Thursday, May 30, 2013

N-Acetyl Cysteine Improves Bone Regeneration

Free radicals and pro-inflammatory cytokines can be powerful promoters of the aggressive osteoclastic bone-resorbing activity we often see in osteoporosis. N-acetyl cysteine (NAC) is a very powerful antioxidant that can neutralize these free radicals and limit pro-inflammatory cytokines. Considerable research has demonstrated NAC's ability to limit bone loss via these mechanisms. Now, a new study out of Japan by Yamada et al., demonstrates NAC's capacity to regenerate bone. In experiments using rat cell cultures these researchers observed that "NAC can function as an osteogenesis-enhancing molecule to accelerate bone regeneration by activating differentiation of osteogenic lineages."

There are many scientific reasons why we include NAC (600 mg) in our OsteoStim product. For example, prior studies have demonstrated NAC's ability to restore estrogen-dependent regeneration of a powerful antioxidant enzyme in the body called glutathione peroxidase (GPx). GPx is important for neutralizing the free radials (reactive oxygen species) that activate osteoclasts and increase their destructive resorption of bone. When estrogen levels decline at menopause, so do GPx levels. This accelerates bone loss. NAC helps to restore GPx levels to normal and slow down bone loss. The findings from this Japanese study add additional support for using supplemental NAC to improve bone health.

Yamada, M., et al. 2013. N-acetyl cysteine as an osteogenesis-enhancing molecule for bone regeneration. Biomaterials May 24 [Epub ahead of print].

Wednesday, May 29, 2013

Whole-Body Vibration for Improving Bone Density--A short-term study

I often have patients ask me about using whole-body vibration as adjunct therapy for his or her low bone density. If he or she is physically capable of engaging in an exercise program, my answer is that I would rather they go for walks, do coordination exercises, and use light weights to gain strength. If, on the other hand, they are physically unable to exercise then using a vibration platform may be of benefit.

The usefulness of whole-body vibration for treating osteoporosis is still in question. Several studies have demonstrated its benefits while others have not. A recent study out of Spain does not support its usefulness at least when used short-term.

In a study published in the Journal of Science and Medicine in Sport, Gomez-Cabello et al. assessed 49 elderly men and women (vibration and control groups) for changes in bone mineral density after using a whole-body vibration platform 3 times per week for 11 weeks. They concluded that "short-term whole body vibration therapy is not enough to cause any changes on bone mineral content or bone mineral density and it only produces a slight variation on bone structure among elderly people."

Gomez-Cabello, A., et al. 2013. Effects of a short-term whole body vibration intervention on bone mass and structure in elderly people. J Sci Med Sport May 24 [Epub ahead of print].

Monday, May 27, 2013

How the Herbicide Roundup® May Contribute to Chronic Disease

In my last post I wrote about the importance of maintaining gut flora for normal bile salt metabolism and the elimination of bilirubin. Dysbiosis, the overgrowth of yeast, fungi, or "bad" bacteria in the gut, can negatively impact bone health not just by increasing bilirubin levels which is toxic to osteoblasts but by robbing us of vital nutrients and creating inflammation. Gastrointestinal microbial imbalance does not just adversely effect bone health but it has been implicated as a catalyst for many
chronic diseases.

We commonly attribute dysbiosis to the overuse of antibiotics, high sugar low fiber diets, alcohol abuse, and stress...but what about herbicides? What about Roundup® the most popular herbicide used worldwide?

In a review article published in Entropy, Anthony Samsel and Stephanie Seneff explain how glyphosate, the active ingredient in Roundup®, may be pervasive in our food and not as harmless as we are lead to believe. Glyphosate is an organophosphate claimed to be non-toxic to humans and other mammals. Glyphosate's mechanism of action is the disruption of a biochemical pathway (shikimate) found only within plants and not in mammals. The problem is that this pathway is also present in the bacteria that reside in your gut. By interfering with the health of gut flora, Samsel and Seneff claim that glyphosate is not harmless and that its adverse effects may lead to long term chronic health consequences. Although Samsel and Seneff do not mention osteoporosis specifically, they do explain several mechanisms (such as vitamin D deficiency, impaired zinc absorption, and enhanced oxidative stress) whereby exposure to glyphosate could directly impacting bone health.

Samsel, A and Seneff, S. 2013. Glyphosate's suppression of cytochrome P45 enzymes and amino acid biosynthesis by the but microbiome: pathways to modern diseases. Entropy 15:1416-1463.

