Monday, April 29, 2013

DNA damage drives mechanisms behind osteoporosis

As we age, there is a steady decline in the density and quality of our bones. This places us at greater risk for breaking a hip or sustaining a spinal compression fracture. Age-related cellular changes are responsible for this decline. When bone marrow stem cells atrophy, and bone forming osteoblasts wear out, and the bone-resorbing osteoclast cells get their "second wind"...we are faced with unrelenting skeletal deterioration and increased fragility.

The mechanism behind this deterioration is years of accumulated DNA damage. Research by Chen et al. reported in the Journal of Bone and Mineral Research demonstrates (in mice) that a failure to repair DNA damage is the driving force behind age-related bone loss. Constant bombardment by ultraviolet and ionizing radiation from space, and oxidative stress with free radical formation from the body's own metabolic activity are the main causes of cellular DNA damage. If this damage is not repaired, deterioration of cells, tissues, and organs, including bone, will lead to premature aging.  The purpose of Chen's study was to determine the exact mechanism by which a failure to repair DNA damage would lead to bone loss. What they found was that NF-kB, a key regulator of cell death and survival found in the nucleus of cells, is responsible for signaling the driving forces behind osteoporosis in response to accumulated DNA damage.

When proteins, cellular organelles and DNA sustain damage, and it is not repaired by natural repair mechanisms, the production of NF-kB increases. NF-kB initiates degenerative change, including bone loss.  Simple as that. If the DNA in our bone marrow stem cells is damaged and not repaired, NF-kB production within them increases causing them to atrophy and shrivel away. Without these stem cells there is no formation of bone-building osteoblasts. If the DNA in existing osteoblasts isn’t working properly, the resulting increase in NF-kB causes them to shut down. With no osteoblasts to produce new bone, bone density declines. And the kicker, when DNA is damaged and NF-kB production increases instead of leading to decreased osteoclast bone-resorbing activity it actually increases their bone degrading activity! Osteoclasts are the ONLY cells in your body whose sole function is to actually destroy the organ (bone) in which they reside. The osteoclast's ONLY action is to be destructive. An increase in NF-kB serves to increase the osteoclast's bone destructive actions and these are promoted by persistent cellular DNA damage.

This makes sense. Osteoclasts are destructive in nature and they are just doing what they are genetically engineered to do, destroy. As the body deteriorates from DNA damage, so does the skeleton. The combined effect of failing osteoblast bone-formation and increased osteoclast bone resorption leads to osteoporosis. This is why simply taking more calcium to fix osteoporosis doesn’t work. You must improve your body’s natural defenses against free radicals. You must limit DNA damage, improve repair mechanisms, and reduce NF-kB.

Alpha lipoic acid, N-acetyl cysteine, EGCG from green tea, resveratrol, and curcumin (from the spice turmeric) are all powerful natural inhibitors of inflammatory NF-kB. So powerful is curcumin that a recent study by Kim et al. in Molecular Nutrition and Food Research demonstrated its ability to block the proliferation of cancer by suppressing NF-kB.

Chen, Q., et al. 2013. DNA damage drives accelerated bone aging via and NF-kB-dependent mechanism. JBMR 28(5):1214-1228.

Kim, J.H., et al. 2012. Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-kB and NF-kB-reguated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis. Mol Nutr Food Res 56(3):454-465.

Friday, April 26, 2013

Probiotics increase vitamin D levels

It only makes sense...improved gut function enhances nutrient absorption. In a study published in the Journal of Clinical Endocrinology and Metabolism, researchers demonstrated that vitamin D levels increased in response to oral probiotic supplementation. A full 25% increase in vitamin D was observed after supplementing with oral probiotics for only 9 weeks.

If you want to learn more about the importance of gut health and how probiotics can benefit your health, check out Ray Medina's blog at Syonitx. Ray has a great handle on this subject.

Jones, M.L. et al. 2013. Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post-hoc analysis of a randomized controlled trial. J Clin Endocrinol Metab April 22 [Epub ahead of print].

Thursday, April 25, 2013

SNPs and their association with the increased risk of developing osteoporosis

Single Nucleotide Polymorphisms (SNPs) are minor changes in the DNA sequence or genetic code of chromosomes. These genetic variances can change the shape and function of protein-containing structures within the body. These structural changes don't always cause problems but in certain cases they can reduce or enhance body functions and have been linked to greater risk in developing chronic diseases like osteoporosis. Being homozygous positive (carrying the same polymorphism on both sets
of genes) for a particular polymorphism doesn't mean that that individual will develop a disease but it only that they may be at greater risk. Knowing if you have certain SNPs can be useful in designing therapeutics protocol. Two specific examples of SNPs related to increased risk for osteoporosis are: 1) vitamin D receptors (VDRs), and 2) IL-1ra, a molecule that helps control chronic inflammation.

