Bone & Joint Health

More than 45 million Americans currently suffer the aches and pains associated with arthritic conditions, with a similar number afflicted by the bone loss and fractures of osteoporosis. While these conditions are often seen as a simple side effect of aging, consumers are increasingly turning to nutraceuticals to alleviate the effects and maximize the health of their bones and connective tissues to stay strong in the long term.

Arthritis

Comprising more than 100 different diseases and conditions, arthritis is the leading cause of physical disability in the United States, according to the Center for Disease Control and Prevention (CDC). More than 49 million Americans have some form of doctor-diagnosed arthritis, with another 21 million Americans reporting chronic joint symptoms (CJS), and total costs are estimated to be more than $86 billion annually, including $51 billion in medical costs. These numbers will likely continue to rise with the aging population, as the number of people age 65 and older with arthritis or CJS expected to nearly double from 21 million in 2001 to 41.4 million by 2030.

Osteoarthritis (OA) is the most common arthritic disease. Characterized by degradation of articular cartilage, loss of joint function and pain, OA usually targets joints in the neck, lower back, knees, hips and fingers. Joints that were previously injured or subjected to heavy lifting or strain are also prone to OA. Among the factors associated with onset and progression of OA are age, family history, weight, trauma and metabolic abnormalities. OA affects 12 percent of U.S. adults, and the American College of Rheumatology (ACR) notes by the age of 75, virtually everyone will have OA in at least one joint.

The other common form of arthritis is rheumatoid arthritis (RA), which is a chronic autoimmune disease that can impact any joint. RA is found primarily in women, with onset between the ages of 20 and 45. Affecting primarily the hands and feet, RA is characterized by a malfunctioning immune system that attacks healthy joints, inflaming the lining of the joints and leading to cartilage degeneration and joint malformation.

Joints are the points between two moving bones, and are designed to provide shock absorption from movement. Chondrocytes are the cells responsible for the production and maintenance of cartilage, the primary joint tissue. Chondrocytes produce cartilage and proteoglycans, making the cellular matrix.

The joints also contain synovial fluid, a lubricant containing hyaluronic acid and glycoproteins that also delivers nutrients to the cartilage. As with all cells in the body, there is constant turnover in the joints that requires nutrients to sustain maximal health.

The most popular nutraceutical ingredient in the joint health field is glucosamine, a precursor of the glycosaminoglycans (GAG) and proteoglycans found in the body. It is also a key compound in the synthesis of synovial fluid. A Cochrane Database System Review found glucosamine appears to be effective and safe in the treatment of OA based on randomized controlled trials.¹ Additional reviews have agreed with this conclusion, though they point out a need to standardize the preparations to ensure consumers receive an efficacious dosage.² However, the benefits of glucosamine compared to pharmaceutical non-steroidal anti-inflammatory drugs (NSAIDs) include effective symptomatic relief and prevention of arthritic progression without common NSAID side effects such as gastrointestinal disturbances or skin reaction.³

Researchers continue to study glucosamine to broaden the research base on its efficacy as well as explain its mechanism of action. A study from the National Pharmaceutical Academy of Ukraine examined the effects of glucosamine hydrochloride (HCL) in a model of post-traumatic osteoarthrosis in articular cartilage, and found the compound likely stimulates the synthesis of glucosaminoglycans and collagen.⁴ Another in vitro study evaluating glucosamine’s effects on neutrophil function found the compound inhibited the release of the granule enzyme lysozyme and suppressed neutrophil chemotaxins, both linked to neutrophil’s inflammatory actions.⁵

Two three-year studies conducted in Europe investigated whether glucosamine sulfate could modify the progression of joint structure and symptom changes in knee OA. The first, conducted by researchers from Charles University, Prague, Czech Republic, involved 202 patients with knee OA who received 1,500 mg/d of glucsosamine sulfate or a placebo.⁶ After three years, there was -0.19 mm progressive joint space narrowing with placebo, compared to no change with glucosamine use.

