Building healthy bones for life

Building healthy bones for life

Scientific advancements in our understanding of bone physiology, structure and nutrient interaction have resulted in the rollout of a number of new ingredients besides calcium and calcium-fortified foods. Mark J Tallon, PhD, investigates the latest innovations in functional foods for better bone health.

Of all degenerative diseases, osteoporosis and its associated complications are now considered by the World Health Organization to be the second-leading health care problem, behind only cardiovascular disease.1 As a disease largely preventable through the application of resistance exercise and diet, osteoporosis has implications for the functional foods market that have not gone unnoticed; therefore, in a report by Nutrition Business Journal, the bone health food market is projected to grow 25 per cent by 2005.2

Osteoporosis literally means "porous bones." It is a condition that breaks down the skeleton, making bones more fragile, resulting in an increased incidence of spontaneous fractures, especially in the vertebrae and hip. Bone loss can result from a variety of reasons including insufficient dietary intake, pollutants, toxins, smoking, menopause, lack of physical activity and heredity.3

Our skeletal bone structure is made of a thick outer shell and a stronger inner mesh filled with collagen (protein), calcium salts and other minerals, also known as bone matrix. Bones mend and rebuild themselves by the actions of two cell types: osteoblasts that form bone and osteoclasts that resorb (destroy) bone. This continual process of breakdown and renewal is also known as bone turnover. When the activity of the bone-destroying osteoclastic cells outpaces that of bone-forming osteoblasts, the result can only be bone loss and an increased risk of developing osteoporosis.

In an attempt to retard bone loss through therapeutic nutrition, calcium supplementation and food fortification has been shown in well-controlled clinical trials to be efficacious. Indeed, calcium has been the leading dietary intervention in bone nutrition for well over a decade. However, scientific advancements in our understanding of bone physiology, structure and nutrient interaction has resulted in the rollout of a number of new ingredients besides calcium. These ingredients may play a role as important as calcium in maintaining a healthy skeletal system well into old age.

Calcium conundrums

Among the greatest changes in the thinking of the nutritional community over the past decade has been the re-evaluation of the importance and place of dietary and supplemental calcium. Recent work has started to analyse the difference between osteomalacia (lack of dietary calcium) and osteoporosis (a lack of both calcium and other minerals), as well as differences in the biochemical metabolism of calcium under different physiological conditions. One such condition is menopause, during which supplemental calcium is poorly absorbed.4 These factors have led to a different view of dietary and supplemental recommendations for calcium.

Despite the abundance of evidence on the positive influence calcium can have on bone mineral density, milk and other milk derivatives such as yoghurts and cheeses may not be the most efficient sources of calcium when it comes to absorption. As we know, the cost-effectiveness of calcium supplementation depends not only on the cost of the product but on the efficiency of its absorption.

Recent findings from human studies have demonstrated that milk calcium (tri-calcium phosphate) is no better absorbed than many other forms of synthetic calcium used in dietary supplements, including carbonate, gluconolactate, citomalate, chloride, lactate, acetate and citrate.5,6 In fact, the most readily absorbable form of calcium is bis-glycinocalcium taken on an empty stomach, followed by calcium citromalate taken with a meal.7 However, because these forms of calcium were taken in a study both with and without a meal, a direct comparison of absorption between the two forms was not made and is yet to be assessed.


Phosphorous is second to calcium in abundance in the human body, with 85 per cent bound tightly to the human skeleton. Although phosphate is an essential nutrient, there is concern that excessive amounts may be detrimental to bone. For example, raising dietary phosphorous increases serum phosphorous and causes a transient fall in calcium, resulting in elevated parathyroid hormone secretion and, potentially, bone resorption.8,9 Dietary phosphorous intake has risen some 10-15 per cent over the past 20 years because of its increased use in food additives and cola beverages.10 Governmental food databases used by many dietitians will not reflect these changes, but in the US adult population, phosphorous intake is between 1,000-1,500mg/day, well above the currently recommended level for adults of 700mg/day.

