Bone and Joint Health Supplements

Age Related Changes to Bones and Joints

  • The best time to develop bone strength and density is during the times of the rapid bone growth - childhood until about the age of 25 - 30 when we reach the peak bone mass. The bone quality up until that age will greatly impact bone quality through the rest of the life;
  • From about the age of 30, quality of  the bones begins to diminish in both men and women, eventually increasing bone fracture risk. This age-related bone loss is a complex process impacted by a combination of genetic, hormonal (e.g. estrogen), biochemical, and environmental factors, including possibly nutrient deficiency.  There are still gaps in knowledge, particularly on the contribution of individual factors;
  • As we age, joints too are affected by changes in cartilage and in connective tissue. The cartilage may become thinner or less resilient eventually leading to Osteoarthritis, a classical old-age disease. Age-related changes in the connective tissue, ligaments and tendons, may limit the motion of joints.  Just like with the bones, there are numerous interrelated factors. A review of recent studies shows that an increase in inflammation may also be behind osteoarthritis (Loeser, 2010). 
  • A large number of people over the age of 40 are concerned with loose or sagging skin. They typically think that the reason for that sagging is loose skin and skin laxity.  In fact, in people after the age of 40, and especially 50, what looks like and is perceived as skin sagging in reality is NOT caused by the skin, but it is caused by the diminishing size of the structures underlying the skin: bones, muscles, and fat compartments. Preserving the bone mass helps minimizing that skin sagging and stay looking younger longer. 
​Besides age related changes as such, the lack of nutrients that either are a part of bones and joints or participate in the cascades of reactions in the bodies that are necessary for the health of the aforementioned, may also have an impact on the bone and joint health. 

Anti-aging for the musculoskeletal system - 
  • One of the natural and most effective lifestyle changes that may prevent many age reacted changes to the bones, joints, and muscles too is exercise: weight-bearing physical activity stimulates maintenance and strength of the musculoskeletal system.
There are also 'generic' anti-aging strategies, that may be effective for the musculoskeletal system - 
  • fasting (=autophagy),
  • caloric restriction,
  • senolytic supplements (to eliminate senescent cells and decrease their influence on the surrounding environment).  

​The purpose of this article is to provide information on various supplements that may be used in addition to the lifestyle changes and/or other interventions to improve the bone and joint health. 

Calcium + Magnesium + Vitamin D + Vitamin K2

Likely, everyone knows that bones partially consist of Calcium.
​However, for Calcium to absorb/properly metabolize, we need sufficient levels of vitamin D, converted into its active form, and Magnesium is necessary for that conversion. If we take a Calcium supplement, but don't have sufficient Magnesium and vitamin D levels, Calcium may not get properly metabolized, and may become toxic. And then if a person is deficient in vitamin K2, this may lead to the calcification of arteries (deposits of calcium on arteries walls). 
​
​For years, mostly women and men too were recommended by their doctors to take a Calcium supplement, and that considering that Magnesium and vitamin D deficiency is common.
There are a number of recent studies that show that Calcium (taken alone, likely) supplementation does not decrease the risk of bone fractures, and in some cases it increases the risk of cardiovascular disease, and even the risk of hip fracture. Let's look at some of those studies:
  • A meta-analysis of over 20 cohort studies and clinical trials (251,000 men and women): there is little to none decrease in the risk of the bone fracture from Calcium supplementation (Bischoff-Ferrari, 2007); 
  • A Swedish longitudinal cohort study of women (over 14,000 women) found that the highest quantile intake of calcium (over 1,137 mg/d) not only did not decrease the risk of the bone fracture in general, but slightly increased the risk of the hip fracture. That study was multivariable and also recorded vitamin D intake, and those vitamin D levels intake in the participants were extremely low, especially for the upper Northern Hemisphere, - average about 200 IU a day, while we know that 4,000 - 6,000 is what we need. Also, women within the lowest 1/5 of the Calcium intake, also had a slightly higher risk of bone fracture (Warensjö, 2011);​
  • A 2015 meta-analysis of cohort studies and clinical trials: Some of their source studies had vitamin D data intake (200 - 1,000 IU). Conclusions from the meta-analysis: 1) they found no evidence that increasing Calcium intake from dietary sources (think: milk) prevents fractures. 2) "Evidence that Calcium supplements prevent fractures is weak and inconsistent"  (Bolland, 2015). 
  • A recent analysis of other studies showed that supplementation with Calcium PLUS Vitamin D, at least 700 - 800 IU a day did decrease bone risk fracture by 14% (Weaver, 2019);
  • Taking Calcium supplements increases circulating Calcium levels. An analysis of numerous studies showed that increased circulating Calcium levels are associated with an increased risk of the cardiovascular disease. (Reid, 2017). Vitamin K2 counteracts that, described below. 