Symptoms of pain and stiffness were also significantly improved by glucosamine supplementation. The second study, involving 212 patients with knee OA, found the most significant reduction in joint space narrowing was among patients with mild OA, suggesting such patients are more responsive to structure-modifying treatments.⁷

These same researchers, from the World Health Organization Collaborating Center for Public Health Aspect of Osteoarticular Disorders in Liege, Belgium, further combined the results of the two studies to specifically evaluate the impact of glucosamine on postmenopausal women.⁸ Of the total 414 participants, 319 were postmenopausal women; those receiving glucosamine sulfate showed no joint space narrowing and an improvement in pain index scores, compared to a worsening of both conditions in the women taking placebo. The researchers concluded the glucosamine intervention has a disease-modifying effect in this population, which is the most frequently affected by knee OA.

Glucosamine is often found in combination with chondroitin, the most prevalent GAG found in cartilage. There is a great deal of research ongoing into the mechanisms of action and efficacy of glucosamine and chondroitin in OA. The National Center for Complementary and Alternative Medicine (NCCAM) and the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS) are expecting to have final data in March 2005 from a multicenter, five-arm, placebo-controlled study in 1,588 subjects.⁹ The study is investigating the impact of glucosamine sulfate, chondroitin sulfate or a combination of the two compared to placebo and to celecoxib (a COX-2 inhibitor pharmaceutical) for knee OA.

A meta-analysis conducted by researchers from the University of Liege, Belgium, assessed the structural and symptomatic efficacy of glucosamine sulfate and chondroitin sulfate in knee OA, using joint space narrowing and pain indices as outcome determinants.¹⁰ Glucosamine was found to be significantly efficacious on all outcomes, while chondroitin was effective on the Lequesne Index, visual analogue scale pain and mobility; safety was excellent for both compounds.

Chondroitin has been found to produce a slow but gradual decrease in clinical OA symptoms, and may work through anti-inflammatory activity and by modifying the cartilage structure.¹¹ In a study from University Hospital Zurich, Switzerland, researchers randomized 120 patients with knee OA into two groups to receive 800 mg/d of chondroitin sulfate or placebo for two periods of three months during one year.¹²

Chondroitin supplementation significantly decreased pain and improved knee function according to the Lequesne Index outcome, compared to placebo.

Chondroitin has also been studied in OA of the hands. One Italian study divided 24 patients with OA of the hands to receive either 500 mg/d naproxen or the naproxen plus 800 mg/d chondroitin sulfate.¹³ While both groups showed worsening of the condition, the chondroitin patients had less erosion and better global assessment scores compared to the naproxen-only group. An animal study suggests orally administrated low molecular weight chondroitin sulfate may alleviate edema and reduce levels of inflammatory antibodies in the paws, preventing induction of arthritis.¹⁴

Studies have also investigated the effects of hyaluronic acid (HA). In a study with rats subjected to collagen-induced arthritis, a combination of HA and chondroitin sulfate limited the erosive action of the arthritis in the knee and paw joints, and limited synovial neutrophil infiltration.¹⁵ Metaanalyses have confirmed the ability of intra-articular injection of HA to decrease symptoms of OA in the knee, improving pain and functional outcome scores.¹⁶ It appears HA is synthesized by chondrocytes and synoviocytes, helping to promote mobility in the synovial fluid; however, most research has focused on injectible HA, not oral dosing.

Sodium hyaluronate, the chief component of synovial fluid, is available as a nutritional compound. In an unpublished study conducted at the University of Barcelona Science Park, researchers investigated the effects of sodium hyaluronate (as Hyal-Joint™ from Bioiberica S.A.) on prostaglandin and metalloproteinase 1 inflammatory cells. They found a statistically significant dose-effect relationship, with higher doses of the nutritional compound reducing inflammation in human dermal fibroblast cells. In another unpublished study on Hyal-Joint, researchers at the Universitat Autonoma de Barcelona investigated the intestinal absorption of the compound in male rats; 38 percent absorption was found in the duodenum (the site of highest intestinal absorption), followed by 22 percent absolute absorption in the jejunum and 9 percent in the ileum.