Sunday, May 26, 2013

Bile and its role in bone health

Bile fluid is a watered-down slurry of salts, cholesterol, and bilirubin that is produced by the the liver and stored in the gallbladder. When released into the small intestine, bile fluid helps us digest fats, including improving the absorption of fat soluble vitamins such as D and K which are important to bone health. New research out of Spain shows us that there is a second mechanism whereby bile salts benefit bone...but only if the gut and its microbiota are healthy.

When fats are ingested, bile salts are released into the small intestine where they disperse fat into small digestible particles. This process is called emulsification. Without emulsification, ingested fat usually passes directly into the toilet bowl providing little or no nutrient value to the individual. Bile is therefore important for digestion but it also serves a second function. Bile acts as a medium for ridding the body of a waste product called bilirubin. Bilirubin is formed from the breakdown of old red blood cells and gives bile its yellowish color. If bile excretion is blocked, fat digestion suffers and the acid flows out into the blood stream causing the individual to turn yellow or jaundiced. This condition is called cholestasis and may be a sign of severe liver disease.

We have long known that patients with chronic cholestatic liver disease are prone to developing osteoporosis. Only recently have we understood why. We now know that the bilirubin and lithocholic acid (a secondary bile salt) in bile are toxic to osteoblastic cells and reduces their capacity to form new bone. A back-up of bilirubin and lithocholic acid laden bile in liver disease often results in the development of low-bone-turnover osteoporosis.

Dubreuil, et al. from the University of Barcelona have shown that elevated bilirubin and lithocholic acid levels can be detrimental to osteoblast cell function. In normal circumstances, when bile is secreted for fat emulsification the bilirubin within it is converted into a secondary bile acid called ursodeoxycholic acid (UDCA) by commensal (beneficial) bacteria in the gut. (The lithocholic acid is bound by fiber and excreted.*) A healthy balance of gut bacteria promotes this conversion of bilirubin to UDCA, neutralizing the bilirubin's adverse effects on osteoblasts. In other words, when the gut microbes are of the "good" kind, bilirubin is turned into UDCA which simply helps improve the digestion of fats. In dysbiosis, where there is microbial imbalance with an overgrowth of "bad" bacteria in the gut, conversion of bilirubin to UDCA does not take place, bilirubin levels increase in the blood, and osteoblastic bone formation is adversely effected.

Healthy conversion of bilirubin into secondary bile salts such as UDCA can be promoted by including pre and probiotics in the diet. Prebiotics are complex, non-digestible, but fermentable sugars such as inulin, a fructooligosaccharide that acts as a "fertilizer" for promoting "good" bacteria growth. Probiotics are the "good" bacteria themselves and can be obtained in supplement form or in cultured foods such as yogurt, kefir, kombucha, and cultured vegetables. For a great web site for learning how you can culture your own food check out Cultured Food Life. Take the time to listen to Donna Schwenk's story. If I can't convince you how important cultured foods are for maintaining health, Donna will.

I am always singing the virtues of using laboratory tests to help define and monitor treatment for patients with bone loss. The findings in this new research demonstrate why testing for bilirubin can be of help when evaluating a patient with osteoporosis. If an individual has signs and symptoms of poor digestion of fats, such as abdominal bloating, gas, steatorrhea (greasy, pale, smelly stools) or jaundice skin or sclerae of the eyes, further evaluation for gall bladder and/or liver involvement is warranted. Jaundice can be a sign of serious liver disease or even tumors. Elevated bilirubin can also indicate Gilbert's Syndrome a common hereditary condition where bilirubin levels rise due to reduced activity of an enzyme that conjugates bilirubin.

After overt liver disease and Gilbert's have been ruled out**, improving gut health with pro and prebiotics can help to lower bilirubin levels and improve osteoblastic bone formation by encouraging secondary bile salt (such as UDCA) formation.

* Lithocholic acid binds to vitamin D receptors in the gut thereby blocking its action of increasing calcium absorption. Dietary fiber binds this secondary bile acid and aids in its excretion.

