November 13, 2007
More than 206 fused and individual bones form the human adult skeleton, a rigid, living structure that provides support for organs, anchor points for muscles, tendons and ligaments, and protection for organs such as the brain, lungs and heart. The bones are primarily formed from calcium and collagen, as well as phosphorus, magnesium and trace minerals; in fact, the body regulates the levels of minerals in the body by breaking down and building up bones. Osteoclasts break down bone in a process called resorption, which releases minerals and proteins into the bloodstream. Osteoblasts then rebuild the bone by releasing a protein matrix that includes collagen—the most common protein in the body that plays a large part in the creation of connective tissue and bones.
Osteoporosis is defined as low bone mass and deterioration of bone tissue. This leads to increased bone fragility and a higher risk of bone fracture in the spine, wrist, hips or ribs. About 10 million Americans suffer from osteoporosis, with another 34 million people at risk for the disease.
A 2007 major meta-analysis, published in The Lancet, found calcium supplements, either alone or in combination with vitamin D, are an effective preventive treatment for osteoporosis in older adults.1 In trials that reported fracture as an outcome, supplementation was associated with a 12 percent risk reduction in all types of fractures; fracture risk reduction was significantly greater (24 percent) in trials reporting high compliance. Trials using BMD as a primary outcome found supplementation could reduce the rate of bone loss of 0.54 percent at the hip and 1.19 percent in the spine. Treatment effects were also greater when supplementation was at least 1,200 mg of calcium and 800 IU of vitamin D.
Compliance and dosage are two of the major sticking points when reviewing studies involving calcium and/or vitamin D supplementation and BMD or osteoporosis. For example, in a nested cohort of the Women’s Health Initiative (WHI), 36,282 postmenopausal women received placebo or 400 IU/d vitamin D3 plus 1,000 mg/d calcium carbonate for seven years.2 While hip bone density was 1.06-percent higher in the supplement group, risk of hip fractures was not affected by the nutrient supplements; however, the authors noted the doses used might not have been enough to demonstrate the nutrients’ expected positive benefits on fracture risk. In two trials out of the United Kingdom, supplementation with 800 IU/d vitamin D3 and 1,000 mg/d calcium among high-risk women for two years made no impact on fracture incidence.3,4 However, in both studies, compliance was extremely low (only 60 percent of respondents took the supplements more than 80 percent of the time by the two-year mark), suggesting regular intake may be necessary to gain the benefits of supplementation.
While supplementation with calcium is almost a given among women, it is important to balance calcium intake with another critical mineral, magnesium. In a review from the University of Southern California (USC), Los Angeles, researchers noted studies have demonstrated magnesium deficiency results in bone loss and abnormal mineralization of bones, contributing to skeletal fragility.5 Women with lower BMD generally have low magnesium levels,6 while higher intake of magnesium correlates with higher BMD.7
In another indirect approach, specialty fibers, such as short chain fructooligosaccharides (scFOS), may increase absorption of calcium, magnesium and other important trace elements, thereby contributing to improved bone health. Japanese scientists reported in a crossover trial, adding scFOS (as NutraFlora®, from GTC) to malt drinks improved calcium absorption in young women.8 French researchers further reported adding 10 g scFOS to the diet increased magnesium absorption by 12 percent, increasing plasma magnesium levels.9 Japanese researchers examined the effect of scFOS on induced osteopenia in rats, and found adding 7.5-percent scFOS to the diet could prevent the 30-percent decreases in BMD seen in rats on the sham diet.10
Another important basic nutrient for bone health is vitamin K. It activates certain proteins that are involved in bone metabolism, and deficiencies have been linked to reduced BMD and increased fracture risk.11 Vitamin K2 also appears to prevent osteoclastic bone resorption stimulated by magnesium deficiency, thus normalizing bone remodeling.12 In vitro, vitamin K2 has demonstrated transcriptional regulation of bone marker genes in osteoblasts and may also assist in collagen accumulation of those bone-building cells.13
Natural vitamin K2, known as menaquinone-7 (MK-7), may have particular health benefits. MK-7 (as MenaQ7™, from P.L. Thomas & Co.) was superior to K1 in several measurements in healthy humans, including markers of bone turnover, bioavailability and bioactivity in the body, according to a study out of the University of Maastricht, Netherlands.14 Serum vitamin K species were used as a marker for absorption, and osteocalcin carboxylation as a marker for activity. In a separate trial, the research team found MK-7 (as MenaQ7) showed significant potential benefits for bone health in postmenopausal women; supplementation was shown to completely preserve hip bone strength during a three-year intervention.15 The 325 postmenopausal women received either placebo or 45 mg/d of MenaQ7 for three years. MenaQ7 did not affect BMD, but bone mineral content (BMC) and the femoral neck width increased relative to placebo. In the treated group, hip bone strength remained unchanged during the three-year intervention period, whereas with placebo, bone strength decreased significantly.
