ArthClear

Osteoarthritis

The tissues involved most in osteoarthritis are the cartilage and underlying subchondral bone. The cartilage is the smooth white material that forms over the ends of the bones and forms the moving surface of the joint on both sides. Cartilage is tough, elastic, very durable, and comprised of collagen and water molecules. Cartilage does not have a blood supply and receives its oxygen and nutrition from the surrounding joint fluid by diffusion. The ability of cartilage to absorb nutrients and fluid allows it to function without a blood supply.

When we move a joint, the pressure across the joint expresses fluid and waste products out of the cartilage cells, and when the pressure is relieved, the fluid diffuses back, together with oxygen and nutrients. Hence the health of the cartilage depends on movement of the joint.

Over many years and with activity and use of a joint, the cartilage may become frayed, injured, torn, and may even wear away entirely. When this occurs, the bone surface on one side of the joint tends to rub or glide against the bone on the opposite side of the joint, providing a less elastic joint surface, and generating higher contact pressures at the end of the bone. Over time, the contacting bone surfaces become hardened and ‘sclerotic’; a process that causes the bone to look polished and on x-rays produces a whitened appearance.

There are three common forms of osteoarthritis, and many people have some of each type. All people will develop OA to some degree, involving one or more joints, throughout their lifetime as the aging process advances. The most common sites for OA include the base of the thumb joint, the knees, and the hands.

The first and mildest form causes bony enlargement of the finger joints. The end joints of the fingers become bony (this is due to osteophyte formation, or reactive bone at the joint surfaces) and the hand begins to assume the appearance we associate with old age – i.e., a swollen joint involving the fingers. The base of the thumb may become swollen with bony enlargement and is the most frequently encountered site of OA.

The second form involves the spine (neck and mid- and low-back regions). Bony growths (osteophytes) appear on the spine in the neck region or in the lower back. Usually the bony growths are associated with some narrowing of the space between the vertebrae. Similar to the long-bone cartilage joint space degeneration, the process of OA in the spine begins with a degeneration of the cartilage in the disc spaces. These disc spaces degenerate, narrow, and lead to increased forces on the bones, with subsequent osteophyte formation.

The third form involves the weight-bearing joints, most frequently involving the knees, which are followed by the hips.

The symptoms of OA may become quite severe. Osteoarthritis of the weight-bearing joints, particularly the hip and knee, develops slowly and often (but not always) involves both sides of the body. Pain in the joint may remain fairly constant or may wax and wane for a period of years, and usually is activity related. In advanced cases, walking or regular activities of daily living may become difficult or even impossible. Reactive fluid (an effusion) may accumulate in the affected joint, giving it a swollen appearance. This fluid is generated from the soft tissue in the knee known as synovium, which reacts by trying to create more lubrication to make the joint surfaces smoother. A knee may feel unsteady, stiff, or have a sensation of giving out when weight is placed on it. Additionally, a feeling of locking or grinding may be felt in the joint.

Rheumatoid Arthritis


Rheumatoid arthritis is a chronic inflammatory disease, primarily involving the peripheral joints (finger joints, wrists, toes and knees) and surrounding muscles, tendons, ligaments and blood vessels

This disease is among the autoimmune disorders (an abnormal immune response to oneself which leads to a sequence of tissue reactions and damage that may produce diffuse, systemic signs and symptoms).

Rheumatoid Arthritis (RA) can be one of the most disabling types of arthritis. It occurs worldwide, affecting more than 6.5 million people in the U.S. alone. It affects about 1% of people. The disease strikes women three times more often than men. Although it can occur at any age, the peak onset period is between the ages of 35 and 50. The disease may come on slowly or appear suddenly.

RA usually requires lifelong treatment and sometimes surgery. In most people with RA, the disease follows an intermittent course with a variety of symptoms, from just a few symptoms to severe and painful deformities that may be disabling. Factors that predict aggressive disease include onset at older age, high rheumatoid factor, and cigarette smoking.