A series of studies from Creighton University in Nebraska, under the direction of Robert Heaney, PhD, suggest it may not be the finite intake of phosphate or calcium that is detrimental to each other's absorption but the ratio consumed. 11 A study from this group demonstrated that two variables, faecal calcium and dietary phosphorous, were positively and independently associated with faecal phosphorous excretion accounting for up to 77 per cent of net phosphorous absorbed. 11 By adjusting for the relationship between faecal calcium and calcium intake, it follows that with each increase in calcium intake of 0.5g, phosphorous absorption decreases by 0.166g. Therefore, if calcium intake increases without a corresponding increase in phosphorous intake, the risk of phosphorous insufficiency rises.

Intake of high calcium:phosphorous ratios (above 1:2) can occur with use of supplements or food fortificants consisting of non-phosphate-bound calcium salts or chelates.12 The take-home message is that patients with osteoporosis should receive at least some of their calcium therapy in the form of a calcium-phosphate preparation.


There are approximately 25g magnesium in the human body, with two thirds located in the skeleton. The magnesium in bone is an integral part of hydroxyapatite (the preferred storage form for calcium) formation, and without adequate dietary intake of magnesium, calcium metabolism is negatively altered. A series of studies carried out in the late 1990s showed that magnesium deficiency can lead to an uncoupling of bone formation and increased resorption.13,14 Among 19 post-menopausal women, a daily intake of 300-400mg/day magnesium resulted in significant increases in mineral bone density after one year.15


Some governments are still considering adding fluoride to drinking water in 2004. The question really is whether sodium fluoride supplementation benefits bone health. There are data to suggest that fluoride is a potent stimulator of osteoblastic bone formation resulting in an increase in spinal bone mass of about 5-10 per cent annually.16 However, a large-scale study carried out at the Mayo Clinic has shown that even when bone densities were elevated with fluoride treatment, there was no measurable impact on incidence of fracture rates.17 The addition of supplementary fluoride to drinking water has been an area of concern for some time due to the dangers of skeletal fluorosis, which can occur if levels are elevated beyond 4mg/L.18 Until a greater understanding of total daily fluoride intake is available, the issue of dietary fortification, supplementation or artificially fluoridated water will remain a contentious one.


The human body contains about 2g zinc and about 90 per cent can be found in bone, skin, muscle and hair. Zinc plays a vital role in connective tissue metabolism as a co-factor for several enzymes, including alkaline phosphatase, necessary for bone mineralisation, and collagenase, which is essential for the development of the collagenous structure of bone.19 During periods of zinc deficiency, bone levels are greatly reduced, and excessive excretion of zinc is related to osteoporosis.20 In rats, supplementation with zinc has been observed to increased femoral bone mass in conjunction with treadmill exercise.21

The times for possible supplementation with zinc are during adolescence or for those involved in excessive exercise, during a period of dietary restriction, or following periods of prolonged illness where zinc levels may be under stress due to increased rates of growth and/or bone turnover. The current RDA is 12mg/day, but research suggests optimal bone health is better achieved at a level of 30mg/day.

Vitamin D (cholecalciferol)

Vitamin D mediates serum calcium and phosphorous concentrations within the normal range to maintain essential cellular functions and to promote mineralisation of the skeleton. As such, D3 deficiency has been shown to play an important role in osteoporosis. Although vitamin D3 (D3 metabolised to biologically active form 1-alpha, 25-dihydroxy vitamin) is synthesised in the skin via exposure to sunlight, well-controlled studies have shown deficiency can still result even in countries with prolonged sunlight exposure.22

Because of recent advances in gene technology and the identification of the vitamin D receptor gene (VDR) that may indicate greater susceptibility to osteoporotic disease, vitamin D is back under scientific scrutiny.23 A review of 16 studies that assessed hip fracture and the use of 1g calcium/day demonstrated a decrease in the incidence of fracture by 24 per cent. However, when combined with vitamin D, hip fractures decreased 54 per cent in some cases.24

A meta-analysis of supplementary vitamin D for prevention of osteoporotic fractures concluded that the effectiveness of vitamin D alone is uncertain.25 Therefore, it seems evident that the place of supplemental vitamin D is in conjunction with calcium.26 Recommended daily intakes range from 100-400IU/day. The European Community has redefined the RDA for vitamin D for those age 65 and older at 400IU/day.27 It is clear, when levels between 400-600IU/day are recommended, that supplementation at some level is required.

