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Advanced Bone Support
Helps Prevent Bone Loss

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This formula for advanced bone support contains four vital nutrients which boost the natural processes of the body to promote healthy bone structures, particularly in older men and post-menopausal women.  The four nutrients are genistein, omega-3, vitamin D, and Vitamin K.

 

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Genistein:

 

Genistein works by assisting the action of osteoblasts, which are responsible for creating new bone tissue, and by limiting the action of osteoclasts, which are responsible for breaking down bone tissue.  The body is constantly breaking down and renewing bone tissue, but in individuals with osteoporosis, the rate at which tissue is broken down begins to exceed the rate at which tissue is renewed.  According to the Tokyo Medical and Dental University, genistein may be used in drugs which fight osteoporosis.
 

“Genistein can prevent bone resorption diseases by the promotion of bone formation and the prevention of bone resorption…”  Japanese study cited by the National Institutes of Health

Studies have shown that genistein, a soy isoflavone, performs the same function as estrogen in bone formulation.  Both estrogen and genistein bind with the nuclear receptors ER-beta and ER-alpha.  ER-beta is dominant in bone tissue, while ER-alpha is dominant in breast and uterus tissue.  Genistein binds more strongly with ER-beta in bone tissue than with ER-alpha in breast and uterus tissue, so that genistein actually performs more efficiently than estrogen does in bone formulation. 

Omega-3:

Omega-3 is an essential fatty acid found naturally in substances like fish oil, evening primrose, black currant, and borage oil.  Studies in South Africa and at Purdue University have indicated that calcium supplements alone are not sufficient to promote bone strength in older adults, and that the addition of omega-3 acids significantly increases the body’s ability to formulate new bone tissue.  Omega-3 works by inhibiting cytokines, a common protein which negatively affects bone strength.  The precise means by which omega-3 contributes to healthy bones is not known for sure, but experiments have clearly shown that omega-3 significantly improves the body’s natural ability to strengthen bones.

Vitamin D:

Vitamin D is produced naturally by the body, but as one ages, the body produces less and less of this essential nutrient.  For this reason, vitamin D is a crucial supplement to the diet of all older adults.  Vitamin D regulates calcium intake and increases the production of osteocalcin by osteoblasts.  When combined with other minerals like calcium and magnesium, vitamin D helps the body maintain bone strength.  Studies indicate that vitamin D can have a particularly strong effect on alleviating the symptoms of rheumatoid arthritis.

Vitamin K:
Vitamin K also assists in the production of osteocalcin by osteoblasts.  In addition, vitamin K decreases calcium excretion, thereby greatly enhancing the body’s ability to make efficient use of calcium supplements.  Like omega-3, vitamin K reacts with the cytokines which are responsible for the breaking down of bone tissue.  When combined with omega-3 acids and vitamin D, vitamin K may significantly improve the health of bones.


Healthy Bones

Bone loss can be caused by a number of conditions, including bowel diseases, food allergies, and Lyme disease.  Bone loss is also responsible for further ailments, such as depression. It is therefore vitally important to maintain healthy bones throughout one’s lifetime.  As the body ages, its ability to naturally maintain healthy bones decreases, but with the right combination of nutrients, the body’s natural processes may be greatly enhanced.


To see a summary of research on these four ingredients, click here. Further references may be found below.

 

 

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References:

Broadhurst, C. Leigh, PhD.  “Polyunsaturated Fatty Acids (PUFA) for Bone Growth and Repair”.  Nutrition Science News.  March, 2001.

Haynes, D.R., Crotti, T.N., Loric, M., et al. Osteoprotegrin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology (2001); 40:623-630.

Heaney, R.P., Carvey, R., Harkness L. Roles of vitamin D, n-3 polyunsaturated fatty acid, and soy isoflavones in bone health. J Am Diet Assoc (2005);105:1700-1701

Shen, C.L., Yeh, J.K., Rasty, J., et al. Protective effect of dietary long-chain n-3 polyunsaturated fatty acids on bone loss in gonad-intact middle-aged male rats. Brit J Nutr (2006) 95:462-468

McCarty, M.F. Isoflavones made simple – Genistein’s agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses (2006);66:1093-1114.

