The main outcome criteria were reduction of symptoms of OA using WOMAC scores and reduction of pain using visual analogue scale (VAS). The secondary outcome was a decrease in the use of analgesics. Study subjects were randomly assigned to Pycnogenol 50 mg tid or placebo. Patients were allowed to continue with their medication with NSAIDs or analgesics if they were using them before the start of the study and were allowed to change medication as needed but then reported dosage or frequency changes at each visit. Patients were evaluated at baseline, at 3 months and 4 weeks after completing the treatment. The WOMAC questionnaire for pain, stiffness and daily activities was completed by the patient every 2 weeks during the whole study. The VAS for pain was filled in by each patient weekly during the whole study.

Results: The WOMAC-A score, summarizing pain scores, improved significantly in the Pycnogenol group (p=00004) over the time of the study. The statistical difference for pain reduction compared to baseline in the Pycogenol group was evident after weeks 8,12 and 14 (p < 0.001). The difference between treatment group and placebo was near statistical significant at week 8 (p= 0.08).

The WOMAC-B score, the stiffness score, improved statistically significant (p=0.01) in the Pycnogenol groups versus baselines after weeks 8,12 and 14. Statistically significant differences between treatment group and placebo group were observe at weeks 8 and 12 (p< 0.05).

The WOMAC score in regards to the ability to perform daily activities improved significantly versus baseline in the Pycnogenol group at weeks 8,12 and 14 (p< 0.01). The change in the placebo group was not significant and the difference between the Pycnogenol and placebo groups was not significant.

Pain scores by VAS was somewhat higher in the placebo group than the Pycnogenol group at baseline although not significant. After treatment for 4 weeks, the treatment group reported less pain when compared to the placebo and pain continued to diminish until month 3. The correlation of decreased pain over time was statistically significant (p< 0.04) for the Pycnogenol group, but the correlation was poor for the placebo group (p<0.17). Only a marginal significance was seen between Pycnogenol versus placebo was seen at weeks 4 ( p=0.08) and 8 (p=0.07).

Patients in the Pycnogenol group were able to reduce their use of analgesics or NSAIDs at a higher percentage than those in the placebo group and 10% of placebo group patients had to increase their dose of analgesics whereas no higher doses were needed in the Pycnogenol group.

Cisar P, Jany R, Waczulikova I, et al. Effect of Pine Bark Extract (Pycnogenol) on symptoms of knee osteoarthritis. Phytotherapy Research 2008;22:1087-1092

Commentary: I’m encouraged to see this study and am looking forward to using this in patients with milder to moderate OA symptoms, especially of the knees. Pycnogenol is a special standardized extract from the bark of the French maritime pine. It is composed of polyphenols, several phenolic acids, catechins, taxifolin and procyanidins. In laboratory research Pycnogenol selectively inhibits matrix metalloproteinases (MMPs). MMPs are one of the inflammatory responses in arthritic joints induced by interleukin-1. The matrix degrading activity contributes to the loss of cartilage and is associated with chronic inflammation. Other in nvitro research has shown that Pycnogenol inhibits other inflammatory cells and specifically inhibits COX1 and COX2. These previously observed anti-inflammatory effects as a background to the current study, contributes a body of information that enables us to have another viable alternative treatment in early OA of the knee as well as an approach to possibly reduce the use of analgesics and NSAIDs in pain management.

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 nontraumatic events. Bone turnover is an independent predictor of fracture risk.

While 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 bone density in women. Soy appears to have a pro estrogen effect on bone in some experimental evaluations. The bone density of ovariectomized rats was evaluated in which soy replaced casein in the diet, 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 the bone losing cells (osteoclasts), both in the test tube and in vivo. Arjmandi also did a double-blind, randomized, 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 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 soybean diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip as well. Soybean seems 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 an ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging.

A study of the relation of soy isoflavone intake and bone mineral density was conducted within 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, average intakes of genistein was too low to pursue analyses. For Chinese women, no association between genistein and bone mineral density was found. Pre-menopausal, but not peri-menopausal, Japanese women whose intakes were greater had a higher bone density of the spine and femoral neck. 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 very recent analysis of nine studies further increases our optimism about using soy to inhibit bone resorption. Nine studies with a total of 432 menopausal women were evaluated for 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) of bone turnover demonstrated that when all nine study results are combined, those who consumed isoflavones had a decrease in these biomarkers of -2.08 nmol/mmol when compared to those who did not consume isoflavones. In five of the studies, isolated soy protein was used, as a group, there was no significant effect on urinary deoxypyridinoline. In the current analysis, significant reduction in urinary deoxypyridinoline did not occur in those studies with isoflavones of less than 90 mg/day. In a review of the research in 2003, the author concluded that 90mg 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 recent study mentioned about analyzing nine studies 10 the significant effects on urinary peptides occurred in Asian women but not Caucasian women. This may be due to the conversion of isoflavones into its active metabolite equol in intestinal flora, and 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.

