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Chapter 7.
Dietary Supplements in Bone Health/Osteoporosis- Efficacy and Safety
Maureen Geraghty, PhD, RD/LD
Introduction
1
Dietary supplements contain ingredients intended to supplement the diet, such as vitamins,
minerals, herbs, other botanicals, amino acids and other substances.1 “An ounce of prevention is
worth a pound of cure” is never more appropriate than when it comes to the nutrition
interventions and bone health. As with most medical/nutrition interventions, optimal nutrient
intake is simpler and more cost- effective, than the medical treatment necessitated by the medical
sequelae following an osteoporotic fracture.
Osteoporosis results when osteoclastic activity (bone resorption) exceeds that of osteoblastic
activity (bone formation), ultimately leading to osteoporosis. One in every 3 women and one in
every 12 men suffers an osteoporosis-related fracture at some point in their lives, with the most
common sites being the hip, spine, or wrists.2 Estrogen decreases bone resorption by
decreasing osteoclastic activity. Rapid bone loss ensues in women as estrogen levels fall after
menopause, losing up to 20% of bone in the first 5-7 years following menopause. Men have 20%
more bone than women, thus bone loss progresses more slowly and occurs later in life than it
does in women.3
Lifestyle factors and nutrition play instrumental roles in the attainment of ideal peak bone mass
as well as in the acceleration of bone loss. Lifestyle factors which positively affect bone mass
are weight-bearing exercise and estrogen, though estrogen is not without major risks. Those
lifestyle factors which have a negative effect on bone mass are smoking (associated with lower
bone density in women4,5 and a strong predictor of bone mass in men,6 and alcohol ingestion,
which has been shown to have a dose-response relationship with hip and forearm fractures.7
Nutrition factors affecting bone mineral density are numerous. Major vitamins and minerals such
as vitamin D and calcium, and even magnesium play a significant role in bone health, and
vitamins C and K are important in the synthesis and function of select bone proteins. Other
2
nutrients playing moderate to minor roles include fluoride, boron, copper, manganese, strontium,
and zinc. In addition to conventional vitamins and minerals, dietary/herbal supplements have
become widely used in the prevention and treatment of osteoporosis. A list of these non-
vitamins, non-mineral dietary/herbal supplements purported to be advantageous in bone health
can be found in Table 1.
Table 1. Non-vitamin, non-mineral Dietary Supplements Purported to be Beneficial for
Bone Health.18
•Supplement •Latin or chemical name
•Alfalfa
•DHEA
•Dong quai
•Licorice
•Ginseng
•Flaxseed
•Red Clover
•Soy
•Medicago sativa
•Dehydroepiandrosterone
•Angelica sinensis
•Glycyrrhiza glabra
•Panax Ginseng
•Linum usitatissimum
•Trifolium pratense
•Glycine max
The following is a brief review regarding the role of conventional nutrients as well as
dietary/herbal supplements in the prevention and treatment of osteoporosis.
Major Vitamins and Minerals
Calcium and Vitamin D
Adequate calcium and vitamin D are considered first line therapy for preventing and treating
osteoporosis. Sufficient calcium intakes are especially important when young: during
childhood, adolescence and the young adult years, allowing for the full genetic expressing of
peak skeletal mass, which occurs in young adulthood (early 20s-early 30s).3 It has been shown
that this optimal intake earlier in life is correlated with improved bone mass and mineral density
in children and teens8,9 and correlates with bone mineral density when women are in their 30s.10
3
Even though peak bone mass is achieved by early adulthood, calcium continues to be required
throughout life to maintain serum calcium levels, optimal muscle function, and to prevent
resorption of calcium from bone, if possible. It has been shown in premenopausal women over
40 that the rate of bone loss averages by 0.5%-1.0% in women taking eating calcium food
sources and/or taking supplement, and even higher in women not ingesting adequate levels.11,12
This is a key period where bone loss can be significantly minimized if supplementation levels are
at 1000 mg/day. Unfortunately, it has been demonstrated that in the 5 years following actual
menopause, the estrogen deficiency renders calcium supplementation virtually ineffective.13,14
This estrogen deficiency leads to an accelerated loss of bone (resorption) and concomitant
elevated serum calcium levels, which can negate the usual enhancer mechanisms of intestinal
calcium absorption.15 Following this 5-year time frame, calcium supplementation again has
significant positive effects on preventing bone loss. A plethora of calcium research has been
conducted in this area; it has been shown that the unsupplemented postmenopausal woman loses
approximately 2% bone/year16,17 while the supplemented woman (1000-1600 mg calcium/day)
will experience a 0.25%-1% decrease in the rate of bone lost.11-14,16-22 The Institute of
Medicine’s Daily Reference Intake (DRI) chart for all age groups for elemental calcium intake
can be found in Table 2.