In my opinion, the ​limitation of those studies is that they looked at the Calcium only consumption, in case with the Swedish study, vitamin D data is available, but none looked at the data on all four discussed here - Calcium, Magnesium, vitamin K2 and vitamin D combined, and none compared sufficient intake of Ca + Mg + vitamin D + vitamin K2 to baselines of insufficient intake of either all or some of Mg, D, K2.   

A couple of points on Vitamin K2 - 
  • It activates a special protein (MGP) that inhibits the deposits of calcium on the walls. This may be the reason why vitamin K-2 supplementation decreases the risk of Coronary Heart Disease (Geleijnse, 2004);
  • ​Vitamin K2 deficiency may be a leading factor in vascular calcification (Flore, 2013);
  • The name of this study is the same as its findings: 'Menaquinone-7 (Vitamin K2) to Reduce Calcification in Patients with Coronary Artery Disease' (Vossen, 2015). The authors theorize that vitamin K-2 may be a viable option against vascular calcification. 
The above points combined show that vitamin K2 may be necessary along with Calcium intake, so that Calcium (+Mg + vitamin D) can delivery its benefits without calcifying arteries. 

Therefore, based on the data we have today, it is most likely that Calcium should be taken with Magnesium, Vitamin D, and vitamin K2, or the latter three should be obtained in sufficient quantities from dietary sources (and vitamin D from sun exposure). As of today there are well-designed conclusive studies that confirm that.

Glucosamine/Chondroitin, Marine Omega-3, Turmeric, Hyaluronic Acid, Collagen

I included links to some studies that look at the effectiveness of these compounds.

Glucosamine/Chondroitin
  • Shows some clinical effectiveness in select groups with joint pain. For example, this study showed that oral chondroitin shows more effectiveness than placebo in relieving pain and improving physical function in osteoarthritis (Zhu, 2018);
  • This study's findings were different; it concluded that "there is currently no convincing information for the efficacy" of glucosamine and chondroitin on osteoarthritis (Vasiliadis, 2017);
  • From talking to Dr. Jason Theodosakis, the author of 'Arthritis Cure', those two supplements have to be taken together and in a specific proportion to be effective: 1500 mg of glucosamine to 800 mg of chondroitin. He is also recommending combining them with Avocado Soybean Unsaponifiables and taking Omega-3;
  • This study suggests that glucosamine, chondroitin, Omega-3s and anti-oxidants may help with osteoarthritis without the negative side effects of NSAIDs (Jerosch, 2011). 

Collagen
  • Collagen is a strong, elastic protein which is a major component of bone and joint tissue and skin;
  • A clinical trial, a 24 week treatment with collagen hydrolysate (25 mL of a liquid formulation that contained 10 g of collagen hydrolysate (CH-Alpha)) in athletes showed an improvement of joint pain (Clark, 2008);
  • Gelatin (some people take gelatin supplement) is created by a partial breakdown of collagen derived from the skin and bones of animals;
  • Young men who took 15 g of gelatin enriched with 48 mg of vitamin C 1 hour prior to exercise showed an increased collagen synthesis (blood analysis) (Shaw, 2017);
  • Young athletic men and women took 5 g of a gelatin supplement (Gelita, Germany) for 6 months. Key findings: 1) Collagen peptides significantly improved subjectively perceived function of the ankle in activities of daily living and sports exercise; 2) A decrease in ankle sprains and in the risk of ankle injuries were shown in a three-month follow-up period (Dressler, 2018).

Hyaluronic acid (hyaluronan)
  • Hyaluronic Acid is a natural polysaccharide and a component of cartilage, and, a​mong other things, its function is to bind water and to lubricate movable parts of the body, such as joints and muscles;
  • Hyaluronic Acid is naturally produced by our bodies, but its production and levels in the body decline as we age;
  • This study looked at oral administration of 200 mg of HA per day for 12 months and established that "oral administration of HA may improve the symptoms of knee OA in patients aged 70 years or younger when combined with the quadriceps strengthening exercise" (Tashiro, 2012).

Turmeric
  • One of the best multi-functional anti-aging supplements that has, among other things, anti-inflammatory effect;
  • Turmeric has low bioavailability and has to be taken either in a specific bioavailable form or combined with black pepper, the active component of which, piperine, makes turmeric more bioavailable. 