Much more is known about the damage that results from RA than its causes. More than two thirds of patients develop bone damage (erosions) within the first two years of disease. If uncontrolled, joint inflammation progresses in four stages:

1. First stage, synovitis (inflammation of the synovial membrane) develops from congestion and oedema of the synovial membrane (membrane lining the capsule of a joint) and the joint capsule.

2. Formation of pannus (thickened layers of granulation tissue) marks the onset of the second stage. Pannus covers and invades cartilage and eventually destroys the joint capsule and bone.

3. Progression to the third stage is characterized by fibrous ankylosis - fibrous invasion of the pannus and scar formation that occludes the joint space. Bone atrophy and misalignment cause visible deformities and disrupt the articulation of opposing bones, causing muscle atrophy and imbalance and possibly partial dislocations or subluxations.

4. In the fourth stage, fibrous tissue calcifies, resulting in bony ankylosis and total immobility.

Patients with mild disease have fewer than six joints involved, no bone erosion on x-rays and no RA activity outside of the joints. Patients with moderate disease have 6-20 involved joints and may have joint space narrowing or erosions on x-rays. Severe RA patients have more than 20 joints involved, anaemia, rapid joint destruction on x-rays and RA activity outside the joints.

Causes and Risk Factors of Rheumatoid Arthritis

What causes RA is unknown, but various theories point to infections, genetics and endocrine factors.

This disease is not contagious. A genetically susceptible person may develop abnormal or altered antibodies when exposed to a virus or antigen (a substance which induces the formation of antibodies). The body doesn't recognize these altered antibodies as "self," and the person forms an antibody (known as a rheumatoid factor) against them. This rheumatoid factor then generates inflammation of the joint lining.

Symptoms of Rheumatoid Arthritis

The onset may be insidious with non-specific symptoms, including fatigue, malaise, anorexia, persistent low-grade fever, weight loss, and vague articular symptoms; or it may have an abrupt onset with simultaneous inflammation in multiple joints. The symptoms usually occur bilaterally and symmetrically, and may extend to the wrists, elbows, knees and ankles.

The person may have stiff joints after inactivity, especially on rising in the morning. This morning stiffness may last for an hour or more. The person may also complain that joints are tender and painful, at first only when he/she moves them, but eventually even at rest. Ultimately, joint function is diminished.

Other complaints include stiff, weak or painful muscles. If the patient has peripheral neuropathy, he/she may report numbness or tingling in the feet or weakness or loss of sensation in the fingers. Sometimes rheumatoid arthritis can cause inflammation in the lungs, eyes or blood vessels; this is known as extra-articular disease.

Inspection of the person's joints may show deformities and contractures, especially if active disease continues. The fingers may appear spindle-shaped from marked oedema and congestion in the joints. The joints may even be red and hot to the touch.

Research:Considerable cross reactivity of IgM and IgA antibodies was documented by absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in RA patients. Three of the five RA patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies; these became normalized after treatment, but clinical improvement was better reflected in a reduced erythrocyte sedimentation rate.

Conclusions: The production of cross-reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints (Gut 2006; 55: 1240-1247).

Vitamin D

Studies have shown that most people are not getting a sufficient amount of this vitamin for bone formation. Vitamin D is essential for normal bone growth and development, and to maintain bone density (Holick, 2004). It is also necessary for utilization of both calcium and phosphorus. Vitamin D acts as a hormone and increases reabsorption of calcium and phosphorus by the kidneys and increased bone turnover. Vitamin D may also increase the calcium around damaged joints in persons with gout and rheumatoid arthritis.

Original man's diet was dominated by fruits, vegetables, and lean wild meats, which have a low saturated fat content. The main foods introduced by agriculture are grains, dairy products, and meat from domesticated animals, which has a very high saturated fat content.

Grains contain phytate or phytic acid, which counters the action of vitamin D. The only common grain with a very low phytate content is rice.