Table 2. Institute of Medicine’s Dietary Reference Intakes (DRIs) for Calcium in Men and
Women.23
Age DRI
4
1-3 years 500 mg (mg= milligrams)
4-8 years 800 mg
9-18 years 1200 mg
19-50 years 1000 mg
51+ years 1200 mg
Pregnant/Lactating –under 19 years 1300 mg
Pregnant/Lactating-19-50 years 1000 mg
Estimations by clinical scientists postulate that 30 years of uninterrupted calcium
supplementation following menopause could result in a 10% improvement in bone mineral
density, and an impressive 50% reduction in fracture rates when compared with women not
adhering to calcium supplementation regimens.15 It has been shown that successful
supplementation must be continued throughout life, since the bone mineral density effects of 2
years of calcium supplementation are essentially negated within 2 years of discontinuing
supplementation.17,24,18,21,25
Calcium supplements come in different forms (calcium carbonate, calcium citrate, calcium
citrate maleate, calcium phosphate, calcium lactate, and calcium gluconate.18 Bioavailability of
the supplements ranges from 29-31 % 26 but the actual amount of elemental calcium is higher in
the carbonate and citrate calcium salts. It is advantageous for the clinician to know that calcium
carbonate is best absorbed when taken with food, whereas other calcium salts can be taken when
convenient for the patient; without regard to mealtimes. It is useful to know that calcium citrate
is preferential for the patient with low gastric acidity, as in the elderly or those taking
antacids/acid-blocking medications.18
Vitamin D (also known as calcitriol or Vitamin D3- as 1,25 (0H)2 D3) is a cornerstone nutrient in
bone health, for it is enhances intestinal absorption of calcium via both genomic and
nongenomic mechanisms. Genomically, the vitamin/hormone works both with cell membrane
and nuclear receptors to impact gene expression of calbindin, a calcium binding protein.3 Non-
5
genomically, calcitriol induces changes in the intestinal brush border composition and topology
to increase calcium absorption.3 Calcitriol also maintains serum calcium levels26 participates in
cell differentiation, and increases the mobilization of osteoblast stem cells.16,26 Vitamin D is in
the form of vitamin D2 in our food (ergocalciferol), and is from cholecalciferol ( vitamin D3)
from the sun. The liver converts cholecalciferol (vitamin D3) to 25-hydroxycholecalciferol (25-
(OH)D3) and the kidney in turn converts it to 1,25dihydroxycholecalciferol (1,25-OH)D3).26
Several studies demonstrate that long-term calcium supplementation, combined with Vitamin D
therapy, can decrease primary fracture rates by 25% for the hip bone and 30-35% for spinal
vertebrae.17,18,27-35 A study by Jackson et al demonstrated that participants who were adherent to
a calcium (1000 mg) vitamin D regimen (400IU) significantly reduced the risk of hip fractures
by almost 30%.36 Recommended daily dosages of vitamin D, based on the literature, range from
400 IU (10 mcg) to 800 IU (20 mcg) and taken with 1000-1200 mg/day of calcium, this
combination is safe and efficacious for preventing and treating osteoporosis.
Magnesium
Magnesium has been the mineral du jour in terms of popularity in bone health, as evidenced by
the increased number of bone health products including this major mineral. The Institute of
Medicine-Food and Nutrition Board’s DRI (Dietary Reference Intake) panel indicated that a
magnesium deficiency is considered a risk factor for osteoporosis in postmenopausal women.37
Conversely, adequate magnesium intake is associated with improved bone mineral density, as
seen in several epidemiological studies.18,38-41 Interestingly, in this postmenopausal population,
higher dietary magnesium intake also appears to decrease type 2 diabetes risk in overweight,
middle-aged women.18 Preliminary data suggests that actual magnesium supplements are
associated with a decrease in bone loss in postmenopausal osteoporotic women.42 It is important
6
to note that a greater supplemental intake than 350 mg of magnesium/day can cause diarrhea.18
Table 3 depicts all the vitamin or minerals implicated in bone health, their DRIs, and food
sources.
Vitamins C and Vitamin K
Vitamin C and K are involved in bone protein synthesis, with collagen dependent on ascorbic
acid (vitamin C) for this synthesis to occur. Over the last two decades, studies have
demonstrated positive correlations between vitamin C intake and bone mineral density in both
adolescents.43 and adult women.44 There are 3 forms of vitamin K: vitamin K1 (phylloquinone)
is plant-derived, vitamin K2 (menaquinone) is found in foods of plant origin and is also
synthesized by intestinal bacteria, and vitamin K3 (menadione) is the synthetic form.45 Three
other important bone proteins, osteocalcin, matrix Gla protein, and anticoagulant protein S have
been isolated from bone and are dependent on vitamin K. If vitamin K status is compromised,
these three proteins are not carboxylated, thus they are nonfunctional in binding calcium to
enhance bone mineralization. Clinical trials have demonstrated that large doses of vitamin K2
can decrease loss of BMD and decrease fracture rates.46 It has also been reported that vitamin
K1 can decrease BMD loss in postmenopausal women.47 Serum levels of undercarboxylated
osteocalcin are an indicator of poor vitamin K status and have been shown to be correlated with
BMD in the femoral neck and in Ward’s triangle (an area within the hip region) in women’s first
decade of menopause.48 In elderly men and women, a low vitamin K dietary intake is associated
with an increased incidence of hip fractures49 and in elderly women, serum levels of
