA and anti-enterovirus antibodies in serum. Exposure to enteroviruses in early life and of the mothers during gestation increases the risk of developing T1D and the peak in enterovirus infections tends to occur before the peak in onset of T1D [33]

Other infections are associated with other autoimmune diseases:

· EBV infections with multiple sclerosis [1] and lupus [34]

· Helicobacter pylori infections with autoimmune chronic gastritis [1]

· HSV infection with stromal keratitis (herpetic keratoconjunctivitis) [1]

Allergies and Asthma

While this post is about autoimmune disease it’s also relevant to allergies and asthma. All three conditions are evidence of a dysfunctional immune system and are all associated with dysbiosis.

Food allergies may also require intestinal permeability to expose dietary antigens to the immune system, whereas other allergies and asthma wouldn’t require intestinal permeability

	Dysfunctional Immune System	Intestinal Permeability
Autoimmunity	X	X
Food Allergy	X	X
Other Allergy	X
Asthma	X

Summary

Molecular mimicry and the bystander effect don’t tell the full story of autoimmune disease. The autoimmune process can be experimentally turned off and on by extreme manipulation of the Th17:Treg cell ratio or zonulin levels and intestinal permeability. In real life scenarios both factors may need to be involved – the immune system may have to be both dysfunctional and continuously exposed to the antigen for there to be an autoimmune disease.

Things that increase the Th17:Treg cell ratio and intestinal permeability include alcohol, antibiotics, FODMAPs, gliadin, infections, inflammation, NSAIDs and stress.

Things that decrease the Th17:Treg cell ratio and intestinal permeability include vitamin A, vitamin D, soluble fibre/butyric acid and probiotics (supplemental good bacteria)

Osteoporosis

2012-04-09T18:29:00.004+10:00

Bone mineral density is used to diagnose osteoporosis. Normal bone mineral density is considered less than or equal to 1 standard deviation below the mean bone mineral density of 30 year old men and women. Osteopenia is diagnosed when between 1 to 2.5 standard deviations below the mean and osteoporosis is diagnosed when greater than or equal to 2.5 standard deviations below the mean.

Discussions about osteoporosis are largely concerned with bone mineral density, but the actual end point we want to avoid are fractures. Sometimes bone mineral density is unrelated to fractures. For example, osteopetrosis is a rare inherited disorder and an uncommon side effect of bisphosphonates (a class of drugs used to treat osteoporosis), which leads to extremely dense bones and ironically, increased fracture rates.

Normal Bone

Osteoporotic Bone

The Calcium Paradigm

We have a calcium-centric view of osteoporosis. The common belief is that osteoporosis is due to a negative calcium balance. Under this paradigm dairy foods are essential and calcium supplements are therapeutic, but using an evolutionary perspective the notion we need dairy or calcium supplementation for adequate bone mineral density is absurd. Is calcium really a dominant factor in osteoporosis?

Calcium supplements without vitamin D reduce fractures by 10%, but increase cardiovascular diseases (CVD) (stroke and heart attack/myocardial infarction) by 30% [1].

Calcium supplements without vitamin D reduce fractures by 9% and 12% (one study found they increased the risk by 50%), but increase heart attacks by 27%, 31% and 112% and strokes by 37%. Calcium supplements with vitamin D only increase the risk of heart attacks by 22% and CVD by 17% [2].

“Treating 1,000 people with calcium or calcium and vitamin D for five years would cause an additional six myocardial infarctions or strokes and prevent three fractures.” [3]

Total calcium intakes greater than 900 mg or below 700 mg were associated with higher fracture rates (see graph below) [4].

The fourth study is observational so we can’t draw any conclusions along the lines of ‘calcium supplementation increases fracture rates’ as people who were at risk of osteoporosis likely tried to compensate with a higher intake of calcium. But the higher intakes of calcium didn't seem to help people, which it should have done if calcium is a dominant factor in osteoporosis. These results support another study that found calcium balance to occur at intakes of 741 mg (no mention of vitamin D) [5], so calcium intake is quite important, but only up to a certain point.

If osteoporosis is merely a function of calcium in, calcium out (another CICO and another disregard for the regulatory factors in our physiology) then extra calcium should be highly therapeutic and a very low calcium intake should ruin your bones, but neither of these is happening. The benefit of extra calcium is underwhelming and the relative risk for very low calcium intakes isn’t even that high. These results suggest a low calcium intake can be part of the problem, but not the problem we are facing.