intake has been linked to positive bone health parameters. A Chinese cohort study in approximately 24,403 postmenopausal women reported higher soy intake, particularly earlier in menopause, reduced bone mineral loss and risk of fracture.16 Researchers from Iran assessed the impact of soy protein (35 g/d) on markers of bone metabolism in 15 menopausal women, and found after 12 weeks the intervention reduced some markers of bone resorption.17 And a nine-month, double blind intervention trial at the University of Illinois at Urbana-Champaign in postmenopausal women (n=43) found consumption of soy protein isolate significantly reduced markers of bone resorption and formation compared to milk protein isolate.18
Phytoestrogen compounds in soy, isoflavones, may have the ability to inhibit osteoclast formation and activity, and dosedependently affect osteogenesis.19 In a double blind, placebo-controlled, randomized trial from the Chinese University of Hong Kong, 203 postmenopausal Chinese women received 500 mg/d calcium and 125 IU/d vitamin D3 plus either placebo, mid-dose (40 mg/d isoflavones) or high-dose (80 mg/isoflavones) supplements for one year.20
Women in the high-dose isoflavone group had statistically significant increases in BMC at the hip and trochanter, particularly among women with low initial bone mass. Another study, conducted at Cleveland’s Case Western Reserve University, found 110 mg/d of soyisoflavones provided to 19 postmenopausal women for six months had a positive impact on bone resorption, and showed nonsignificant increases in total spine and hip BMD and BMC.21
Research conducted by DSM Nutritional Products in Switzerland found its proprietary genistein formulation (as BONISTEIN®) was safe and well tolerated in a two week study.22 Thirty healthy volunteers received 30, 60 or 120 mg/d; repeated intake of the formula was well-tolerated, with only mild adverse events and no changes in clinical laboratory or vital signs. Research supported by DSM also found BONISTEIN inhibited bone marrow adipogenesis (formation of adipose cells), causing the cells to differentiate to osteoblasts,23 and increased osteoblast survival through a genomic signaling process.24 Unpublished research from DSM further found BONISTEIN upregulated certain bone marker genes, including type 1 collagen, an important matrix protein in bone.
A synthetic derivative of the isoflavone genistein, ipriflavone (supplied in the United States by TSI Health Sciences as Ostivone®), has no estrogenic activity but appears to favorably impact BMD, and has been approved for the treatment of osteoporosis in Japan and some European countries. Studies out of Oklahoma State University, Stillwater, have found ipriflavone could enhance calcium uptake in the intestines of ovariectomized rats,25 and increase rates of bone formation in such animals.26 Intervention studies in women have had contrasting results. A four-year, double blind, placebocontrolled study involving 474 postmenopausal women found 200 mg of ipriflavone three times daily did not prevent bone loss.27 However, a study out of Kei University involving 60 women with postmenopausal osteoporosis or osteopenia found 600 mg/d of ipriflavone suppressed bone resoprtion, helping maintain BMD over the year-long intervention.28 A pilot study in postmenopausal women found taking ipriflavone for three months decreased markers of bone breakdown by almost a third.29
Specialty formulas may also offer benefits to bone health for postmenopausal women. OsteoSine Complex™ from NuLiv Science is a botanical blend from seeds of Cuscuta chinesis that contains many phenolic compounds, including isoflavones. The estrogenic flavones may stimulate osteoblasts, improve collagen synthesis and increase bone cell proliferation. Cuscuta, also called Tu Si Zi, was among four other Traditional Chinese Medicine (TCM) compounds studied by Taiwan researchers for their effects on bone cell regeneration.30 When added to bone cell culture, Tu Si Zi clearly promoted the proliferation and differentiation of the osteoblasts from their precursor cells, according to the scientists. Subsequent unpublished in vitro and in vivo studies conducted at National Taiwan University Medical School, Tapei, and China Pharmaceutical University, Nanjing, have shown OsteoSine can reverse bone loss in both ovariectomized rats and retinoic-induced, acute osteoporotic rats.