HA is also found as a naturally occurring compound in other supplements. A clinical study using sternal hydrolyzed Type II collagen with HA (as BioCell Collagen II® from BioCell Technology) involved 16 subjects with OA taking 1,000 mg/d for eight weeks.¹⁷ Patients reported a decrease in joint pain and stiffness in the knees, hands and hips, as well as overall improvements to quality of life. Further analysis showed no significant adverse effects related to supplementation.

Undenatured collagen Type II has also been investigated for its ability to alleviate arthritic symptoms. The most recent research involved undenatured Type II collagen (as UCII ® from InterHealth Nutraceuticals given to 15 dogs suffering from osteoarthritis.¹⁸ Dogs receiving 1 mg/d or 10 mg/d of the treatment showed marked decreases in pain and lameness. Previous research has primarily focused on the ability of undenatured Type II collagen to induce tolerance in RA patients, mitigating the immune response and downregulating inflammation and joint pain. In a pilot study, five females suffering from joint pain received 10 mg/d of undenatured Type II collagen (as UC-II) for 42 days, and realized significant pain reduction, leading researchers to suggest the compound could be a therapeutic tool for joint inflammatory conditions.¹⁹

Often, chondroitin and glucosamine are supplied in sulfated forms, as there has also been research on the efficacy of sulfur in arthritic conditions. Sulfur baths, for example, have been long used to alleviate joint pain. A recent study in Germany investigated the effects of daily sulfur baths over three weeks in OA patients.²² Those patients taking the sulfur baths had reduced oxidative stress and a tendency toward improved endogenous antioxidant activity. A review of sulfur and human nutrition noted organic sulfur can be used to increase synthesis of Sadenosylmethionine (SAMe), and that SAMe and methylsulfonylmethane (MSM) may have clinical applications in conditions such as arthritis.²³

MSM contains 34 percent sulfur and is a major contributor of sulfur in the human diet. To date, there have been no published studies on MSM and arthritis, though a randomized, double blind, placebo-controlled trial of MSM in OA is nearing completion, according to Cardinal Nutrition, the supplier of OptiMSM® and supporter of the study.

SAMe, meanwhile, has been shown useful for OA; an evidence report released in late 2002 by the Agency for Healthcare Research and Quality (AHRQ), an arm of the Department of Health and Human Services (HHS), found SAMe was more effective in decreasing OA pain than placebo and performed similar to NSAIDs. Corroborating results were presented in a meta-analysis from the University of Maryland, Baltimore.²⁴ In addition to SAMe’s ability to alleviate pain as well as NSAIDs, the researchers also found it did so with significantly fewer adverse effects. SAMe also appears to be as efficacious as COX-2 inhibitors, according to a recent study from the University of California, Irvine.²⁵ The double blind, crossover study involved 61 adults with knee OA who received 1,200 mg/d of SAMe or 200 mg/d of the COX-2 drug celecoxib (as Celebrex). While the onset of action was slower with SAMe, the treatment was as effective in treating symptoms of pain and function.

Beyond the glyconutrients, there are a number of vitamins and minerals that also play a role in preventing arthritis. Dietary studies have linked lower intakes of antioxidants, including vitamin C and vitamin E, to a higher incidence of inflammatory arthritis.²⁶

German researchers found mice given a diet supplemented with antioxidants prior to inducement of OA were significantly less likely to develop OA than control mice; the diet also increased expression of endogenous antioxidants in articular cartilage, leading the researchers to suggest generation of free radicals may be involved with onset of OA.²⁷ Greater intakes of zinc²⁸ and vitamin C²⁹ have also been linked to lower incidence of RA development.

Beyond its role as an antioxidant, vitamin C is also essential for the formation of collagen. A multicenter, double blind, placebo-controlled, randomized trial involving 133 patients with OA of the hip or knee investigated the impact of 1 g/d of calcium ascorbate.³⁰ The treatment significantly reduced pain compared to placebo, though the effect was not as pronounced as with NSAIDs. However, studies have not been entirely positive. A study investigating the effects of eight months’ exposure to low, medium and high doses of ascorbic acid on the development of knee OA in guinea pigs found the highest dose in fact worsened severity of spontaneous OA.³¹ The researchers noted this was in contrast to previous findings in which the same high dose slowed progression of OA in guinea pigs, leading them to conclude more studies are needed.