Vitamin D Absorption
Vitamin D is known to be of critical importance in the absorption of calcium and phosphate, bone formation, immune regulation, and many other functions of the body. But the key to all that vitamin D you take in from being out in the sun or through your diet or supplements is that it must successfully bind to and stimulate vitamin D receptors (VDRs) on cells in order to be useable. A recent article "Molecular Mechanisms of Vitamin D Action" published in Calcified Tissue International summarizes the vast biological responses that take place when vitamin D binds successfully to its receptor.

Receptors (made up of proteins) are located on or in cells throughout the body and when the proper molecules successfully bind to them, signals for metabolic change take place. For example, when vitamin D successfully binds to a VDR, good things happen. In the gut, VDR stimulation by vitamin D helps improve calcium and phosphate absorption; in osteoblast cells it helps stimulate bone formation; in other parts of the body it helps maintain normal blood cell formation, immune function, kidney regulation of calcium reabsorption, proper balance of the nervous and endocrine systems, and even things like hair growth.

For any molecule (also called a ligand) such as vitamin D to successfully activate its receptor it must  mesh exactly to the surface of its receptor (picture velcro). All the nooks and crannies of each surface have to match perfectly when they come into contact. If not, the ligand/receptor interaction can be foiled by SNPs. If vitamin D can't fit exactly into it's receptor, the person may not be able to efficiently absorb calcium or stimulate osteoblasts to form bone.

If you are homozygous positive for this SNP, one obvious response is to ensure not just an "adequate" vitamin D blood level of 32 ng/ml but a more robust level of 50 to 80 ng/ml. The more vitamin D ligands available, the better the chance of successful attachment to a VDR. Another helpful approach is to use non-vitamin D ligands. Yes, there are molecules other than vitamin D that happen to fit "well enough" into the VDR that they can essentially mimic vitamin D. Two non-vitamin D ligands are docosahexaenoic acid (an omega-3 fatty acid found in cold-water fish) and curcumin, from the spice turmeric

Inflammation Control
Osteoporosis is an inflammation-associated disease process linked to elevated levels of pro-inflammatory cytokines such as interleukin-1 (Il-1), interleukin-6 (Il-6) and tumor necrosis factor (TNF). High levels of Il-1 have been shown to increase bone loss and promote osteoporosis. Interleukin 1-receptor antagonist (Il-1ra) is a competitive inhibitor of Il-1 that occurs naturally in all of us. Its function is to reduce inflammation by jumping on to Il-1 receptors, thereby blocking the pro-inflammatory cytokine Il-1. If the bonding is not successful, the protective effect (reducing inflammation) of Il-1ra will not succeed. When it comes to diseases such as osteoporosis, this ligand/receptor interaction can be foiled by SNPs. This defect in the genetics of Il-1ra will make a person more susceptible to prolonged inflammatory responses which activate osteoclasts and increases their risk for osteoporosis.

If you are homozygous positive for this SNP, one response is to improve the Il-1ra : Il-1 ratio by eating a low-inflammatory diet. This means a diet rich in anti-oxidant packed fruits and vegetables, omega-3 fatty acids from cold-water fish, and botanicals such as milk thistle (silymarin), and curcumin from the spice turmeric. Curcumin is one of the best botanical anti-inflammatory compounds available and has been shown to reduce Il-1 (and Il-6 and TNF).
The Il-1 receptor is similar in shape to another group of receptors called toll-like receptors. This is important because certain white blood cells found in your gut are equipped with these special toll-like receptors that help them find and kill bad bacteria. Because of this similarity between Il-1 receptors and toll-like receptors, if a person has gut bacterial overgrowth AND hyperpermeability (leaky gut syndrome) AND a homozygous SNP for Il-1ra, the adverse effects of inflammation would be greatly compounded.

I happen to be homozygous positive for both VDR and Il-1ra. I also happen to have had about as severe of osteoporosis (T-score -4.3 and 12 fractures in 5 years) as you can get and not break down crying. Do my SNPs have anything to do with my poor bones?...maybe....

Haussler, M.R. et al. 2013. Molecular mechanisms of vitamin D action. Calcified Tissue International 92(2):77-98.

Sunday, April 7, 2013

Testing Vitamin D Levels...No Matter What Supplement Company You Choose

In my last post I wrote about the importance of testing vitamin D levels. In fact, what I was really suggesting was that serial lab testing in general should be a vital part of a person's approach to improving bone health (if it is financially and logistically possible). Testing vitamin D levels is just one (albeit an important one) test that should be almost a yearly ritual. This suggestion was prompted by a recent article in JAMA Internal Medicine that reported on quality control issues of supplement manufacturers.

