Category Archives for "Nutrition"

0 Are you missing a key mineral in your diet?

I hope your summer is off to a great start. It’s definitely going to be a different kind of summer given the landscape of the pandemic. A good reason to make sure our bodies are fueled with proper nutritious foods and that we correct any nutrient depletions we may be experiencing. I get a lot of questions about magnesium, it’s such a powerful mineral in the body and one that unfortunately is depleted in our soil with modern farming practices. This post was written by Dr. Kristina Burban, PharmD who was an intern with us in April. We will be sharing part 2 later this week where we will discuss various forms of magnesium.

Magnesium is an essential mineral that plays a role in healthy cell function and bone structure. Sources of dietary magnesium include legumes, whole grains, vegetables, nuts, dark chocolate, fish, and beef.¹ Magnesium deficiency is common in the United States; one study found that 68% of Americans do not consume the recommended amount (310-420 mg) of magnesium daily.² Signs and symptoms of magnesium deficiency include muscle cramps, headaches, fatigue, mood changes, and irregular heartbeat¹. Your provider can test blood magnesium level through a simple blood draw. Problems with absorbing magnesium or not enough intake of magnesium have been associated with developing osteoporosis, high blood pressure, diabetes, and heart disease.¹ People commonly use magnesium for constipation or heartburn, but it can be useful for other reasons as well.

Benefits of Magnesium:

Heart health:

• Having enough magnesium is important for heart health. Studies have shown various cardiac benefits with either dietary or supplemental magnesium. Magnesium intake has been shown to decrease stroke risk. Most of these studies looked at magnesium from dietary sources.^3-8  In heart disease patients with low magnesium levels, taking magnesium supplements reduced heart pain. Also, heart disease patients with low magnesium levels had worse outcomes than heart disease patients with normal magnesium levels.⁹  Supplementing magnesium in coronary artery disease may help reduce blood clots.¹⁰  Patients who took 800-1200 mg magnesium oxide daily for 3 months had 35% less clots than patients who did not take magnesium.

 Diabetes:

• Multiple studies show that increasing dietary magnesium reduces the risk of developing type 2 diabetes.^11-14  A review combined and analyzed existing data about type 2 diabetes and magnesium in 2016. It found that more magnesium intake corresponded to less risk for developing type 2 diabetes. This study also found that increasing dietary magnesium by 100mg/day reduced the risk of developing type 2 diabetes by 8-13%.¹⁵ In people who have diabetes, there is evidence that taking magnesium can increase insulin sensitivity.¹⁶ 

Metabolism:

• Magnesium helps support a healthy metabolism. There is evidence that supplementing magnesium can reduce the risk of developing metabolic syndrome¹⁷, a combination of conditions including high blood pressure, blood sugar, body fat, and cholesterol. People with metabolic syndrome are more likely to have low magnesium levels.¹⁸  Studies have shown that taking supplementing magnesium can have slight benefits on blood pressure and cholesterol.^19-23 A study of adults in the United States found that 68% consumed less than the recommended daily amount of 310-420 mg magnesium daily. Also, it found that people who didn’t consume enough magnesium were more likely to have inflammation. C-reactive protein, a marker of the body’s inflammation, was more likely to be elevated in those patients.²

Mental Health:

• Through what we know about brain function, magnesium has a potential role in altering mood. GABA, a calming neurotransmitter, needs magnesium to be able to function properly in the brain. Magnesium can also change how glutamate, a neurotransmitter that excites, functions in the brain. Therefore, it must be important to have enough magnesium. 
• Research suggests that magnesium could have benefits in anxiety.  One study tested a preparation of 300mg magnesium with hawthorn and poppy plant extracts in patients with anxiety disorders.  The group that took the magnesium preparation showed clinical improvement. ²⁴ In a 2017 review of existing data, researchers found that 4 out of the 8 total clinical studies about magnesium and anxiety reported positive effects on anxiety outcomes.²⁵ However, all of the studies tested a combination of ingredients, not magnesium by itself. More research is needed to establish the effectiveness of magnesium on reducing anxiety.
• Clinical research about magnesium’s effects on depression are also promising, but limited. In animal studies, magnesium seems to have an antidepressant effect, but there is less evidence in humans. One study tested 2,000 mg magnesium daily for 6 weeks in patients with symptoms of depression. The study showed improvement in depression symptoms, but there was no placebo group and the patients knew they were taking magnesium, which could have affected the results.²⁶  Another study tested supplementing 500 mg magnesium versus placebo in patients with depression and low magnesium levels. After 8 weeks, the patients taking magnesium showed improvement in depression status.²⁷ Again, more research is needed to see how effective magnesium is in improving depression.
• A national health and nutrition survey showed that people who report under 7 hours of sleep have lower intake of calcium, magnesium, and vitamin D.²⁸ This reinforces how important it is to have enough mineral and vitamin intake, whether through dietary sources or supplementation. Overall, having enough magnesium is likely to help improve rest, relaxation, and mood. 
• Magnesium is also helpful for sleep. In one particular study of insomnia in the elderly statistically significant increases in sleep time, sleep efficiency, and melatonin, and also resulted in significant decrease in time to sleep onset and serum cortisol concentration.²⁹

References:

1. Magnesium. In: Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty. [Updated January 23, 2020]. 
2. King DE, Mainous AG 3rd, Geesey ME, Woolson RF. Dietary magnesium and C-reactive protein levels. J Am Coll Nutr 2005;24:166-71.
3. Adebamowo SN, Spiegelman D, Willett WC, Rexrode KM. Association between intakes of magnesium, potassium, and calcium and risk of stroke: 2 cohorts of US women and updated meta-analysis. Am J Clin Nutr. 2015;101(6):1269-77. 
4. Suter PM. The effects of potassium, magnesium, calcium, and fiber on risk of stroke. Nutr Rev 1999;57:84-8.
5. Ascherio A, Rimm EB, Hernan MA, et al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation 1998;98:1198-204.
6. Nie ZL, Wang ZM, Zhou B, Tang ZP, Wang SK. Magnesium intake and incidence of stroke: meta-analysis of cohort studies. Nutr Metab Cardiovasc Dis 2013;23(3):169-76.
7. Xu T, Sun Y, Xu T, Zhang Y. Magnesium intake and cardiovascular disease mortality: a meta-analysis of prospective cohort studies. Int J Cardiol 2013;167(6):3044-7. 
8. Zhang W, Iso H, Ohira T, Date C, Tamakoshi A; JACC Study Group. Associations of dietary magnesium intake with mortality from cardiovascular disease: the JACC study. Atherosclerosis 2012;221(2):587-95.
9. Lasserre B, Spoerri M, Moullet V, et al. Should magnesium therapy be considered for the treatment of coronary heart disease? II. Epidemiological evidence in outpatients with and without coronary heart disease. Magnes Res 1994;7:145-53. 
10. Shechter, M., Merz, C. N., Paul-Labrador, M., Meisel, S. R., Rude, R. K., Molloy, M. D., Dwyer, J. H., Shah, P. K., and Kaul, S. Beneficial antithrombotic effects of the association of pharmacological oral magnesium therapy with aspirin in coronary heart disease patients. Magnes.Res. 2000;13(4):275-284.
11. Meyer KA, Kushi LH, Jacobs DR, et al. Carbohydrates, dietary fiber, and incident type 2 diabetes in older women. Am J Clin Nutr 2000;71:921-30.
12. Song Y, Manson JE, Buring JE, Liu S. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care 2004;27:59-65.
13. Fung TT, Manson JE, Solomon CG, et al. The association between magnesium intake and fasting insulin concentration in healthy middle-aged women. J Am Coll Nutr 2003;22:533-8. 
14. Lopez-Ridaura R, Willett WC, Rimm EB, et al. Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care 2004;27:134-40.
15. Fang X, Han H, Li M, et al. Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies. Nutrients. 2016;8(11)
16. Barbagallo M, Dominguez LJ. Magnesium and type 2 diabetes. World J Diabetes. 2015;6(10):1152‐1157. doi:10.4239/wjd.v6.i10.1152
17. He K, Liu K, Daviglus ML, et al. Magnesium intake and incidence of metabolic syndrome among young adults. Circulation 2006;113:1675-82.
18. Guerrero-Romero F, Rodriguez-Moran M. Low serum magnesium levels and metabolic syndrome. Acta Diabetol 2002;39:209-13. 
19. Hoogerbrugge N, Cobbaert C, de Heide L, et al. Oral physiological magnesium supplementation for 6 weeks with 1 g/d magnesium oxide does not affect increased Lp(a) levels in hypercholesterolaemic subjects. Magnes Res 1996;9:129-32.
20. Jee SH, Miller ER 3rd, Guallar E, et al. The effect of magnesium supplementation on blood pressure: a meta-analysis of randomized clinical trials. Am J Hypertens 2002;15:691-6.
21. Dickinson HO, Nicolson DJ, Campbell F, et al. Magnesium supplementation for the management of essential hypertension in adults. Cochrane Database Syst Rev 2006;3:CD004640.
22. Kass L, Weekes J, Carpenter L. Effect of magnesium supplementation on blood pressure: a meta-analysis. Eur J Clin Nutr 2012;66:411-8.
23. Zhang X, Li Y, Del Gobbo LC, et al. Effects of magnesium supplementation on blood pressure: a meta-analysis of randomized double-blind placebo-controlled trials. Hypertension. 2016 Aug;68(2):324-33. 
24. Hanus M, Lafon J, Mathieu M. Double-blind, randomised, placebo-controlled study to evaluate the efficacy and safety of a fixed combination containing two plant extracts (Crataegus oxyacantha and Eschscholtzia californica) and magnesium in mild-to-moderate anxiety disorders. Curr Med Res Opin 2004;20:63-71.
25. Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. 2017;9(5):429. Published 2017 Apr 26. doi:10.3390/nu9050429
26. Tarleton EK, Littenberg B, MacLean CD, Kennedy AG, Daley C. Role of magnesium supplementation in the treatment of depression: a randomized clinical trial. PLoS One. 2017 Jun 27;12(6):e0180067. 
27. Rajizadeh A, Mozaffari-Khosravi H, Yassini-Ardakani M, Dehghani A. Effect of magnesium supplementation on depression status in depressed patients with magnesium deficiency: A randomized, double-blind, placebo-controlled trial. Nutrition. 2017 Mar;35:56-60. doi: 10.1016/j.nut.2016.10.014. Epub 2016 Nov 9.
28. Ikonte CJ, Mun JG, Reider CA, Grant RW, Mitmesser SH. Micronutrient Inadequacy in Short Sleep: Analysis of the NHANES 2005-2016. Nutrients. 2019 Oct 1;11(10). pii: E2335. doi: 10.3390/nu11102335. 
29. Abbasi, et al. J Res Med Sci. 2012 Dec; 17(12): 1161–1169.

