This study involved more than 61,000 women between the ages of 63 and 97. During the 19 year period of follow-up on these women, almost 15,000 of them, or about one-quarter, had some type of fracture for the first time. Among those, 3,871, or 6% of them, experienced a hip fracture. Among another subcohort of 5,000 women, 20% of them met the criteria for osteoporosis.

While perhaps surprising to some, the researchers found that the rates of fracture risk were not related to dietary calcium in a linear fashion. It’s true that those women who were in the lowest calcium intake quintile (less than 751 mg/day), had the highest risk for a first time hip fracture, but the group at the next highest risk for hip fracture was the fifth quintile (greater than 1,137 mg per day). A low vitamin D intake made the rate of hip fracture in the lowest calcium quintile group even more pronounced.

Commentary: This is yet one more study that teaches us that more is not always better. In fact in this case, the most was worse. While these results are inconsistent with current U.S. guidelines, I still think it would be a good opportunity to review those guidelines. For women ages 51-70, the Recommended Dietary Allowance (RDA), the intake that meets the needs of 97.5% of the North American population is 1,200 mg per day; the Estimated Average Requirement (EAR)- a number based on the intake that meets the needs of 50% of the North American population, is 1,000 mg per day for women ages 51-70.

Reference

Warensjo E, Byberg L, Melhus H, et al. Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. BMJ. 2011;342:d1473.

A committee of experts evaluated more than one thousand studies and reports as well as listening to testimony from scientists and others. This committee considered that studies about the health benefits beyond bone health were most often from studies that provided mixed results, inconclusive results, or were not from randomized controlled trials. Thus, these were not considered reliable. Their focus then was on the bone growth and bone maintenance data.

Their new Recommended Dietary Allowance (RDA) is now 600 IU per day for people ages 1 to 70 and 800 IU per day for those 71 and older. The old guidelines from 1997 were 200 IU per day through age 50, 400 IU per day for ages 51 to 70 and 600 IU per day for 71 and older. While I would consider these guidelines conservative to the extreme, (really a one year old and a 70 y.o. need the same amount????) they at least increased a new safe upper limit of 4,000 IU a day for those 9 years old and above, pregnant or not. The greatest concern I have with these guidelines is that they based their bone dosing guidelines on a target blood level of 20 ng/ml per day, rather than 30 ng/ml per day minimum published in most research about levels needed to suppress the parathyroid gland and avoid unnecessary bone loss.

Most practitioners and a studious group of consumers realize that there are scores of studies on other potential health benefits found in observational/epidemiological studies including colorectal cancer, breast cancer, select autoimmune disorders, cardiovascular disease and much more. It is too bad… that these were not considered, and once again, we may not have optimal prevention, risk reduction guidelines from our government agencies.

For a full list of the dosing guidelines by age group, gender, and pregnancy status, you can find these at www.iom.edu/vitamind

Fifty-two patients received C. domestica extracts and 55 patients received ibuprofen with 45 patients in the curcuma and 46 patients in the ibuprofen group completing the study. The mean scores of pain on level walking, pain on stairs, and functions of the knee were significantly improved when compared with the baseline values in both groups. There were no significant differences in those measurements between the patients receiving ibuprofen and C. domestica extracts, except pain on stairs was more favorable with curcumin and a greater degree of moderate to high degree of satisfaction with treatment in the curcumin group (90.1%) vs. 82.8% in the ibuprofen group. There was a bit better compliance with the ibuprofen at twice daily than the curcumin four times daily, but there were no patients who reported dissatisfaction in the curcumin group.

Reference

Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, et al. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J alternative and Complementary Medicine 2009;15(8): 891-897

My interest in this product is spurred on by the multiple mechanisms in which these triterpenes seem to impact the joint: regulating cytokines, reducing TNF-a, IL-6, reducing osteocalcin, improving circulation of the joint matrix, slowing inflammatory bone loss, reducing cartilage destruction and restoring collagen.

