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The Bone Zone

virtuvian man bones

In October 2009, scientists announced the discovery of Ardi in the journal Science. When they uncovered her fossil skeleton, they discovered the oldest human ancestor to be found to date. The bones of this small-brained, 110-pound female of the Ardipithecus ramidus species offered a clue as to what the last common ancestor of humans and living apes might have been like. She walked the earth 3.2 million years ago and her bones told scientists that humans did not evolve from chimps, but that they shared a common ancestor.

Her bones are a window to the prehistoric world; and its a good thing they survived these millions of years, or at least fossils of her bones did. While it might be said her diet was a natural one (wear patterns on her teeth suggest a diet that included fruits, nuts and other forest foods), she did not have access to the numerous natural product supplements and fortified foods that can help preserve current consumers bones today. But, then again, she also didnt have the choice of fast food or an unhealthy microwave meal for lunch. And, its certain she got more exercise than the average television-loving American as she traversed Ethiopia's harsh Afar desert.

Besides for walking on two legs, current humans and Ardi also shared the same bone characteristics. Bone is a living, dynamic tissue made of a hard outer shell and spongy inner tissue. It is continually being remodeled; this is how the body repairs small fractures, be they from knocking shins on the coffee table or foraging for food in the desert. Bone is constantly reforming and resorbing, and this delicate balance allows the body to remodel the bone. Resorption breaks down bone tissue before it is reformed. Osteoclasts are cells that break down the skeleton and osteoblasts are cells that build bones. In present-day humans, the entire skeleton is replaced about every seven years or so; but, with age, the balance shifts from formation to resorption, which means more bone is broken down than built. Peak bone mass, when bone density is at its maximum, is usually reached between the ages of 18 and 25, after that, bone loss occurs. For women at about age 30 and men a bit later in life, bone resorption will begin to outpace bone formation. When women hit menopause, bone resorption significantly exceeds formation, due to shifts in hormones.

The weakening of bones can lead to osteoporosis, which can develop without symptoms until a fracture occurs. After the first fracture, the risk for subsequent breaks is much higher, and all osteoporotic fractures increase patient morbidity.1 Osteoporosis usually occurs in people aged 50 and older, when loss of muscle strength and mass can also reduce bone strength and density. The National Osteoporosis Foundation (NOF) estimates it affects 44 million Americans, or 55 percent of the people 50 years of age and older, and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis. It is expected the number of osteoporotic fractures will double during the next 50 years, due in part to the aging population.

While osteoporosis is often thought of as an older person's disease, it can strike at any age, according to the NOF; and that means supplementing with bone health nutrients can benefit many segments of the population. Post-menopausal women have traditionally been the largest consumers of bone health supplements, but younger women seem to be realizing establishing a higher peak bone mass earlier in life can reduce the risk of developing osteoporosis. Other bone health consumers may include those with bone-related illnesses or those who are suffering from a bone injury and are looking for temporary support to aid recovery. Sports players and athletes may also be looking for bone health support to complement their high-impact lifestyles, as well as teenagers who are at a critical time in their bone-building process.

Consumers may also be encouraged by dietitians to seek bone health supplements. In the LifeSupplemented 2009 Healthcare Professional (HCP) Impact Study, 70 percent of surveyed registered dietitians said they recommend bone health supplements to their clients. And, it seems consumers are getting the message. The 2009 International Food Information Council (IFIC) Functional Foods/Food for Health Consumer Trending Survey found 88 percent of consumers are already eating or want to eat food to improve bone health.

However, consumers are also getting mixed messages regarding bone health supplements. In March 2009, Consumer Reports found dosing and label claim problems in a review of 34 bone health supplements. The tests included products for adults and children in a variety of delivery forms, including tables, chewables, capsules, softgels, liquids, wafers and powders. One calcium supplement contains 87 percent of the label claim and one calcium/vitamin K combo only had 52.5 percent of the claimed vitamin K. One vitamin D/vitamin K supplement contained only 67.2 percent of its vitamin K claim and a vitamin D/calcium supplement only contained 89.2 percent of its calcium claim.

Even with these issues, the U.S. market for ingredients that support bone health is strong. A September 2009 report from Frost & Sullivan said sales for bone and joint health ingredients topped at $178.4 million in 2008 and are expected to reach $246.4 million in 2015. Frost analysts cited the aging population, increased consumer awareness of the benefits for supplements and functional foods on bone and joint health, and the rise in osteoporosis and osteoarthritis (OA).