0 Preventing the Most Common Cause of Chronic Pain with Nutrition

The end of February is almost here, which means that our next Functional Medicine CE symposium is 1 week away! Dr. Frank Bodnar is rounding out his contribution to the blog with a great discussion on chronic pain and how we can use nutrition to improve inflammation. If you want to learn more and hear from Dr. Bodnar and our other speakers. Please make sure you sign up!

You’ve seen many patients walk into your clinic with a limp, antalgic posture or heard the grunts and groans of pain as they get in and out of their chairs. Thousands of people visit their local pharmacy for a remedy to ease their chronic ache and recurring nagging pain. There’s no doubt that inflammation is an underlying cause in the majority of your patient’s pain. We can help our patients break the cycle of grabbing a Tylenol off the shelf, only to return a few weeks later looking worse. At the end of the day, are your patients getting better?

You’re probably wondering where to start. You can get started by focusing on the most common cause of chronic pain, arthritis. And if we drill down into the term arthritis and look at a specific diagnosis, we see that osteoarthritis (OA) is the most common cause of chronic pain from a single disease standpoint. Not only is it the most common cause of chronic pain but also the leading cause of disability worldwide, affecting mobility, physical function and quality of life.¹OA, or joint degeneration is the culprit behind the majority of your patients’ aches and pains.

Unfortunately, the problem isn’t going away any time soon. Epidemiological data shows that the US population continues to age, and by 2040, 1 in 5 people in the United States will be 65 or older—about equal in size to the cohort of those who are 18 years of age or younger. One in two adults aged 65 and older already have some form of arthritis, but nearly two-thirds of those with arthritis are under 65. By 2030, it is projected some form of arthritis will affect 67 million adults. Both osteoarthritis and inflammatory forms of arthritis are more common in women.² 

The problem of OA and joint degeneration isn’t new to any clinician but may be one of the most neglected in the functional medicine and pharmacy arenas because we assume patients may not seek us out as an option for such an uncomplicated condition. Most patients rely on self-care via anti-inflammatory and analgesic medication as a remedy. While this approach may get them through their day, we know this is symptom management and doesn’t really do anything to reduce inflammation over the long-term or prevent further joint degeneration. 

If we want to make a dent in the pain problem and prevent more invasive therapies in our aging population, we need to offer safe and effective treatments for the musculoskeletal system, which is the largest contributor to chronic pain.² We’re going to cover the a few specific options that can make an immediate impact in breaking the vicious pain cycle your patients are stuck in. The aging process affects all aspects of a joint beyond just cartilage breakdown. The surrounding muscle begins to lose strength due to a decrease in muscle fibers and fiber size, and a reduction in muscle protein synthesis. Surrounding tendons also lose the ability to maintain water, lose tensile strength and elasticity and fibroblasts decrease glycosaminoglycan (GAG) production. Bones that surround primary weight bearing loads begin to decrease in strength due to less mineral content leading to more fragility, and the process of bone remodeling slows as well. Cartilage also loses its ability to decompress and hold water, along with a decreased ability to maintain joint lubrication through less hyaluronic acid production.³

When most clinicians think of OA, the first thing that comes to mind is a disease of “wear and tear.” We consider what we were taught during our training, which is to focus on the loss of joint space and a degradation of cartilage. While this isn’t completely inaccurate what we now know is that OA is much more involved than what we learned in pharmacy school even 10 years ago. A more accurate description of OA would be “whole joint failure,” just as loss of full function on the heart is diagnosed as heart failure and loss of full function of the kidney is diagnosed as renal failure. Whole joint failure involves not only the cartilage, but helps us take into consideration the underlying bone, synovial membrane, synovial fluid, tendons, muscles, nerves, nociceptor sensitivity and underlying metabolic factors (TIMP/MMP activity).⁴

Traditional drugs such as aspirin, ibuprofen, naproxen, celecoxib and steroids target primarily 5-LOX, COX-1, COX-2, PLA2 inflammatory pathways via oral medication or intraarticular injection to provide pain relief. Analgesics such as acetaminophen, narcotics and oxycodone may also provide symptomatic relief. However, this relief comes at a cost of more also blocking the body’s repair process and more cartilage loss than previously thought and higher risks than many are aware. Given the constraints of NSAIDs, especially in those with high cardiovascular risk, gastrointestinal and renal comorbidities, and constraints of acetaminophen in those with high risk of liver injury or at risk for multiple medication adverse reactions safer alternatives should be a primary consideration. In fact, a recent study at Boston University School of Medicine found accelerated arthritis and joint destruction can be the unintended result of intra-articular corticosteroid injections.⁵ Given the chronicity of OA we need alternatives that are safe and effective and can be taken long-term without the major side effects. 

Dietary Changes Can Reduce Inflammation and OA Progression

Diet has been shown to greatly influence the rate of joint degeneration, especially when obesity and insulin resistance are involved. Obesity is now a recognized generator of inflammation and adds to the mechanical pressure on a joint. The inflammatory and metabolic mechanisms as contributing factors to OA can no longer be ignored. A recent laboratory study testing synovial tissue from mice and individuals with type 2 diabetes suggested that the insulin resistance of type 2 diabetes may promote OA.⁶

Research also has shown that diet plays a key role in the regulation of inflammation, elevating C-reactive protein (CRP)⁷, and because there is a relationship between inflammation and the development and progression of OA, consuming diets shown to have anti-inflammatory effects may be an important step in preventing and halting the progression of the disease. In fact, even a single meal high in calories, fat, and highly palatable carbohydrates can induce an acute inflammatory response,⁸possibly contributing to flare-up and pain in OA.