undercarboxylated osteocalcin has been reported to predict an increased risk of hip fracture.50
Table 3. Functional Foods and DRIs
Micronutrient Micronutrient Function Food Sources Daily
DRI > 50
yrs
7
Calcium • Forms structural matrix of bone and teeth • Dairy products • Collards 1200 mg
• Fish with bones • Legumes
• Fortified foods • Spinach
Vitamin D • Calcium homeostasis • Fish 400+ IU
• Bone health • Shiitake Mushrooms
• Cell differentiation • Fortified milk and cereal
Magnesium • Forms structural matrix of bones • Dairy products • Chocolate
• Regulation of steroid hormone function • Legumes • Nuts 320 mg
• Involved in energy metabolism • Unprocessed
rice
• Seafood
• Green leafy vegetables
Vitamin A • Balances bone formation and breakdown • Liver
• Growth, cell differentiation • Pumpkin 700 μg
• Immune function • Carrot
• Vision • Sweet Potato
Vitamin C • Collagen synthesis • Citrus fruits •Strawberries
• Recharge enzymes • Brussels
sprouts
• Peppers 75 mg
• Broccoli • Papayas
Vitamin K • Carboxylation of proteins for bone and teeth
formation
• Brussels
sprouts
• Kale
• Spinach 90 μg
• Blood clotting • Broccoli
Phosphorous • Forms structural matrix of bones • dairy products • nuts
• Make up cell membranes • meat • seeds 700 mg
• seafood
Boron •Bone • Fruits • Legumes
• Nuts None
known
• Reproduction • Leafy vegetables
Copper • Connective tissue synthesis • Liver • Mushrooms
• Antioxidant function • Shellfish • Nuts 900 μg
• Related to strong bones in infants • Whole-grain • Legumes
Fluoride • Maturation of bone formation cells • Potatoes • Tea
• Strengthens bones • Fish with bones • Legumes 3 mg
• Protective against dental caries • Fluoridated water
Manganese • Required for bone formation • Spinach • Nuts
• Required for gluconeogenesis • Pineapples • Legumes 1.8 mg
• Whole-grain products
Zinc • Stabilize gene expression • Shellfish • Dairy
products 8 mg
• Antioxidant function • Meat • Legumes
• Stabilize cell membranes • Organ meats • Chocolate
Other major nutrients
Protein and phosphorus are also considered bone health nutrients, yet deficiencies in the Western
diet are rare. Adequate phosphorus is necessary for bone health, although the issue in the United
States and Europe revolves more around the possible deleterious effects of high phosphorous
8
intakes (including soft drinks) and low calcium intakes on bone turnover. Diets high in
phosphorus are usually high in protein as well.3 Prolonged ingestion of high phosphorus, low
calcium diets have been documented to result in a mild form of secondary
hyperparathyroidism.51,52 Increased PTH can stimulate bone resorption of calcium, with possible
long-term detrimental effects on bone mineral content (BMC),51-53 however, other high
phosphorus diet studies have not been shown to affect biomarkers bone resorption,54,55 thus the
jury is out and further research is necessary.3
Trace Minerals
Boron
Animal studies suggest that boron may enhance calcium and vitamin D metabolism or increase
the positive effect of estrogen on bone.56,57 The first human study investigating bone health and
boron involved 12 menopausal women who initially consumed a boron deficient diet (0.25 mg
boron/2000 kcals) for 119 days, then the same diet with 3 mg boron for 48 days. The boron
supplemented diet resulted in reduced total plasma, and increased serum 17β-estradiol and
testosterone; changes in postmenopausal women that are “consistent with the prevention of
calcium loss and bone demineralization.58 In another group of women, it was concluded that
boron supplementation enhanced the positive effects of β-estradiol on bone metabolism.59
Copper
A copper deficiency is rare and usually only seen in hospitalized patients receiving improper
nutrition support or in preterm infants. It has been documented that infants and young children
with copper deficiencies have weak bones (osteomalacia).45 It has been shown that copper’s role
9
in bone health is the inhibition of osteoblastic and osteoclastic activity, thus slowing bone
turnover.60 Spinal bone loss is prevented and BMD increased when copper and other trace
minerals (manganese and zinc) are taken in addition to calcium, when compared to calcium
supplementation alone. 18,61,62
Fluoride
It has long been recognized that dietary fluoride strengthens bones and teeth. Very few foods
provide even small amounts of fluoride (See Table 3), thus the American Dental Association
recommends that water be fluoridated to contain 1 to 2 parts fluoride per million parts water (1 to
2 ppm).63 Fluoride is also provided through most toothpastes. It has been noted that fluoride
stimulates osteoblast activity and may increase BMD (18-NMCD) but high doses have been
associated with a weakening of the bones referred to as skeletal fluorosis64 and can increase the
risk of fractures. There is preliminary data regarding a low-dose, 25 mg/day supplement in a
controlled-release form that demonstrates a reduction in fracture risk, in conjunction with the
conventional calcium and vitamin D supplementation.65 However, fluoride taken as a separate
supplement at doses greater than 25 mg/day is highly discouraged.
Manganese and zinc
Manganese is a cofactor for numerous metalloenzymes, including those for bone formation, and
decrease serum levels have been seen in women with osteoporosis.64 Zinc is also cofactor for an
estimated 300 enzymes, has a multitude of functions,64 and is concentrated in bone and muscle
tissue. It has been shown that a deficient zinc intake can lead to reduced osteoblastic activity
and compromise the synthesis of both chondroitin and collagen.65 Preliminary research61,62
suggests that the trace minerals, copper, manganese, and zinc, along with calcium, slow bone
turnover and can increase bone density.