Marine Omega-3 (fish oil)
These Marine Omega-3 acid are called DHA and EPA. I will have a separate publication on the importance of Marine Omega-3.
Regarding their impact on the bone and joint health, consider that -
  • Marine Omega-3 are a vital nutrient, and must be consumed from a diet/supplements. If we only take ALA, another, non-marine Omega-3, our bodies' ability to convert it to DHA and EPA is very limited;
  • DHA is a part of all cell membranes. And we are made of cells;
  • EPA participates in a large number of metabolic processes in our bodies and is anti-inflammatory.

Some people also use green tea, ginger and rosehip extracts for the joint health. 

Three more ingredients: 5-Loxin, Aflapin, and Cyplexinol

Three more patented ingredients that have some data on their possible effectiveness - 

5-LOXIN™ 
  • 5-Loxin is a concentrated extract of the active ingredient AKBA from Boswellia serrata, a traditional herbal remedy that has been long used for joint pain. ;
  • Boswellia (5 -Loxin) works by inhibiting Lox enzymes that contribute to inflammation and possibly through reducing cartilage degradation. There are 6 Boswellia acid, all of which are LOX inhibitors, and AKBA is the most effective. in 5-Loxin it is standardized to 30%;
  • ​A study found that  both 100 mg and 250 mg of 5-Loxin daily significantly reduced pain and improved mobility of the joints in osteoarthritis patients as early as 7 days after commencing supplementation (Sengupta, 2008).
​
​Aflapin 
  • is also derived from Boswellia serrata; this extract is enriched with 20% AKBA and B.serrata nonvolatile oil;
  • A study found that 100 mg of Aflapin once a day significantly reduced pain and improved joint mobility in osteoarthritis patient as early as 5 days after commencing supplementation (Vishal, 2011);
  • This study compared 5-Loxin and Aflapin and concluded that 1) both are safe, 2) both are effective in improving pain, stiffness and mobility, 3) in in-vitro studies, both are capable of inhibiting cartilage regarding enzyme MMP-3, 4) at 100 mg/d Aflapin was and Aflapin was found more effectiv (see the table) (Sengupta, 2010).


Cyplexinol
​Whereas 5-Loxin and Aflapin are for joint health only, Cyplexinol may also help with improving bone density  - 
  • Cyneplex ​consists of a complex of bone proteins with a collagen network, bone morphogenic proteins (BMP) and other growth factors;
  • Cyneplex works likely by releasing BMP in blood, then BMPs bind to specific receptors on the skeletal stem cells (osteoprogenitor cells, can develop into any type of skeletal cells), this supposedly changes gene expression for the growth of new skeletal tissue 
  • 2 to 5 years of supplementation in four people with documented bone loss resulted in the positive bone density change of 18 to 64%.  The limitation of this study is that it only looked at four people, no placebo control. (Tripodi, 2017). In theory, Cyneplex should indeed facilitate growth of new bone tissue, however this is the only study available on the Cyneplex impact on bone density.
  • 4 weeks of supplementation with 150 mg of Cyplexinol a day in 44 people with orteoarthritis results din self-assessed pain intensity and frequency decrease, and in the the increase of activity level and strength (Spinks, 2015)

References and Literature 

Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, Burckhardt P, Li R, Spiegelman D, Specker B, Orav JE, Wong JB, Staehelin HB, O'Reilly E, Kiel DP, Willett WC. Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr. 2007;86:1780–1790. doi: 10.1093/ajcn/86.6.1780. 
https://www.ncbi.nlm.nih.gov/pubmed/18065599​

Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, Kanis JA, Orav EJ, Staehelin HB, Kiel DP, Burckhardt P, Henschkowski J, Spiegelman D, Li R, Wong JB, Feskanich D, Willett WC. Milk intake and risk of hip fracture in men and women: a meta-analysis of prospective cohort studies. J Bone Miner Res. 2011;26:833–839. doi: 10.1002/jbmr.279. 
https://www.ncbi.nlm.nih.gov/pubmed/20949604​ 
​
Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015;351:h4580. Published 2015 Sep 29. doi:10.1136/bmj.h4580
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784799/​

Boskey AL, Coleman R. Aging and bone. J Dent Res. 2010;89(12):1333–1348. doi:10.1177/0022034510377791
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991386/

Clark K.L., Sebastianelli W., Flechsenhar K.R., Aukermann D.F., Meza F., Millard R.L., Deitch J.R., Sherbondy P.S., Albert A. 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Curr. Med. Res. Opin. 2008;24:1485–1496. doi: 10.1185/030079908X291967.
https://www.ncbi.nlm.nih.gov/pubmed/18416885​