Calcium, King of Bone Nutrients

Ask most consumers what the number one nutrient for bone health is and they most likely will say calcium. The IFIC survey found 93 percent of them know calcium promotes bone health, and 93 percent said they are already eating or want to eat foods with calcium to promote bone health.

Even with knowledge, a study as recent as 2007 found many Americansparticularly men, ethnic minorities and the socially disadvantagedare not meeting the current recommendations for adequate calcium of 1,200 mg/d through diet or supplements.2

Those who dont meet the recommended amount of calcium may want to rethink their dietary choices so their bones dont suffer, as studies have shown calcium supplementation reduced the risk of all fractures and minimal trauma fractures among healthy individuals.3 The benefit appeared to dissipate after treatment was stopped. Participants (n=930) younger than 80 years old who were generally healthy were randomly assigned to receive four years of treatment with 3 g/d of calcium carbonate (CaCO(3)) (1,200 mg/d elemental calcium) or placebo and were followed for a mean of 10.8 years. Forty-six fractures (15 from minimal trauma) occurred in 464 participants in the calcium group and 54 fractures (29 from minimal trauma) in 466 participants in the placebo group. The overall risk of fracture differed significantly between groups during the treatment phase, but not during the subsequent post-treatment follow-up. Minimal trauma fractures were also less frequent in the calcium group during treatment.

And, a 2006 study found supplementation with calcium carbonate tablets supplying 1,200 mg/d was effective in preventing clinical fractures in the elderly population, as long as those patients are compliant.4

Other data showed consumers may want to look for supplements with calcium rather than upping their intake of dairy.5 Boston researchers conducted a 12-year prospective study among 77,761 women, aged 34 through 59 years in 1980, who had never used calcium supplements. Dietary intake was assessed with a food-frequency questionnaire in 1980, 1984 and 1986. Fractures of the proximal femur (n=133) and distal radius (n=1,046) from low or moderate trauma were self-reported on biennial questionnaires. They found no evidence that higher intakes of milk or calcium from food sources reduce fracture incidence. Women who drank two or more glasses of milk per day had relative risks of 1.45 for hip fracture and 1.05 for forearm fracture when compared with women consuming one glass or less per week. Likewise, higher intakes of total dietary calcium or calcium from dairy foods were not associated with decreased risk of hip or forearm fracture.

 

Sun Shining on Bones

Calcium is the ruler when it comes to natural bone support and many other nutrients are helpful in that they support calcium in its bone-building ways. Calcium is often paired with vitamin D, the sunshine vitamin, in natural products, as well as in studies on supplements for bone health. A 2007 Denmark study found a one-year intervention with calcium and vitamin D reduced bone turnover, significantly increased bone mineral density (BMD) in patients younger than 70 years, and decreased bone loss in older patients.6 This double blind study showed 1,400 IU of vitamin D (as cholecalciferol) in addition to sufficient calcium was more effective in improving BMD when compared to 200 IU of vitamin D alone. In elderly patients, prolonged supplementation of calcium and vitamin D has been shown to prevent bone loss, and in some intervention studies to prevent fragility fractures.7

More recently, this vitamin D and calcium combo was further studied for its benefits on bone health, and researchers found together, the nutrients reduced hip fractures and total fractures, and probably vertebral fractures, in both men and women of all ages whether they had previous fractures or not.8 However, researchers found vitamin D alone was not effective in preventing fractures. In January 2010, researchers at the Copenhagen University Hospital Gentofte reviewed seven major randomized trials that tested the anti-fracture efficacy of vitamin D or vitamin D plus calcium. The group studied, known as the DIPART (vitamin D Individual Patient Analysis of Randomized Trials) Group, yielded a total of 68,517 participants (mean age 69.9 years, 47 to 107 years old and 14.7 percent men). Trials using vitamin D with calcium showed a reduced overall risk of fracture by 8 percent  and hip fracture by 16. For vitamin D alone in daily doses of 10 µg or 20 µg, no significant effects were found.

With all the recent buzz around vitamin D, consumers are catching on to its bone health benefits. The IFIC survey found 90 percent of consumers know vitamin D promotes bone health and 94 percent said they are already eating or want to eat foods with vitamin D to promote bone health.