The Standard American Diet is characterized by a high intake of processed meat, refined sugars, saturated fat, little fiber, and high arachidonic acid. This dietary pattern triggers the release of proinflammatory cytokines and reduce the production of anti-inflammatory cytokines.⁹Consuming trans fats from cakes, cookies, pie crusts, biscuits, margarine, and commercially fried foods have been shown to increase biomarkers of inflammation, specifically CRP and IL-6, especially in people who are overweight.^10,11Focusing on whole unprocessed foods appears to be the most prudent strategy. One study using an inflammatory food index found that an anti-inflammatory diet consisting of foods rich in fish, fruits and vegetables, and olive oil was associated with lower levels of CRP.¹²

Specific Nutraceuticals to Mitigate Joint Degeneration and OA Progression

The other part of the equation is offering patients options that have been clinically proven to be effective for OA. Glucosamine sulfate and chondroitin sulfate are two nutraceuticals that are structural building blocks of the GAG polymers found in cartilage that play key roles in absorbing water, contributing to greater joint space, cartilage volume and give cartilage its ability to compress and decompress from forces and friction encountered throughout the day.¹³ Glucosamine sulfate and chondroitin sulfate at low-molecular weights (<17,000 kD) have also shown potent anti-inflammatory action by modulating the COX-1 and COX-2 pathways, and the ability to decrease cartilage degradation markers in human OA studies.

In a 2008 study published in the Journal of Orthopedics Traumatology, 104 patients diagnosed with OA of the hands, knee or hip were evaluated on pain scores (VAS), radiographic imaging and had biomarkers of cartilage degradation measured via urinary C-terminal crosslinking telopeptides of type II collagen (uCTX-II), and bone degradation measured via urinary C-terminal cross-linking telopeptides of type I collagen (uCTX-I). Scientists used these tests to evaluate the structural progression of OA and potential therapeutic efficacy of glucosamine sulfate and chondroitin sulfate. All measures were taken at baseline, 6 months and 1 year to gauge progression. After 6 months and 1-year they found the uCTX-I and uCTX-II markers were significantly lower in the glucosamine sulfate and chondroitin sulfategroups, along with VAS scores, compared to baseline measures. Radiographic evaluation showed a reduced progression in the hand OA group after 1 year. The authors concluded that glucosamine sulfate and chondroitin sulfatein combination can provide a protective effect in OA patients and shows evidence that they slow the progression of OA.¹⁴

Other notable clinical trials include a randomized, double-blind, placebo-controlled study called the GAIT Trial, which is the largest NIH funded study on joint health supplements to date. In the trial GS and CS where evaluated individually and in combination and compared to celecoxib for therapeutic efficacy.  In the study 1,583 OA patients were evaluated and it was found that those who received the most benefit in the moderate to severe pain group were given 1500 mg/day of glucosamine sulfate and 1200 mg/day of chondroitin sulfate. The study ran for 2-years with patients receiving a daily dose of glucosamine sulfate and chondroitin sulfate. Initial conclusions found no benefit for mild OA, however upon secondary analysis in the moderate to severe OA pain group glucosamine sulfate and chondroitin sulfatewas found to not only be effective for pain reduction but outperform celecoxib at the doses mentioned.¹⁵

In another randomized, double-blind, placebo-controlled study,called the MOSAIC Trial, 194 OA patients at five medical centers in Quebec were enrolled to gauge the efficacy of low-molecular weight chondroitin sulfatein comparison to celecoxib. Half of the patients received 1200 mg/day chondroitin sulfateand half received 200 mg/day of celecoxib over a 2-year period. Three MRIs, a clinical assessment, and WOMAC score were used to assess structural changes. These evaluation methods were done at the beginning, one year in and the end of the study. Loss of cartilage was a primary assessment. It was found that the chondroitin sulfatepatients had much slower progression of OA in comparison to celecoxib group. Both treatments were equal in pain reduction, maintaining function, joint stiffness, joint swelling and both improved symptoms by 50%. The authors noted the positive outcomes with chondroitin sulfate, as well as the fact that chondroitin sulfate doesn’t carry the risk of side effects as anti-inflammatory medications.¹⁶

Another randomized, double-blind, placebo-controlled study, called the CONCEPT Trial, compared celecoxib therapy to low-molecular weight chondroitin sulfate. Over 600 OA patients received either 800 mg/day of chondroitin sulfateor celecoxib. The study found 800 mg/day of low-molecular weight chondroitin sulfateto be superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee OA patients. The authors concluded that this formulation of chondroitin sulfateshould be considered a first-line treatment in the medical management of knee OA.¹⁷

Finally, a study recently just published in Diabetes Carein January 2020. Found an association between glucosamine users and a lower incidents of Type 2 Diabetes (T2D). Since glucosamine is a glycosaminoglycan (GAG), the authors were looking to see if there was an association between glucosamine supplement use and an increase occurrence of diabetes. Previous scientific commentaries on glucosamine have hinted at glucosamine being avoided in the general population, and by diabetics, due to “possible” negative blood sugar consequences that would worsen insulin sensitivity and contribute to the onset or worsening of diabetes.

This study shows however that glucosamine may actually be protective against or hinder the onset of diabetes. The study analyzed over 400,000 individuals that had data input into the UK Biobank who were free of diabetes, cancer and cardiovascular disease at baseline (8 years prior). The authors then evaluated the association between glucosamine supplementation and risk of incident of Type 2 Diabetes (T2D). After adjusting for age, sex, BMI, race, lifestyle factors, history of disease, genetics and other supplement use they found that glucosamine was associated with significantly lower risk of T2D. The really exciting part was that that they found the strongest association in those that had the highest inflammatory levels of C-reactive protein (hs-CRP).¹⁸

How could a sugary protein possibly influence a metabolic disease like T2D? While most of us think about glucosamine as simply a “building block” in cartilage, pharmaceutical-grade glucosamine (low molecular weight) actually has a robust anti-inflammatory mechanism that is overlooked.¹⁹ This anti-inflammatory mechanism is most likely why glucosamine displayed such a strong association of less incidents of T2D in those with higher hs-CRP levels. Inflammation can affect everything from our cell’s ability to metabolize sugar efficiently to our pancreas’s ability to produce insulin, leading to hyperinsulinemia.

Glucosamine’s anti-inflammatory action also makes it ideal as a chondroprotective, helping cartilage cells, that grow and reproduce very slowly, stay alive longer and thrive by decreasing the inflammatory signaling that damages the cells directly and inhibits the activation of a class of cartilage degrading enzymes called matrix metallopeptidases (MMPs).¹⁹

Quality is the key when it comes to recommending a glucosamine sulfateor chondroitin sulfate product. Martel-Pelletier (2015) showed discrepancies of chondroitin quality and ranging levels of efficacy due to quality. It was found that low-molecular weight chondroitin sulfateis the only reliable form on the market, and larger chondroitin sulfate molecules could actually be pro-inflammatory in nature.²⁰ Previous studies have also shown that large chondroitin sulfate molecules will not pass through the intestinal epithelium barrier, further contributing to the poor results of past trials with lower quality chondroitin sulfate. 

Glucosamine should be dosed at 1500 mg/day and chondroitin sulfate in combination at 800-1200 mg/day. Glucosamine does carry a precaution as a shellfish warning, and if pregnant or nursing it is recommended to consult a physician prior to use. Taking chondroitin in combination with glucosamine might increase the anticoagulant effects of warfarin (Coumadin) and increase the risk of bruising and bleeding as well. Generally both glucosamine sulfate and chondroitin sulfate are broken up to 2 or 3 daily doses and taken on an empty stomach.