10
Strontium
Chemically, strontium bears resemblance to calcium and approximately 90% is found in bone.18
Preliminary studies reveal that strontium supports replication of preosteoblatic cells and may
increase bone formation and decrease bone resorption by the inhibition of osteoclastic activity.66-
69 Strontium ranelate, a particular form of strontium used in clinical trials, has been shown to
reduce postmenopausal vertebral risk fracture in 40% of study participants70-72 but is not
available on the market at this time.
Clinical Pearl
Regarding vitamin and minerals and supplementation for bone health, it is recommended for
every individual that a multivitamin/mineral supplement be included in the daily regimen, along
with an additional calcium and vitamin D supplement to ensure that Dietary Reference Intakes
are being met. At this time, individual vitamins and minerals other than these two (calcium and
vitamin D), in addition to a multivitamin/mineral supplement are not widely recommended until
studies further elucidate safety and efficacy of individual nutrient supplementation beyond
dietary intakes.
Non-vitamin, Non-mineral Dietary/Herbal Supplements used in Bone Health and
Osteoporosis
Estrogenic agents
Dietary/herbal supplements commonly associated with bone health have actual estrogenic or
estrogenic-like effects18 and have been promoted for the prevention of osteoporosis. Often,
11
healthcare consumers substitute a “natural” substance for a prescription medication, under the
assumption that it will be safe and efficacious. Alfalfa, Dong quai, licorice (root) and Panax
ginseng are all herbal supplements purported to have natural estrogenic qualities (See Table 1).
Despite the marketing efforts touting these for menopause/bone loss prevention, there are no
well-designed clinical studies that can demonstrate these are effective (or safe) for prevention of
bone loss or osteoporosis.18 In terms of safety, alfalfa can cause drug-induced lupus,73 and Dong
quai can cause a severe photodermatitis (burn) from the sun,74 and has been implicated in causing
cancer.75 Licorice root is contraindicated in anyone with heart disease, hypertension or kidney or
liver disease as it can cause fluid retention, hypokalemia, and metabolic alkalosis.76 Ginseng,
while very popular, is associated with multiple side effects (hypertension, insomnia, vaginal
bleeding, acne, edema, headache, and anxiety,) and can inhibit platelet aggregation, thus
increasing bleeding time.77
DHEA (dehydroepiandrosterone)
DHEA is considered a dietary supplement (as opposed to a dietary supplement) and is the most
abundant hormone secreted by the adrenal glands.78 Long-term safety is unknown and can
increase the risk of hormone- stimulated cancers such as breast or endometrial cancer,79 decrease
serum high density lipoprotein (good cholesterol) levels,80 and can adversely affect liver
function.78 Despite these safety concerns, this hormone has been studied in men and women for
the improvement of BMD, and preliminary results indicate it may be effective.81-82 One needs to
weigh the benefits vs the negative health effects with this and any supplement.
Selected Estrogen Receptor Modulators (SERMs)
SERMS are estrogen-like substances like the prescription medication, Raloxifene, or herbal
supplements, also called phytoestrogens (plant estrogens) such as soy, flaxseed, and red clover.
12
It is postulated that a phytoestrogen would have more effect on a postmenpausal woman as
opposed to a premenopausal woman due to diminished effects of physiologic estrogen.
Soybeans are legumes that contain up to 50% protein, 24% carbohydrate, and 25% oil (stearic,
linoleic, and palmitic).83
Soy Protein usually contains 1-3 mg isoflavone/g, (a flavonoid found in soy) and it is these
isoflavones that are heterocyclic phenols with structural similarity to estradiol and selective
estrogen selective modulators. Soy isoflavones bind to both alpha- and beta- estrogen receptors,
but may a higher affinity for the beta receptor, especially in the postmenopausal woman. Beta-
estrogen receptor predominates in the heart, vasculature, bone and bladder and may account for
some of the beneficial effects A plethora of data exists, both positive and negative, regarding
the effects of soy on many aspects of women’s health, including hypercholesterolemia,
cardiovascular disease, cancer, menopausal/vasomotor symptoms, diabetes, renal disease, and
osteoporosis.84
Numerous studies have been conducted addressing the role of soy/isoflavones in bone health,
yielding mixed results. In several studies the provision of soy was shown to slow bone loss and
increase bone mineral density,85-92 with the beneficial effects in some studies contingent on
isoflavone content.87-89 Not all studies/reviews report significant effects or extol the benefits of
soy in general or on bone health.93-97 These inconsistent results reflect the heterogeneity of the
study designs and the type of soy protein and or isoflavones used.
Flaxseed
Flaxseed is a seed comprised of 35% fat, 28-30% protein, 35% fiber and 6% ash, and is seen in
healthy diets because of its omega-3 fatty acid and lignan content. There is an abundance of data
regarding the health benefits of omega-3 fatty acids,45 but these do not include bone health.
13
Flaxseed contains 100-800 times more plant lignans (a type of phytoestrogen) than any of the
other major seeds.45 While flaxseed improves lipid profiles in postmenopausal women, it does
not have a significant effect on BMD in postmenopausal women.98-99
Red Clover
Red clover, like soy, contains isoflavones and its effect on bone mineral density was studied in
postmenopausal women. A specific commercial red clover extract containing 40 mg isoflavones
taken for 12 months did not significantly increase bone mineral density or bone mineral content
in women aged 49-65 years old.100 Additional clinical trials studies are indicated as higher doses
have not been studied.