Still, health organizations have noted vitamin D deficiency is a worldwide problem. Boston University School of Medicine researchers called this problem a pandemic.9 They stated a circulating level of vitamin D of greater than75 mol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health; and in the absence of adequate sun exposure, at least 800 to 1,000 IU vitamin D3/d may be needed to achieve this in children and adults. Unfortunately, another recent study of more than 6,000 children found seven out of 10 U.S. children had low levels of vitamin D, raising their risk of bone and heart disease.10

These low levels have prompted many within the industry to urge the Institutes of Medicine (IOM) to raise the dietary reference intake (DRI) for vitamin D. And, science is backing that encouragement. Researchers from University of California, Davis, said vitamin D recommendations are way too low in a January 2010 study.11 Results of the study found those with lighter skin (European ancestry) and high sun exposure need 1,300 IU/d of vitamin D in the winter; and darker-skinned individuals (African ancestry) with low sun exposure need from 2,100 to 3,100 IU/d year round. The current DRI for vitamin D from the IOM is 200 IU/d. IOM announced in 2009 it plans to review recommendations on vitamin D and calcium and a report is expected in spring 2010.

With consumer interest and need, and a hopeful increase in DRIs, supplements and functional foods for vitamin D should continue to grow.

K Keeping Em Strong

 Just like vitamin D, vitamin K helps calcium do its job more efficiently. Osteoblasts produce a vitamin K-dependent protein called osteocalcin, which helps remove calcium from the blood and bind it in the bone matrix as mineral content. Osteocalcin needs vitamin K to function, and long-term deficiency in vitamin K will lead to reduced BMD and bone quality. Vitamin K comes in two formsphylloquinone (K1), which comes from foods, such as green, leafy vegetables and green tea; and menaquinone (K2), which comes from bacteria in the gut.

Vitamin Ks calcium-retention abilities seem to aid bone health. A 2008 Japanese study found vitamin K was strongly associated with a reduction in hip fracture in men and women; this association was stronger than magnesium, vitamin D and calcium alone.12

In postmenopausal women, high-dose vitamin K1 and K2 supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures, according to researchers who reviewed seven studies that lasted at least two years each.13 Vitamin K2 helped maintain bone strength in the neck and hip in postmenopausal women, whereas the women taking a placebo experienced a weakening of their bones,14 and 5 mg of vitamin K1 supplementation for two to four years may protect against fractures and cancers in postmenopausal women with osteopenia, a condition where BMD is lower than normal.15

Its not just adults who gain bone benefits from vitamin K. In children, high vitamin K intake is related to heather bone mass,16 and children with juvenile idiopathic arthritis who had high vitamin K states had higher bone properties.17 In healthy, prepubescent children, modest supplementation with MK-7 (a version of vitamin K2) increased circulating concentrations of MK-7 and increased osteocalcin carboxylation.18

Regardless of age, evidence has shown vitamin K2 is more effective than K1 in preventing bone loss,19 and Japanese fermented soybeans (aka natto), which contains a large amount of vitamin K2 has shown to be effective in preventing postmenopausal bone loss and fracture risk.20,21

However, results from at least one 2009 study did not support vitamin K in its role in preventing osteoporosis among healthy, postmenopausal, North American women who were also receiving calcium and vitamin D supplements.22 In the double blind, placebo-controlled study, 381 postmenopausal women received vitamin K1 (1 mg/d), MK-4 (another form of K2) (45 mg/d) or a placebo for 12 months. All participants received daily calcium and vitamin D3 supplements. Vitamin K1 and MK4 treatment reduced serum undercarboxylated osteocalcin, but did not alter bone-specific alkaline phosphatase (BSALP) or n-telopeptide of type 1 collagen (NTX). No effect of vitamin K1 or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed.

Soy Good

Soy does not have to be fermented to have an effect on bone health. Many soy foods are naturally high in calcium, which may be why it is beneficial to bone health. Soy also contains magnesium and boron, which are important in bone health. In addition, the isoflavones in soy foods may inhibit the breakdown of bones.