References

1. Neogi, T. (2013). The epidemiology and impact of pain in osteoarthritis. Osteoarthritis and Cartilage, 21(9), 1145-1153. 
2. Castillo, S. (2016). The Burden of Musculoskeletal Diseases in the United States: Prevalence, Societal and Economic Cost (3rd Edition), United States Bone and Joint Initiative, NFP (USBJI) 
3. Effects of Aging – OrthoInfo – AAOS. (2009), from https://orthoinfo.aaos.org/en/staying-healthy/effects-of-aging/
4. O’Neill, T. and Felson, D. (2018). Mechanisms of Osteoarthritis (OA) Pain. Current Osteoporosis Reports,16(5), pp.611-616. 
5. Andrew J. Kompel, Frank W. Roemer, Akira M. Murakami, Luis E. Diaz, Michel D. Crema, Ali Guermazi. Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought? Radiology,2019; 190341 
6. Hamada D, Maynard R, Schott E, et al. Suppressive effects of insulin on tumor necrosis factor-dependent early osteoarthritic changes associated with obesity and type 2 diabetes mellitus. Arthritis Rheumatol. 2016;68(6):1392-1402
7. Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48(4):677-685.
8. Emerson, S., Kurti, S., Harms, C., Haub, M., Melgarejo, T., Logan, C., & Rosenkranz, S. (2017). Magnitude and Timing of the Postprandial Inflammatory Response to a High-Fat Meal in Healthy Adults: A Systematic Review. Advances In Nutrition: An International Review Journal, 8(2), 213-225. 
9. Clinton CM, O’Brien S, Law J, Renier CM, Wendt MR. Whole-foods, plant-based diet alleviates the symptoms of osteoarthritis. Arthritis. 2015;2015:708152.
10. Mozaffarian D, Pischon T, Hankinson SE, et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004;79(4):606-612.
11. Lopez-Garcia E, Schulze MB, Meigs JB, et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005;135(3):562-566.
12. Cavicchia PP, Steck SE, Hurley TG, et al. A new dietary inflammatory index predicts interval changes in serum high-sensitivity C-reactive protein. J Nutr. 2009;139(12):2365-2372.
13. Tang, Y., Cui, Y., De Agostini, A., & Zhang, L. (2019). Biological mechanisms of glycan- and glycosaminoglycan-based nutraceuticals. Progress In Molecular Biology and Translational Science, 445-469. 
14. Scarpellini, M., Lurati, A., Vignati, G. et al.Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the “Magenta osteoarthritis study”. J Orthopaed Traumatol9, 81–87 (2008).
15. Clegg, D., Reda, D., Harris, C., Klein, M., O’Dell, J., & Hooper, M. et al. (2006). Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. New England Journal Of Medicine, 354(8), 795-808. 
16. Pelletier, J., Raynauld, J., Beaulieu, A., Bessette, L., Morin, F., & de Brum-Fernandes, A. et al. (2016). Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. Arthritis Research & Therapy, 18(1). 
17. Reginster J, Dudler J, Blicharski T, et al. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT)Annals of the Rheumatic Diseases2017;76:1537-1543.
18. Ma, H., Li, X., Zhou, T., Sun, D., Liang, Z., & Li, Y. et al. (2020). Glucosamine Use, Inflammation, and Genetic Susceptibility, and Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank. Diabetes Care, dc191836. 
19. Jerosch, J. (2011). Effects of Glucosamine and Chondroitin Sulfate on Cartilage Metabolism in OA: Outlook on Other Nutrient Partners Especially Omega-3 Fatty Acids. International Journal Of Rheumatology, 2011, 1-17.
20. Martel-Pelletier J, Farran A, Montell E, Vergés J, Pelletier JP. Discrepancies in composition and biological effects of different formulations of chondroitin sulfate. Molecules. 2015;20(3):4277–4289. Published 2015 Mar 6.

0 Sub-Acute Pain and Healing Support with Nutraceutical and Lifestyle Recommendations

Pain is the number #1 reason why people enter the system. Pharmacists get questions about pain management strategies on a daily basis regardless of their setting. This is one of the reasons we choose pain and inflammation to be our next symposium topic for FxMedCE.com. We want more providers to understand the types of pain and how to help our patients. I hope you enjoy another great blog post from Dr. Frank Bodnar, DC. He is will be one of the speakers, make sure you sign up to hear from him as well as others who have spoken across the globe. Continuing Education Credit is available for Pharmacists and Certified Nutrition Specialists (CNS). Others are welcome to join!

One of the most overlooked phases of pain and healing is the sub-acute phase. There’s some uncertainty about how to best approach sub-acute pain from a pharmacist’s perspective since it’s not really acute, and it’s not chronic. Often this puts patients in a “no-man’s-land” of self-management with no clear direction of where we want them to go and why, so patients do what they’ve always done. They go back to the medicine cabinet for another pain reliever. 

Helping patients navigate the middle ground of pain and healing presents a fantastic opportunity where pharmacists can help prevent the cycle of pill dependency for pain. This shift allows the body to do the healing. After all the injury didn’t occur by a deficiency in ibuprofen or acetaminophen and won’t fully support the body’s middle phase of structural healing if the cycle continues. The cycle of dependency may lead the patient down a road of more potent like a cortisone injection or even a prescription opioid. Pharmacists can alter this trajectory.

The majority of the time the sub-acute phase of care is treated with the exact same approach as an acute phase, despite there being clear physiologic differences. It’s understandable that there is some overlap between the acute and sub-acute phases and major guidelines may overlook the need for a different approach.  

Traditionally the American College of Physiciansrecommends a number of both pharmaceutical and non-pharmaceutical options for sub-acute low back pain,¹and within the realm of therapies available there are a number of other options available as well:

• Cryotherapy
• Heat
• Electrotherapy
• Ultrasound
• Low level laser
• TENS Machine
• Electrical Stimulation
• Spinal manipulation
• Massage
• Acupuncture
• Dry needling
• Kinesio taping
• Instrument assisted soft tissue mobilization
• Exercise rehabilitation
• Anti-inflammatory drugs
• Topical analgesic 
• Skeletal muscle relaxants

While all of the therapies listed above are traditionally appropriate in the management of sub-acute pain and healing, they are primarily focused on symptom management and leave out nutrition completely. Healing is a complex process that requires proper key nutrients for inflammatory control, new tissue formation, and tissue remodeling to occur within a specific time frame to get back to optimal function. Simply reaching for the bottle in the medicine cabinet isn’t sufficient.

In some cases, all three phases of the healing process may take 12-18 months to be fully completed depending on the tissue type and injury severity.²Managing patient expectations is an essential part of pain management. If patients understand the phases of healing and goal of therapies at each phase, you can begin to provide the roadmap to a pain-free future.

During sub-acute pain the focus of the body with many injuries is connective tissue repair and rebuilding structural integrity. Connective tissue regeneration and repair begins with fibroblasts producing type I and type III collagen fibers, which are randomly orientated, immature, and weak in comparison to the well-organized, dense fibers of type I collagen. Depending on the structure, type II collagen and extracellular matrix material like hyaluronic acid and other polysaccharides help to aggregate, organize and allow proper structure movement to occur.³

The remodeling phase requires gradual collagen and connective tissue cross-linking, which is dependent on the vital cofactor vitamin C. Vitamin C activates hydroxylases, allowing proper collagen fiber assembly and helical structure formation to occur.⁴If connective tissue alignment and aggregation is limited, collagen fiber orientation remains disorganized and overall function remains limited. This area will likely be a site of reinjury, and vitamin C plays a key role in preventing this.⁵

Clinical studies on nutraceuticals as bioactive collagen peptides, type I collagen, hyaluronic acid and essential cofactors for collagen formation have shown they not only reduce rehabilitation time, but also endogenously stimulate chondrocytes, fibroblasts and synovial cells to produce their native raw materials. In addition, these studies also show reduced cytokines such as IL-1β, which stimulate a class of connective tissue-degrading enzymes called matrix metalloproteinases (MMPs) .^6-8Structural support and inflammatory support at the cellular level are essential to reducing the risk of re-injury in all connective tissues.

The best nutraceuticals to offer patients during a sub-acute pain episode is a combination of high-quality type I and type II collagen peptides, hyaluronic acid, mucopolysaccharides, vitamin C and magnesium. These nutrients cover over 90% of the connective tissue in the body and undoubtedly would enhance he sub-acute phase of healing and repair. Not only do they support the connective tissue cells, the process of protein synthesis and collagen cross-linking but they also have clinical studies with positive clinical outcomes. Of course, sometimes simply offering an alternative to a muscle-relaxer may be appropriate as well. 