Studies on vitamin E intake have also not shown a positive link between vitamin E and OA. While knee OA was found in a population study to be inversely associated with serum alpha-tocopherol in blacks and in men, it was positively associated with serum gammatocopherol in men.³² Double blind supplementation studies have not shown any link between vitamin E and OA. Two Australian studies—one six-month study involving 77 OA patients taking 500 IU/d of vitamin E,³³ and the other a two-year study of 136 OA patients taking 500 IU/d of vitamin E³⁴—showed no benefit on pain levels or cartilage loss.

While minerals such as zinc may individually support joint function, a patented, proprietary mineral complex may work to alleviate OA symptoms. An in vitro mechanism of action study using human cartilage tissues and cells from OA patients and a macro and trace mineral supplement (as SierraSil™ from Sierra Mountain Minerals) found the mineral treatment reduced the breakdown of mature cartilage cells by 68 percent to 73 percent within a week, following an acid wash to mimic the digestive process of the stomach.³⁵ Based on results of a pilot study, the mineral complex is being investigated in a randomized, double blind, placebo-controlled human clinical trial involving 120 patients with OA of the knee.

Other essential nutrients that may support joint function include the essential fatty acids (EFAs). The omega-3 EFAs appear to downregulate inflammatory prostaglandins, while the omega-6 EFAs increase inflammatory cytokine production; the ratio of n- 6 to n-3 EFAs is therefore important to controlling inflammation in the body.³⁶ More specifically, the long-chain polyunsaturated fatty acids (LC-PUFAS) found in fish oil have demonstrated anti-inflammatory effects in the body.³⁷ A review from Epsom General Hospital, England, suggested fish oil supplements may help suppress inflammatory cytokine production, and other oils of marine origin may have indirect anti-inflammatory actions, leading the researchers to suggest such dietary supplements may be important adjuncts in treating inflammatory disorders like RA and OA.³⁸

An in vitro study at Cardiff University, England, investigated the impact of omega-3 and omega-6 EFAs in a model of cartilage degradation.³⁹ The researchers found omega-3 EFAs (but not omega-6s) decreased both degradative and inflammatory aspects of chondrocyte metabolism, which may account for its ability to reduce pathogenesis of degenerative joint diseases. Work from the same researchers indicates omega-3 EFAs may reduce the release of proteoglycan metabolites from cartilage and abolish the expression of inflammatory cytokines, including COX-2.⁴⁰

Beyond fish oil, other marine products may benefit joint health. Green-lipped mussel powder was the subject of a review at the University of California, Davis, which noted a freeze-dried, stabilized New Zealand greenlipped mussel powder (as Lyprinol) shows significant anti-inflammatory activity in animal and human studies, which researchers have attributed to its omega-3 EFA and antioxidant content.⁴¹ A clinical trial in which 60 patients with hip and knee OA received 2 capsules/d of Lyprinol found treatment led to significant improvement in signs and symptoms of OA by all efficacy measures.⁴² There was significant pain relief, improved joint function and no reported adverse events.

Cetylated fatty acids may also serve a beneficial role in joint function. In a placebocontrolled study of 64 patients with chronic knee OA, those who received an oral dosage of a cetylated fatty acid product (as Celadrin® from Proprietary Nutritionals) experienced significant increase in knee flexibility compared to the placebo group and a trend toward significant improvement in overall function.⁴³

Another study at the University of Minnesota showed an oral dose of Celadrin produced appreciable activity in blood collected from rats, and that application of Celadrin in a cream format showed appearance in the blood with significant localization at the site of application.⁴³ Finally, a study at the University of Connecticut involving 40 patients with knee OA who used a cream with Celadrin or a placebo cream found the treatment cream increased knee range of motion and unilateral reach and decreased times for stair climbing and rising from a chair.⁴⁵