In one randomized placebo controlled trial, 117 patients with radiographic and clinical evidence of osteoarthritis of the knee or hip were given shea nut extract or placebo for 15 weeks.[1] TNF-alpha reduced 17.9% overall and 23.9% in the group with elevated levels. IL-6 fell by 30.9%; C-reactive protein reduced by 20.6%; CTX-II, a cartilage marker fell by 28.7% in patients with elevated levels vs. an increase in placebo of 17.6%; and osteocalcin reduced by 9.2% in the elevated group indicating bone repair mechanisms.

Animal studies are also being conducted by the manufacturers of high triterpene shea nut extract showing comparable anti-inflammatory effects of ibuprofen but no adverse effects as are often seen in ibuprofen. Other studies are in development and I look forward to those publications.

I have surveyed some retailers and consumers in the natural products market who have been aware of and using high triterpene shea nut extract for several months and been pleased to hear of the consistent anecdotal, yet positive reports. For practitioners, shea nut extract yielding 70% triterpenes is available as BSP 201. I look forward to increasing my own clinical usage of this product and hope to see the same positive results in my patients. With its multiple mechanisms of actions, early research, and anecdotal reports, shea nut extract leaves me optimistic.

Reference:

[1] Cheras PA, Myers SP, Outerbridge K, & Nielsen G. Randomised Placebo Controlled Trial on the Safety and Efficacy of BSP-201 in Osteoarthritis. Australian Centre for Complementary Medicine Education and Research (ACCMER). Sept. 4, 2007

Soybeans contain a class of compounds called phytoestrogens, comprising mostly genistein, daidzein and glycitein, all of which have a biochemical structure similar to 17- beta estradiol.  The binding of isoflavones to estrogen receptors is preferential for the estrogen receptor beta and thus indicates that soy isoflavones act as selective estrogen modulators.  Daidzein is similar in shape to a drug called Ipriflavone, which is used in Europe to treat osteoporosis.  In the U.S., Ipriflavone is available as a nutritional supplement. 

Bone mineral density (BMD) is the gold standard for determining fracture risk due to non-traumatic events.  Bone turnover is an independent predictor of fracture risk.  While research on the effects of soy on bone metabolism has been inconsistent, many positive studies do exist that suggest a role for soy in slowing bone turnover and increasing bone density in women.  Soy appears to have an estrogenic effect on bone in some experimental evaluations. The bone density of ovariectomized rats was evaluated in a study in which soy replaced casein in the diet and compared to another group that received estrogen. The addition of soy inhibited bone loss, although not to the same extent as was achieved with the estrogen treatment.  Another study of ovariectomized rats also reported a positive effect of the soy phytoestrogen, genistein in maintaining bone.  These authors also reported that genistein suppresses osteoclasts, the cells responsible for bone resorption, both in the test tube and in vivo.  Arjmandi also did a double-blind, randomized, and controlled trial using 40g of soy protein containing isoflavones over 3 months in postmenopausal women.  Bone resorption was decreased, when compared to milk protein.

Several human studies have provided further insight and comfort in the possible role of soy in our bone health. A study conducted at the University of Illinois found that menopausal women had an increase in mineral levels and density in their lumbar spines after taking 55-90 mg of soy isoflavones for six months.  The placebo group showed the lowest bone density and the greatest bone loss, while the estrogen group showed the highest bone density and the slowest bone loss. What was surprising was that the isoflavone diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip. Soy isoflavones seem to have more of an effect on trabecular bone (more predominant in the spine) than on cortical bone (more predominant in the hip). The soy did not show as great of ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging. 

An analysis of the relationship of soy isoflavone intake and bone mineral density was conducted from the Study of Women’s Health Across the Nation, a US cohort study of women aged 42-52 years.  For African-American and Caucasian women, median intakes of genistein were too low to pursue analyses. For Chinese women, no association between genistein and bone mineral density was found. Premenopausal, but not perimenopausal Japanese women whose intakes were greater had a higher bone density of the spine and femoral neck. The mean spinal bone density of those women in the highest group was 7.7% greater than that of women in the lowest group. Bone density of the femoral neck was 12% greater in the highest intake group versus the lowest.
 
Other positive studies on soy and bone density also give some credence to the role of soy and bone health. In a study estimating the daily intakes of soy isoflavones in the diets of 478 postmenopausal Japanese women who reported soy consumption, high consumption of soy products was associated with increased bone mass.