Tendinopathies are largely an overuse injury and represent a good example of what will also support connective tissue regeneration and repair during a sub-acute phase of pain and healing. A 2014 study out of Barcelona and Madrid, Spain treated tendinopathy patients at multiple hospitals and sports rehabilitation clinics around the area with high-quality type I collagen peptide that also contained vitamin C, magnesium and naturally occurring mucopolysaccharides. A total of 98 patients with Achilles tendinitis, patellar tendinitis and lateral epicondylitis received a dose of 435 mg mucopolysaccharides, 75 mg type I collagen peptides and 60 mg of vitamin C for 90 days. Clinical symptoms improved by 38% (during activity and rest) on average and a decrease in tendon thickness was observed upon ultrasound evaluation – indicating less inflammation and tendon hypertrophy.⁹

There are valid options available that get results and support the body during the healing process and your patients should be aware. Below are some key evidence-based sub-acute pain and healing nutraceuticals:

Nutrient	Dose	Mechanism
GABA10	250mg/day for 30 days	Primary inhibitory neurotransmitter of the brain promotes relaxation and inhibits over-firing that results in muscle spasm and pain. Also shown clinically to improve sleep, promote alpha brain waves and improve REM sleep cycle.
Glycine11	225mg/day for 30 days	Primary inhibitory neurotransmitter of the spinal cord promotes relaxation and inhibits over-firing that results in muscle spasm and pain, as well as promoting sleep quality.
Cramp Bark12	200mg/day for 30 days	Anti-inflammatory and promotes smooth muscle relaxing effects. Not only effective for muscle spasms of the neck and low back but has shown effectiveness with menstrual cramping as well.
Dong Quai Root Extract12	150mg/day for 30 days	Anti-inflammatory and promotes smooth muscle relaxing effects. Not only effective for muscle spasms of the neck and low back but has shown effectiveness with menstrual cramping as well.
Type I collagen peptides with mucopolysaccharides13-16	500 mg/day for 90-180 days	Type I collagen building block and stimulates tenocytes and fibroblasts to produce type I collagen in tendons, ligaments and skin. Clinical studies have shown improvement in medial and lateral epicondylitis, Achilles tendinitis and patellar tendinitis.
Type II collagen peptides17-19	5 g/day for 90-180 days	Type II collagen building block and stimulates chondrocytes and to produce type II collagen in cartilage and stimulates chondrocytes to endogenously produce more type II collagen.
Hyaluronic acid20-22	40-80 mg/day for 90-180 days	Increases hyaluronic acid concentration in synovial fluid and stimulates synoviocytes to increase HA production for joint and connective tissue hydration and lubrication. Clinical studies have shown improvements in pain scores, mobility and decreased synovitis in OA patients.
Vitamin C23	100 mg/day for 90-180 days	Maximizes hydroxylases for optimal collagen and hyaluronic acid production and provides antioxidant support to optimize connective tissue healing, decreases histamine production, modulates immune response and new studies show potential reduction of pain.
Magnesium24	135 mg/day for 90-180 days	Co-factor for over 350 enzymes in the body, decreases chronic pain signaling via NMDA receptors, and shown to decrease pain in low back and headache patients.

Supporting the body’s natural healing process is paramount and in some patients, this means digging a little deeper into lifestyle factors that can limit this process. The final missing variables in the sub-acute pain and healing equation is addressing the patient’s lifestyle by doing a quick evaluation of their stress levels and sleep quality. We know that the stress response can delay healing, and sleep is the primary time when the body is in repair mode. In a clinical trial published in Psychoneuroendocrinology, scientists looked at participants’ cortisol levels, perceived stress and health behaviors and how all of the factors affected wound healing. What they found was that cortisol had a considerable influence on wound healing independent of participants’ health behaviors. ²⁵ 

Multiple studies have also looked at sleep quality on healing, showing that poor sleep elevates cortisol, increases fatigue and errors made at work and results in worse patient health outcomes.^26,27In one study the health of patients recovering in hospitals revealed that sleep was crucial for healing and survival of critically ill patients and greatly influenced the outcomes of patients suffering from a myriad of diseases. In fact, less sleep disruptions in critically ill patients showed much better outcomes in the literature compared to those with constant disruptions from health care practitioners during their recovery time.²⁷       

Changing the patient’s perspective on pain and implementing easy nutrient and lifestyle recommendations doesn’t have to be a complicated process. There are cortisol tests and sleep study methods available, but many patients want an immediate solution that will allow them to improve immediately. Simply having a conversation about how to best serve a patient will reveal the best nutrient offering and implementing a 5-minute stress questionnaire can reveal how stress and sleep may be limiting the sub-acute healing process. Start by simply engaging patients and offering the best recommendation for their specific situation and you’ll put them on the path to letting he body do what it does best.

References:

1. Qaseem, A., Wilt, T., McLean, R., & Forciea, M. (2017). Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline from the American College of Physicians. Annals of Internal Medicine, 166(7), 514. 
2. Reichert, W., Stroncek, J., & Reichert, W. (2008). Indwelling Neural Implants: Strategies for Contending With the in Vivo Environment (Frontiers in neuroengineering)(Chapter 1: Overview of Wound Healing in Different Tissue Types). Boca Raton, FL: CRC Press.
3. Broughton, G., 2nd, J. E. Janis, et al. (2006). “The basic science of wound healing.” Plast Reconstr Surg 117(7 Suppl): 12S-34S
4. DePhillipo, N. N., Aman, Z. S., Kennedy, M. I., Begley, J. P., Moatshe, G., & LaPrade, R. F. (2018). Efficacy of Vitamin C Supplementation on Collagen Synthesis and Oxidative Stress After Musculoskeletal Injuries: A Systematic Review. Orthopaedic journal of sports medicine, 6(10), 2325967118804544. 
5. Ömeroğlu, S., Peker, T., Türközkan, N., & Ömeroğlu, H. (2008). High-dose vitamin C supplementation accelerates the Achilles tendon healing in healthy rats. Archives of Orthopaedic And Trauma Surgery, 129(2), 281-286. 
6. Iwai K, Hasegawa T, Taguchi Y, Morimatsu F, Sato K, Nakamura Y, Higashi A, Kido Y, Nakabo Y, Ohtsuki K, 2005. Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates. J Agric Food Chem, 53, 6531-6536.
7. Oesser S, Adam M, Babel W, Seifert J, 1999. Oral administration of (14) C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). JNutr, 129, 1891-1895.
8. P. Lundquist, P. Artursson . Oral Absorption of peptides and nanoparticles across the human intestine. Advanced Drug Delivery Reviews106 (2016) 256–276
9. Arquer, A., et al. (2014). The efficacy and safety of oral mucopolysaccharide, type I collagen and vitamin C treatment in tendinopathy patients.
10. Yoto, A., et al. (2011). Oral intake of γ-aminobutyric acid affects mood and activities of central nervous system during stressed condition induced by mental tasks. Amino Acids, 43(3), pp.1331-1337. 
11. Kawai, N., et al. (2014). The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus. Neuropsychopharmacology, 40(6), pp.1405-1416. 
12. Nicholson, J. A., Darby, T. D., and Jarboe, C. H. Viopudial, a hypotensive and smooth muscle antispasmodic from Viburnum opulus. Proc.Soc. Exp Biol.Med. 1972;140(2):457-461) 
13. Schunk M and Oesser S. Specific collagen peptides benefit the biosynthesis of matrix molecules of tendons and ligaments. J Int Soc Sports Nutr. 2013; 108. 
14. Shakibaei M, Buhrmann C, Mobasheri A. Anti-inflammatory and anti-catabolic effects of TENDOACTIVE® on human tenocytes in vitro. Histol Histopathol. 2011 Sep;26(9):1173-85.
15. Balius et al. A Randomized, Placebo-Controlled Study to Evaluate Efficacy and Safety of A Dietary Supplement Containing Mucopolysaccharides, Collagen Type I and Vitamin C for Management of Different Tendinopathies. Ann Theum Dis. 2014;73, Suppl. 2:299- 30018. 
16. Proksch E, Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis. Skin Pharmacol Physiol. 2014;27(3):113-9. doi: 10.1159/000355523. 
17. McAlindon TE, Nuite M, Krishnan N, Ruthazer R, et al. Changes in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. Osteoarthritis and Cartilage19 (2011) 399e405 7.
18. Zuckley L, Angelopoulou K, Carpenter MR: Collagen hydrolysate improves joint function in adults with mild symptoms of osteoarthritis of the knee. Medicine and Science in Sports and Exercise 2004, 36 (Supplement), 153 – 155. 
19. Clark KL, Sebastianelli W, Flechsenhar KR, Aukermann DF, Meza F, Millard RL, Deitch JR, Sherbondy PS, Albert A: Long-term use of collagen hydrolysate as a nutritional supplement in athletes with activity-related joint pain. Curr Med Res Opin. 2008 May;24(5):1485-96.6.
20. Torrent A, Ruhí R, Theodosakis J, et al. Comparative efficacy of IB0004, extracted hyaluronic acid (HA) and fermented HA on the synthesis of endogenous HA by human synoviocytes. Osteoarthritis Cartilage. 2009;17(Suppl 1):S278-79. – 10x HA secretion9. 
21. Torrent A, Ruhí R, Martínez C, et al. Anti-inflammatoryactivity and absorption of a natural rooster comb extract. Osteoarthritis and Cartilage. 2010 Oct;18(Suppl 2):S246-47. 
22. Möller I, Martinez-Puig D, Chetrit C. Oral administration of a natural extract rich in hyaluronic acid for the treatment of knee OA with synovitis: a retrospective cohort study. Clinical Nutrition Supplements2009;4(2):171-17211
23. Carr, A., & McCall, C. (2017). The role of vitamin C in the treatment of pain: new insights. Journal of Translational Medicine, 15(1). doi: 10.1186/s12967-017-1179-7
24. Na HS, Ryu JH, Do SH. The role of magnesium in pain. In: Vink R, Nechifor M, editors. Magnesium in the Central Nervous System [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
25. Ebrecht, M., Hextall, J., Kirtley, L., Taylor, A., Dyson, M., & Weinman, J. (2004). Perceived stress and cortisol levels predict speed of wound healing in healthy male adults. Psychoneuroendocrinology,29(6), 798-809. 
26. Niu, S., Chung, M., Chen, C., Hegney, D., O’Brien, A., & Chou, K. (2011). The Effect of Shift Rotation on Employee Cortisol Profile, Sleep Quality, Fatigue, and Attention Level. Journal of Nursing Research, 19(1), 68-81. 
27. Tembo, A., & Parker, V. (2009). Factors that impact on sleep in intensive care patients. Intensive and Critical Care Nursing, 25(6), 314-322. 