In 1991, studies showed that part of the bovine albumin protein or milk is a molecular mimic of the vitamin D receptor. An immune reaction against that milk protein can potentially result in an autoimmune reaction against the vitamin D receptor, which would significantly lower the effectiveness of vitamin D hormone to bind with a variety of cells, including immune cells.

Proteins from various foods introduced by the agricultural revolution (gluten, dairy, legumes) result in autoimmune reactions by increasing intestinal permeability and by mimicking infectious and self-antigens. The great increase in the consumption of saturated fat also contributes to an increase in inflammatory reactions. Food-driven autoimmune reactions occur almost on a daily basis. They have a significant cumulative effect and result in harmless auto-immunity becoming problematic autoimmune disease in genetically susceptible people.

Alcohol consumption also interferes with vitamin D metabolism.

Vitamin D3 has been shown to increase bone density even in patients using corticosteroids (Annals of Int Med, 15/12/1996). Other studies show progression of degenerative arthritis of the knee and hip is faster in people with lower vitamin D concentrations (McAlindon, 1996) & (Lane, Nevitt, Gore & Cummings, 1997).

Osteoporosis is most often associated with inadequate calcium intake. However, a deficiency of vitamin D also contributes to osteoporosis by reducing calcium absorption. While rickets and osteomalacia are extreme examples of vitamin D deficiency, osteoporosis is an example of a long-term effect of vitamin D insufficiency (Parfitt, 1990). Adequate storage levels of vitamin D help keep bones strong and may help prevent osteoporosis in older adults, in those who have difficulty walking and exercising, in post-menopausal women, and in individuals on chronic steroid therapy (LeBoff et al, 1999).

Vitamin D deficiency, which is often seen in post-menopausal women and older Australians, has been associated with greater incidence of hip fractures. (Chapuy et al, 1992), (Dawson-Hughes et al, 1995) & ( Rodriguez-Martinez & Garcia-Cohen, 2002).

In a review of women with osteoporosis hospitalized for hip fractures, 50 percent were found to have signs of vitamin D deficiency (LeBoff et al, 1999). Daily supplementation with 800 IU of vitamin D may reduce the risk of osteoporotic fractures in elderly populations with low blood levels of vitamin D (Reid, 1996).

Manganese

Manganese is a mineral essential to the formation of connective tissue (such as cartilage). Manganese is extremely helpful for sufferers of Arthritis and also aids in keeping bones strong and preventing Osteoporosis. Manganese is involved in protein, fat and energy metabolism. It's primary function, though, is as an antioxidant. Manganese is an essential part of biochemical reactions that affect bone, cartilage and brain function. Manganese superoxide dismutase (MnSOD) is the principal antioxidant enzyme in the mitochondria. Because mitochondria consume over 90% of the oxygen used by cells, they are especially vulnerable to oxidative stress. The superoxide radical is one of the reactive oxygen species produced in mitochondria during ATP synthesis. MnSOD catalyses the conversion of superoxide radicals to hydrogen peroxide, which can be reduced to water by other antioxidant enzymes (Leach & Harris, 1997). The anti-inflammatory effects of recombinant human manganese on adjuvant arthritis were investigated. Local application of this manganese superoxide dismutase given every 2 days not only significantly reduced foot swelling but also retarded radiological bone destruction in adjuvant arthritis (Rheumatology International, 1994).

Manganese helps disperse calcium throughout the body. Inadequate levels of manganese reduce bone-calcium mobility and leads to hypocalcaemia (Calcified Tissue International, 1984).

It has been documented that women with osteoporosis have decreased plasma levels of manganese and also an enhanced plasma response to an oral dose of manganese. This suggests that osteoporotic women may have lower manganese status than women without osteoporosis (Freeland-Graves & Llanes, 1994). A study in healthy postmenopausal women found that a supplement containing manganese (5 mg/day), copper (2.5 mg/day), and zinc (15 mg/day) in combination with a calcium supplement (1,000 mg/day) was more effective than the calcium supplement alone in preventing spinal bone loss over a two-year period (Strause et al, 1994).