Czajka A., Kania E., Genovese L., Corbo A., Merone G., Luci C., Sibilla S. Daily oral supplementation with collagen peptides combined with vitamins and other bioactive compounds improves skin elasticity and has a beneficial effect on joint and general wellbeing. Nutr. Res. 2018;57:97–108. doi: 10.1016/j.nutres.2018.06.001.
https://www.ncbi.nlm.nih.gov/pubmed/30122200​ 
​
Demontiero O, Vidal C, Duque G. Aging and bone loss: new insights for the clinician. Ther Adv Musculoskelet Dis. 2012;4(2):61–76. doi:10.1177/1759720X11430858 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383520/​ ​

Dressler P., Gehring D., Zdzieblik D., Oesser S., Gollhofer A., König D. Improvement of functional ankle properties following supplementation with specific collagen peptides in athletes with chronic ankle instability. J. Bodyw. Mov. Ther. 2018;22:858. doi: 10.1016/j.jbmt.2018.09.037.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950747/

Flore R, Ponziani FR, Di Rienzo TA, Zocco MA, Flex A, Gerardino L, Lupascu A, Santoro L, Santoliquido A, Di Stasio E, 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;17:2433–2440.
https://www.ncbi.nlm.nih.gov/pubmed/24089220 
​
Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):3100–3105.
https://www.ncbi.nlm.nih.gov/pubmed/15514282

Jerosch J. Effects of Glucosamine and Chondroitin Sulfate on Cartilage Metabolism in OA: Outlook on Other Nutrient Partners Especially Omega-3 Fatty Acids. Int J Rheumatol. 2011;2011:969012. doi:10.1155/2011/969012
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150191/

Khosla S. Pathogenesis of age-related bone loss in humans. J Gerontol A Biol Sci Med Sci. 2013;68(10):1226–1235. doi:10.1093/gerona/gls163 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826857/ 
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Loeser RF. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin Geriatr Med. 2010;26(3):371–386. doi:10.1016/j.cger.2010.03.002
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920876/​  

Reid IR, Birstow SM, Bolland MJ. Calcium and Cardiovascular Disease. Endocrinol Metab (Seoul). 2017;32(3):339–349. doi:10.3803/EnM.2017.32.3.339
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620030/ 

Sengupta K, Krishnaraju AV, Vishal AA, et al. Comparative efficacy and tolerability of 5-Loxin and AflapinAgainst osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci. 2010;7(6):366–377. Published 2010 Nov 1. doi:10.7150/ijms.7.366
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974165/​ 

Shaw G., Lee-Barthel A., Ross M.L., Wang B., Baar K. Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis. Am. J. Clin. Nutr. 2017;105:136–143. doi: 10.3945/ajcn.116.138594. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183725/  

Spinks K, Walker M, Scaffidi J. Clinical Assessment of Low-dose Osteoinductive Protein as a Stand-alone Regimen in Self-reported Osteoarthritis. Integr Med (Encinitas). 2015;14(2):23–32.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566473/​  

Tripodi D, Osteoinductive Effects of Cyplexinol in the Management of Osteoporosis: A Case Series. Altern Ther Health Med. 2017 Nov;23(6):42-47.
https://www.ncbi.nlm.nih.gov/pubmed/29055288

Vasiliadis HS, Tsikopoulos K. Glucosamine and chondroitin for the treatment of osteoarthritis. World J Orthop. 2017;8(1):1–11. Published 2017 Jan 18. doi:10.5312/wjo.v8.i1.1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241539/

Vishal AA, Mishra A, Raychaudhuri SP. A double blind, randomized, placebo controlled clinical study evaluates the early efficacy of aflapin in subjects with osteoarthritis of knee. Int J Med Sci. 2011;8(7):615–622. doi:10.7150/ijms.8.615
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198257/

Vossen LM, Schurgers LJ, van Varik BJ, et al. Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial). Nutrients. 2015;7(11):8905–8915. Published 2015 Oct 28. doi:10.3390/nu7115443
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663571/

Warensjö E, Byberg L, Melhus H, et al. Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. BMJ. 2011;342:d1473. Published 2011 May 24. doi:10.1136/bmj.d1473
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101331/ 

Weaver CM, Bischoff-Ferrari HA, Shanahan CJ. Cost-benefit analysis of calcium and vitamin D supplements. Arch Osteoporos. 2019;14(1):50. Published 2019 Apr 30. doi:10.1007/s11657-019-0589-y
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491825/​

Zhu X, Sang L, Wu D, Rong J, Jiang L. Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: a meta-analysis of randomized controlled trials. J Orthop Surg Res. 2018;13(1):170. Published 2018 Jul 6. doi:10.1186/s13018-018-0871-5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035477/​