0 Probiotic FAQ: Part 2

It’s finally Spring in Ohio! Trees are blooming, and it’s warm enough for walking and playing outside. Our daughter learned to ride a bike without training wheels this week and she’s been non-stop asking to go outside. Balance bikes are amazing, she literally tried the real bike for 1 day before she got it after using the balance bike the last few years.

This is the final post in my Probiotic Series at least for now! If you haven’t checked out the other post, please do, it starts with Probiotics 101, then Probiotic FAQ: Part 1 . And now on to Part 2! I also have a post over on my friend Lindsey Elmore’s site you should read as well. Thanks again to my interns Vineeta Rao and Ruth Gunti who worked on this series with me.

I hope these post help explain some of the basics about probiotics and the answer your questions, if you have further questions. Don’t hesitate to reach out.

If I have histamine intolerance, should I avoid certain strains? If so which ones?

Histamine intolerance is a condition in which the body has imbalanced levels of histamine. In this state, through the body’s own metabolic processes or consumption of histamine-rich foods, the body has too much histamine and may react to certain food with allergic-like symptoms such as hives, skin rashes, and other digestive symptoms.¹ Gut bacteria are involved in both producing and degrading histamine, and having too many histamine-producing bacteria or too little histamine-degrading bacteria may cause elevated histamine levels.^2,3 Therefore, it is crucial to select a probiotic that contributes to the proper balance of histamine in the body.

If you have histamine intolerance, it is important to avoid certain species of histamine-producing bacteria when selecting a probiotic. Those that should be avoided are Lactobacillus casei, Lactobacillus Bulgaricus, Streptococcus thermophilus, Lactobacillus delbrueckii, Lactobacillus helveticus.³
In contrast, certain probiotics appear to aid in relieving the imbalances found with histamine intolerance. Lactobacillus rhamnosus strains GG and c705 have been observed to inhibit the effect of histamine in the body.⁴ Additionally, in vitro studies suggest that bifidobacterium lactis and lactobacillus plantarum species promote histamine breakdown. ^5,6

Should I take a probiotic while also taking an antibiotic? If so which one, and for how long?

Although clinicians have generally supported using probiotics with an antibiotic course, this is an area of controversy as new studies suggest that probiotics may interrupt the body’s natural process of restoring the bacterial balance in the gut. There are many studies that support using probiotics to prevent antibiotic-associated diarrhea, and among the tested species S. boulardii has specifically been shown to be effective.⁷ Studies have also shown that Lactobacillus rhamnosus GG, the strain contained in the Culturelle probiotic, appears and effective to prevent antibiotic associated diarrhea (AAD) in an outpatient setting.⁸ The recommended  dose is 10⁷ to 10¹⁰ colony-forming units (CFU) per capsule (taken one to 3 times daily) as that is what has been studied; duration of therapy can be 1-3 weeks or the entire length of time that the patient is on antibiotics.⁹ For reference, Metagenics “UltraFlora LGG” and Culturelle “Digestive Health” products contains 10¹⁰ CFU per dose, and Culturelle “Kids” product contains 10⁹ CFU per dose, making these products good choices for AAD.¹⁰ It is generally recommended to take probiotics for a couple months after therapy and consuming fermented foods. Overall it is said that “probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics.” ^8-10

However, there is emerging research that suggests that probiotics may actually delay spontaneous recovery of the microorganisms in the gut, or the “gut microbiome.” A recent study compared spontaneous gut recovery to probiotic use in humans receiving a broad-spectrum antibiotic course. By performing endoscopies and examining the stool from the patients before and after receiving antibiotics, normal genetic expression of bacteria in the gut was delayed by up to 5 months in the probiotic group versus a matter of weeks in the group allowed to spontaneously recover.^11,12 The in vitro portion of the study suggested that Lactobacillus acidophilus may inhibit the native gut microbiome.¹¹ While this study cautions against the preventative use of probiotics with an antibiotic course, further studies to shed light on the benefit or harm of probiotics are needed to come to a clear conclusion.¹²

In the meantime, it may be wise to avoid probiotics with Lactobacillus acidophilus when taking an antibiotic course. One of the challenges as a provider recommending probiotics is that this was just 1-2 studies in the midst of all the literature and didn’t not look at saccharomyces boulardii and its effect, therefore it really just raises questions for future research and gives us a pause to our practice of using blanket probiotics for everyone on antibiotics habit.

If I have dysbiosis or Small intestinal bacterial Overgrowth, should I avoid pre-biotics or certain probiotic strains?

Small Intestinal Bacterial Overgrowth (SIBO) typically refers to a form of dysbiosis (imbalance of bacteria on the body) attributed to an excessive overgrowth or changes in types of bacteria in the small-intestine.^13,,14 While the small intestine is not sterile, it has far fewer bacteria than the large intestine. Thus, SIBO may result from the specific bacteria that normally grows in the large intestine growing inappropriately in the small intestine.^13,14 Other causes of SIBO include multiple courses of antibiotics and impaired defense mechanisms such as low stomach acid, which may be caused by use of Proton Pump Inhibitors (PPIs). While the definition is constantly changing and expanding to include other forms of dysbiosis, SIBO is typically characterized by non-specific gastrointestinal symptoms such as bloating, abdominal discomfort, diarrhea, fatigue, and weakness and might be treated with an antibiotic course.^13,14

There are several studies that actually support the use of probiotics for this disorder.¹⁵  However, at the moment there is little consensus across the studies as to which probiotics species and strains will provide benefit for SIBO. Regardless of the species, the theoretical concern with using probiotics in SIBO even if the bacteria added to the gut is “good” bacteria, too much bacteria often produces symptoms of bloating and gas, which would worsen symptoms. In SIBO, patients often have an overgrowth of D-lactate-producing bacteria, so it may be best to avoid probiotics that also produce D-lactate such as Lactobacillus acidophilus.¹⁶

In the past it has also been generally recommended that one avoid the use of prebiotics until SIBO symptoms under control. Currently, studies that challenge this notion are frequently emerging, and in time, we may see a demonstrable benefit of certain probiotics and prebiotics in SIBO.¹⁶ However, until studies show which species and strains relieve rather than aggravate SIBO symptoms, it is likely best to avoid prebiotics and probiotics that produce D-lactate. In general, I recommend treating the overgrowth before working on replacing the flora with probiotics. Once those probiotics are tolerated, consider adding prebiotics to support healthy growth of gut flora along with other measures to prevent SIBO recurrence. Specifically, Partially Hydrolyzed Guar Gum (PHGG) is a prebiotic that has been shown to treat SIBO when administered alongside the antibiotic rifaximin better than rifaximin alone.¹⁷ Thus, this product could be a good option for encouraging healthy gut flora growth.