Glucosamine (HCI)

Glucosamine is the most widely accepted non-pharmaceutical treatment for both Osteo (OA) and Rheumatoid (RA) Arthritis with over 500 research articles published on Pubmed. Two representative research articles have shown glucosamine inhibits COX-2 and its products, including PGE2 (J Biol Chem. 2007). A further study using Boswellic Acid has shown a synergistic effect was observed in chronic inflammatory conditions when two chemical entities, glucosamine HCl and Boswellic Acid were administered in combination in preclinical study. This study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan oedema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg/kg), boswellic acids (250mg/kg), glucosamine (250mg/kg) and a combination of boswellic acids (125mg/kg) and glucosamine (125mg/kg). BA when administered at 250mg/kg in rats, carrageenan-induced paw oedema and Mycobacterium-induced developing arthritis were significantly inhibited. In comparison to boswellic acids, glucosamine when administered at 250mg/kg showed a mild effect in carrageenan-induced oedema and moderate inhibition of paw swelling against developing arthritis (Bioorg Med Chem Lett, 2007).

L-Cysteine

L-cysteine is a protein amino acid naturally present in the proteins of life forms. L-cysteine is a sulphur amino acid and contains a sulfhydryl group. Although most cysteine is found in proteins, small amounts of free cysteine are found in body fluids and in plants. The normal diet contributes approximately 1 gram of L-cysteine daily.

L-cysteine is considered a nonessential amino acid, meaning that, under normal physiologic conditions, sufficient amounts of this amino acid are formed from the dietary essential amino acid L-methionine and the nonessential amino acid L-serine via a transsulfuration reaction. L-cysteine is a conditionally essential amino acid under certain circumstances, for example, for preterm infants.

L-cysteine serves as a precursor for synthesis of proteins, glutathione, taurine, coenzyme A and inorganic sulphate. Glutathione itself has a number of biochemical functions, including maintenance of normal cellular redox state. Certain conditions, e.g. an acetaminophen overdose, can deplete hepatic glutathione, and this can be life threatening.

There is some evidence from animal studies that cysteine can help ensure adequate glutathione synthesis during and after inflammatory challenge, thus helping to "ameliorate," in the words of one research group, "adverse effects of oxidative damage induced by disease or drugs."

Cysteine-supplemented mice and guinea pigs have enjoyed significantly extended life spans, and other animals, challenged with various toxins, have, when pre-supplemented with cysteine, survived considerably longer than non-supplemented controls. In one of these studies, 90% of control rats given large doses of acetaldehyde died. But other rats first given a combination of vitamins C and B, along with cysteine, and then exposed to the same dose of acetaldehyde, all survived. Cysteine's protective mechanisms could relate to its own antioxidant properties, its promotion of glutathione (a major antioxidant) or even, it has been hypothesized, to some ability to participate in DNA repair (Anderson et al, 1987)

Selenium

Selenium helps to reduce inflammation and free-radical damage of the body.

The nails of the fingers and toes reflect the health of joints and bones. A new study shows that a mineral deficiency detectable in toenails is linked to risk of OA, and fingernails show conditions that elevate risk for osteoporosis. Research presented at the 2005 American College of Rheumatology annual scientific meeting shows that people with low levels of the trace mineral selenium are more likely to develop knee OA that is detectable by X-ray. In fact, the lower the selenium level, the more severe the OA. For the study, researchers measured the level of selenium in toenail clippings from 940 people. Because toenails grow slowly, they reflect the selenium level in the body from the past several months up to a year ago.

“No one has looked before to see if selenium might be related to OA. We had some suspicions,” says study leader and rheumatologist Joanne Jordan, MD, of the Thurston Arthritis Research Centre , University of North Carolina at Chapel Hill . Selenium deficiency is common in parts of Asia that have selenium-poor soil. In those areas, it is not uncommon for people to develop Kashin-Beck disease, a type of arthritis called “big joint disease (Arthritis Today, May-June 2007).”