Other – Green, oolong, and black tea
While not estrogenic agents, green, oolong, and black tea have been the subject of some studies
investigating their effect on BMD and hip fracture risk.18 In one study, green (unfermented tea)
and oolong (partially fermented tea) increased total body BMD, and spinal and hip BMD on both
men and women who consumed these types of teas for at least 6 years.101 In a study involving
black tea (fully fermented tea), an increase in BMD is correlated with increased BMD and
reduced hip fracture rates in both men and women.102-104 Although the mechanism of action could
be associated with the high fluoride content of tea, or the estrogenic effects of the high
isoflavone content of some teas, or even the effects of the teas’ polyphenols and tannins, it has
not yet been fully elucidated.18
Conclusion
No nutritional supplement can ameliorate the negative effects of certain life style factors-
smoking, excessive alcohol intake, or lack of exercise on bone health. Age-appropriate calcium
14
and vitamin D supplementation are critical for bone health, even if a woman is taking a
medication such as a bisphosphonate for osteoporosis. The other micronutrients also play a key
role in bone health, but at this point, a multivitamin is usually sufficient. The money that is saved
from deferring the purchase individual supplements can be used to support an existing or newly
resolved exercise habit. Most nonvitamin, nonmineral dietary/herbal supplements are not
supported by enough safety and efficacy evidence to warrant their purchase for bone health (with
the exception of perhaps, soy isoflavones and tea), and many have deleterious side effects. A
healthy diet, lifestyle, and additional calcium and vitamin D are just what a doctor/dietitian
recommends for bone health for life.
REFERENCES
1. National Complementary and Alternative Medicine –Dietary Supplements. Available at:
http://nccam.nih.gov/health/ (Accessed 9 January, 2010).
2. Cooper C, Campion G, Melton U. Hip fracture in the elderly: A worldwide projection.
Osteoporosis Int 1992;2:285-89.
3. Osteoporosis and Diet. In: Advanced Nutrition and Human Metabolism, S Gropper, J
Smith, and J Groff, eds. 5th ed. Belmont, CA: Wadsworth/Cengage, 2009:461-467.
15
4. Jensen J, Christiansen C, Rodbro P. Cigarette smoking, serum estrogens, and bone loss
during hormone replacement therapy early after menopause. N Eng J Med 1985;313973-
977.
5. Krall E, Dawson-Huges B. Smoking and bone loss among postmenopausal women. J
Bone Min Res 1991;1985;313:973-77.
6. Slemenda C, Christian J, Read T. Et al. Long-term bone loss in men: Effects of genetic
and environmental factors. Ann Intern Med 1992;117:286-91.
7. Laitinen K, Valimaki M. Alcohol and bone. Calcif Tissue Int 1991;49(suppl):570-73.G-
68
8. Johnston C, Miller J Slemenda C, et al. Calcium supplementation and increases in bone
mineral density in children. N Engl J Med 1992;32782-87.
9. Lloyd T, Andon M, Rollings N et al. Calcium supplementation and bone mineral density
in adolescent girls JAMA 1993;270:841-44.
10. Nieves J, Golden A, Siris E. Teenage and current calcium intake are related to bone
mineral density of the hip and forearm in women aged 30-39 years. Am J Epidemiol
1995;141:342-51.
11. McGarry KA, Kiel DP. Postmenopausal osteoporosis. Strategies for preventing bone loss,
avoiding fracture. Postgrad Med 2000;108:79-82,85-88,90.
12. Bryant RJ, Cadogan J, Weaver CM. The new dietary reference intakes for calcium:
implications for osteoporosis. J Am Coll Nutr 1999;18:406S-412S.
13. Heaney RP. Calcium, dairy products and osteoporosis. J Am Coll Nutr 2000;19:83S-99S.
14. Deal C. Can calcium and vitamin D supplementation adequately treat most patients with
osteoporosis? Cleve Clin J Med 2000;67:696-8.
15. Chiu KM. Efficacy of calcium supplements on bone mass in postmenopausal women. J
Gerontol A Biol Sci Med Sci 1999;54:M275-80.
16. Nieves JW, Komar L,. Cosman F et al. Calcium potentiates the effect of estrogen and
calcitonin on bone mass: review and analysis. Am J Clin Nutr 1998;67:18-24.2572
17. Kanis JA. The use of calcium in the management of osteoporosis. Bone 1999;24:279-90.
2576
18. Natural Medicine Comprehensive Database. Available at: www.naturaldatabase.com
(Accessed 12 January, 2010).
16
19. Storm D, Eslin R, Porter ES, et al. Calcium supplementation prevents seasonal bone loss
and changes in biochemical markers of bone turnover in elderly New England women; a
randomized, placebo-controlled trial. J Clin Endocrinol Metab 1998;83:3817-25.
20. Riggs BL, O’Fallon WM, Muhs J, et al. Long-term effects of calcium supplementation on
serum parathyroid hormone level, bone turnover., and bone loss in elderly women. J
Bone Miner Res 1998;13:168-74.
21. Devine A, Dick IM, Heal SJ et al. A 4-year follow-up study of the effects of calcium
supplementation on bone density in elderly postmenopausal women. Osteoporos Int
1997; 7:23-8.