That’s a wrap. As always you can find great probiotic options on my FullScript Store or at YoungLiving. Feel free to message me if you have specific questions. We have so much science but we are still not quite a place were we absolutely know which probiotic product is going to work for each person. We are moving closer to that each day.

References:

1. Maintz L,  Novak N.Histamine and histamine intolerance.Am J Clin Nutr. 2007;85(5):1185-96.
2. Pugin B, Barcik W, Westermann P, et al. A wide diversity of bacteria from the human gut produces and degrades biogenic amines. Microb Ecol Health Dis. 2017;28(1):1353881.
3. What causes Histamine Intolerance. Facts vs Fitness. https://factvsfitness.com/probiotics-histamine-intolerance/. Updated July 27, 2017. Accessed January 23, 2019.
4. Oksaharju A, Kankainen M, Kekkonen RA, et al. Probiotic Lactobacillus rhamnosus downregulates FCER1 and HRH4 expression in human mast cells. World J Gastroenterol. 2011;17(6):750-9.
5. Mokhtar S., Mostafa G, Taha R. et al. Effect of different starter cultures on the biogenic amines production as a critical control point in fresh fermented sausages. Eur Food Res Technol. 2012;235(3): 527-535.
6. Capozzi V, Russo P, Ladero V, et al. Biogenic Amines Degradation by Lactobacillus plantarum: Toward a Potential Application in Wine. Front Microbiol. 2012; 3: 122.
7. Mcfarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol. 2010;16(18):2202-22.
8. Blaabjerg S, Artzi DM, Aabenhus R. Probiotics for the Prevention of
   Antibiotic-Associated Diarrhea in Outpatients-A Systematic Review and Meta-Analysis. Antibiotics (Basel). 2017 Oct 12;6(4).
9. Rodgers B, Kirley K, Mounsey A. PURLs: prescribing an antibiotic? Pair it with probiotics. J Fam Pract. 2013;62(3):148-50.
10. Antibiotic Use & Associated Diarrhoea Prevention. Probiotic Advisor. https://www.probioticadvisor.com/ Accessed February 9, 2019.
11. Suez J, Zmora N, Zilberman-Schapira G, et al. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018;174(6):1406-1423.
12. Kresser C. RHR: What the Latest Research Says about Probiotics, with Lucy Mailing. https://chriskresser.com/what-the-latest-research-says-about-probiotics-with-lucy-mailing/ Updated November 4, 2018. Accessed February 9, 2019.
13. Drake LE, Guilliams TG. Small intestinal bacterial overgrowth (SIBO): diagnostic challenges and functional solutions. Point Institute. 2018;14(2)1-15.
14. Kresser C. What Causes SIBO (Small Intestinal Bacterial Overgrowth) and Why It’s So Hard To Treat. https://chriskresser.com/sibo-what-causes-it-and-why-its-so-hard-to-treat/ Updated November 4, 2014. Accessed February 9, 2019.
15. Chen WC, Quigley EM. Probiotics, prebiotics & synbiotics in small intestinal bacterial overgrowth: opening up a new therapeutic horizon!. Indian J Med Res. 2014;140(5):582-4.
16. Kresser C. RHR: Treating SIBO, Cold Thermogenesis, and When to Take Probiotics. https://chriskresser.com/treating-sibo-cold-thermogenisis-and-when-to-take-probiotics/. Updated March 12, 2013. Accessed February 9, 2019.
17. Furnari M, Parodi A, Gemignani L, et al. Clinical trial: the combination
    of rifaximin with partially hydrolysed guar gum is more effective than rifaximin alone in eradicating small intestinal bacterial overgrowth. Aliment Pharmacy Ther. 2010;32(8):1000-6.

0 Vitamin C and Diabetes

Sorry for the lack of posts lately on the blog.  We are in a bit of a crazy season,  we are currently living with our gracious neighbors while we await the completion of our home. There was a lot of action today at the house! Can’t wait to share my new kitchen with all of you. Today  I saw this come across on the Designs for Health blog and thought.. I need to share this!  Vitamin C… what an easy thing to add to someone’s nutritional plan to help better control blood sugar.

Recently in my practice, I have been more proactive in evaluating my patients with diabetes for nutritional deficiencies so we can better target supplementation to address glucose control and metabolism.

While this study didn’t identify these patients as vitamin C deficient prior to treatment, it’s amazing that something as simple as Vitamin C 500 mg twice daily can make an impact on blood glucose regulation and blood pressure.  Think about the possibilities when this is combined with a healthy diet, exercise, and other key nutrients like biotin, chromium, alpha-lipoic acid, zinc, berberine and cinnamon. Stay tuned for a post on all of these amazing nutrients.

Head over to the Designs for Health Blog and read all about it at the link below! And don’t forget to order your supplements from my FullScript Store. 10% of your purchase goes to ministry!

New study demonstrates vitamin C supplementation improves glycemic control and blood pressure in patients with type II diabetes. 

0 To Keto or Not to Keto?

What diet is best for me?  This is question that I get a lot.  And my normal approach is very individual, but since I treat a lot of patients with diabetes, I tend to go with a lower carbohydrate approach. My general recommendations are no more than 30 grams of carbs per meal and no more than 15 grams at a snack.  If my patients with diabetes follow this, they tend to do really well as far as controlling their blood sugar.

Even more extreme carb reductions are found in the Keto diet and the Adkins diet.  Adkins focuses on higher protein content and Keto focuses on high fat, moderate protein, and low carb.  Since America is raving about the Keto diet right now, I honestly had plans to get a blog post on it up soon. But I came across this blog this week that hit a lot of my concerns with keto and keto in children (when not using for therapeutic epilepsy) that I thought it was worth sharing!

Is The Ketogenic Diet Safe For Those With Thyroid Disease?

Have you done the Keto diet? Has it worked for you? Have you maintained the Keto diet and maintained the weight loss? Or have you seen other beneficial effects?

Hope your weekend was marvelous and that you are prepping healthy foods for this week’s meals!

0 The NEW Nutrient Duo – Vitamins D and K2

I’ve been meaning to get a post up on this topic for awhile now, my fabulous former student and intern who just graduated with her PharmD, Dr. Kara Lish wrote this for you.  It has a lot of content, so hopefully the length won’t overwhelm you but help you see how Vitamin K2 is an essential nutrient that many of us are lacking in our diets. I will be doing a facebook live on this topic this on Thursday June 14th at 8 pm EST to answer questions!

 

For years, vitamin K has really only been known for its role as a cofactor to assist calcium in the regulation of blood clotting. Likewise, vitamin D was thought to aid calcium absorption to promote strong bones. It was not until recently that we learned it is vitamin K, particularly vitamin K2, that actually assists vitamin D to get calcium into the bones and to keep calcium out of the arteries, organs, and joints. In fact, various studies have shown that the supplementation with vitamin K2 actually strengthens the bone and reduces the risk for osteoporosis, and bone fractures. Additionally, vitamin K has been shown to promote cardiovascular health and arterial elasticity and to boost immune function as well. Read below for a complete guide in understanding how vitamin K works and what types exist and their specific benefits.

What is vitamin K? What types are beneficial and what dietary sources include those types?

Vitamin K is a fat-soluble vitamin that occurs naturally as either vitamin K1 (phylloquinone) or vitamin K2 (menaquinones). Vitamin K1 is found in green vegetables, like spinach, whereas vitamin K2 is found mostly in grass-fed dairy products, such as fermented milk or kefir. To a lesser extent, vitamin K2 can also be produced by bacteria in the digestive tract of animals, like chickens or cows. Unlike K1 where most goes directly to the liver where it stays to regulate normal blood clotting, vitamin K2 quickly passes through the liver before being redistributed throughout the entire body to be absorbed to help aide in various functions. For example, vitamin K2 is redistributed to the bones and blood vessels to support bone and cardiovascular health. Deficiencies of vitamin K1 have been linked to an increased risk of bleeding and less vitamin K2 available to the rest of body since the liver will then hold onto it to clot blood properly. Deficiencies of vitamin K2 have been associated with osteoarthritis, osteoporosis, and vascular calcification among other things, like a decline in cognitive function.^1,2 Because of their vital roles in overall health; men and women, including expecting and lactating mothers, should obtain 120 and 90 μg per day of vitamin K1 and 45-185 μg per day of vitamin K2.^3,4

Where does vitamin D come into play?