Another new compound designed to address joint pain and inflammation is a patented milk protein concentrate (MPC, as MicroLactin™ from Humanetics Corp.). In a study of 42 patients with OA who suffered daily joint pain, stiffness and immobility, researchers provided 2,000 mg/d MPC (as MicroLactin), 500 mg glucosamine sulfate, or placebo.⁴⁶ The MPC-treated group had significant improvements in all scores for stiffness, pain, life activities and total improvement, compared to no changes in the placebo group and changes only in the stiffness and total improvement indices for glucosamine. In another six-week, double blind, placebocontrolled study, subjects with OA of both knees received a beverage containing MPC (as MicroLactin).⁴⁷ The researchers found, “Daily consumption of the nutritional beverage ... was beneficial in alleviating symptoms and dysfunction in subjects with osteoarthritis.”

The botanical world also offers compounds to provide symptomatic relief to sufferers of joint inflammation. A resin extract of Boswellia serrata, an Ayurvedic botanical, has been investigated for its ability to treat OA symptoms.

In a multicenter veterinary clinical trial, 25 dogs with manifestations of OA and degenerative joint conditions received 400 mg/10 kg body weight/d for six weeks.⁴⁸ After two weeks of treatment, efficacy was evident in 71 percent of the dogs, and a statistically significant reduction in severity and resolution of symptoms including lameness, local pain and stiff gait were reported by the end of the study.

A German research review suggested gum resin from boswellia may inhibit neutrophil granulocyte biosynthesis of inflammatory leukotrienes, and noted clinical trials have shown promising results in patients with inflammatory diseases including RA and colitis.⁴⁹ One such clinical study involved 30 patients with knee OA who received boswellia extract or placebo for eight weeks, followed by a washout and crossover.⁵⁰ All patients receiving boswellia reported decreases in knee pain and swelling, increases in knee flexion and increased walking distance. The treatment was also well tolerated with only minor gastrointestinal adverse effects.

Finally, capsaicinoids—compounds derived from chili peppers— appear to impact sensory nerve fibers, assisting in alleviating pain associated with conditions such as arthritis and cystitis.⁵⁴ Researchers from Craigavon Area Hospital Group Trust in Northern Ireland investigated the effects of an analgesic cream with capsaicin on 200 adult patients with OA.⁵⁵ Topical application of capsaicin was found to decrease pain associated with arthritis; the effect was increased by combining the compound with glyceryl trinitrate to increase skin tolerability. Interestingly, a recent study investigating patient treatment preferences for OA found if the patients were responsible for the full cost of treatment, 40 percent would prefer capsaicin.⁵⁶ The researchers also found the patients were willing to forego some treatment effectiveness for a lower risk of adverse effects.

Osteoporosis

While arthritis takes aim at the joints and connective tissue of the body, osteoporosis directly targets the bones. Characterized by low bone mass and structural deterioration of bone tissue, osteoporosis leads to bone fragility and an increased susceptibility to fractures of the hip, spine and wrist. This major public health threat impacts 44 million Americans, 68 percent of whom are women, according to the National Institutes of Health’s (NIH) Osteoporosis and Related Bone Diseases (ORBD) National Resource Center, and is responsible for more than 1.5 million fractures annually. The cost of osteoporosis tops $14 billion annually in direct expenditures for osteoporosis and related fractures.

This condition targets bone—living, growing tissue primarily made of collagen and calcium phosphate. Cells called osteoblasts are responsible for bone formation, while osteoclasts dissolve and remove old bone. During teenage years into adulthood, osteoblasts pile on the bone, increasing the density of the skeleton until peak bone mass is reached at around age 30. After that point, bone resorption exceeds bone formation; this is a generally slow process that becomes much more rapid during menopause.

According to NIH, there are several risk factors that cannot be changed—Caucasian and Asian women, particularly those who are small boned, are more susceptible, particularly as they age. However, many factors are within a consumer’s control, including exercise, specifically weight-bearing exercise to enhance bone density; refraining from smoking or excessive use of alcohol; and consuming a nutritious diet, particularly ensuring adequate intakes of calcium and vitamin D.