An area of soy foods that may be overlooked, is the amount of calcium in some 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.

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. 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), dietary and exercise advice, for these women who already have osteoporosis, I am in favor of proven conventional therapies to reduce fracture risk.

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 D-F, Qin L-Q, 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 isoflavoens 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.
• MeiJ, 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

Vitamin D deficiency is associated with increased parathyroid secretion, increased bone turnover, osteoporosis, and increase risk of hip and other fractures. Lower levels of vitamin D as measured in the blood, is also associated with risks of cancers of the colon, breast and ovary in several observational studies. Vitamin D deficiency has other serious implications and has been associated with multiple sclerosis, type-1 diabetes, Chrohn’s disease , and even increases in the risk of hypertension and cardiovascular disease.
Causes of vitamin D deficiency include hereditary disorders, reduced skin synthesis and absorption of vitamin D, and acquired disorders of vitamin D absorption, metabolism and responsiveness.

We get our vitamin D from exposure to sunlight, from our diet and from supplementation. Vitamin D3 is produced in the skin on exposure to ultraviolet radiation, and vitamin D2 is derived from plants and enters our body only through the diet or supplementation. There are two major supplemental forms of vitamin D; vitamin D2 (ergocalciferol) and vitamin D3 (holecalciferol). Vitamin D2 is manufactured through the ultraviolet irradiation of ergosterol from yeast. Vitamin D3 is made through the ultraviolet irradiation of 7-dehydrocholesterol from lanolin. Vitamin D2 is considered to be vegetarian suitable, and vitamin D3 is animal derived, from the lanolin. Both forms are often added to foods such as milk, orange juices, infant formulas, cheeses and breakfast cereals. Natural food sources of vitamin D3 include salmon, sardines, mackerel, tuna, shiitake mushrooms, egg yolks, cod liver oil and exposure to sunlight. Both vitamin D2 and vitamin D3 are available in over the counter supplements, including low doses, and moderately higher doses, typically not more than 5,000 IU. High and higher doses of vitamin D2 are available by prescription.

The back story on whether or not vitamin D2 and vitamin D3 are equally effective, goes back to studies in the 1930s where they were assumed to be equally effective in humans. Over time, human studies comparing the increase in blood levels of vitamin D with the supplementation of vitamin D2 vs vitamin D3 have been inconsistent in their results and few in number. They have also been wrought with problems in small sample sizes, lack of vitamin D stability of the products used, wide variations in the seasons the blood was drawn (serum levels of vitamin D are naturally higher in the sunnier months), variable intestinal absorption amongst individuals, variable baseline serum levels of vitamin D, previous history of vitamin D supplementation and variations in age (older people have less vitamin D absorption). While common thought is that vitamin D2 is about 30% less potent than vitamin D3, these variables in the studies, make it extremely difficult to make comparisons and draw accurate conclusions. One small study done in 1998 did demonstrate that vitamin D3 yielded a small increase in serum 25-hydroxyvitamin D over the vitamin D2. A study of 30 men in 2004, between the ages of 20 and 61, demonstrated that the rise in blood levels within the first few days of receiving a single high dose was the same for both forms, indicating equivalent absorption. However, the vitamin D3 treated individuals had a continued rise over two weeks and peaked at 2 weeks, while the vitamin D2 treated men, had a decline to their baseline, by day 14. One might conclude from these two well designed studies, that the rise in serum levels with vitamin D3 might be only a very small amount, as in the first study. Or, rather than give one dose to last 2 or more weeks where there was a greater effect with vitamin D3, as in the second, this same study showed that within the first 3 days of either form, the rise in blood levels, was the same, indicating that a daily dose of either form of vitamin D would be equivalent.

The newest study addressing this question, challenges the long held belief that vitamin D2 is less potent or less effective than vitamin D3 in raising and maintaining blood levels. This was a randomized, placebo-controlled, double-blinded study of healthy individuals ages 18-84 years who received either placebo, 1,000 IU of vitamin D3, 1,000 IU of vitamin D2, or 500 IU of vitamin D2 plus 500 IU of vitamin D3 daily for 11 weeks at the end of the winter. Sixty percent of the study subjects were vitamin D deficient at the start of the study (< 20 ng/ml). This three month study of 68 individuals found that supplementation with both forms produced similar results. Neither 1,000 IU of vitamin D2 or vitamin D3 raised 25-hydroxyvitamin D levels in vitamin D deficient subjects to a level above 30 ng/ml. The authors concluded that vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status.

My main point in this article is not to prove that the vegetarian supplementation of vitamin D2 is as potent as the non-vegetarian supplement vitamin D3, but rather, that we cannot state with reasonable certainty that D3 is 30% more potent, as is generally thought. Vegetarians may find some comfort in this article about vitamin D2 and vitamin D3 yielding similar results, at least when taken daily. If not, then the most we could assert, is that we may need a one third higher dose of vitamin D2 to yield the same results.

