If you are not among those who are allergic to soy or have been diagnosed as having hypothyroidism, soy foods can be a great addition to your bone-building diet. Not only are soy foods excellent sources of magnesium and vitamin K1 (plus many are fortified with calcium), but they contain active compounds called isoflavones – genistein and ipriflavone, specifically — that greatly help lessen the activation of osteoclasts, the cells that break down bone.
Genistein improves the RANKL/OPG Ratio
What’s the RANKL/OPG ratio?
To explain this, we need to take a little trip “behind the scenes” for a look at these two molecules, one of which, RANKL, initiates a series of events that results in the production of osteoclasts ready to remove old bone, and another one, OPG, that shuts down this process.
When RANKL, which stands for receptor activator of nuclear factor-kappaB ligand, binds to a cellular receptor called RANK (receptor activator of nuclear factor-kappaB), this turns on nuclear factor-kappaB (NFkappaB), a seriously pro-inflammatory messenger. NFkappaB moves inside your cells and goes right to your DNA, where it sets off the production of a whole bunch of inflammatory actors—one of which is osteoclasts. You may remember we’ve said that anything that promotes chronic inflammation promotes bone loss. RANKL’s activation of NKkappaB, which in turn activates osteoclasts, is behind this connection.
If we want to keep our bones, we must keep RANKL under control. However, RANKL is not an altogether bad guy we can afford to totally eliminate (which is what some medication does – it totally shuts down RANKL). RANKL’s binding to RANK is also necessary for the activation of immune cells (our T and B cells, specifically), and we must have functional immune systems to survive. What good are great bones if we’re easy prey for destruction by infections or cancer?
So, how do we safely put a leash on RANKL? We send in its decoy receptor, osteoprotegerin (OPG), which also binds with RANKL, and thus blocks the interaction between RANKL and RANK, and the activation of NFkappaB. Pretty nifty how our body has worked out this balancing act for us, huh? I envision RANKL as a Conan, the Barbarian, kind of guy, and see OPG as standing for “Oh, Pretty Girl!” Enough OPG around and RANKL will be tamed. Not eliminated (so our immune cells will still mature), but tuned down.
So, what encourages this happy meeting of our cellular characters, RANKL and OPG? You guessed it –soy foods, specifically, a bioactive isoflavone compound in whole soy foods called genistein, which is well known to lessen inflammation. Now we know genistein is doing so, at least in part, by increasing OPG and decreasing RANKL. (Vitamin K2 – in its form as MK-7 – does so as well, but that’s another story – lots more to this, coming to you shortly in another blog.)
A two year-long placebo-controlled study of 389 osteopenic postmenopausal women in Italy found giving them genistein resulted in their having lower RANKL and higher OPG levels by the end of the first year, with further improvements in the ratio of RANKL/OPG by the end of the second year. [i]
In this study, genistein was given to 198 women; the remaining 191 women received a placebo. Both the supplement containing genistein and the placebo supplement contained calcium and vitamin D3, and all the women received the same information about healthy diet. A significant (-0.021) reduction in the RANKL/OPG ratio occurred in the women given genistein, while in the women receiving placebo, the RANKL/OPG ratio worsened (+0.004).
This bone-happy outcome is almost definitely due to genistein’s anti-inflammatory effects, which have been reported in numerous studies in relation to many other aspects of our physiology. For example:
Genistein inhibits activation of the pro-inflammatory enzyme COX-2. This is the enzyme inhibited by aspirin, ibuprofen, acetaminophen and other non-steroidal drugs, and the mechanism through which they provide pain relief.[ii]
Genistein lessens vascular inflammation, which is one of the ways soy foods help lower blood pressure.[iii]
Genistein has been referred to as an “anticancer agent,” since it lessens inflammation in cells throughout the body, and uncontrolled cellular inflammation promotes both the initiation and metastasis (spread) of cancer.[iv]
Since inflammation plays such a key role in the production and activation of osteoclasts, it’s not surprising to learn that genistein helps prevent both, and in doing so, protects our bones.