22. Castelo-Branco C, Pons F, Vicente JJ et al. Preventing postmenopausal bone loss with
ossein-hydroxyapatite compounds. Results of a two-year, prospective trial. J Reprod Med
1999;44;601-5.
23. Institute of Medicine’s (IOM) Food and Nutrition Board website (IOM-FNB). Available
at: http://www.iom.edu/Activities/Nutrition/DRIVitDCalcium.aspx. (Accessed 14
January 2010).
24. Dawson-Hughes, B, Harris SS, Krall EA et al. Effect of withdrawal of calcium and
vitamin D supplements on bone mass in elderly men and women. Am J Clin Nutr 2000;
72:745-750.
25. Shea, B, Wells G, Cranny A. et al. Calcium supplementation and bone loss in
postmenopausal women. Cochrane Database Syst Rev 2004: (1)CD004526.
26. Calcium. In :Nutritional Sciences- From Fundamentals to Food. M McGuire and K A
Beerman, eds. Belmont, CA: Thompson-Wadsworth. 2007, p 508.
27. Dawson-Hughes, B, Harris SS, Krall EA et al. Effect of calcium and vitamin D
supplementation of bone density in men and women 65 years of age or older. N Eng J
Med 1997;337:670-676.
28. Chapuy MC. Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip
fractures in the elderly woman. New Eng J Med 1992;327:1637-42.1836
29. Chapuy MC, Pamphile R, Paris E, et al. Combined calcium and vitamin D3
supplementation in elderly women: confirmation of reversal of secondary
hyperparathyroidism and hip fracture risk.
30. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy.
JAMA 2001;285:785-95.
17
31. National Osteoporosis Foundation. Clinician’s to Prevention and Treatment of
Osteoporosis. Available at : http:/www.nof.org/professionals/Clinicians_Guide.htm
(Accessed 17 January 2010).
32. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents
osteoporotic fractures in elderly community dwelling residents: a pragmatic population-
based 3-year intervention study. J Bone Miner Res 2004;19:3712930.
33. Bischoff-Ferrari HA, Willett WC et al. Fracture prevention with vitamin D
supplementation: a meta-analysis of controlled trials. JAMA 2005;293:2257-64.
34. Boonen S, Body JJ, Boutsen Y et al. Evidence-based guidelines for the treatment of
postmenopausal osteoporosis: a consensus document of the Belgian Bone Club.
Osteoporos Int 2005;16:239-54.
35. Papadimitropoulos E, Wells G, Shea B et al. Meta-analysis of the efficacy of vitamin D
treatment in preventing osteoporosis in postmenopausal women. Endocr Rev
2002:23:560-90.
36. Jackson RD, LaCroix AZ, Gass M. Calcium plus vitamin D supplementation and the risk
of fractures. N Eng J Med 2006:354:669-83.
37. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin
A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese,
Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC. National Academy
Press, 2002.
38. Tucker KL, Hannan MT, Chen H 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;69:727-36.
39. Houtkeeper, LV, Ritenbaugh C, Aickin, et al. Nutrients, body composition, and exercise
are related to change in bone mineral density in premenopausal women. J Nutr
1995;125:1229-37.
40. New SA, Bolton-Smith C, Grubb DA et al. Nutritional influences on bone mineral
density: a cross-sectional study in pre-menopausal women. Am J Clin Nutr
1997;65:1831-9.
41. Tranquilli AL, Lucino E, Garzetti GG et al. Calcium, phosphorus and magnesium intakes
correlate with bone mineral content in postmenopausal women. Gynecol Endocrinol
1994;8:55-8.
42. Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two year
controlled trial of peroral magnesium in osteoporosis. Magnes Res 1993;6:155-639104
18
43. Gunnes M, Lehmann E. Dietary calcium, saturated fat, fiber, and vitamin C as predictors
of forearm cortical and trabecular bone mineral density in health children and
adolescents. Acta Paediatr 1995;84:388-92.
44. Freudenheim J, Johnson N, Smith E. Relationships between usual nutrient intake and
bone mineral content of women 35-65 years of age: Longitudinal and cross-sectional
analysis. Am J Clin Nutr 1986;44:863-76.
45. Bone Health Nutrients. IN: The Health Care Professional’s Guide to Popular Dietary
Supplements, 3rd ed. Fragakis AS, Thompson C., eds. Chicago: American Dietetic
Association, 2007.
46. Weber, P. Vitamin K and bone health. Nutrition; 2001;17:880-887
47. Braam, LA. Knapen MH, Guesens P et al. Vitamin K1 supplementation retards bone loss
in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int.
2003;73:21-26.
48. Knapen M, Kruseman A, Wouters R et al. Correlation of serum osteocalcin fractions with
bone mineral density in women during the first 10 years after menopause. Calcif Tiss Int
1998; 63:375-79.
49. Booth S, Tucker K, Chen H et al. Dietary vitamin K intakes are associated with hip
fracture but not bone mineral density in elderly men and women. Am J Clin Nutr
2000;71:1201-8.
50. Szulc P, Arlot M, Chapuy M et al. Serum undercarboxylated osteocalcin correlates with
hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591-95.
51. Calvo M, Kumar R, Heath H. Persistently elevated parathyroid hormone secretion and
action in young women after four weeks of ingesting high phosphorus, low calcium diets.