A recent meta-analysis further increases our optimism about using soy to inhibit bone resorption.  Nine studies with a total of 432 menopausal women were evaluated in this meta-analysis.  Amount of soy intake varied amongst the nine studies from 37 mg of isoflavones per day to 118 mg of isoflavones per day. Testing for urinary peptides (deoxypyridinoline), a marker of bone turnover, demonstrated that those who consumed isoflavones had a decrease in these biomarkers of -2.08nmol/mmol, when compared to those who did not consume isoflavones.  In five of the studies where isolated soy protein was used there was no significant effect on urinary deoxypyridinoline.  In the current analysis, a significant reduction in urinary deoxypyridinoline was not observed in those studies with isoflavones of less than 90 mg/day.  In a review of the research in 2003, the author concluded that 90 mg of isoflavones per day is required to achieve benefits on bone health.

In contrast to the positive studies, several clinical trials using a variety of soy protein isolate formulations found no clinically important effects of soy on bone metabolism and bone turnover markers.  Further inconsistent research can be seen with several clinical trials using soy protein or isoflavones demonstrating a positive effect on BMD, while others have not had positive findings.

I mentioned variations in dosing, duration, soy formulations used, and different study populations as possible reasons for inconsistent results on the effects of soy isoflavones on bone turnover and bone density.  But, another significant consideration may be due to how the isoflavones are metabolized in the gut.  In the meta-analysis mentioned above which analyzed nine studies the significant effects on urinary peptides occurred in Asian women but not Caucasian women.  This may be due to the conversion of daidzein into its active metabolite equol by intestinal flora, and by the fact that only one-third of Caucasian women can metabolize isoflavones into equol, whereas more than half of Asian women possess this ability. 

Soy isoflavones may also have more of an effect in post-menopausal women than in pre or perimenopausal women.  In one study, 53.3 mg of isoflavones per day was associated with an increase in bone density in postmenopausal women, but not pre-menopausal women.

A nutritional influence of soy foods that may be overlooked is the amount of calcium in some of these foods or in diets that contain soy foods. A diet that includes greater amounts of soy products can account for a meaningful amount of calcium, and some soy foods can offer as much, or more, calcium than a serving of dairy products.
 

CALCIUM CONTENT OF SELECTED SOY FOODS

With the inconsistent research, it is difficult to draw confident conclusions about the role of soy in bone health.  My clinical advice is to increase soy foods as part of a regular diet in prevention strategies for all pre, peri and postmenopausal women.  For all women who have significant risk factors for osteoporosis, I would in addition, recommend soy supplementation so that their total daily soy isoflavone intake would deliver approximately 90 mg of soy isoflavones per day.  For treatment of peri and postmenopausal women who already have osteoporosis, I would not consider soy an adequate treatment alone.  For these women who already have osteoporosis, I am in favor of proven conventional therapies to reduce fracture risk in addition to the 90 mg per day of soy isoflavones and typical supplementation including calcium, vitamin D and other potential nutrients (K, boron, magnesium, manganese, and more), and dietary and exercise advice.

References
  Weaver C, Cheong J.  Soy isoflavones and bone health: the relationship is still unclear.  J Nutr 2005; 135:1243-1247.

  Setchell K.  Soy isoflavones-benefits and risk from nature’s selective estrogen receptor modulators (SERMS).  J Am Coll Nutr 2001; 20: 354S-362S.

  Garnero P, Hausherr E, Chapuy M, et al.  Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study.  J Bone Miner Res 1996; 11:1531-1538.

  Arjmandi B, Alekel L, Hollis B, Amin D, Stacwicz-Sapuntzakis M, Guo, Kukreja S.  Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis.  J Nutr 1996;126:161-167.

  Blair H, Jordan S, Peterson T, Barnes S.  Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J Cell Biochem  1996;61:629-637.

  Arjmandi B, Khalil D, Smith B, et al.  Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. J Clin Endocrinol Metab  2003; 88: 1048-1054.