Ipriflavone adds to genistein’s bone-protective benefits
But soy foods’ special benefits for bones don’t stop with genistein – the other major isoflavone in soy foods, ipriflavone, has also been shown—in many studies now — to prevent bone loss in postmenopausal women.
Soy isoflavone extracts have been shown to increase BMD in the spine – a recent meta-analysis (published in 2010) includes studies showing increases in spine BMD with isoflavone intake of more than 90 mg/day for 6 months of 28.5mg/cm(2) and 27 mg/cm(2). The authors of this review concluded: “Isoflavone intervention significantly attenuates bone loss of the spine in menopausal women. These favorable effects become more significant when more than 90 mg/day of isoflavones are consumed. And soy isoflavone consumption for 6 months can be enough to exert beneficial effects on bone in menopausal women.”[x]
The highly positive results of yet another recent study conducted on ipriflavone led the researchers to conclude that ipriflavone can inhibit bone resorption and promote bone formation, and is effective for the prevention and treatment of menopausal symptoms (hot flushes) as well as osteoporosis.[xi]
In the case of ipriflavone, the mechanism behind soy food’s bone protective effects is thought to be soy isoflavones’ chemical structure which is similar to that of human (bio-identical) estrogens (bi-est). Bio-identical hormone replacement therapy with bi-est is well known to increase BMD in menopausal women.[xii]
Why might this be? Again, a key way in which estrogen supports our ability to maintain healthy bones is by lessening inflammation, and thus osteoclast activation.[xiii]
The most recent (March 2012) medical journal paper to be published about the benefits of soy isoflavones for bone health is very impressive, in part because it is a “systematic review” – a meta-analysis of the results of many studies.[xiv] This meta-analysis includes 14 randomized controlled trials that met the criteria of having their primary focus be the impact of soy isoflavones on osteoporosis in women.
What did these 14 trials show? Soy isoflavones significantly increased the bone mineral density (by 54%!) and decreased a marker of bone breakdown called urinary deoxypyridinoline (DPD) by 23% in the women in these studies, compared to where they were when the study began. The studies ranged in duration from just one month to two years. Greatest bone benefits were seen in postmenopausal women whose consumption of isoflavones, either in the form of supplements or as constituents of soy foods, was at least 75 mg/day.
Yet another even larger review, published December 2011, also looked at the impact of soy isoflavones on bone turnover markers in menopausal women – the time when bone loss accelerates to its highest pitch.[xv] This review was a meta-analysis of other meta-analyses of randomized controlled trials – so it included data from a lot of studies! The results: Soy isoflavones significantly decreased levels of the marker of bone breakdown noted above, deoxypyridinoline. And, consuming soy isoflavones for just six months was long enough to significantly improve the women’s lumbar spine BMD.
So, you’re probably wondering: Do I have to take a supplement or can I get 75-90 or even more mg of isoflavones per day by simply enjoying soy foods?
Good news – soy can help you eat our way to healthy bones. No need to spend money on a supplement. Just enjoy soy foods, and you can, as the table below shows—easily—get at least 75-90 mg of isoflavones each day.
Isoflavone Content of Commonly Eaten Soy Foods*
Total Isoflavones (mg)
Soybeans, dry roasted
Soybeans, boiled (Edamame)
Soy “hot dog”
1 “soy dog”
Soy cheese, mozarella
Be aware though that the isoflavone content of soy foods can vary considerably among brands and between lots of the same brand. However, the above values provide a decent estimate. Also, many brands list the amount of isoflavones they contain on the label.