A note of caution is warranted regarding excessive intake of vitamin D: Hypocalcaemia and extra-osseous calcification may result, particularly in arterial walls and in the kidney. However, the dose of vitamin D that causes significant hypocalcaemia is highly variable between individuals but is rarely less than 1,000mcg/day.28

Vitamins K1 and K2

The K vitamins are a group of napthoquinones required for the carboxylation of a limited number of proteins, including the bone matrix protein osteocalcin. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) differ regarding food source (green vegetables and fermented products, respectively), bioavailability and intermediate metabolism. However, both of these forms seem to retard bone loss in elderly populations.

A recent study from the University of Maastricht assessed the influence of K1 on post-menopausal bone loss.29 Using a double-blind, randomised design, 1mg/day vitamin K1 plus a mineral and vitamin D combination (8mcg/day) was prescribed to 181 healthy post-menopausal women between the ages of 50 and 60. During the three-year treatment period, participants received a daily supplement containing either a placebo; calcium, magnesium, zinc and vitamin D; or the same formulation with additional vitamin K1. Both intervention groups had a significant influence on reducing bone loss, but with the K1 intervention being more effective.

In a similar study on K2, 72 post-menopausal women were treated with 45mg/day.30 Lumbar spine bone mineral density (BMD) was measured by dual energy X-ray absorptiometry before the therapy and at six and 12 months after the treatment. Vitamin K2 suppressed any decrease in spinal BMD as compared to the no treatment group. The authors concluded that vitamin K2 therapy may be a useful method for preventing post-menopausal spinal bone mineral loss and that supplementation should be started early in the onset of post-menopause.

A cell culture study has started to shed some light on the mechanisms of K2 in bone health. The aim of the relevant study was to investigate whether K2 has a direct effect on circulating osteoclast precursors to influence osteoclast differentiation. The results indicated that menatetrenone directly affected osteoclast differentiation in contrast to K1 or phytol, the side chain, which had no influence.31

This outcome suggests K2 may have a greater effect in maintaining bone mineral density than K1. Although it seems K2 may be the most important supplementary form of vitamin K for bone health, based on these studies, the majority (approximately 60-70 per cent) of the daily dietary intake of K1 is lost to the body by excretion. This emphasises the need for a continuous dietary supply of both forms to maintain tissue reserves.32

Polyunsaturated fatty acids

There are many factors produced in the bone micro-environment that affect skeletal biology, including prostaglandins, cytokines and insulin-like growth factors. Over the past decade, a series of studies has begun to uncover the relationship between specific long-chain polyunsaturated fatty acids (PUFAs) that influence the differentiation and activity of cells in bone and cartilage-like tissues. The mechanisms behind PUFAs appear to be in the alteration of prostaglandin formation, cell-to-cell signalling and an effect on transcription factors in vivo.33 Although the data on rats and other vertebrates seem conclusive, human studies are some way behind.

In a randomised, placebo-controlled design, 40 women with age-related osteoporosis were divided into four groups.34 For 16 weeks, each day they received one of four treatments: 4g evening primrose oil; 4g fish oil; 4g of a fish and evening primrose oil mixture; or 4g olive oil placebo. In the fish oil-only group, serum calcium, osteocalcin and collagen increased while alkaline phosphatase decreased. Evening primrose oil alone had no significant effects, but the positive results from the fish oil group were enhanced when combined with evening primrose oil. Researchers suggest that evening primrose oil may synergistically enhance the effect of fish oil.

A follow-up study in humans by the same group confirmed earlier animal data that gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) enhance calcium absorption, reduce excretion and increase deposition in bone.35 Sixty-five women older than 70, taking a background diet low in calcium, were randomly assigned to GLA + EPA or coconut oil placebo capsules, in addition to 600mg/day calcium as the carbonate. Markers of bone formation/degradation and BMD were measured at baseline, 6, 12 and 18 months. A cohort of 21 of the original patients continued on treatment for a further period of 18 months (36 months total), after which BMD was measured. At 18 months, osteocalcin and deoxypyridinoline levels fell significantly in both groups, indicating a decrease in bone turnover, whereas bone-specific alkaline phosphatase rose, indicating the beneficial effects of calcium given to all the patients.