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.

Watkins, B.A., Li, Y., Lippman, H.E., et al. Omega-3 polyunsaturated fatty acids and skeletal health. Exp Biol Med (2001);226:485-497.

Weber, P. Vitamin K and bone health. Nutrition (2001);17:880-887.

Ullmann, U., Bendik, I., Fluhmann, B. Bonsitein™ (synthetic genistein), a food component in development for a bone health nutraceutical. J Physiol Pharmacol (2005);56(suppl 1):79-95.

 

The following are studies cited by the
National Institutes of Health:

 “Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.”

Authors:  Braam LA, Knapen MH, Geusens P, Brouns F, Hamulyak K,
Gerichhausen MJ, Vermeer C.

Department of Biochemistry, University of Maastricht, The Netherlands.

Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K1 supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K1 (1 mg/day) and a mineral + vitamin D supplement (8 microg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K1 (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K1 showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35-3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10-3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K1 may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck.

“Eicosapentaenoic acid inhibits bone loss due to ovariectomy in rats.”
Authors: Sakaguchi K, Morita I, Murota S.

Section of Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Japan.

Eicosapentaenoic acid (EPA), one of the polyunsaturated fatty acids, is well-known to have a wide variety of beneficial biological functions. In the present work we demonstrate another new beneficial effect of EPA on bone metabolism in vivo. Ovariectomized rats were divided into 4 groups under the same calorie intake condition; (1) normal diet, (2) low calcium diet (1.5 mg/day), (3) EPA-enriched diet (160 mg/day/kg), (4) EPA-enriched and low calcium diet. These diets were continued for 35 consecutive days. The bone weight of the femora and tibiae decreased significantly in the low calcium group, but the decrease was inhibited in the EPA-low calcium group. Moreover, in the rupture test, which indicates bone strength, the femora in the low calcium group were easier to break than in the normal calcium diet groups. In the EPA-low calcium group the strength of the bone was equivalent to that in the normal diet group. These results suggest that an EPA-enriched diet prevents the loss of bone weight and strength caused by oestrogen deficiency or inadequate nutrition. There is a possibility that EPA could be developed to be a novel anti-osteoporosis drug.

“Genistein prevents bone resorption diseases by inhibiting bone resorption and stimulating bone formation.”

Authors: Li B, Yu S.

Department of Oral Pathology, Peking University School of Stomatology, 22 South Zhongguancun Avenue, Haidian District, Beijing 100081, P.R. China

Genistein, a soybean-derived isoflavone, has been shown to suppress osteoclastic bone resorption. To clarify the mechanisms underlying this action, we investigated the effects of genistein on the differentiation, cytoskeleton and function in mice osteoclasts in vitro and bone metabolism in ovariectomized rats. Study design: Primary OCs were isolated from 3 week-old mice and induced by 1,25(OH)(2)D(3). Then OCs were exposed to genistein at various concentration of 0 M, 10(-9) M, 10(-8) M, 10(-7) M, 10(-6) M, and 10(-5) M. The number of TRAP+ cells were counted as well as the surface area of bone resorption on bone slice. F-actin change was observed by Confocal. In vivo, forty 12 week-old female SD rats were randomly assigned to four groups: (1) sham operated (Sham); (2) (OVX); (3) ovariectomized and treated with estradiol (OVX-E); (4) ovariectomized and received genistein (OVX-G). After 12 weeks, BMD, body weight, serum level of alkaline phosphatase (ALP), acid phosphatase (ACP), osteocalcin (OC), IL-1beta, TNFalpha, IL-6 and calcitonin (CT) were evaluated. Femur were sectioned. In addition, the serum estradiol, the weight of uteri and histological behavior were also examined to indicate the side effect of genistein to the uteri. Results: In vitro, the number of TRAP+ cells decreased depending on the concentration of genistein as well as the area of bone resorption. F-actin became disorder under Confocal. In vivo, after treated with genistein, BMD and the serum level of ALP, ACP, osteocalcin increased significantly, while the serum level of IL-1beta and TNFalpha decreased. Especially, the increase of ALP and osteocalcin of OVX-G was higher than that of OVX-E. Histologically, the pachy-trabecula were observed as well as the more mineral deposition lines. Additionally, the uterus weight index and the serum estradiol in OVX-G rats were lower significantly than those of OVX-E. The epithelia of uteri gland in OVX-G appeared cubic while those of OVX-E became squamous. Conclusions: Genistein can prevent bone resorption diseases by the promotion of bone formation and the prevention of bone resorption with slight side effect.

“Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial.”

Authors: Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM.

Medical College of Virginia, Richmond, USA.

BACKGROUND: Therapy with low-dose corticosteroids is commonly used to treat allergic and autoimmune diseases. Long-term use of corticosteroids can lead to loss of bone mineral density and higher risk for vertebral fractures. Calcium and vitamin D3 supplementation is rational therapy for minimizing bone loss, but little evidence for its effectiveness exists. OBJECTIVE: To assess 1) the effects of supplemental calcium and vitamin D3 on bone mineral density of patients with rheumatoid arthritis and 2) the relation between the effects of this supplementation and corticosteroid use. DESIGN: 2-year randomized, double-blind, placebo-controlled trial. SETTING: University outpatient-care facility. PATIENTS: 96 patients with rheumatoid arthritis, 65 of whom were receiving treatment with corticosteroids (mean dosage, 5.6 mg/d). INTERVENTION: Calcium carbonate (1000 mg/d) and vitamin D3 (500 IU/d) or placebo. MEASUREMENTS: Bone mineral densities of the lumbar spine and femur were determined annually. RESULTS: Patients receiving prednisone therapy who were given placebo lost bone mineral density in the lumbar spine and trochanter at a rate of 2.0% and 0.9% per year, respectively. Patients receiving prednisone therapy who were given calcium and vitamin D3 gained bone mineral density in the lumbar spine and trochanter at a rate of 0.72% (P = 0.005) and 0.85% (P = 0.024) per year, respectively. In patients receiving prednisone therapy, bone mineral densities of the femoral neck and the Ward triangle did not increase significantly with calcium and vitamin D3. Calcium and vitamin D3 did not improve bone mineral density at any site in patients who were not receiving corticosteroids. CONCLUSION: Calcium and vitamin D3 prevented loss of bone mineral density in the lumbar spine and trochanter in patients with rheumatoid arthritis who were treated with low-dose corticosteroids.

Polyunsaturated Fatty Acids (PUFA) for
Bone Growth and Repair

From The March 2001 Issue of Nutrition Science News

by C. Leigh Broadhurst, Ph.D

The omega-3 polyunsaturated fatty acids linoleic acid and alpha-linolenic acid can help increase bone formation and reduce bone resorption Bone strength is not normally associated with conditions such as osteo- and rheumatoid arthritis, inflammatory bowel diseases, severe food allergies, Lyme disease or the autoimmune condition known as ankylosing spondylitis. However, these conditions are known to interfere with the absorption and utilization of nutrients needed to construct healthy bone and cartilage.1 Moreover, some biochemical messengers associated with these chronic inflammatory conditions directly interfere with bone growth and repair.2
In addition, all nonsteroidal anti-inflammatory drugs (NSAIDs)— as well as scores of medicinal plants used to relieve the pain and inflammation associated with conditions such as arthritis, headaches, sports injuries and tendinitis — work wholly or partly by inhibiting cycloxygenases such as prostaglandin E2 (PGE2). And high levels of PGE2 may do more than simply aggravate aching joints. Evidence exists that lowering PGE2 levels can actually help increase bone formation and reduce bone resorption rates.3

Investigation into this aspect of inflammation has revealed that balancing essential fatty acids in the body can prevent abnormalities in bone protein matrix growth and/or mineralization.
In the case of mammals, essential fatty acids are conventionally defined as the polyunsaturated fatty acids (PUFA) linoleic acid and alpha-linolenic acid. Both have 18 carbons in the fatty acid chain. Linoleic acid is the head of the n-6 PUFA family, and alpha-linolenic is the head of the n-3 PUFA family. These two families are not interchangeable. They are like men and women—both sexes are humans, but one sex can never replace the other, and both are needed to continue the species.