A recent study from Helen Hayes Hospital in West Haverstraw, N.Y., noted diet is the key to optimizing bone health.¹ “The nutritional needs easily can be met by a diet that is high in fruits and vegetables ... adequate in protein but moderate in animal protein, and with adequate calcium and vitamin D intakes through the consumption of low fat dairy or calcium fortified foods,” it read. Other reviews echoed the importance of calcium intake, as well as the roles of magnesium, boron, vitamin K and vitamin C.²

In fact, results of a long-term longitudinal study in the United Kingdom were released in the American Journal of Clinical Nutrition.³ The study involved 891 women aged 45 to 55 at baseline, who were examined five to seven years later; nutrient intakes were assessed by use of a food frequency questionnaire. Higher intakes of calcium and of fruits and vegetables were correlated with reduced loss of bone, particularly in early menopause.

A Cochrane Database System Review noted the importance of calcium to bone health was recognized by the Food and Drug Administration (FDA), which has permitted a bone health claim for calcium-rich foods. NIH also approved a statement by its Consensus Development Process that high calcium intake reduces the risk of osteoporosis.⁵ The review further examined data from 15 trials, representing more than 1,800 people, which found calcium supplementation alone had a small positive effect on bone density and a reduction in vertebral fractures.

The most common source of calcium in the diet is dairy products, which have been studied for their impact on bone density. In a controlled study of 200 Chinese postmenopausal women, those who received high-calcium skim milk (containing 1,200 mg/d of calcium) had significantly less bone loss in the lumbar spine and hip.⁶ Milk minerals may also serve to enhance bone mineralization. An unpublished, company-sponsored study conducted on milk minerals (as LactoCalcium™ from Cyvex Nutrition) investigated the bioavailability and biological activity of milk minerals in vitro. The researchers found the bioavailability of calcium from the product increased following simulated digestion, and treatment of bone cells with the digested calcium promoted the formation of mineralized bone nodules.

Calcium is often found with vitamin D, which increases uptake of the critical mineral. A Canadian health claim granted for bone health promotes adequate calcium intake as well as the importance of adequate vitamin D, and notes phosphorous content must be less than the calcium content in foods carrying the health claim.⁷ Researchers from Rutgers University in Piscataway, N.J., recently proposed the U.S. government consider mandatory enrichment of cereal-grain products with calcium and vitamin D to impact both osteoporosis and colon cancer.⁸ Approval by authorities of the importance of calcium and vitamin D appears critical, as a study in Massachusetts found patients with recent bone fractures whose primary care physicians recommended calcium or vitamin D were more likely to take supplements and increase their intake of dairy products, which led to fewer subsequent fractures.⁹

Vitamin D intake itself has been shown to be important in bone health, with intake between 500 IU/d and 800 IU/d—with or without calcium supplementation—shown to increase bone mineral density (BMD).¹⁰

While approximately 15 minutes per day of exposure to sunlight allows the body to produce bone-healthy levels of vitamin D, obtaining this exposure can be difficult for people during the darker winter months or for those who are bedridden. Australian researchers found cyclic variations in serum vitamin D, which corresponded to changes in ultraviolet radiation, and a corresponding increase in bone resorption and bone fracture as vitamin D levels fell.¹¹ Further, a study in 74 women with acute osteoporotic hip fracture and 73 women with osteoporosis found vitamin D deficiency was common in both groups of housebound women, with the condition more common in women suffering fracture.¹²

Vitamin D deficiency is also found concomitantly with a lack of vitamin K, which could lead to osteoporosis and fracture due to undercarboxylation of osteocalcin.¹³ Japanese researchers found independent and simultaneous application of vitamins D and K in rats inhibited the development of osteoporosis induced by a protein-deficient diet.¹⁴ And in a three-year study from the University of Maastricht, The Netherlands, researchers administered 155 women either placebo; a supplement with calcium, magnesium, zinc and vitamin D; or the supplement plus vitamin K1.¹⁵ The group that received the supplement with vitamin K1 showed a substantial reduction in postmenopausal bone loss of the femoral neck.