From my last post I wrote: "Quality control in the supplement industry is certainly a problem. This is why I encourage my patients to have lab tests, and then retest just to make sure that what they are doing nutritionally to improve their health is working. That said, we at OsteoNaturals do everything we can to ensure that what you see on our labels is what you get. Our products are made in an FDA approved and fully GMP compliant facility. The raw materials that go into our products all meet US FDA and Health Canada guidelines and are subject to Certificate of Analysis verification as well as potency, composition, and purity testing. We try very hard to give you excellent products. But I also understand that it can be enticing to purchase cheaper, similar looking products at your local discount store. The nice thing about vitamin D is that it is easy to test whether or not the brand you are using is working. Just ask your doctor to test your 25 hydroxyvitamin D level....just to be sure."

I in no way was saying that if you take our OsteoNaturals products that you don't need to test your vitamin D levels. Yes, we try hard to make sure our products are what we say they are...but THEY MAY NOT BE PERFECT! If you take our products you STILL need to test! And not only test for vitamin D levels but also test to see if markers (relevant to bone health) in general are improving. I don't advocate taking supplements and "hoping for the best." I have NEVER said that ONLY our supplements will do...there are many other companies out there with GREAT products. Sure I would like you to purchase OsteoNaturals (I wouldn't have started this company if I didn't have a passion to help people...that is my number one goal...really!) but my patients know all to well that I REGULARLY recommend products from other companies...Designs for Health, Metagenics...etc....even if our products are similar. And if a person comes in to my office and they are taking a quality product similar to OsteoNaturals, I don't try to make them switch to ours. I have quite a few patients who remain on OsteoForce, the Designs for Health calcium/magnesium supplement that is similar to our OsteoSustain. I keep them on it because they were already using it before OsteoNaturals was born....OsteoForce is a great product... and if it is working for them...why change? So I can sell a few more bottles of my stuff?...NOT ON YOUR LIFE! (or my life for that matter!)

That said, do I think you should be a little more hesitant about purchasing nutritional supplements from drug stores or discount houses vs paying a bit more for professional line products? Yes. But even when taking professional line products...YOU STILL NEED TO TEST. The proof is in the pudding, as they say.

Saturday, April 6, 2013

This is Why It is SO Important To TEST Vitamin D Levels

In case you needed another reason to have your doctor test the vitamin D level in your blood, a recent article in JAMA Internal Medicine should be all you need to be convinced. The title of the article is "Over-the-counter and compounded vitamin D: Is potency what we expect?"...and the answer is NO!

Researchers purchased vitamin D supplements from 5 stores and compounding pharmacies, and analyzed 55 over-the-counter (OTC) and compounded products from 12 manufactures. The final results showed that the supplements contained 9 to 145 percent of what was listed on the label. "In our test, just over one-half of the OTC pills and only one-third of compounded vitamins met USP convention standards. Compounded vitamin D3 (cholecalciferol) supplements varied significantly in potency." The researchers were surprised by the variation in potency but they did not feel that these products put consumers at risk. "The biggest worry is for someone who has low levels of vitamin D in their blood. If they are constantly taking a supplement with little vitamin D in it, they could face health risks." ...Well...yes!

Quality control in the supplement industry is certainly a problem. This is why I encourage my patients to have lab tests, and then retest just to make sure that what they are doing nutritionally to improve their health is working. That said, we at OsteoNaturals do everything we can to ensure that what you see on our labels is what you get. Our products are made in an FDA approved and fully GMP compliant facility. The raw materials that go into our products all meet US FDA and Health Canada guidelines and are subject to Certificate of Analysis verification as well as potency, composition, and purity testing. We try very hard to give you excellent products. But I also understand that it can be enticing to purchase cheaper, similar looking products at your local discount store. The nice thing about vitamin D is that it is easy to test whether or not the brand you are using is working. Just ask your doctor to test your 25 hydroxyvitamin D level....just to be sure.

LeBlanc, E.S., et al. 2013. Over-the-counter and compounded vitamin D: Is potency what we expect? JAMA Intern Med, Feb. 11 (published online).

Thursday, April 4, 2013

The Effect of Exercise Combined with Isoflavones on Bone

This will surprise you. It certainly surprised me!

It has been demonstrated that exercise has a small but beneficial effect on the bone mineral density of postmenopausal women. Other studies have shown the benefits of phytoestrogens such as soybean isoflavones for improving bone health. You would think, therefore, that combining these two therapies would provide even greater benefit to the skeleton. Makes good hypothetical sense doesn't it? Well, not so fast! In this month's issue of the Journal of Bone and Mineral Research, Canadian researchers report on a study that tested this exact hypothesis. They combined exercise with isoflavone supplementation to determine (among other things) the effect on the bone density of postmenopausal women.