Over the first 18 months, lumbar spine density remained the same in the treatment group but decreased 3.2 per cent in the placebo group. Femoral bone density increased 1.3 per cent in the treatment group but decreased 2.1 per cent in the placebo group. During the second period of 18 months, with all patients now on active treatment, lumbar spine density increased 3.1 per cent in patients who remained on active treatment and 2.3 per cent in patients who switched from placebo to active treatment. Femoral BMD in the latter group showed an increase of 4.7 per cent. This pilot study suggests that GLA and EPA have beneficial and safe effects on bone in elderly patients over a prolonged period of time. To date there are only two human-based clinical trials; although suggestive, convincing evidence from these studies on the effect of n-3 PUFA on prostaglandin formation is still lacking.

Soy, ipriflavone

Ipriflavone is a synthetic form of naturally occurring isoflavones synthesised from the soy isoflavone daidzein. Ipriflavone shows promise for its ability to prevent deterioration of BMD. In a study conducted by researchers in Italy, 56 post-menopausal women were given 1g calcium + 200mg (three times/day) of ipriflavone or a placebo. After two years of treatment, women taking calcium showed only a five per cent decline in BMD, but no significant decline was reported in those taking ipriflavone.36 Similar data has been shown in a recent study from Japan.37 These data suggest that ipriflavone suppresses bone resorption, and new research released in 2003 has shown beneficial effects on patients who have undergone ovariectomy and steroid use.38,39

The current crop of research studies shows that some nutritional bioactive compounds can have a therapeutic effect by decreasing bone resorption. These nutrients may also reduce the susceptibility of dietary deficiencies in elderly populations. Although there has been some progress in bone health and the impact of nutratherapeutics, long-term studies are required from a perspective of optimising bone health from a young age, where the latest studies suggest peak bone density is derived.40

Mark James Tallon, PhD, is CEO and chief science officer of Oxygenics Ltd, a nutritional consulting firm based in the UK. [email protected]
Respond: [email protected]

Table 1: Global food health foods market

Bone health supplements




% of market
(in $millions)































Source: Bone Health Condition-Specific Markets: Supp, Rx 1999-2001. Nutrition Business Journal

Table 2: Benefits of nutrients to bone health



Health benefit

Clinically effective dose


Increases bone mineral density (BMD)



Decreases susceptibility to fracture in some populations


Vitamin D

Maintains serum calcium and phosphorous



Decreases fracture incidence


Increases calcium transport


Vitamin K

Influences synthesis and excretion of osteocalcin



Increases synthesis of interlukin 1 and 6


Increases bone mineral density


Decreases fracture rate



Increases bone mineral density

200mg 3x/day


Increases alkaline phosphatase



Mediates prostaglandin release

GLA: 250mg-2g EPA: 900mg-3g


Increases bone formation



Increases calcification of bone

In-vitro data only


Increases alkaline phosphatase activity



Possible modulator of hormonal osteoblast and osteoclast differentiation



Increases augmentation of osteoproteginin



Increases bone formation in the elderly



Decreases bone resorption in the elderly


Transglacto-Oligosacchaides (TGO)

Increases absorption of essential bone minerals, including calcium and magnesium

20g 2x/day

Research needs to catch up to marketing

Over the past decade there is no doubt that the nutrition and functional foods market has grown in its understanding of the science of bone health. The biggest change has been the re-thinking of the calcium story and the development of efficacious products. As a result, technologists, scientists and the food industry as a whole have increased their interest and investment in developing new and novel ways of turning evolving technologies into marketable niches. However, due to restrictions in food labelling and health claims laws, this task has been a challenging one.

Schiff, a subsidiary of Salt Lake City-based Weider Nutrition International, has attempted to integrate new science into their products, yet with little success. Luke Bucci, PhD, VP of research at Schiff, comments: "We tried to integrate a multimineral bone health product with calcium, but sales were so slow we discontinued it a couple of years ago."

Bucci went on to say: "Part of the difficulty of implementing novel ingredients is that cost inhibits wide-scale distribution. There is still a great deal of potential in delivering value for calcium and other bone nutrients, and this is the short-term goal of Schiff's bone-health product line."

In contrast, experts in bone health see a slightly different future in the application of novel ingredients. Robert P Heaney, MD, from Creighton University in Nebraska, is one of the world's leading researchers in bone health. He commented: "I think we will begin to see serious efforts at food fortification rather than any specific dietary supplementation for most countries in Europe and North America." Indeed, recent advances in calcium absorption have been achieved with the application of prebiotic foods.1 This may suggest one possible future food in the bone-health market.