In addition, there are other important minerals for bone health. Phosphorus, though it does impact calcium uptake, is important to maintain bone structure. A review from Creighton University Medical Center in Omaha, Neb., noted calcium phosphate may be a preferable calcium supplement source to help spare food phosphorus, which can be sub-par in some elderly women.¹⁶

More well-known in the bone health field is magnesium. Deficiencies have been shown to cause bone loss in animals due to increased bone resorption and/or inadequate bone formation.¹⁷ In a oneyear study of rats given a magnesium-deficient diet, their BMD and bone architecture was significantly decreased compared to rats given adequate magnesium.¹⁸ Similarly, even moderate dietary magnesium restriction was found to reduce bone magnesium content and increase osteoclast activity after two months.¹⁹

Minerals and vitamins also function as antioxidants. A study of 75 osteoporotic women and 75 controls found plasma levels of endogenous and dietary antioxidants were significantly lower in osteoporotic subjects, though the mechanisms of antioxidant depletion in osteoporosis are currently unknown.²⁰ Antioxidants may work by alleviating structural damage to bone. For example, researchers at Ankara University, Turkey, induced osteoporosis in rabbits through injections of heparin and studied whether selenium, vitamin E and vitamin C together, or the vitamins together, would prevent disease progression.²¹ While heparin caused alterations in bone, the vitamins partially prevented bone tissue destruction, and the combination of vitamins plus selenium resulted in long bone tissue structure that was almost the same as in normal rabbits.

Another three-month rat study using glucocorticoid treatment (known to cause osteoporosis) and a palm oil-derived vitamin E mixture found the palm oil-derived isomer gamma tocotrienol increased lumbar bone calcium content, preventing glucocorticoid bone degeneration.²² And a population study in Eastern England found women with the lowest intake of vitamin C had a significantly faster rate of BMD loss.²³

Not all vitamins are positively associated with skeletal health. Overconsumption of vitamin A can increase the rate of bone resorption, hypercalcaemia and bone abnormalities, according to a review from the University of Sheffield, England.²⁴ The authors added high habitual intake of vitamin A could adversely affect bone mineral content and increase fracture risk. A population study from the University of North Carolina, Chapel Hill, investigated the impact of excessive retinol intake in 570 women and 388 men, aged 55 to 92 years.²⁵ After four years, researchers compared BMD to baseline and found retinol intake at levels not far beyond the recommended daily allowance were negatively associated with skeletal health.

In a study from Oklahoma State University, Stillwater, researchers randomly assigned 71 postmenopausal women to receive 40 g/d of soy protein or milk-based protein for three months in a double blind parallel design.²⁷ While both supplements positively influenced serum insulin growth factor (IGF) I, known to correlate with bone formation, soy protein had a greater effect on IGF-I. In addition, women on the milk protein had a 33 percent increase in urinary calcium excretion, while the soy group had no such increase. The results were more pronounced among women not taking hormone replacement therapy (HRT). The same researchers used the same study design in a group of men and also found soy increased serum IGF-I levels.²⁸

Another study investigating the impact of soy on bone health divided 187 healthy postmenopausal women into three groups— control, HRT or a soy-rich diet.²⁹ While diet was not as effective as HRT in reducing postmenopausal bone loss, the soy diet stimulated bone osteoblast activity and osteocalcin concentrations. Also, both treatment groups showed no significant decrease in BMD, while the control group did. Other studies have not found such positive results; a three-month study of postmenopausal women receiving placebo or soy protein found no significant differences between groups in excretion of bone resorption markers.³⁰ This is in contrast to most other findings, including a three-month open-group diet study in which 42 postmenopausal women consumed whole soy foods contributing 60 mg/d of isoflavones, which significantly increased serum osteocalcin over the treatment period.³¹

Soy’s isoflavones, natural phytoestrogens with structural similarities to the body’s natural estrogen, may be one of the key components of soy in supporting bone health. While researchers note there is as yet no determination of optimal isoflavone intake of boneprotective effects, the balance of data suggests diets rich in phytoestrogens do support bone health. ³² Specific isoflavones include genistein and daidzein. A review of genistein noted it appears to bind to the estrogen receptor, and stimulates protein synthesis in osteoblast cell lines,³³ while an animal study using purified daidzein and high calcium in ovariectomized mice found the combination favorably effected cortical and trabecular bone.³⁴