One caveat – only consume ORGANIC soy. Soy foods not clearly labeled organic will be GMO – genetically modified. For lots of information on why you do not want to expose your body to GMO foods, here’s a link to the most comprehensive source of GMO health risk information on the web, the non-profit Institute for Responsible Technology: http://www.responsibletechnology.org/
[i] Marini H, Minutoli L, Polito F, et al. OPG and sRANKL serum concentrations in osteopenic, postmenopausal women after 2-year genistein administration. J Bone Miner Res. 2008 May;23(5):715-20. PMID: 18433304
[ii] Maldonado-Rojas W, Olivero-Verbel J. Potential interaction of natural dietary bioactive compounds with COX-2. J Mol Graph Model. 2011 Sep;30:157-66. Epub 2011 Jul 12. PMID: 21803623
[iii] Babu PV, Si H, Fu Z, Zhen W, et al. Genistein Prevents Hyperglycemia-Induced Monocyte Adhesion to Human Aortic Endothelial Cells through Preservation of the cAMP Signaling Pathway and Ameliorates Vascular Inflammation in Obese Diabetic Mice.J Nutr. 2012 Apr;142(4):724-30. Epub 2012 Mar 7.PMID: 22399524
[iv] Ghiringhelli F, Rébé C, Hichami A, et al. Immunomodulation And Anti-Inflammatory Roles Of Polyphenols As Anticancer Agents. Anticancer Agents Med Chem. 2012 Jan 31. [Epub ahead of print] PMID: 22292769
[v] Elmarakby AA, Ibrahim AS, Faulkner J, et al. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol. 2011 Nov-Dec;55(5-6):149-56. Epub 2011 Jul 23. PMID: 2180712
[vi] Kim JM, Uehara Y, Choi YJ, et al. Mechanism of attenuation of pro-inflammatory Ang II-induced NF-κB activation by genistein in the kidneys of male rats during aging. Biogerontology. 2011 Dec;12(6):537-50. doi: 10.1007/s10522-011-9345-4. Epub 2011 Jun 29. PMID: 21713398
[vii] Palanisamy N, Kannappan S, Anuradha CV. Genistein modulates NF-κB-associated renal inflammation, fibrosis and podocyte abnormalities in fructose-fed rats. Eur J Pharmacol. 2011 Sep 30;667(1-3):355-64. Epub 2011 Jun 17. PMID: 21704028
[viii] Valsecchi AE, Franchi S, Panerai AE, et al. The soy isoflavone genistein reverses oxidative and inflammatory state, neuropathic pain, neurotrophic and vasculature deficits in diabetes mouse model. Eur J Pharmacol. 2011 Jan 15;650(2-3):694-702. Epub 2010 Nov 2. PMID: 21050844
[ix] Ibrahim AS, El-Shishtawy MM, Peña A Jr, et al. Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation. Mol Vis. 2010 Oct 8;16:2033-42. PMID: 21042558
[x] Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women:meta-analysis of randomized controlled trials. Clin Nutr. 2008 Feb;27(1):57-64. Epub 2007 Dec 11.PMID: 18063230
[xi] Zhang X, Li SW, Wu JF, Dong CL, et al. Effects of ipriﬂavone on postmenopausal syndrome and osteoporosis. Gynecol Endocrinol. 2010 Feb;26(2):76-80. PMID: 19672742
[xii] Nielsen TF, Ravn P, Bagger YZ, et al. Pulsed estrogen therapy in prevention of postmenopausal osteoporosis. A 2-year randomized, double blind, placebo-controlled study. Osteoporos Int. 2004 Feb;15(2):168-74. Epub 2003 Nov 25. PMID: 14647880
[xiii] Ratiani L, Parkosadze G, Cheishvili M, et al. Role of estrogens in pathogenesis of age-related disease in women of menopausal age. Georgian Med News. 2012 Feb;(203):11-6. PMID: 22466534
[xiv] Wei P, Liu M, Chen Y, Chen DC. Systematic review of soy isoflavone supplements on osteoporosis in women. Asian Pac J Trop Med. 2012 Mar;5(3):243-8. PMID: 22305793
[xv] Taku K, Melby MK, Nishi N, et al. Soy isoflavones for osteoporosis: an evidence-based approach. Maturitas. 2011 Dec;70(4):333-8. Epub 2011 Sep 29. PMID: 21958941