When ingested and metabolized in the body, linoleic and alpha-linolenic acids are converted with enzymes to the more biochemically active long-chain polyunsaturated fats (LC-PUFAs). After years of laboratory studies, however, researchers have found that in humans this conversion is often slow or incomplete. Presumably this is because we are omnivores and evolved eating diets containing LC-PUFAs, thus we did not have to create them. Hence, some researchers now consider some LC-PUFAs as essential or conditionally essential.4

The 20-carbon n-6 LC-PUFA arachidonic acid (AA) is one such fatty acid that could be considered essential. Arachidonic acid is found in cell membranes throughout the body because it is necessary for numerous body processes. It also makes up about half of the PUFAs in our brains and nervous systems. The placenta and sperm are rich in AA. Infants, growing children, and pregnant and nursing women in particular appear to require arachidonic acid in the diet in order to achieve optimal growth and health.

Arachidonic acid is best known as the substrate for the series-2 eicosanoids. Eicosanoids are hormonelike biochemicals that control activities locally where they are produced. There are three series of eicosanoids, which all function in virtually the same manner.

The biochemical reactions required to make series-2 eicosanoids from arachidonic acid are controlled by the sister enzyme systems cycloxygenase and lipoxygenase. Cycloxygenases are well known for their ability to change arachidonic acid into eicosanoids such as prostaglandin E2 (PGE2). PGE2 production is an important reaction to trauma and injury, which increases inflammatory mediators as the body tries to react to the damage. Unfortunately, in many chronic conditions this process becomes unbalanced and an overproduction of PGE2 results in a chronic inflammatory response. Such a response can have long-term effects on bone health.

Bone Modeling and Remodeling

The human skeleton is not static. Bone is a highly active metabolic tissue, continually changing throughout life. The process of bone modeling is associated with body growth in children, teenagers, and young adults, when 100 percent of their bone surface is active. Modeling adds length, width, and weight to bones and increases overall skeletal mass. Bone remodeling, on the other hand, is the process of bone growth associated with maintaining a fixed adult bone mass. In remodeling, only about 20 percent of the bone surface is active. Older bone tissue is destroyed (resorption) and replaced by new bone tissue (formation) in a cyclical process.5 In the case of osteoporosis, the basic problem is that resorption gets ahead of formation, resulting in a net bone loss.

Bone supports and protects, manufactures various immune and blood cells, and is a "metabolic reservoir" for calcium, magnesium, and phosphorus. While minerals such as calcium and magnesium are necessary for bone formation, they do not supply enough to produce bone. For example, calcium intake beyond dietary requirements does not stimulate bone formation. Instead, bone metabolism is under the control of many hormones and growth factors, including activated vitamin D, estrogen, growth hormone, insulin, insulinlike growth factor, parathyroid hormone, and various eicosanoids—with PGE2 playing a major role.6

At low levels, PGE2 apparently stimulates bone formation. The mechanism for this may be that PGE2 increases the production of insulinlike growth factor, a powerful "master" growth stimulator for bone, cartilage, and muscle. Surprisingly, high or excessive levels of PGE2 swamp this effect, and bone formation is reduced and resorption is increased.7 In bone modeling, this pattern leads to reduced skeletal growth. In bone remodeling, this pattern leads to osteoporosis. Growth opportunity lost in childhood can never be fully compensated for in adulthood and may put an individual at greater risk for osteoporosis later in life. Therefore, it is important to maintain low levels of PGE2 throughout one's lifetime.