A report in the 1990s showed that inulin-type fructans enhance Ca2+ and Mg2+ absorption and also increase iron and zinc without a significant effect on Cu2+ bioavailability.2 As such, prebiotic science has become a buzz research field. The application of prebiotics to mineral absorption was recently assessed in three infant formulas fortified with soluble dietary fibres (3 per cent dry weight) and modified starches (16 per cent pregelatinised rice starch and 1.9 per cent maltodextrin dry weight).3 Pooled mature human milk was used as the reference standard. Calcium availability from a standard formula was elevated by 30 per cent after inulin supplementation (17.2 per cent), whereas locust bean gum (11.9 per cent) and high esterified pectin (11.7 per cent) reduced availability by approximately 10 per cent.

In a similar double-blind crossover study, a group of post-menopausal women consumed 200mL of yoghurt containing 20g of transgalacto-oligosaccharides (TOS) or a sucrose placebo twice a day.4 The use of the TOS-fortified yoghurt led to a true increase in calcium absorption of 16 per cent. This was not accompanied by increased urinary calcium excretion, meaning that TOS also may indirectly increase the uptake of calcium by bones and/or inhibit bone resorption. These studies show that the addition of soluble dietary fibre affects calcium availability in both positive (inulin or TOS) and negative ways, depending on the type of the dietary fibre.

On a final note, cutting-edge research carried out in Japan by Dr Miyake and colleagues suggests the flavonols kaempferol and quercetin may be the next line of promising agents for the prevention or treatment of bone loss, as a recent study has shown both these flavonols inhibit bone resorption.5 The action of kaempferol alone can also up-regulate alkaline phosphotase activity and calcium deposition. However, when combined, these nutrients provided a greater synergistic effect on the induction of alkaline phosphotase and calcium deposition.6 Although these studies are promising, in vivo data are desperately needed to confirm a significant functional effect of prebiotics or flavonols to long-term bone health.



1. van den Heuvel EG, et al. Oligofructose stimulates calcium absorption in adolescents. Am J Clin Nutr 1999;69(3):544-8.

2. Coudray C, et al. Effect of soluble or partly soluble dietary fibres supplementation on absorption and balance of calcium, magnesium, iron and zinc in healthy young men. Eur J Clin Nutr 1997;51(6):375-80.

3. Bosscher D, et al. Availabilities of calcium, iron, and zinc from dairy infant formulas is affected by soluble dietary fibers and modified starch fractions. Nutrition 2003;19(7-8):641-5

4. van den Heuvel EG, et al. Transgalactooligosaccharides stimulate calcium absorption in postmenopausal women. J Nutr 2000;130(12):2938-42.

5. Wattel A, et al. Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption. Biochem Pharmacol 2003;65(1):35-42.

6. Miyake M, et al. Promoting effect of kaempferol on the differentiation and mineralization of murine pre-osteoblastic cell line MC3T3-E1. Biosci Biotechnol Biochem 2003;67(6):1199-205.

1. WHO Scientific Group on the Burden of Musculoskeletal Conditions at the Start of the New Millennium.(2003: Geneva, Switzerland). The burden of musculoskeletal conditions at the start of the new millennium: report of a WHO scientific group. WHO technical report series 919:1-177

2. Bone Health Condition Specific Markets: Supp, Rx 1999-2001 ($M). Nutrition Business Journal (San Diego, CA;

3. O'Neill TW, Roy DK. The epidemiology and scale of the problem. Hosp Med 2003;64 (9):517-20.

4. Gennari C. Intestinal calcium absorption in postmenopausal osteoporosis. Bibl Nutr Dieta 1983;(33):100-6.

5. Recker RR, et al. Calcium absorbability from milk products, imitation milk, and calcium carbonate. Am J Clin Nutr 1988;47:93-5.

6. Smith TM, et al.Absorption of calcium from milk and yogurt. Am J Clin Nutr 1985;42:1197-1200.

7. Heaney RP, et al. Absorbability of calcium sources: The limited role of solubility. Calcif Tissue Int 1990;46:300-4.

8. Calvo MS, et al. Elevated secretion and action of parathyroid hormone in young adults consuming high phosphorus, low calcium diets assembled from common foods. J Clin Endocrinol Metab 1988;66:823-9.