1. Tang B et al. “Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis.” Lancet. 2007;370(9588):657-666.
2. Jackson RD et al. “Calcium plus Vitamin D Supplementation and the Risk of Fractures.” NEJM. 2006;354(7):669-83. http://content.nejm.org
3. Grant AM et al. “Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomized placebo-controlled trial.” Lancet. 2005;365(9471):1621-8. www.thelancet.com
4. Porthouse J et al. “Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.” BMJ. 2005;330(7498):1003. http://bmj.com
5. Rude RK, Gruber HE. “Magnesium deficiency and osteoporosis: animal and human observations.” J Nutr Biochem. 2004;15(12):710-6. www.elsevier.com/locate/jnutbio
6. Saito N et al. “Bone mineral density, serum albumin and serum magnesium.” J Am Coll Nutr. 2004;23(6):701S-3S. www.jacn.org
7. Ryder KM et al. “Magnesium intake from food and supplements is associated with bone mineral density in healthy older white subjects.” J Am Geriatr Soc. 2005;53(11):1875-80.
8. Fukushima Y et al. “Calcium absorption of malt drinks containing fructooligosaccharides and safety in humans.” J Nutrition Food. 2002;5(1):49-60.
9. Tahiri M et al. “Five-week intake of short-chain fructooligosaccharides increases intestinal absorption and status of magnesium in postmenopausal women.” J Bone Min Res. 2001;16(11):2152-60. www.jbmr-online.org
10. Morohashi T, Ohta A, Yamada S. “Dietary fructooligosaccharides prevent a reduction of cortical and trabecular bone following total gastrectomy in rats.” Jpn J Pharmacol. 2000;82:54-8.’
11. Adams J, Pepping J. “Vitamin K in the treatment and prevention of osteoporosis and arterial calcification.” Am J Health Syst Pharm. 2005;62(15):1574-81. www.ajhp.org
12. Amizuka N, Li M, Maeda T. “[The interplay of magnesium and vitamin K2 on bone mineralization.]” Clin Calcium. 2005;15(7):57-61.
13. Ichikawa T et al. “Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extra-cellular matrix-related genes and collagen accumulation in osteoblastic cells.” J Biol Chem. 2006;281(25):16927-34. www.jbc.org
14. Schurgers LJ et al. “Vitamin K–containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.” Blood. 15 April 2007;109(8):3279-83.
15. Knapen MHJ, Schurgers LJ, Vermeer C. “Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.” Osteoporos Int. DOI:10.1007/s00198-007-0337-9.
16. Zhang X et al. “Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women.” Arch Intern Med. 2005;165(16):1890-5. http://archinte.ama-assn.org
17. Roudsari AH et al. “Assessment of soy phytoestrogens’ effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial.” Nutr J. 2005;4:30. www.nutritionj.com
18. Evans EM et al. “Effects of soy protein isolate and moderate exercise on bone turnover and bone mineral density in postmenopausal women.” Menopause. 2007;14(3):481-88. www.menopausejournal.com
19. Dang ZC, Lowik C. “Dose-dependent effects of phytoestrogens on bone.” Trends Endocrinol Metab. 2005;16(5):207-13.
20. Chen YM et al. “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(10):4740-7. http://jcem.endojournals.org
21. Harkness LS et al. “Decreased bone resorption with soy isoflavone supplementation in postmenopausal women.” J Womens Health (Larchmt). 2004;13(9):1000-7.
22. Ullmann U et al. “Repeated oral once daily intake of increasing doses of the novel synthetic genistein product Bonistein in healthy volunteers.” Planta Med. 2005;71(10):891-6.
23. Heim M et al. “The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells.” Endocrinology. 2004;145:848-59. http://endo.endojournals.org/
24. Heim M et al. “The phytoestrogen genistein activated human osteoblast survival via genomic TGF-beta signaling.” Presented at International Congress for Medicinal Plant Research, Florence, Italy, August 2005.
25. Arjmandi BH, Khalil DA, Hollis BW. “Ipriflavone, a synthetic phytoestrogen, enhances intestinal calcium transport in vitro.” Calcif Tissue Int. 2000 Sep;67(3):225-9.
26. Arjmandi BH et al. “The synthetic phytoestrogen, ipriflavone, and estrogen prevent bone loss by different mechanisms.” Calcif Tissue Int. 2000 Jan;66(1):61-5.
27. Alexandersen P et al. “Ipriflavone in the Treatment of Postmenopausal Osteoporosis, A Randomized Controlled Trial.” JAMA. 2001;285:1482-88. www.jama.com.
28. Ohta H et al. “Effects of 1-year ipriflavone treatment on lumbar bone mineral density and bone metabolic markers in postmenopausal women with low bone mass.” Horm Res. 1999;51(4):178-83.
29. Halpner AD et al. “The effect of an ipriflavone-containing supplement on urinary N-linked telopeptide levels in postmenopausal women.” J Womens Health Gend Based Med. 2000;9(9):995-8.
30. Yao CH et al. “Fabrication and evaluation of a new composite composed of tricalcium phosphate, gelatin, and Chinese medicine as a bone substitute.” J Biomed Mater Res B Appl Biomater. 2005;75(2):277-88.
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