Acid-Base

One of the arguments veg*ns love to use against eating meat is that all that protein, in particular the sulphur amino acids (methionine and cysteine) that animal foods are rich in, make the body acidic. Then calcium (which is alkaline) is leeched from the bones to balance the net renal acid load. Loren Cordain used this argument to his favour by saying the Paleo Diet is rich in fruit and vegetables, which are alkaline (or basic) and neutralise the acidity of meat. On the other hand the SAD with grains, dairy and limited fruit and vegetables is net acid yielding so calcium is leeched, hence the high RDI for calcium and osteoporosis.

The acid-base theory of osteoporosis doesn’t make much sense to me. I tend to view chronic disease as the result of a breakdown in self-regulation caused by an underlying pathology. If our bodies were at the mercy of acid-base ratios from the diet we would be ruined and many of the traditional cultures at higher latitudes would have been severely osteoporotic. Funnily enough our bodies have a means to regulate pH called the bicarbonate buffering system, it’s really simple.

Below is carbonic acid (H₂CO₃), which is slightly acidic. It is formed by carbon dioxide (CO₂) and water (H₂O) bonding, which happens fairly spontaneously. Carbon dioxide and water are what sugars and fats are broken down to, so they aren’t exactly scarce resources.

Below is bicarbonate (HCO₃^-) which is alkaline. All we have to do to make bicarbonate is remove one of the hydrogen protons from carbonic acid, a process called deprotonation.

If our body is slightly alkaline we make more carbonic acid, if it’s slightly acidic we make more bicarbonate. Likely for this reason a meta-analysis finds:

“A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health.” [6]

The body might fail to regulate its pH if you severely increase protein and phosphorus and have a low intake of calcium, magnesium and potassium or if you have metabolic acidosis, which is likely to be the result of poor kidney function and may be caused by progressive degeneration of the kidney’s from reactive oxygen species and energy deficiency due to mitochondrial dysfunction.

The Regulatory Factors

Osteoblasts produce osteocalcin and a matrix of osteoid, which is the unmineralised, organic part of bone and mostly made of collagen. Osteocalcin is a mineral binding protein, which helps to mineralise osteoids. When osteoids are mineralised they become osteocytes, the most common cell in bone. Osteocytes then release a protein called sclerostin to control the amount of bone by inhibiting further bone growth. I’ll refer to this process as bone formation. Osteoclasts break down bone tissue and release the bound minerals in a process called bone resorption.

Bones have a natural turnover rate where osteoblasts form bone and osteoclasts break down bone. Osteoporosis is largely due to too little osteoblast activity (bone formation) and/or too much osteoclast activity (bone resorption).

Serum calcium is tightly regulated by two main hormones: parathyroid hormone and calcitonin. Parathyroid hormone is released in response to low serum calcium to increase it by stimulating osteoclasts to break down bone and release calcium, activating vitamin D (to 1,25-hydroxyvitamin D) to increase calcium absorption in the intestine and increase reabsorption in the kidneys. Calcitonin is released in response to high serum calcium to decrease it by decreasing osteoblast activity, calcium absorption and reabsorption (essentially the opposite of parathyroid hormone).

This may lead one to think that osteoclasts and parathyroid hormone are ‘bad’ while osteoblasts and calcitonin are ‘good’. Some bisphosphonates increase bone mineral density by killing osteoclasts, but remember that the symptoms of osteopetrosis (increased fracture rates) are due to insufficient osteoclasts. Bone goes through the remodelling process to repair micro-damage and improve bone quality (sort of like muscle), and both osteoblasts and osteoclasts are part of the remodelling process. Hyperparathyroidism is bad and can lead to osteoporosis from excessive osteoclast activity. It can be caused by cancer, vitamin D deficiency and poor kidney function. Intermittent pulses of parathyroid hormone (the normal physiological condition) actually improve bone mineral density and bone quality by increasing IGF-1, preventing osteoblast apoptosis and inhibiting sclerostin [7].

The Inflammation Paradigm

Inflammatory cytokines are associated with osteoporosis and one study found serum IL-6 to be the best predictor of bone mineral density [8].

Free radicals such as hydrogen peroxide and malondialdehyde (a product of the lipid peroxidation of PUFA) are associated with lower bone mineral density [9]. They are one cause of elevated pro-inflammatory cytokines such as IL-1, IL-6 and TNFα, which increase PGE₂, a prostaglandin derived from arachidonic acid (20:4 n-6). IL-1, TNFα and PGE₂increase osteoclast synthesis and activity, leading to a higher rate of bone resorption and TNFα also induces osteoblast apoptosis, leading to a lower rate of bone formation [10] [11].