Nutritional Strategy for Lowering PGE2

Just as the n-6 LC-PUFA arachidonic acid gives rise to series-2 eicosanoids, eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA) serve as substrates for the series-1 and -3 eicosanoids, respectively. DGLA and EPA compete with arachidonic acid for the cycloxygenase and lipoxygenase enzymes, thereby reducing—but not eliminating—the production of series-2 eicosanoids. High intakes of fish, black currant, evening primrose, and borage oils have been shown to moderately increase production of series-1 and -3 prostaglandins at the expense of PGE2; therefore, specialized PUFA supplementation may help optimize bone modeling and remodeling.12

In a 2000 study conducted at Purdue University in West Lafayette, Ind., this nutritional approach was tested on bone modeling in growing rats.8 For 42 days, groups of 15 rats were fed identical diets except that the n-6 to n-3 PUFA ratios differed. Fish oil and safflower oil were mixed to produce n-6 to n-3 ratios of 23:8, 9:8, 2:6, and 1:2. Rat liver and bone tissue samples showed both PGE2 levels and serum alkaline phosphatase decreased as the proportion of n-6 to n-3 decreased. High levels of alkaline phosphatase indicate bone is being resorbed. Moreover, rats fed the 1:2 ratio diet had slightly higher rates of bone formation.

Only a single 1995 South African human study has specifically examined the effects of LC-PUFA supplementation on osteoporosis.9 Forty elderly women with age-related osteoporosis were divided into four groups. They received one of four treatments daily for 16 weeks: 4 g evening primrose oil; 4 g fish oil; 4 g of a fish and evening primrose oil mixture; or 4 g olive oil placebo. The women took no other medications, supplements, or special foods. In this study fish oil increased serum calcium, osteocalcin and collagen, and decreased alkaline phosphatase. Evening primrose oil alone had no significant effects, but the positive results from the fish oil group were also seen in the fish oil plus evening primrose oil group. According to the research team, evening primrose oil may have potentiated the effects of fish oil.

Mood and Bone

Clinical depression in both women and men has been correlated with reduced bone density. In a 1997 National Institutes of Health study, 24 women with a history of major depression were compared to 24 controls. Subjects were matched for age, race, body-mass index, and menopausal status. Upon testing, various bone sites showed densities 6.5 to 13.6 percent lower in the depressed women.10 Clinical depression is known to be associated with strongly reduced levels of n-3 LC-PUFAs, and clinically depressed people have been found to respond to fish oil supplementation. Deficiencies of n-3 PUFA may be a common link between depression and reduced bone density, both prevalent in older people.11

Bone is a complex tissue whose health and maintainence needs a great deal of nutritional support. Yet many postmenopausal women still take excessive amounts (1.5 to 2 g) of calcium per day—often at their doctor's recommendation—without any complementary supplements such as magnesium, silicon, boron, protein and vitamin D. Even in the natural products industry we actively push menopausal women toward soy milks and cheeses that do not naturally contain vitamin D and are not necessarily fortified with vitamin D like their dairy counterparts are. With the insights that the n-3 to n-6 PUFA ratio directly affects bone modeling, and that fish oil may increase the rate of bone formation, perhaps we can broaden our thinking beyond single "bone health" products and toward an integrated protocol approach.

Doses of 2 g per day of fish oil, evening primrose, or black currant or borage oil are reasonable and safe, and may enhance bone formation, especially when used on a long-term, preventive basis.12 We can expect that those in the medical community interested in bone health will embrace these nutrients in the next five years, as was calcium in the 1990s. For those who create and dispense such supplements, the time is now.

C. Leigh Broadhurst, Ph.D., heads 22nd CenturyNutrition, a nutritional/scientific consulting firm, and is the author of Diabetes: Prevention and Cure (Kensington, 1999)

References:

1. Fukuda K, et al. Superoxide dismutase inhibits interleukin-1-induced degradation of human cartilage, Agents Actions 1994;42:71-3.

2. Bonjour JP, Tsang RC, editors. Nestle Nutrition Workshop Series, Volume 41: Nutrition and bone development, Philadelphia (PA): Lippincott-Raven Publishers; 1999.