J Clin Endocrinol Metab 1990; 70:1334-40.
52. Anderson J. The role of nutrition in the functioning of skeletal tissue. Nutr Rev
1992;50:388-94.
53. Calvo M. Dietary phosphorus, calcium metabolism and bone. J Nutr 1993;123:1627-33.
54. Zemel M, Linkswiler H. Calcium metabolism in the young adult male as affected by level
and form of phosphorus intake and level of calcium intake. J Nutr 1981;11:315-24.
55. Bizik B, Ding W, Cerklewski F. Evidence that bone resorption of young men is not
increased by high dietary phosphorus obtained from milk and cheese. Nutr Res
1996;16:1143-46.
19
56. Chapin, RE Ku WE, Kenney MA et al. The effect of dietary boron on bone strength in
rats. Fund App Tox 1997;35:205-15.
57. Sheng MHC, Taper LJ, Viet H et al. Dietary bone supplementation enhanced the action
of estrogen, but not that of parathyroid hormone to improve trabecular bone quality in
ovariectomized rats. Bio Trace Elem Res 2001;82:109-23.
58. Neilsen FH, Gallagher SK, Johnson, LK et al. Effect of dietary boron on mineral,
estrogen, and testosterone metabolism in postmenopausal women. FASEB J 1987;1:394-
397.
59. Neilsen, FH Gallagher SK, Johnson, LK et al. Boron enhances and mimics some effects
of estrogen therapy in postmenopausal women. J Trace Elem Exp Med. 1992;5:237-246.
60. Gur A, Colpan L, Nas K, et al. The role of trace minerals in the pathogenesis of
postmenopausal osteoporosis and a new effect of calcitonin. J Bone Miner Metab
2002;20:39-43.
61. Strause L, Saltman P, Smith KT et al. Spinal bone loss in postmenopausal women
supplemented with calcium and trace minerals. J Nutr 1994; 124:1060-4.
62. Food and Nutrition Board- Interactive materials. Available from:
http://fnic.nal.usda.gov/nal_display/index.php (Accessed 18 January 2010).
63. American Dental Association. American Dental Association supports fluoridation.
Available from: http://www.ada.org/professionalstatements/fluoride3.asp. (Accessed 18
January 2010).
64. The Trace Minerals, IN Nutritional Sciences- From Fundamentals to Food. M McGuire
and K A Beerman, eds. Belmont, CA: Thompson-Wadsworth. 2007, p 508.
65. Rubin CD, Pak CY, Adams-Huet B et al. Sustained-release sodium fluoride in the
treatment of the elderly with established osteoporosis. Arch Intern Med 2001;161:2325-
33.
66. Marie PJ, Ammann, P, Boivin G, et al. Mechanisms of action and therapeutic potential of
strontium in bone. Calcif Tissue Int 2001 1:69:121-9.
67. Brandi ML, New treatment strategies: Ipriflavone, strontium, vitamin D metabolites and
analogs. Am J Med 1993;95:69S-74S.
68. Meunier PJ, Slosman DO. Delmas PD et al. Strontium ranelate: dose-dependent effects in
established postmenopausal vertebral osteoporosis—a 2 –year randomized placebo-
controlled trial. J Clin Endocrinol Metab 2002;87:2060-6.
20
69. Dahl SG, Allai P, Marie PJ et al. Incorporation and distribution of strontium in bone.
Bone 2001;28:446-53.
70. Meunier PJ, Roux C, Seerman E, et al. The effects of strontium ranelate on the risk of
vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med
2004;350:459-68.
71. El-Hajj Fuleihan G. Strontium ranelate –a novel therapy for osteoporosis or a
permutation of the same? N Engl J Med 2004;350:504-6.
72. Natural Medicine Comprehensive Database. Strontium.
www.naturaldatabase.com/strontium. (Accessed 18 January, 2010).
73. Alcocer-Varela J, Iglesisa A, Llorente L et al. Effects of L-canavanine on T-cells may
explain the induction of systemic lupus erythematosus by alfalfa. Arthritis Rheum
1985;28:52-7.
74. Dong Quai. In: The Health Care Professional’s Guide to Popular Dietary Supplements,
3rd ed. Fragakis AS, Thompson C., eds. Chicago: American Dietetic Association, 2007, p
158.
75. Dr. Duke’s Phytochemical and Ethnobotanical Databases. Available at: http//www.ars-
grin.gov/duke/. (Accessed 18, January 2010).
76. Licorice root. In: The Health Care Professional’s Guide to Popular Dietary Supplements,
3rd ed. Fragakis AS, Thompson C., eds. Chicago: American Dietetic Association, 2007, p
331.
77. Ginseng. In: The Health Care Professional’s Guide to Popular Dietary Supplements, 3rd
ed. Fragakis AS, Thompson C., eds. Chicago: American Dietetic Association, 2007, p.
246.
78. DHEA. In: The Health Care Professional’s Guide to Popular Dietary Supplements, 3rd
ed. Fragakis AS, Thompson C., eds. Chicago: American Dietetic Association, 2007, p.
148
79. Dorgan JF, Stanczyk, FZ, Longcope C, et al. Relationship of dehydroepiandrostrone in
experimental animals and humans. Proc Soc Exp Biol Med. 1998; 218:174-191.