** When I was first being evaluated by endocrinologists for my severe osteoporosis, my bilirubin level was elevated. I was told that I had Gilbert's Syndrome and this condition was "totally harmless and has nothing to do with your osteoporosis." (Yes...how many times have we all heard that line? "Oh don't worry about it." When someone says that to me now, especially if they are a doctor, I REALLY start worrying!) This diagnosis, turned out to be totally false AND I now know that my suspicions (that the bilirubin could somehow be connected to my bone loss) were totally founded. By changing my diet, improving my gut health, taking probiotics, drinking kefir, and taking herbs such as curcumin and milk thistle...my bilirubin level dropped to normal and it has never been elevated since. I wonder how many people being diagnosed with Gilbert's Syndrome actually have poor gut health and systemic inflammation...both which increase bilirubin levels and reduce osteoblast bone-forming activity.

Dubreuil, M., et al. 2013. Ursodeoxycholic acid increases differentiation and mineralization and neutralizes the damaging effects of bilirubin on osteoblastic cells. Liver Int March 1 [Epub ahead of print].

Thursday, May 23, 2013

The Brain's Influence on Aging and Bone

As we age, our body slowly loses function--cell activity weakens, tissue loses strength, organs fail--until a point where biological function can no longer sustain life. But some people age more rapidly than others. Why is this? Genes certainly have a lot to do with how long you will live but is this process coordinated, and if so how and by what? An article published recently in Nature suggests that the aging process is actually programmed from within the brain, and it looks like we may be able to influence our longevity!

Chronic systemic inflammation is the predominant force behind the development of chronic disease. This type of inflammation is characterized by the elevation of the immune system's proinflammatory signaling molecules and the activation of a cell protein called NF-kB. This protein is found in every cell. When activated, NF-kB commands the cell's nucleus to turn on inflammatory genes within its DNA. The destructive forces of NF-kB-directed inflammation can be insidious, slowly but steadily burrowing into every organ of the body.

In a study conducted using mice, researchers Zhang et al. discovered that inflammation not only damages cells and tissues in the body but it also activates NF-kB in the hypothalamous of the brain. The hypothalamus links the nervous system to the endocrine system and is responsible for many metabolic processes attributed to the autonomic nervous system. When the body is stressed and inflamed, microglia cells within the hypothalamus sense this and trigger a release of the proinflammatory cytokine TNF-alpha which then stimulates NF-kB activation in surrounding neurons.

The TNF-alpha-induced NF-kB activation, in turn, inhibits the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH controls fertility through follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland, but the actions of GnRH don't stop there. This hormone is also involved in maintaining skin integrity, memory, and muscle and bone mass. When GnRH levels decline, we age...our skin thins, we begin to forget things, we loose muscle tone, and our bones become more fragile.

Chronic systemic inflammation, therefore, is behind this aging process and it is orchestrated by the hypothalamus. The domino effect goes something like this: stress, inflammation, oxidative stress...activation of NF-kB within microglia cells in the hypothalamus...increase TNF-alpha in the hypothalamus...increase NF-kB activity in neurons of the hypothalamus...decrease production of GnRH from these neurons.

Highlights of the author's conclusions:

  • Aging is a life event that is programmed by the hypothalamus
  • The hypothalamus is important for systemic aging and lifespan control
  • The underlying causes of aging includes integration between immunity and the neuroendocrine system of the hypothalamus.
  • Calming of the immune system's inflammatory response and GnRH restoration in the hypothalamus represent two potential strategies for combating aging-related health problems.
This discovery has the potential to help us all optimize our lifespan and fight aging-related health issues such as osteoporosis. By maintaining a healthy low-inflammatory diet, adding antioxidants such as alpha-lipoic acid, N-acetyl cysteine, berberine, and curcumin to the menu, and exercising regularly we can all reduce inflammation, limit oxidative stress, and live a longer, more productive and healthy life.

Zhang, G., et al. 2013. Nature. Hypothalamic programming of systemic ageing involving IKK-B, NF-kB and GnRH. doi:10.1038/nature12143.

Sunday, May 19, 2013

Stem Cell Therapy for Osteoporosis

Still in its infancy but looking promising is stem cell therapy for osteoporosis. California's UC Davis is home to the Institute for Regenerative Cures, a leading player in regenerative medicine. Preliminary research with mice, published in Nature Medicine, demonstrated that bone density and strength could be improved using a molecule called LLP2A-Ale that directs mesenchymal stem cells to the surface of bone. Dr. Nancy Lane, a professor of Internal Medicine at UC Davis, will be the lead researcher in a clinical trial to test LLP2A-Ale beginning in 2014. A commentary by Herberg and Hill in IBMS Bone Key explains some of the difficulties faced by researchers in using stem cells to treat osteoporosis.