Human studies of isoflavone intake and bone health have had mixed results. A 10-week study of 40 postmenopausal Japanese immigrants living in Brazil divided the women into control or isoflavone (37.3 mg/d) groups.³⁵ Urinary excretion of bone resorption markers was reduced in the isoflavone group, possibly inhibiting osteoporotic progression. In contrast, a study of 65 postmenopausal women receiving one of three treatments (soy with 96 mg/d isoflavones, soy with 52 mg/d isoflavones or soy without isoflavones) for nine months with a six-month follow up found no differences in spine or femoral BMD, while BMD increased in the trochanter only in the isoflavone-free group.³⁶

Contrarily, a one-year study in 90 postmenopausal women had three groups—placebo, HRT or genistein (54 mg/d) treatments.³⁷ Genistein treatment significantly reduced markers of bone resorption and increased serum levels of bone-specific proteins and osteocalcin. In addition, both genistein and HRT increased femoral and lumbar BMD. Similar findings were reported in a study from the Chinese University of Hong Kong, China, in which mid-dose (40 mg/d) and high-dose (80 mg/d) isoflavone treatments positively affected BMD, particularly among women with lower body weight or calcium intake.³⁸

Studies have also investigated the impact of ipriflavone, a synthetic isoflavone shown to have a protective effect on bone mineral density and used in several Asian countries as a pharmaceutical treatment for prevention of osteoporosis. Researchers have suggested it may work in part by enhancing calcium absorption in the duodenum.³⁹ However, results of clinical work have been inconsistent. A study of 37 Japanese women in early-stage menopause and 52 Japanese women in late-stage menopause compared the impact of ipriflavone (600 mg/d) or placebo on BMD.⁴⁰ Women in the early-stage group receiving ipriflavone had a 6.7 percent BMD decrease over one year, compared to a 10.7 percent decrease in early-stage women on placebo. The differences were less pronounced in the late-stage group (0.3 percent increase in BMD in those taking ipriflavone, 2.3 percent decrease in placebo) at six and 18 months of treatment.

Similar results were reported by researchers from the Center for Clinical and Basic Research in Denmark, who conducted a four-year, placebo-controlled, randomized, double blind study across four centers in Belgium, Denmark and Italy.⁴¹ The study involved 474 postmenopausal women who received ipriflavone (200 mg three times daily) or placebo.

The percentage change in BMD for all sites did not differ significantly between groups, nor did the response in biochemical markers; however, there was a 40 percent dropout rate during the study, as well as contradictions in some of the data presented.

Researchers are also branching out beyond only soy and basic nutrients to explore how different compounds may impact bone health. For example, essential fatty acids (EFAs) may have an impact on bone health. A review from Hull Royal Infirmary, England, noted diets with a low omega-6- to-omega-3 ratio may have a beneficial effect on BMD.⁴² It has been suggested that omega-3 EFAs may work to reduce inflammatory cytokines (which mediate postmenopausal bone loss) while also increasing calcium absorption, bone calcium and BMD.⁴³ Intervention studies have been less conclusive. A study in ovariectomized rats given the omega-3 eicosapentaenoic acid (EPA) found the EFA decreased the levels of inflammatory omega-6 EFAs, but had a detrimental effect on femur BMD.⁴⁴

In contrast, another study in ovariectomized rats found administration of omega-3 EFAs inhibited osteoclast generation and activation.⁴⁵ Two recent studies investigated the impact of botanical substances on bone health. A study from Presidency College in Calcutta, India, looked at the impact of black tea on bone loss in ovariectomized rats.⁴⁶

Researchers found significant improvements in BMD in animals given black tea compared to the unsupplemented group; the rats not given black tea also had significant decreases in bone levels of calcium and phosphate, which were mitigated by black tea. These researchers used the same model to examine the effect of garlic on bone health.⁴⁷ They found low bone densities that developed in the ovariectomized group were mitigated by garlic extract, which also prevented a rise in plasma markers of bone resorption.

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