3. Plotquin D, et al. Prostaglandin release by normal and osteomyelitic human bones. Prostglandins Leukot Essent Fatty Acids 1991;43:13-15.

4. Crawford MA, et al. Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids 1999;34:S39-S47.

5. Watkins B. Regulatory effects of polyunsaturates on bone modeling and cartilage function. World Rev Nutr Dietetics 1998;83:38-51.

6. Watkins B, et al. Importance of dietary fat in modulating PGE2 responses and influence of vitamin E on bone morphometry. World Rev Nutr Dietetics 1997;82:250-9.

7. Baylink DJ, et al. Growth factors to stimulate bone formation. J Bone Min Res 1993;8:S565-S572.

8. Watkins B, et al. Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats. J Nutr 2000;130:2274-84.

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

10. Michelson D, et al. Bone mineral density in women with depression. NEJM 1996;335:1176-81.

11. Horrobin DF, Bennet CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Prostglandins Leukot Essent Fatty Acids 1999;60:217-34.

12. Broadhurst CL, Winther M. Evening primrose oil: pharmacological and clinical applications. In Mazza JG, Ooma BD, editors. Functional foods: herbs, botanicals and teas. Lancaster, (PA): Technomic Publishing;2000. P 213-64

Genistein reverses bone loss

- Literature Review & Commentary

Townsend Letter for Doctors and Patients,  May, 2003  by Alan R. Gaby

Ninety healthy postmenopausal women (aged 47-57 years) with osteopenia (bone mineral density [BMD] of the femoral neck of less than 0.795 g/[cm.sup.2]), were randomly assigned to receive, in double-blind fashion, either 1) continuous hormone-replacement therapy (HRT; 1 mg of l7beta-estradiol combined with 0.5 mg of norethisterone acetate daily), 2) genistein (54 mg/day), or 3) placebo for 1 year. Genistein significantly reduced the excretion of pyridinium cross-links (an indicator of bone resorption) at 6 and 12 months; a similar decrease was seen in the HRT group. Genistein also significantly increased serum levels of bone-specific alkaline phosphatase and osteocalcin (markers of bone formation) at 6 and 12 months, whereas HRT significantly decreased these values at 6 and 12 months. At 12 months, compared with baseline, the mean BMD of the femoral neck increased by 3.6% in the genistein group and by 2.4% in the HRT group, compared with a 0.65% decrease in the placebo group (p < 0.01 for each active treatment vs. placebo). At the lumbar spine the mean changes in BMD were 3.0% for genistein, 3.8% for HRT, and -1.6% for placebo (p < 0.001).

Comment: These results indicate that administration of genistein (an isoflavone present in soybeans) to osteopenic postmenopausal women reduced bone resorption, increased bone formation, and increased BMD of the femoral neck and lumbar spine. The effect on BMD was similar to that of conventional hormone-replacement therapy. The results of this study are consistent with those of previous research, in which genistein stimulated osteoblastic bone formation, inhibited osteoclastic bone resorption, and prevented bone loss in ovariectomized rats. Beneficial effects of isoflavone-rich soy protein on BMD have also been reported in both animals and postmenopausal women. The effect of genistein may be mediated, in part, by its estrogenic activity. However, the response to genistein in the present study differed from that of conventional HRT. Specifically, both treatments reduced markers of bone resorption, but only genistein increased markers of bone formation. Because their actions are not the same, it is possible that genistein (or soy protein) might enhance the effect of HRT; it is also possible that soy isoflavones might increase the risks associated with HRT. Additional research is needed to investigate these possibilities.

Canadian Medical Association Journal

 “Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 8. Vitamin D metabolites and analogs in the treatment of osteoporosis.”

G Jones, D B Hogan, E Yendt, and D A Hanley. Department of Biochemistry, Queen's University, Kingston, Ont.