Genistein, the principal isoflavone found in soybeans and soy foods has been associated with good bone health. A 2007 Italian study found 24 months of treatment with genistein caused an increase in BMD in osteopenic postmenopausal women at the anteroposterior lumbar spine and the femoral neck, whereas placebo recipients experienced a decrease in BMD.23 A study from the Center for Health Studies in Seattle in 2006 noted soy protein containing 83 mg of isoflavones (45.6 mg genistein and 31.7 mg daidzein) showed a modest benefit in preserving spine, but not hip BMD in older women.24

However, researchers from the University of Connecticut Health Center in 2006 found soy protein and isoflavones (either alone or together) did not affect BMD.25 Researchers conducted a randomized, double blind, placebo-controlled clinical trial in 97 healthy ambulatory women older than 60 years. After a one-month baseline period, subjects were randomly assigned into one of four intervention groups: soy protein (18 g) and isoflavone tablets (105 mg isoflavone aglycone equivalents), soy protein and placebo tablets, control protein and isoflavone tablets, and control protein and placebo tablets. No significant differences in BMD were observed between groups from baseline to one year after the intervention or in BMD change between equol and non-equol producers. However, there were significant negative correlations between total dietary protein (per kg) and markers of bone turnover (P<0.05).

Prebiotics Helping Calcium

Along with vitamin D and K, prebiotic fibers may also help bones absorb more calcium. Galactooligosaccharides (GOS) are an animal-derived prebiotic manufactured by extracting milk sugars from dairy products and using enzymes to break them down. Its association with bone health is based on its impact on mineral absorption. GOS is fermented by various bacteria in the colon, which creates short-chain fatty acids. These acids lower the pH of the colon creating an environment that improves the uptake and absorbtion of calcium.

In a Netherlands study of postmenopausal women, greater calcium absorption was observed after consumption of a product rich in transgalactooligosaccharides (TOS) compared with the reference treatment.26 Researchers noted the increased calcium absorption was not accompanied by increased urinary calcium excretion, meaning that TOS also may increase the uptake of calcium by bones and/or inhibit bone resorption. A 2006 Spanish study found infant formulas supplemented with probiotics (Bifidobacterium bifidum and Bifidobacterium longum) and/or GOS at 12, 50 and 100 gkg for 30 days increased calcium, magnesium and phosphorus bioavailability in rats.27 Mineral apparent absorption and retention ratios were higher than 90 percent for calcium and phosphorus and 80 percent for magnesium during the first balance period. And, a 1995 Japanese study determined GOS enhanced volatile fatty acid production, and thus prevented bone loss and lower serum total cholesterol concentration in ovariectomized Wistar rats.28 Rats fed a diet containing GOS absorbed calcium more efficiently than those on the control diet after eight to 10 days and 18 to 20 days, and the bone (femur and tibia) ash weight and tibia calcium content of rats on the GOS diet were significantly higher than those of the control animals.

Inulin is another prebiotic that has shown bone benefits. Beneo Orafti offers Synergy 1, an oligofructose-enriched inulin that increased calcium retention and accretion in bones by 15 percent after one year of supplementation in children. The study was conducted by Dr. S. Abrams from the Baylor College of Medicine and the Texas Childrens Hospital in Houston. In a randomized sample of 100 males and females aged 9 to 13, half of whom took 8 g/d of Synergy 1 and the other half took a placebo. The increase in calcium absorption was seen after both two months and one year after supplementing.

More Minerals

Iron may also be helping calcium do its bone-building job. A University of Arizona study examined 242 healthy nonsmoking postmenopausal women, aged 40 to 66 years in the Bone, Estrogen and Strength Training (BEST) Study.29 In this study, iron was associated with greater BMD at five sites (lumbar spine L2-L4, trochanter, femur neck, Ward's triangle and total body) (P < or = 0.01), even after adjusting for protein and/or calcium. Increasing levels of iron intake (greater than20 mg) were associated with greater BMD at several bone sites among women with a mean calcium intake of 800 to 1,200 mg/d. Elevated iron intake was not associated with greater BMD among women with higher (greater than 1,200 mg/d) or lower calcium intakes (less than 800 mg/d).

With 50 percent of total body magnesium found in bone, its no wonder that its essential to good bone health. This mineral also helps calcium regulation, and magnesium deficiency has been shown to alter calcium metabolism and the hormones that regulate calcium, which can lead to a reduced BMD.30 Further, researchers at Tuffs University in Boston found magnesium contributes to maintenance of BMD in elderly subjects.31 They found magnesium intake was associated with greater BMD at one hip site for both men and women and in the forearm for men.