  Erdman J, Stillman R, Lee K, Potter S.  Short-term effects of soybean isoflavones on bone in postmenopausal women.  Program and Abstract Book, Second International symposium on the Role of Soy in Preventing and Treating Chronic Disease.  Brussels, Belgium, 1996.

  Greendale G, FitzGerald G, Huang M, et al.  Dietary soy isoflavones and bone mineral density: Results from the study of women’s health across the nation. Amer J Epidemiology 2002;155(8):746-754.

  Somekawa Y, Chiguchi M, Ishibashi T, Takeshi A. Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstet Gynecol  2001;97:109-115.

  Ma DF, Qin LQ, Want P-Y, Katoh R.  Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women:  meta-analysis of randomized controlled trials.  European J of Clinical Nutrition 2008; 62:155-161.

  Branca F.  Dietary phyto-oestrogens and bone health.  Proc Nutr Soc 2003; 62: 877-887.

  Wangen K, Duncan A, Merz-Demlow B, et al.  Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women.  J Clin Endocrinol Metab 2000; 85:3043-3048.

  Knight D, Howes J, Eden J, Howes L.  Effects of menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric 2001; 4:13-18.

  Dalais F, Ebeling P, Kotsopoulos D, McGrath B, Teede H.  The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women.  Clin Endocrinol 2003; 58:704-709.

  Potter S, Baum J, Teng H, et al.  Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.  Am J Clin Nutr 1998; 68:1375S-1379S.
  Alekel D, Germain A, Peterson C, et al.  Isoflavone-rich soy protein attenuates bone loss in the lumbar spine of perimenopausal women.  Am J Clin Nutr 2000; 72:844-852.

  Morabito N, Crisafulli A, Vergara C, et al.  Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women:  a randomized double-blind placebo controlled study. J Bone Miner Res 2002; 17:1904-1912.

  Chen Y, Ho S, Lam S, Ho S, Woo J.  Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4740-4747.

  Lydeking-Olsen E, Beck-Jensen J, Setchell K, Holm-Jensen T.  Soymilk or progesterone for prevention of bone loss: a 2 year randomized, placebo-controlled trial. Eur J Nutr 2004;43:246-257.

  Gallagher J, Satpathy R, Rafferty K, Haynatzka V.  The effect of soy protein on bone metabolism.  Menopause 2004; 11:290-298.

  Kreijkamp-Kaspers S, Kok L, et al.  Effects of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women.  JAMA 2004; 292:65-74.

  Mei J, Yeung S, Kung A.  High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab 2001; 86:5217-5221.

Commentary

This randomized, double-blind, placebo-controlled trial of daily supplementation of 1000 mg of elemental calcium with 400 IU vitamin D3 had no effect on the incidence of breast cancer. Some observational studies have demonstrated an association between higher calcium and vitamin D intake and reductions in breast cancer risk in postmenopausal women, while others have not. Studies in postmenopausal women have also been mixed in showing an association with lowered breast cancer risk in those with higher serum levels of 25-hydroxyvitamin D. Several thoughts regarding these mixed results are worth considering: 1) Different thresholds of serum 25-hydroxyvitamin D are used to assess associations and it may be that a higher threshold (52 nmol/L says some research; 75 nmol/L says other research) is needed to show an association. 2) Higher doses of vitamin D may be needed to demonstrate consistent results. 3) The doses of vitamin D used in different trials are not consistent. 4) The seven year duration of the current study may be insufficient given the latency of breast cancer. 5) Results may be confounded by lean women vs. overweight or obese women, recreational activity and sunlight exposure.

Given the wide variety of preventive effects of vitamin D supplementation, the multiple disease reduction benefits associated with higher serum levels, and the selected benefits on intervention with supplementation, for now, I will continue to be assertive in vitamin D dosing. The list of benefits and potential benefits spans so many diseases (heart disease, hypertension, peripheral vascular disease, osteoarthritis, osteoporosis, fractures, autoimmune diseases, depression, insulin resistance, ovarian cancer, breast cancer, colon cancer), that it remains compelling to recommend one of the most economical and safe supplements currently available.

References

• Chlebowski R, Johnson K, Kooperberg C, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2008 100: 1561.