9. Calvo MS, et al. Persistently elevated parathyroid hormone secretion and action in young women after 4 weeks of ingesting phosphorous, low calcium diets. J Clin Endocrinol Metab 1990;70:823-1334.

10. Petridou E, et al. The role of dairy products and non alcoholic beverages in bone fractures among school age children. Scand J Soc Med 1997;25:119-25.

11. Heaney RP, Nordin BE. Calcium effects on phosphorous absorption: implications for the prevention and co-therapy of osteoporosis. J Am Coll Nutr 2002;21(3):239-44.

12. Draper HH, Scythes CA. Calcium, phosphorous, and osteoporosis. Fed Proc 1981;40(9):2434-8.

13. Rude RK, et al. Magnesium deficiency induces bone loss in the rat. Miner Electrolyte Metab 1998;24:314-20.

14. Rude RK, et al. Magnesium deficiency-induced osteoporosis in the rat: Uncoupling of bone formation and bone resorption. Magnes Res 1999;12:257-67.

15. Abraham GE, Grewal H. A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy. J Reprod Med 1990;35(5):503-7.

16. Resch H, et al. Evidence that fluoride therapy increases trabecular bone density in a peripheral skeletal site. J Clin Endocrinol Metab 1993;76:1622-4.

17. Riggs BL, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Eng J Med 1990;322:802-9.

18. Kaminsky LS, et al. Fluoride: benefits and risks of exposure. Crit Rev Oral Biol Med 1990;1(4):261-81

19. Beattie J, Avenell A. Trace element nutrition and bone metabolism. Nutr Res 1992;5:167-88.

20. Calhoun NR, et al. The role of zinc in bone metabolism. Clin Orthop 1974;20:212-34.

21. Seco C, et al. Effects of zinc supplementation on vertebral and femoral bone mass in rats on strenuous treadmill training exercise. J Bone Miner Res 1998;13:508-12.

22. Alagol F, et al. Sunlight exposure and vitamin D deficiency in Turkish women. Endocrinol Invest 2000;23(3):173-7.

23. Colin EM, et al. Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk. J Clin Endocrinol Metab 2003;88(8):3777-84.

24. Reid IR. The roles of calcium and vitamin D in the prevention of osteoporosis. Endocrinol Metab Clin North Am 1998;27(2):389-98.

25. Gillespie WJ, et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Oxford, UK: Cochrane Review, The Cochrane Library; 2000.

26. Lips P. Vitamin D Deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocrine Rev 2001:22(4):477-501

27. European Commission 1998 Report on osteoporosis in the European community: action for prevention. Luxembourg: European Commission Directorate General V Directorate for Public Health.

28. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69(5):842-56.

29. Braam LA, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 2003;73(1):21-6.

30. Iwamoto I, et al. A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women: a comparative study with vitamin D3 and estrogen-progestin therapy. Maturitas. 1999;31(2):161-4.

31. Taira H, et al. Menatetrenone (vitamin K2) acts directly on circulating human osteoclast precursors. Calcif Tissue Int 2003;73(1):78-85.

32. Shearer MJ, et al. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr 1996;126(4):S1181-S6.

33. Watkins BA, et al. Omega-3 polyunsaturated fatty acids and skeletal health. Exp Biol Med 2001;226(6):485-97.

34. van Papendorp DH, et al. Biochemical profile of osteoporotic patients on essential fatty acid supplementation. Nutr Res 1995;15:325-34.

35. Kruger MC, et al. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano) 1998;10(5):385-94.

36. Gennari C, et al. Effect of ipriplavone—a synthetic derivative of natural isoflavone—on bone mass loss in early years after menopause. Menopause 1998;5(1):9-15.

37. Ohta H, et al. Effect of 1 year ipriflavone treatment on lumbar one mineral density and bone metabolism markers in postmenopausal women with low bone mass. Hormone Res 1999;51:178-83.

38. Katase K, et al. Effects of ipriflavone on bone loss following a bilateral ovariectomy and menopause: a randomised placebo-controlled study. Calcif Tissue Int 2001;69(2):73-7.

39. Head KA. Ipriflavone: an important bone-building isoflavone. Altern Med Rev 1999;4(1):10-22.

40. Hirano J, Ishii Y. Effects of vitamin K2, vitamin D, and calcium on the bone metabolism of rats in the growth phase. J Orthop Sci 2002;7(3):364-9.

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