Guan, M., et al., 2012. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat Med 18(3):456-462.

Friday, May 17, 2013

Vitamin K2 MK7 and Healthy Bones

Vitamin K is commonly known as an essential factor in making sure our blood clots, to help wounds heal properly. Vitamin K is also a vital cofactor in the carboxylation (a specific chemical reaction) of osteocalcin, a protein released by osteoblasts during bone formation. Once vitamin K initiates carboxylation, osteocalcin can then help guide calcium into bone (and not into soft tissues where it can harden blood vessels), increasing bone density and acting as a tempering agent keeping bone flexible and less prone to breaking

There are two major types of K.
Vitamin K1 (phylloquinone) comes from leafy green vegetables like kale, chard and spinach. While it is a capable cofactor for carboxylating proteins, it is better suited for making blood clotting factors in the liver.
Vitamin K2 (menaquinones) has an easier time traveling throughout the body and into places such as bone, so ingesting K2 is the better type for affecting bone health. Of the dietary sources of vitamin K2, the two most related to bone health are MK4 and MK7. MK4 comes from meats (especially organ meats such as liver), eggs and hard cheeses; it may act somewhat more broadly in its activity, but it has a half life of only an hour or so. MK7 comes from fermented soy and has a much longer half life, which would ensure a more thorough and steady carboxylation capacity. As far as bone health is concerned, it may be best to use a combination of these forms of vitamin K2 but the jury is still out as far as how to achieve optimal skeletal benefit from vitamin K.

A three-year study from The Netherlands investigated the effects of vitamin K2 MK7 supplementation in healthy postmenopausal women (n=244). The results, published in Osteoporosis International, demonstrated that 180 mcg oral supplemental vitamin K2 MK-7 per day was beneficial to bone. "MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC [bone mineral content] and BMD [bone mineral density] at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae."

There is no doubt this is an important study and one that helps establish K2 MK7 as a valuable supplement for individuals focused on keeping their bones healthy.

That said, we must keep in mind that this study was performed on HEALTHY postmenopausal women. For individuals who have a metabolic disease such as osteoporosis, simply adding therapeutic levels of vitamin K may not result in the same level of benefit. Reversing substantial bone loss usually takes promoting change throughout all aspects of the person's physiology: adequate levels of vitamins K and D, a healthy gut that can absorb nutrients, a reduction in chronic inflammation causing oxidative stress, and a body pH that is not acidic. These and a host of other physical factors for whole-body health and thus bone health must all be assessed and corrected if possible.

Knapen, M.H., et al. 2013. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. March 23 [Epub ahead of print].




Thursday, May 16, 2013

Teriparatide (Forteo) and Denosumab (Prolia) Combo: Two is Better Than One

Just released online by Lancet are the 12-month findings from a study combining two osteoporosis drugs. Researchers found that by combining teriparatide and denosumab, two drugs with different mechanisms, bone density improved more than if either drug was used on its own.

Findings: % improvement of bone mineral density after 12 months:
Lumbar spine:  teriparatide alone 6.2%, denosumab alone 5.5%, combined therapy 9.1%.
Femoral neck:  teriparatide alone 0.8%, denosumab alone 2.1%, combined therapy 4.2%.
Total hip:          teriparatide alone 0.7%, denosumab alone 2.5%, combined therapy 4.9%.

Although the results do look impressive, I'm sure the companies that funded the study (Amgen, manufacturer of Prolia; and Eli Lilly, manufacturer of Forteo) were even more ($) excited.


Wednesday, May 15, 2013

Soaking Up the Kudos

I just got an email from a patient that I had worked with about 4 or 5 years ago. Seana is a super elite runner but was diagnosed with low bone density and came to me for help. Her symptoms and a battery of lab tests indicated some problems that we were able to address through diet, nutrition and life-style changes. Seana moved away from the area and I lost contact with her until this recent email. This is an excerpt from her letter:

"I retired from racing, focused on getting my body to where it wanted to be normally, without trying to have it be as lean as possible to race. I moved to the beach, which really helped my spirit, fell in love, and then my period came back. I just kept doing what I was doing after that to maintain it. I really just followed what you suggested. You are truly the one who helped me get back on track because you helped me understand what I was doing to myself and the implications, and it gave me the permission I needed to stop doing that and make changes and honestly, if you had not cared so much to help me, I wouldn't have likely heeded the guidance. If I hadn't stopped that going down the path I was on, I may not have been able to conceive, and my son is by far the most joyful aspect of my life. So thank you so much Keith! I am so grateful to you!
That is so awesome about the new company, what an incredibly amazing asset for folks. I will indeed pass on the info about your blog too!
I really appreciate your help with my concern and thank you so much for your time!
No one I have found even remotely comes close to being as gifted a healer as you!"   Seana
Wow...now THAT's what makes being in practice worth it! :)

Thursday, May 2, 2013

Zoledronic Acid: New Research

Medications play an important role in the treatment of chronic diseases, but they need to be used judiciously and wisely. A recent article on zoledronic acid (Reclast and Zometa) -- a bisphosphonate medication used to treat osteoporosis and high blood levels of calcium caused by cancer -- illustrates how a stop-gap method for one diagnosis can have dire consequences for an individual's health in the long run.

We already knew that zoledronic acid dramatically inhibits osteoclasts from destroying bone and this can be a good thing, especially when someone has severe osteoporosis and is at great risk for fracturing. In a study published in the Journal of Clinical Endocrinology and Metabolism, ¹ Catalano et al. from the University of Messina, Italy focused on forty postmenopausal women with osteoporosis, looking at the effects zoledronic acid has on sclerostin, a protein secreted by osteocytes that inhibits Wnt signaling ² in osteoblasts and reduces their ability to form bone. The findings from this study are somewhat alarming: those given zoledronic acid had a dramatic increase (three fold) in sclerostin serum levels for a full year before returning to baseline. To repeat, bone formation stops within several days of beginning treatment and for a full 12 months the bones essentially become dormant. Nothing happens. Bone remodeling is shut down, setting the stage for osteonecrosis ³ of the jaw (ONJ) and bone fragility leading to atypical femur fractures.

What I found most disturbing about this study was the way many researchers (and the pharmaceutical companies) interpreted the results. Instead of questioning the length of time remodeling is shut down and how long bone can survive before it becomes really unhealthy, researchers saw the results of this study as an "opportunity" to investigate a new drug that could be used in combination with zoledronic acid to lower sclerostin levels, increase bone formation and reinstate remodeling. Of course, there no doubt would be adverse effects brought about by anti-sclerostin drugs (there are actually several anti-sclerostin drugs currently in trials) that could again be countered by a third medication.

Zoledronic acid commonly causes flu-like aches and pains, fever, muscle and joint pains, chest pain, bone pain, difficulty breathing, persistent cough, vision problems, headaches, dizziness, anxiety, numbness, hair loss, fatigue, diarrhea, constipation, kidney failure, anemia, nausea, conjunctivitis, atrial fibrillation, high or low blood pressure, rapid heart beat, rash, depression, confusion, urinary tract infections, cancer. An FDA Alert shows that from 11/01/1997 to 8/27/2012, there have been 17,897 reports of a serious adverse event where ZOMETA was identified as the primary suspect drug causing that event; the top three were: osteonecrosis, death and osteonecrosis of the jaw. For Reclast the numbers were somewhat lower at 10,091 reported serious side effects (top 3 adverse events being death, arthralgia and pain). I would hate to see what those numbers would be if we added another drug to the mix. [Note: Zometa is a more concentrated (4 mg/5ml) form of zoledronic acid than Reclast (5 mg/100 ml). Zometa is also infused more often than Reclast. For these reasons the incidence of severe adverse effects is lower for Reclast. That said, similar adverse effects are seen with both drugs but the incidence is proportional to cumulative dosage.]

Every drug has its adverse effects. That isn't to say we shouldn't use medications, but we must also recognize that the body's physiology is extremely complex. Natural repair and regenerative measures to positively influence whole-body health should be first and foremost in our therapeutic arsenal. In the case of osteoporosis, let's  try and encourage anabolic mechanisms that naturally promote healthy bone remodeling. Relying on a medication or a combination of medications to return our skeleton back to health probably won't succeed.


¹ Catalano, A. et al. 2013. Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis. J Clin Endo Metab April 17 [Epub ahead of print].

² The Wnt signaling pathway is a network of proteins that passes signals from receptors on the surface of the cell through the cytoplasm and ultimately to the cell's nucleus where the signaling cascade leads to the expression of target genes.

³ Osteonecrosis is the loss of blood supply to bones -- causing bone tissue to die.






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