References

• MacLaughlin J, Holick M. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985; 76: 1536-1538.
• Parfitt A. Osteomalacia nd related disorders. In: Avioli L, Krane S, eds. Metabolic bone disease and clinically related disorders. 2nd ed. Philadelphia: WB Saunders; 329-396.
• Trivedi D, Doll R, Khaw K. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomized double blind controlled trial. BMJ 2003; 326: 469- 474.
• Garland C, Garland F, Gorham E, et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006; 96: 252-261.
• Cantorna M, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004; 80: Suppl 6: 1717S-1720S.
• Ponsonby A-L, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological reearch. Toxicology 2002; 181-182:71-78.
• Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol 2006; 92: 39-48.
• Rostand S. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension 1997; 30: 150-6.
• Trang H, Cole D, Rubin L, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2.
• Armas L, Hollis B, Heaney R. Vitamin D2 ismuch less effective than vitamin D3 in humans. J Clinical Endocrinology and Metabolism. 2004;89(11): 5387-5391.
• Holick M, Biancuzzo R, Chen T, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 2007; Dec 18.

389 postmenopausal women aged 49 to 67 with a femoral neck bone mineral density (BMD) of less than 0.795 g/cm2 received either genistein or placebo. All women received calcium and vitamin D. After 2 years, BMD at the femoral neck increased in the group that received the genistein and declined in the women who received placebo. A mean change of 0.035 gm/cm2 for genistein vs – 0.037 gm/cm2 for placebo. A smaller positive change was seen at the lumbar spine for genistein and a smaller loss in the placebo group.

Bone turnover decreased significantly in the women who received genistein, and bone-specific alkaline phosphatase and IGF-1 also significantly increased. None of these markers changed in the placebo group. Genistein did not significantly change the endometrial thickness but did reduce the mean number of hot flashes. Side effects included gastrointestinal symptoms and the withdrawal rate from the study due to these side effects was 19% in the genistein group vs 8% in the placebo group.

Marini H, Minutoli L, Polito F, et al. Effects of phytoestrogen genistein on bone metabolism in osteoenic postmenopausal women: a randomized trial. Ann Intern Med 2007;146:839-847.

Comments: Previous studies have reported that women with high soy diets had a lower risk for osteoporosis. The current report provides additional compelling evidence that 54 mg of genistein per day, along with 500 mg of calcium and vitamin D 400 IU for 2 years can increase the BMD of the lumbar spine and femoral neck. Further evidence is provided by the decreased urinary markers for bone resorption and the increase in circulating levels of the bone formation markers.

More than twice as many women had side effects in the genistein group and discontinued treatment because of these symptoms. That said, these side effects are considerably less than those reported for many women who utilize bisphosphanates for bone loss. Although I would not consider genistein an adequate treatment for women with osteoporosis, I would consider genistein an important treatment in women with osteopenia, especially up to the age of 65, prior to higher age related risks for fracture.

Lappe J, et al. Â Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Â Am J Clin Nut 2007; une 85: 1586-1591

Lin J et al.  Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007, May 28; 167:1050-1059.

Three hundred and eighty nine postmenopausal women aged 49 to 67 with a femoral neck bone mineral density (BMD) of less than 0.795 g/cm2 received either genistein or placebo. All women received calcium and vitamin D. After 2 years, BMD at the femoral neck increased in the group that received the genistein by 0.035 gm/cm2 and declined in the women who received placebo by – 0.037 gm/cm2. A smaller positive change was seen at the lumbar spine for genistein and a smaller loss in the placebo group.

Bone turnover decreased significantly in the women who received genistein, and bone-specific alkaline phosphatase and IGF-1 increased significantly. None of these markers changed in the placebo group. Genistein did not significantly change the endometrial thickness but did reduce the mean number of hot flashes.Side effects included gastrointestinal symptoms. The withdrawal rate from the study due to these side effects was 19% in the genistein group vs 8% in the placebo group.

Marini H, Minutoli L, Polito F, et al. Effects of phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med 2007;146:839-847.

Comments: Previous studies have reported that women with high soy diets had a lower risk for osteoporosis. This current report provides additional compelling evidence demonstrating that 54 mg of genistein per day, along with 500 mg of calcium and 400 IU of vitamin D for 2 years can increase the BMD of the lumbar spine and femoral neck. Further evidence is provided by, the decreased urinary markers for bone resorption and the increased circulating levels of bone formation markers.

More than twice as many women had side effects in the genistein group and discontinued treatment because of these symptoms. That said, these side effects are considerably less than those reported for many women who utilize bisphosphanates for bone loss. Although I would not consider genistein an adequate treatment for women with osteoporosis. I would consider genistein an important treatment for osteopeninic women under 65, before they arrive at the age where they are at increased risk of age related fractures.