80. Mortola JF, Yes SS. The effects of oral dehydroepiandrosterone on endocrine-metabolic
parameters in postmenopausal women. J Clin Endocrinol Metab 1990:71:696-704.
81. Sun Y. Mao M, Sun L, et al. Treatment of osteoporosis in men using
dehydroepiandrosterone sulfate. Chin Med J (Engl) 2002;115:402-4.
21
82. Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replacement on bone mineral
density and body composition in elderly women and men. Clin Endocrinol (Oxf)
2000;53:561-8.
83. http://www.soyconnection.com/health_nutrition/technical_info/nutritional_composition.p
hp.
84. Soy protein and isoflavones. In Fragakis, A, Thompson, C. , eds. A Health Professional’s
Guide to Popular Dietary Supplements. Third ed. Chicago, IL: American Dietetic
Association; 2007: 490-499).
85. Harkness LS< Fiedler K, Sehgal AR, et al. Decreased bone resorption with soy
isoflavone supplementation in postmenopausal women. J Women’s Health. (Larchmt).
2004;13:1000-1007.
86. Mei J, Yeung SS, Kung AW. High dietary phytoestrogen intake is associated with higher
bone mineral density in postmenopausal but not premenopausal women. J Clin
Endocrinolo Metab 2001;86:5217-5221.
87. Potter SM, Baum JA, Teng H, et al. Soy protein and isoflavones: their effects on blood
lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68:1375S-
9S.842
88. Alekel DL, St. Germain A, Peterson CT et al. Isoflavone-rich soy protein isolate
attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr
2000;72:844-52.
89. Arjmandi BH, Khalil DA, Smith BJ et al. Soy protein has a greater effect on bone in
postmenopausal women not on hormone replacement therapy, as evidenced by reducing
bone resorption and urinary calcium excretion. J Clin Endocrinol Metab 2003;88:1048-
54.
90. Ho SC, Chan SG, Yi Q et al. Soy intake and the maintenance of peak bone mass in Hong
Kong Chinese women. J Boner Miner Res 2001;16:1363-9.11081
91. Chen YM, Ho SC, Lam SS et al. Soy isoflavones have a favorable effect on bone loss in
Chinese postmenopausal women with lower bone mass: a double-blind, randomized
controlled trial. J Clin Endocrinol Metab 2003;88:4740-7.
92. Setchell KDR, Lydeking-Olsen E. Dietary phytoestrogens and their effect on bone:
evidence from in vitro and in vivo, human observational, and dietary intervention studies.
Am J Clin Nutr 2003; 78:593S-609S.
22
93. Khalil DA, Lucas EA, Juma S, et al. Soy protein supplementation increases serum
insulin-like growth factor-I in young and old men but does not affect markers of bone
metabolism. J Nutr 2002;132:2605-2608.
94. Gallagher JC, Satpathy R, Rafferty K et al. The effect of soy protein isolate on bone
metabolism. Menopause 2004;11:290-8.
95. Kreijkamp-Kaspers S, Kok L, Brobbee DE et al. Effect of soy protein containing
isoflavones on cognitive factors, bone mineral density, and plasma lipids in
postmenopausal women: A randomized controlled trial. JAMA 2004;292:65-74.
96. Balk E, Chung M, Chew P, et al. Effects of soy on health outcomes. Summary, Evidence
Report/Technology Assessment: Number 126. AHRQ Publication Number 05-E024-1,
August 2005. Agency for Healthcare Research and Quality (AHRQ) Rockville, MD.
Available at: http//www.ahrq.gov/clinic/epcsums/soysum.htm (Accessed 18 January
2010).
97. Sacks FM, Lichtenstein A, Van Horn L, et al. Soy protein, isoflavones, and
cardiovascular health. An American Heart Association Science Advisory for
Professionals from the Nutrition Committee. Circulation 2006;113: 1034-44.
98. Lucas EA, Wild RD, Hammond LJ et al. Flaxseed improves lipid profile without altering
biomarkers of bone metabolism in postmenopausal women. J Clin Endocrinol Metab
2002;87: 1527-32.
99. Dodin S, Lemay A, Jacques H et al. The effects of flaxseed dietary supplement on lipid
profile, bone mineral density, and symptoms in menopausal women: a randomized,
double-blind, wheat germ placebo-controlled clinical trial. J Clin Endocrinol Metab
2005;90: 1390-7.
100. Atkinson C, Compston JE, Day NE et al. The effects of phytoestrogen isoflavones on
bone density in women: a double-blind, randomized, placebo-controlled trial. Am J Clin
Nutr 2004;79: 326-33.
101. Wu CH, Yang YC, Yao WJ et al. Epidemiological evidence of increased bone mineral
density in habitual tea drinkers. Arch Intern Med 2002;162: 1001-6.
102. Hegarty VM, May HM, Khaw K. Tea drinking and bone mineral density in older
women. Am J Clin Nutr 2000;71: 1003-7.
103. Johnell O, Bullberg B, Kanis JA. Risk factors for hip fracture in European women: The
MEDOS study. Mediterranean Osteoporosis Study. J Bone Miner Res 1995;10:1802-15.
23
104. Kanis J, Johnell O, Gullberg B et al. Risk factors for hip fracture in men from southern
Europe: the MEDOS study. Mediterranean Osteoporosis Study. Osteoporos Int
1999;9:45-54.
24