Besides for magnesium, phosphorus and fluoride are thought to play a role in bone mass development.32

Vitamins B & C

Other letter vitamins besides for vitamin D and K hold potential for manufactures who want to create natural bone health products. Vitamin C and B6 are needed to make collagen, an essential part of the organic material that holds bone together. A 2008 USDA study found total vitamin C intake was positively associated with femoral neck BMD (P=0.04) among male nonsmokers.33 Higher total vitamin C intake was associated with less femoral neck and trochanter-BMD loss in men with low calcium (P </= 0.03) or vitamin E intakes (P=0.03). And, in a 17-year follow up to Framingham Osteoporosis Study, subjects in the highest tertile of total vitamin C intake had significantly fewer hip fractures (P = 0.04) and non-vertebral fractures (P=0.05) compared to subjects in the lowest tertile of intake.34 Subjects in the highest category of supplemental vitamin C intake had significantly fewer hip fractures (P= 0.02) and non-vertebral fractures (P=0.07) compared to non-supplement users. However, those taking vitamin C may want to stick with supplements and fortified foods because the researchers found dietary vitamin C intake was not associated with fracture risk (P>0.22). Previously, the Framingham Study found subjects with higher total or supplemental vitamin C intake had fewer hip fractures and non-vertebral fractures as compared to subjects with lower intakes

In the B complex arena, researchers at the Institute for Aging Research in Boston discovered low B-vitamin concentration may be a risk factor for decreased bone health in elderly men and women.35 Multivariable-adjusted mean bone loss was inversely associated with vitamin B6 (P=0.01) and vitamins B12 and B6 were inversely associated with hip fracture risk (P<0.05).

Fish and Botanicals

From B to the sea, fish oils have shown to promote bone formation. In 2008, researchers from Iran reviewed the current knowledge of dietary fatty acids and osteoporosis by searching Medline/Index Medicus and EMBASE/Excerpta Medica for relevant papers regarding the effects of omega-3 fatty acids on osteoporosis between 1963 and 2007 using the key words: osteoporosis, bone health, n-3 fatty acids, and PUFA.36 Generally, they found animal studies support the beneficial effects of omega-3 fatty acids on bone health and osteoporosis. However, they concluded dissimilar lipid metabolism in human and animals, the various study designs, and controversies over the human study outcomes made it difficult to draw a definite conclusion for human health. The authors said conclusive findings in humans were still lacking in this area and it needs to be further investigated.

Lastly, botanicals have shown to aid the skeleton. Cissus quadrangularis Linn. (CQ), for example, is a plant used in folk medicine that was studied on an osteoporotic rat model developed by ovariectomy in a 2009 Indian study.37 In this experiment, healthy female Wistar rats were divided into four groups of six animals each. Group 1 was sham operated. All the remaining groups were ovariectomized. Group 2 was fed with an equivolume of saline and served as ovariectomized control (OVX). Groups 3 and 4 were orally treated with raloxifene (5.4 mg/kg) and petroleum-ether extract of CQ (500 mg/kg), respectively, for three months. The study revealed for the first time that the petroleum-ether extract of CQ reduced bone loss, as evidenced by the weight gain in femur, and also reduced the osteoclastic activity there by facilitating bone formation when compared to the OVX group. Researchers concluded CQ might be a potential candidate for prevention and treatment of postmenopausal osteoporosis and the biological activity of CQ on bone may be attributed to the phytogenic steroids present in it.

While current American bones may not last as long as Ardis fossilized skeleton, manufacturers that fortify products with these natural bone building ingredients can help keep bones healthy for at least one lifetime. And who knows? Maybe with calcium, vitamin D, vitamin K, probiotics, vitamin C, B vitamins, omega-3s and botanicals, the scientists of the future will be able to look back and learn how the modern-day humans appreciated natural remedies.

 

References are on the next page...

 

References for "The Bone Zone"

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2.       Ma J, Johns RA, Stafford RS. Americans are not meeting current calcium recommendations. Am J Clin Nutr. 2007 May;85(5):1361-6.

3.       Bischoff-Ferrari HA, et al. Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. Am J Clin Nutr. 2008 Jun;87(6):1945-51.

4.       Prince RL, et al. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med. 2006 Apr 24;166(8):869-75.

5.       Feskanich D, et al. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am J Public Health. 1997 Jun;87(6):992-7.

6.       Hitz MF, Jensen JE, Eskildsen PC. Bone mineral density and bone markers in patients with a recent low-energy fracture: effect of 1 y of treatment with calcium and vitamin D. Am J Clin Nutr. 2007 Jul;86(1):251-9.

7.       Bonjour JP, et al. Minerals and vitamins in bone health: the potential value of dietary enhancement. Br J Nutr. 2009 Jun;101(11):1581-96. Epub 2009 Apr 1.