The two-year study included 351 postmenopausal women. Participants engaged in an exercise regimen of weight training and walking in combination with supplementing their diet with high doses (165 mg) of isoflavone containing genistin, daidzin, and glycitin. [Participants also received supplemental calcium (1,200 mg) and vitamin D (800 IU) each day.]

The researchers hypothisized that since prior studies had shown the benefits of exercise and isoflavones to bone health individually, that a combination of these two therapies would result in an additive benefit. To their surprise, the combination of these therapies resulted in decreased total hip bone mineral density (BMD)! "Thus, contrary to our hypothesis, there was a negative interaction between the two therapies for total hip BMD."

"Our results indicated a beneficial effect of exercise training or isoflavone by itself for preserving BMD at the total hip." "This beneficial effect was lost when exercise training and isoflavone supplementation were combined (i.e., the group combining the two interventions did not differ over time compared to the control group)."

The researchers were obviously surprised by their findings and offered a possible explanation. "One explanation for the apparent interference of isoflavone supplementation with exercise involves the types of estrogen receptors on bone for the detection and transduction of mechanical strains to increase signals for bone formation (i.e. activation of osteoblasts). Estrogen receptor-ɑ, when activated by exercise, will increase osteoblast proliferation, whereas estrogen receptor-β seems to block the beneficial effects of exercise on bone and has been termed the "anti-mechanostat" (because it downregulates the mechanical strain on bone induced by exercise). Phytoestrogens, such as istoflavones, have a stronger affinity for estrogen receptor-β than for estrogen receptor-ɑ. The activation of estrogen receptor-β by isoflavones may cause a downregulation in the detection of strains from exercise: thereby reducing the effectiveness of exercise loading on bone. Our study is in contrast to a number of animal studies that demonstrated a beneficial effect of consuming isoflavones during exercise training."

"In summary, isoflavone supplementation combined with exercise training appeared to interact negatively on BMD at the proximal part of the femur."

I've never been a huge fan of soy. Concern over allergies, genetically modified soy, and results from some studies that fail to show benefit to bone have made me less than enthusiastic to recommend supplemental isoflavones to my patients. I'm not saying that soy has no benefits...only that this study did not help improve my opinion. There are many approaches to bone health...I'm not sure that supplementing with soy isoflavones should be one of them.

Chilibeck, P.D., et al. 2013. Effect of exercise training combined with isoflavone supplementation on bone and lipids in postmenopausal women: A randomized clinical trial. Journal of Bone and Mineral Research 28(4):780-793.

Tuesday, April 2, 2013

Magnesium Deficiency Leads to Bone Loss

Adequate magnesium intake (350 to 400 mg/day) is vital for maintaining overall health. This mineral is involved in cell energy metabolism, nerve conduction, electrolyte balance, cell membrane integrity, and the function of over three hundred enzymes. Magnesium is also important for bone health. If you are deficient in magnesium (50 to 70% of people are thought to be deficient!), your production of calcitonin and parathyroid hormones for bone remodeling may be disturbed. Osteoblasts need magnesium to form new bone collagen during the remodeling process. Magnesium's effect on the bone resorbing osteoclasts is unknown but researchers recently found that they too are impacted by low magnesium levels. 

According to a study just published in the Journal of Nutritional Biochemistry, magnesium deficiency in mice increased osteoclast formation and hindered their activity.

My thoughts are that substance P, a neuropeptide involved in pain perception and mediating inflammation, and the inflammatory cytokine TNF-alpha, are probably involved in this magnesium-deficiency-related increase in osteoclast formation. Magnesium deficiency leads to increases in substance P and TNF-alpha.

Common signs of low magnesium are: muscle tightness or spasms, muscle twitching, constipation,
hypertension, depression, muscle weakness, heart arrhythmias, irritability and skin hypersensitivity. I'm amazed at how many of my patients complain of these symptoms. Tight calf and lower back muscles abound! Simply having these patients increase their magnesium intake (vegetables, dried fruit such as prunes, nuts, seeds, and supplemental magnesium) often dramatically lowers their muscle tightness and pain.

Lab testing can help identify low magnesium levels. In addition to the direct assessment of magnesium through red blood cell analysis, low magnesium is also correlated with low serum calcium, low potassium, low 1,25 dihydroxyvitamin D, mildly elevated PTH, and increased hs-CRP.

Belluci, M.M., et al. 2013. Magnesium deficiency results in an increased formation of osteoclasts. J Nutr Biochem March 18 [Epub ahead of print].
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