Focusing on vitamin K2 and bone health, there are three vitamin K2 dependent non-clotting proteins regulated by vitamin D3 that have been shown to prevent osteoarthritis, osteoporosis, and vascular calcification (strengthening) of bone. Vitamin D controls how much calcium is absorbed from the diet. Vitamin K2 directs the absorbed calcium to the bones where its new role is to promote bone building and prevent its breakdown.

 

Vitamin D3 regulates the amount of calcium and production of a certain protein, osteocalcin, which plays a vital role in bone health once vitamin K2 activates it. Once activated, vitamin K2 then helps bind osteocalcin to calcium before directing the absorbed calcium to the bones, where it binds to the bone matrix to build bone and prevent its breakdown. Without vitamin K2, osteocalcin would remain inactivated and calcium would neither be able to bind to it nor reach its destination in the bones. As a result, it would be impossible for the body to build or strengthen bone to prevent against fractures or breaks.^1,2,5,6

In fact, studies have demonstrated an increase in activated osteoclacin after the administration of vitamin K2, and thus, correlated inactivated osteocalcin with the risk for clinical fractures.⁵ Vitamin K has also even been shown to help maintain bone mineral density or bone strength. It does this by decreasing the breakdown of bone.⁷ Thus, vitamin K2 stimulates cells that promote bone building, while inhibiting cells that break down bone, resulting in greater calcification or bone strength.

Evidence showed that vitamin K2 helps to strong bones and to reduce bone fractures.⁸ Gajic-Veljanoski and group found that the daily use of 800 IU vitamin D, 45 μg vitamin K2, and 1200 mg calcium reduced the lifetime risk of a fracture by 25%.⁹ Similarly, Cockayne and colleagues demonstrated that vitamin K2 supplementation reduced bone loss and prevented hip, nonvertebral, and vertebral fractures by 77%, 81%, and 60%, respectively.¹⁰ Comparing osteoporotic patients who received 150 mg calcium with or without 45 μg vitamin K2, those who received only calcium lost 2.5% of their bone strength and experienced 45% more fractures versus those who received both, calcium and vitamin K2.¹¹ More so, other studies have proven that vitamin K2 can even reduce bone fractures induced by certain medications, like glucocorticoids, as well as to maintain and increase bone strength in liver-dysfunction-induced osteoporosis and paralytic patients with cerebrovascular disease.⁸

Not only are adequate levels of vitamin K2 desired in adults, particularly in the elderly population and pregnant women, but also in children.⁶ Recent studies have shown that even most healthy, prepubertal and pubertal children have high levels of inactive osteocalcin, which in turn signifies inadequate levels of vitamin K2, when compared to adults. Long-term, this could prevent the nonessential vitamin-K proteins from functioning, prohibiting optimal bone development to cause early onset osteoporosis. Karpinski and group’s study actually identified children as being the most deficient in vitamin K2 due to only 10% of it being found in the typical Western diet. Like the previous studies, they too recommend at least 45 μg vitamin K2 daily to increase levels to then increase osteocalcin activation, which to reiterate is the vitamin K dependent protein that helps bind calcium to promote bone mineralization, and thus, bone health.² On the other hand, other studies found that the relationship between the administration of supplemental vitamin K2 and the improvement in osteocalcin carboxylation is dose dependent, so Inaba and group recommend ≥100 μg vitamin K2 per day.¹²

How do I get more vitamin K2 in my daily diet?

To obtain more, you can either eat foods high in vitamin K2 (see below) or choose an appropriate supplement for you. When choosing a supplement, it is important to keep these 5 things in mind:

• Choose the right vitamin K2: MK-7 is best due to it’s longer half-life, but a mixture of MK-4/MK-7 is fine.

• Pick an appropriate dose: Adults opt for at least 100 μg (MK-7) daily.

• Eat with fat: It is fat-soluble; intake with fat sources maximizes absorption.
• Remember its companion: Vitamin D and K work synergistically. Other supplements, like magnesium and zinc, can further increase bone mineralization.

Adults and children require adequate amounts of both, vitamin D and vitamin K to create the ultimate duo for bone health!

• Consider current medications/dietary needs: If you are on a blood thinner, like warfarin, then talk to your doctor or pharmacist before supplementing with vitamin K2. If you have an allergy, intolerance, or dietary preference, then rest assured knowing there are options to meet these needs as well!

Take a look at these different products as well as the dietary options below, and talk to your doctor and pharmacist to see which may work best for you, but remember… Adults and children require adequate amounts of both, vitamin D and vitamin K to create the ultimate duo for bone health! If you don’t need additional Vitamin D, Orthomolecular also as a K2 only product. Dr. Hartzler recommends the liquid D3/K2 frequently because when it is in the MCT oil drops, the oil helps the nutrients absorb since they are fat soluble.

Dr. Hartzler will be on Facebook live this Tuesday evening June 12th at 8 pm EST to answer any questions you have about Vitamin D/K2. There some additional benefits to K2 as well that we will discuss beyond bone building!

Other Dietary Foods High in Vitamin K2, specifically MK-4/MK-7.

---

References:

1. Flore R, Ponziani FR, Di Rienzo TA, et al. Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis. Eur Rev Med Pharmacol Sci. 2013;17(18):2433-2440.
2. Villa JKD, Diaz MAN, Pizziolo VR, Martino HSD. Effect of vitamin K in bone metabolism and vascularization: A review of mechanisms of action and evidences. Crit Rev Food Sci Nutr. 2017;57(18):3959-3970. doi: 10.1080/10408398.2016.1211616.
3. Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001.
4. Mercola J. Mercola. Vitamin D and K2 work in tandem to slow arterial calcification. https://articles.mercola.com/sites/articles/archive/2013/10/19/vitamin-d-vitamin-k2.aspx. Published October 19, 2013. Accessed February 10, 2018.
5. Vergnaud P, Garnero P, Meunier PJ, et al. Undercarboxylated osteoclacin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS study. J Clin Endocrinol Metab. 1997;82(3):719-724. doi: 10.1210/jcem.82.3.3805.
6. Karpiński M, Popko J, Maresz K, Badmaev V, Stohs SJ. Roles of Vitamin D and K, nutrition, and lifestyle in low-energy bone fractures in children and young adults. J Am Coll Nutr. 2017;36(5):399-412. doi: 10.1080/07315724.2017.1307791.
7. Weber P. Management of osteoporosis: Is there a role for vitamin K? Int J Vitam Nutr Res. 1997;67(5):350-356.
8. Iwamoto J, Takeda T, Sato Y. Effects of vitamin K2 on osteoporosis. Curr Pharm Des. 2004;10(21):2557-2576. doi: 10.2174/1381612043383782.
9. Gajic-Veljanoski O, Bayoumi AM, Tomlinson G, Khan K, Cheung AM. Vitamin K supplementation for the primary prevention of osteoporotic fractures: Is it cost-effective and is future research warranted? Osteoporos Int. 2012;23(11):2681-2692. doi: 10.1007/s00198-012-1939-4.
10. Cockayne S, Adamson J, Lanham-New S, et al. Vitamin K and the prevention of fractures: systemic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(12):1256-1261. doi: 10.1001/archinte.166.12.1256.
11. Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (Menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res. 2000;15(3):515-521. doi: 10.1359/jbmr.2000.15.3.515.
12. Inaba N, Sato T, Yamashita T. Low-dose daily intake of vitamin K(2) (Menaquinone-7) improves osteocalcin y-carboxylation: a double-blind, randomized controlled trials. J Nutr Sci Vitaminol (Tokyo). 2015;61(6):471-480. doi: 10.3177/jnsv.61.471.

0 Can Fat be Healthy?

Thanks to Danielle Baker, PharmD Intern who wrote the majority of this post while on rotation with me in the fall!