8.       Abrahamsen B, et al. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010 Jan 12;340:b5463. doi: 10.1136/bmj.b5463.

9.       Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.

10.   Kumar J, et al. Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001-2004.Pediatrics. 2009 Aug 3.

11.   Hall LM, et al. Vitamin D Intake Needed to Maintain Target Serum 25-Hydroxyvitamin D Concentrations in Participants with Low Sun Exposure and Dark Skin Pigmentation Is Substantially Higher Than Current Recommendations. J Nutr. 2010 Jan 6.

12.   Yaegashi Y, et al. Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K. Eur J Epidemiol. 2008;23(3):219-25.

13.   Iwamoto J, et al. High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature. Nutr Res. 2009 Apr;29(4):221-8.

14.   Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007 Jul;18(7):963-72.

15.   Cheung AM, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008 Oct 14;5(10):e196. 

16.   van Summeren MJ, et al Vitamin K status is associated with childhood bone mineral content. Br J Nutr. 2008 Oct;100(4):852-8. Epub 2008 Feb 18.

17.   van Summeren MJ, et al. Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2008 May-Jun;26(3):484-91.

18.   van Summeren MJ , et al. The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children. Br J Nutr. 2009 May 19:1-8.

19.   Yamaguchi M, et al. Effect of vitamin K2 (menaquinone-7) in fermented soybean (natto) on bone loss in ovariectomized rats. J Bone Miner Metab. 1999;17(1):23-9.

20.   Ikeda Y, et al. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. Nutr. 2006 May;136(5):1323-8.

21.   Kaneki M, et al. Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition. 2001 Apr;17(4):315-21.

22.   Binkley N Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Miner Res. 2009 Jun;24(6):983-91.

23.   Marini H, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 2007 Jun 19;146(12):839-47.

24.   Newton KM, et al. Soy protein and bone mineral density in older men and women: a randomized trial. Maturitas. 2006 Oct 20;55(3):270-7. Epub 2006 May 26.

25.   Kenny AM, et al. Soy proteins and isoflavones affect bone mineral density in older women: a randomized controlled trial. Am J Clin Nutr. 2009 Jul;90(1):234-42.

26.   van den Heuvel EG, Schoterman MH, Muijs T. Transgalactooligosaccharides stimulate calcium absorption in postmenopausal women. J Nutr. 2000 Dec;130(12):2938-42.

27.   Pérez-Conesa, D. et al. Bioavailability of calcium, magnesium and phosphorus in rats fed probiotic, prebiotic and synbiotic powder follow-up infant formulas and their effect on physiological and nutritional parameters. J Sci Food Agric. 2006 Sep 25;86(14):2327-2336

28.   Chonan O, Matsumoto K, Watanuki M. Effect of galactooligosaccharides on calcium absorption and preventing bone loss in ovariectomized rats. Biosci Biotechnol Biochem. 1995 Feb;59(2):236-9.

29.   Harris MM, et al Dietary iron is associated with bone mineral density in healthy postmenopausal women. J Nutr. 2003 Nov;133(11):3598-602.

30.   Elisaf M, Milionis H, Siamopoulos KC. Hypomagnesemic hypokalemia and hypocalcemia: clinical and laboratory characteristics. Miner Electrolyte Metab. 1997;23(2):105-12.

31.   Tucker KL, et al. Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women. Am J Clin Nutr. 1999 Apr;69(4):727-36.

32.   Vicente-Rodríguez G, et al. Independent and combined effect of nutrition and exercise on bone mass development. J Bone Miner Metab. 2008;26(5):416-24.

33.   Sahni S, et al. High vitamin C intake is associated with lower 4-year bone loss in elderly men. J Nutr. 2008 Oct;138(10):1931-8.

34.   Sahni S, et al. Protective effect of total and supplemental vitamin C intake on the risk of hip fracture--a 17-year follow-up from the Framingham Osteoporosis Study. Osteoporos Int. 2009 Nov;20(11):1853-61.

35.   McLean RR, et al. Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women. J Clin Endocrinol Metab. 2008 Jun;93(6):2206-12.

36.   Salari P, et al. A systematic review of the impact of n-3 fatty acids in bone health and osteoporosis. Med Sci Monit. 2008 Mar;14(3):RA37-44.

37.   Potu BK, et al. Evidence-based assessment of antiosteoporotic activity of petroleum-ether extract of Cissus quadrangularis Linn. on ovariectomy-induced osteoporosis. Ups J Med Sci. 2009;114(3):140-8.

 

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