OBJECTIVE: To review recent findings on the skeletal actions of vitamin D and to examine results of the latest clinical trials of vitamin D in the treatment of osteoporosis. OPTIONS: The vitamin D analog 1-alpha hydroxycholecalciferol (1 alpha-OH-D3); the vitamin D metabolite calcitriol. OUTCOMES: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with vitamin D therapies. EVIDENCE: Relevant laboratory and clinical studies and reports were examined. Greatest reliance was placed on recent large-scale, randomized, controlled trials; others were noted and their methods critiqued. Clinical practice in Japan was also considered. VALUES: Reducing fractures, increasing bone mineral density and minimizing side effects of treatment were given a high value. BENEFITS, HARMS AND COSTS: Vitamin D maintains the dynamic nature of bone and so presumably helps to keep it healthy. Calcitriol and 1 alpha-OH-D3 may be effective in increasing bone mass and preventing fractures in osteoporosis. Calcitriol may be an alternative treatment in the prevention and management of corticosteroid-induced osteoporosis. Possible side effects of vitamin D analogs and metabolites are hypercalcemia, hypercalciuria, renal calcification and renal stones. RECOMMENDATIONS: The use of 1 alpha-OH-D3 for the treatment of osteoporosis in Canada cannot be supported without larger and longer randomized, controlled clinical trials. Calcitriol appears to prevent vertebral fractures in patients with osteoporosis. More information is needed on its mechanism of action and efficacy in preventing hip fractures. Future studies should focus on comparisons with other effective therapies and on determining whether its effect on fractures is greater than that achieved through improved vitamin D nutrition. Patients taking calcitriol at dose levels required for antifracture effects should be monitored for serum and urine calcium response to the drug. Calcitriol should not be given to patients whose calcium intake is at current generally recommended levels. At present, prescription of calcitriol for the treatment of osteoporosis should be reserved for physicians with a special interest in the treatment of metabolic bone disease.

Genistein and Osteoporosis:

Journal of bone and mineral research  (J. bone miner. res.)  ISSN 0884-0431   CODEN JBMREJ  2002, vol. 17, no10, pp. 1904-1912 (41 ref.); American Society for Bone and Mineral Research, Duham, NC, ETATS-UNIS (1986) (Revue)

The natural isoflavone phytoestrogen genistein has been shown to stimulate osteoblastic bone formation, inhibit osteoclastic bone resorption, and prevent bone loss in ovariectomized rats. However, no controlled clinical trial has been performed so far to evaluate the effects of the phytoestrogen on bone loss in postmenopausal women. We performed a randomized double-blind placebo-controlled study to evaluate and compare with hormone-replacement therapy (HRT) the effect of the phytoestrogen genistein on bone metabolism and bone mineral density (BMD) in postmenopausal women. Participants were 90 healthy ambulatory women who were 47-57 years of age, with a BMD at the femoral neck of <0.795 g/cm[2]. After a 4-week stabilization on a standard fat-reduced diet, participants of the study were randomly assigned to receive continuous HRT for 1 year (n = 30; 1 mg of 17β-estradiol [E[2]] combined with 0.5 mg of norethisterone acetate), the phytoestrogen genistein (n = 30; 54 mg/day), or placebo (n = 30). Urinary excretion of pyridinoline (PYR) and deoxypyridinoline (DPYR) was not significantly modified by placebo administration either at 6 months or at 12 months. Genistein treatment significantly reduced the excretion of pyridinium cross-links at 6 months (PYR = -54 ± 10%; DPYR = -55 ± 13%;p < 0.001) and 12 months (PYR = -42 ± 12%; DPYR = -44 ± 16%; p < 0.001). A similar and not statistically different decrease in excretion of pyridinium cross-links was also observed in the postmenopausal women randomized to receive HRT. Placebo administration did not change the serum levels of the bone-specific ALP (B-ALP) and osteocalcin (bone Gla protein [BGP]). In contrast, administration of genistein markedly increased serum B-ALP and BGP either at 6 months (B-ALP = 23 ± 4%; BGP = 29 ± 11%; p < 0.005) or at 12 months (B-ALP = 25 ± 7%; BGP = 37 ± 16%; p < 0.05). Postmenopausal women treated with HRT had, in contrast, decreased serum B-ALP and BGP levels either at 6 months (B-ALP = -17 ± 6%; BGP = -20 ± 9%;p < 0.01) or 12 months (B-ALP = -20 ± 5%; BGP = -22 ± 10%; p < 0.001). Furthermore, at the end of the experimental period, genistein and HRT significantly increased BMD in the femur (femoral neck: genistein = 3.6 ± 3%, HRT = 2.4 ± 2%, placebo = -0.65 ± 0.1%, and p < 0.001) and lumbar spine (genistein = 3 ± 2%, HRT = 3.8 ± 2.7%, placebo = -1.6 ± 0.3%, and p < 0.001). This study confirms the genistein-positive effects on bone loss already observed in the experimental models of osteoporosis and indicates that the phytoestrogen reduces bone resorption and increases bone formation in postmenopausal women.