Estrogen inhibits pro-inflammatory cytokines and increases both glutathione peroxidase and nitric oxide synthesis. Those two are antioxidants, glutathione peroxidase specifically for hydrogen peroxide and nitric oxide also inhibits osteoclast activity [12]. Menopause causes a reduction in estrogen, which leads to elevated hydrogen peroxide and pro-inflammatory cytokines, which likely explains the rapid bone loss during menopause [10] [13]. After menopause bone loss is not quite so rapid, but leaves postmenopausal women at greater risk compared to men.

Two common risk factors for osteoporosis are smoking and drinking. Alcohol and the numerous chemicals in cigarettes increase oxidative stress and inflammation [14] [15].

Osteoporosis is associated with many inflammatory diseases such as liver cirrhosis [16], rheumatoid arthritis, coeliac disease, lupus, inflammatory bowel disease [17] and cardiovascular disease (independent of other risk factors including age*) [18]. The link between osteoporosis and cardiovascular disease is quite interesting.

“In general, postmenopausal women are advised to take calcium supplements to prevent or treat osteoporosis, implying that bone loss is due to insufficient dietary calcium. Yet, in many patients with osteoporosis, loss of bone tissue from the skeleton occurs at the same time as formation of bone in the artery wall.” [19]

“Coronary calcification and osteoporosis have been associated with presence of infectious agents, such as Chlamydia pneumoniae and Helicobacter pylori, as well as markers of chronic infection, such as C-reactive protein.” [19]

Mitochondrial dysfunction is largely responsible for the ‘aging process’ that osteoporosis is part of and can explain why age is associated with increased pro-inflammatory cytokines [20]. With this, the degenerative nature of osteoporosis and the strong connection between cardiovascular disease and inflammation, I suspect oxidative stress plays a major role in the development of osteoporosis for most people.

Obesity is thought to be protective against osteoporosis, but obesity is associated** with elevated pro-inflammatory cytokines, which increase bone resorption. High leptin and low adiponectin are also seen in obesity and are more factors which increase bone resorption. Some studies show an inverse association between bone mineral density and obesity and associations between obesity and higher fracture rates [21]. If you’re overweight you may not be necessarily protected from osteoporosis and if you fall those bones will be tested.

* Total cholesterol is associated with lower bone mineral density

** Whether this is cause or effect is in some ways a redundant question for osteoporosis because excessive leptin is pro-inflammatory. I think it’s part cause as inflammation can increase weight gain via IL-6 >> SOCS3 >> leptin resistance, and part effect because obese people have an oversized endocrine organ whose job it is to synthesise pro-inflammatory cytokines.

Exercise

Exercise is recommended to prevent osteoporosis and build strong bones. Weight bearing exercise is more effective as swimmers only have slightly more bone mineral density than sedentary people, while other athletes like gymnasts have much more [22]. Unfortunately there aren’t any RCTs that find exercise reduces fracture rates, but there are some good mechanisms that suggest it would.

Exercise inhibits sclerostin through mechanical stress [23]. Sclerostin seems to act like a ‘mechanosensor’ or ‘mechanostat’ to communicate to the body how much bone is needed to endure anticipated mechanical stressors. Exercise raises the bone mass setpoint.
Mechanical stress from exercise increases IGF-1, IGF-2, PGE₂*, and nitric oxide, which has the effect of increasing osteoblasts and their activity. This mechanism is like 'a response to injury’. Bone desensitises to mechanical stress after a few repetitions and is most sensitive when there are breaks every few reps, when exercise is spread throughout the day and when there are week long rest periods. Inhibiting prostaglandin or nitric oxide synthesis suppresses mechanically induced bone formation [24].
Bones can convert mechanical/kinetic energy to electrical energy (piezoelectricity) as a fuel for protein synthesis for bone formation. Electrical stimulation of muscle and electromagnetic fields can also protect against bone loss [25].
Exercise increases nitric oxide synthesis [22] and can also reduce oxidative stress by increasing mitochondrial biogenesis.
Exercise improves a number of physical competencies that reduce falls such as strength, power, flexibility and coordination.

That being said, overtraining may lead to osteoporosis because of elevated cortisol, a reduction in sex hormones, nutrient depletion and elevated pro-inflammatory cytokines such as IL-6 (which increases during exercise) [26]

Vitamin K2

Osteocalcin is another name for bone gamma-carboxyglutamic acid-containing protein. Vitamin K2 carboxylates osteocalcin to activate it, stimulates protein synthesis in osteoblasts and inhibits osteoclast activity [27]. This process is quite important as high levels uncarboxylated osteocalcin are associated with a much higher risk (odds ratios: 1.9, 3.1 and 5.9) of fracture compared to normal levels [28]. Vitamin K2 has some very successful outcomes:

Vitamin K2 protects against bone loss from age-related decline, testosterone deficiency (males), estrogen deficiency (females), glucocorticoids, stress and calcium deficiency [27] [29]
Vitamin K2 supplements of 45 mg increase bone mineral density and decrease fracture rates by 67% [30]
Vitamin K2 supplementation and a bisphosphonate reduced fracture rates by 69% [31]
Vitamin K2 supplementation (possibly calcium and vitamin D as well) reduces vertebral fracture rates by 60%, hip fracture rates by 77% and non-vertebral fractures by 81% [32]
Vitamin K2 supplementation decreases fracture rates by 52% compared to calcium supplementation [33]

The vitamin K2 supplements were often megadoses of 45 mg. 1.5 mg supplements result in much lower uncarboxylated osteocalcin [34], but even this is much more than what is possible from the diet. Looking at this resource from the USDA I think you would do well to get 50 µg from the diet, which is 30 times lower than 1.5 mg and 900 times lower than 45 mg. Grass-fed animal products may have much more vitamin K2, but I doubt they have 30 or 900 times more.

(Vitamin K2 supplements of 1.5 mg decreased 25-hydroxyvitamin D levels over 4 weeks [34]. Vitamins A, D and K2 work together so increasing one may increase the need for the others.)

Other Factors

Inflammation, vitamin K2 and exercise got their own section because they’re likely to be the dominant factors behind osteoporosis, but there are some other factors involved.

Deficiencies in a number of other minerals besides calcium can cause osteoporosis such as magnesium, zinc and copper. These minerals have other biological roles: magnesium is part of the enzyme that activates vitamin D* [35], zinc is part of the growth hormone receptor, which signals the synthesis of IGF-1 [36] and copper is important for osteoblast activity [37].

Vitamin D increases estrogen in arteries and bone, and decreases pro-inflammatory cytokines. Vitamin D deficiency can lead to hyperparathyroidism, which can cause osteoporosis through excessive osteoclast activity [38]

Carnitine supplementation increases osteoblast activity and slows bone loss.Carnitine levels decrease with age and insufficiency deprives osteoblast of energy needed for protein synthesis as 40-80% come from fats [39].

Conjugated linoleic acid and long chain omega 3s (EPA+DHA) increase bone mineral density by decreasing pro-inflammatory cytokines and PGE₂ [40] [41] [42]. Vitamin C reduces oxidative stress, decreases bone resorption by enhancing collagen synthesis then stabilisation and is negatively associated with fracture rates [9]. Vitamin E protects against osteoporosis by decreasing inflammation through inhibiting COX-2 and reducing oxidative stress [43].

Other sex hormones such as DHEA, progesterone, testosterone and DHT are less studied and may have similar antioxidant and anti-inflammatory effects as estrogen, perhaps to a lesser extent [10]. The sex hormones tend to be anabolic, which helps promote bone growth. Two common research techniques to induce animal models of osteoporosis are estrogen or testosterone deficiency. Estrogen gets a lot attention as women have higher rates of osteoporosis and because of the role of menopause.

* 25-Hydroxyvitamin D >> 1,25-hydroxyvitamin D

Conclusion

Osteoporosis is not all about calcium in, calcium out. Deficiencies in many nutrients or in exercise can cause osteoporosis. I suspect that when there is a deficiency it’s in vitamin K2 or D due to our low consumption of animal fats or exposure to sunlight. K2 deficiency can explain the superior results of K2 supplementation compared to calcium, with only positive CVD side effects I should add.

A main cause of osteoporosis is chronic inflammation. Throwing bisphosphonates or more calcium at the problem doesn’t solve the underlying cause. Common sources of chronic inflammation include:

Lipopolysaccharide (which is often used in studies to trigger inflammation)
Oxidative stress from the causes and the effects of mitochondrial dysfunction
Other chronic diseases (autoimmune, diabetes, etc)
Psychological stress, poor sleep, overtraining

Welcome Living La Vida Low Carb Readers

2012-03-14T10:29:00.002+11:00

Welcome Living La Vida Low Carb readers.

I recently did a submission to the Dietary Guidelines for all Australians. You can download the 51 page PDF (with roughly 150 scientific references). Other things in my blog include:

The posts that make up the submission, which can be found here. Probably the one of most interest to you is Low Fat or Low Carb

A look into the causes of obesity, which generally supports a low carb, Paleo diet

Research into the role of mitochondrial dysfunction in disease, which again supports a low carb, Paleo diet

A downloadable excel spreadsheet, compiled with data from the USDA nutrient database, which can help you find what nutrients are in what foods/food groups and you can easily input what you eat to see how you’re tracking nutrient wise

A troubleshooting guide for high cholesterol and for weight loss on Paleo and low carb diets