“The Effect of Genistein on Alveolar Bone Resorption in Vitro and in Vivo”

B. LI1, S. YU2, and S. PANG2, 1Beijing Medical University, Peking University School of Stomatology, China, 2Beijing Medical University, China

Objective: To investigate the effect of genistein, a soybean-derived isoflavone, on the osteoclastic bone resorption in vitro and in vivo. Methods: Primary osteoclast-like cells (OLCs) were exposed to genistein at various concentration.The number of TRAP+ cells was counted as well as the surface area of bone resorption on bone slice. The mRNA level of RANKL and OPG were tested by RT-PCR. Additionally, forty 12 wk-old female SD rats were randomly assigned to four groups: ¢Ùsham operated (Sham group); ¢Úovariectomized (OVX group); ¢Ûovariectomized and treated with estradiol (E group); ¢Üovariectomized and received genistein (G group). After 12 weeks, alveolar bone, mandible,tibia and uteri were fetched and sectioned. The indexes of distance of double label(DDL) and mineral appositional rate (MiAR) were calculated under the fluorescent microscope. The serum estradiol were also examined by immunoradiometric assay. Results: In vitro, the number of TRAP+ cells decreased depending on the concentration of genistein as well as the area of bone resorption. Genistein could enlarge the ratio between the mRNA level of OPG and RANKL in the pattern of dosage-depended and time-depended. Histologically, there were more osteoblasts attached in the alveolar and mandible in G group and no osteoclastic bone resorption were observed after treated with genistein. The indexes of DDL and MiAR were also decreased after treated with genistein. The uterus weight index and the serum estradiol in G group rats were lower than those of E group. The epithelia of uteri gland in G group appeared cubic while those of E group became squamous. Conclusion: Genistein inhibited OLCs' bone resorption through suppression the differentiation of pre-osteoclasts, and the ratio between OPG and RANKL may be the key factor. Histologically genistein can prevent osteoclastic bone resorption and stimulate bone formation in vivo with slight side effect on the uteri.  
                  

 “Selective Effects of Genistein, a Soybean Isoflavone, on B-Lymphopoiesis and Bone Loss Caused by Estrogen Deficiency”1

Authors: Yoshiko Ishimi, Chisato Miyaura, Mineko Ohmura, Yoshiko Onoe, Toshiyuki Sato, Yosuke Uchiyama, Masako Ito, Xinxiang Wang, Tatsuo Suda and Sachie Ikegami
Department of Food Science (Y.I., M.O., X.W., S.I.), The National Institute of Health and Nutrition, Tokyo 162, Japan; Department of Biochemistry (C.M., Y.O., T.Su.), School of Dentistry, Showa University, Tokyo 142, Japan; Exploratory Research Laboratories III (T.Sa., Y.U.), Daiichi Pharmaceutical Company Ltd., Tokyo 134, Japan; Department of Radiology (M.I.), School of Medicine, Nagasaki University, Nagasaki 852, Japan; and Department of Biochemistry (C.M.), School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji 192, Japan
These results indicate that genistein exhibits estrogenic action in bone and bone marrow, to regulate B-lymphopoiesis and prevent bone loss, without exhibiting estrogenic action in the uterus. Phytoestrogens may be useful for preventing bone loss caused by estrogen deficiency in females.

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