Selenium is an essential trace element involved in several key metabolic activities via selenoproteins, enzymes that are essential to protect against oxidative damage and to regulate immune function. Selenium also may have other health benefits unrelated to its enzymatic functions. It may provide important health benefits to people whose oxidative stress loads are high, such as those with inflammatory or infectious diseases like rheumatoid arthritis or human immunodeficiency virus/acquired immunodeficiency syndrome, or who are at high risk for cancers, particularly prostate cancer. Some studies have generated compelling evidence that selenium is beneficial, either alone or in conjunction with other micronutrients. Additional data from large clinical trials that provide the highest level of evidence will be key to determining the benefits accrued at various selenium intake levels. When the strength of the evidence becomes sufficient, clinical health professionals will need to use dietary and clinical assessment methods to ensure that people at increased risk for cancer or inflammatory and infectious diseases can be appropriately advised about selenium intake (Can J Diet Pract Res. 2005).

Boswellia Serrata (Boswellia)

Boswellia is probably best for Rheumatoid Arthritis, but due to its anti-inflammatory properties, it is also effective for Osteoarthritis. Boswellia inhibits pro-inflammatory mediators in the body, such as leukotrienes. Long-term use of Boswellia, as opposed to NSAIDs, does not appear to cause irritation or ulceration of the stomach.

Orally, Boswellia is used for osteoarthritis, rheumatoid arthritis (RA), rheumatism, bursitis, and tendonitis. Other uses include ulcerative colitis, abdominal pain, asthma, allergic rhinitis, sore throat, syphilis, painful menstruation, pimples, and cancer. It is also used as a stimulant, respiratory antiseptic, diuretic, and for stimulating menstrual flow.

Boswellic acids maintain healthy 5–lipoxygenase (5–LOX) activity, moderating leukotriene biosynthesis. Data suggests that of the various boswellic acids, 3–acetyl–11–keto–beta–boswellic acid, or AKBA, is considered the most powerful. AKBA helps preserve the structural integrity of joint cartilage, promotes gastrointestinal health and maintains a healthy immune mediator cascade at the cellular level.

Boswellic acids inhibit 5-lipoxygenase and leukotriene synthesis, and inhibit leukocyte elastase, which are the likely mechanisms for its anti-inflammatory properties. Boswellic acids also might have disease-modifying effect, decreasing glycosaminoglycan degradation and cartilage damage. Indian frankincense also might inhibit mediators of autoimmune disorders. It seems to reduce production of antibodies and cell-mediated immunity (Sander, Herborn & Rau, Z Rheumatol 1998), (Etzel, 1996) & (Kimmatkar, Thawani, Hingorani & Khiyani, 2003).

Quercetin (water soluble) / Curcumin (95%)

Curcumin studies have also indicated its usefulness in helping slow the progression of MS, Alzheimer's disease, and to suppress tumour vascularization. Because of its powerful anti-inflammatory properties, curcumin has also been shown to effectively reduce pain and discomfort due to inflammation from arthritic symptoms. In addition, it's also used in the treatment of Crohn's disease and ulcerative colitis (Antony S, et al. 1999).

Quercetin is a dietary flavonoid found in many plants. Buckwheat tea has a high concentration of quercetin. The most common form of quercetin is rutin, in which quercetin is bound to a glucose-rhamnose moiety. Quercetin is also found bound to one or two glucose molecules (monoglycoside and diglycoside forms). Quercetin has antioxidant, anti-inflammatory, nitric oxide inhibitor, and tyrosine kinase inhibitor (leading to inhibition of the division and growth of T-cells and some cancer cells) activity. The anti-inflammatory effects of quercetin might be due to inhibition of the production and activity of leukotrienes and prostaglandins, and inhibition of histamine release by basophils and mast cells. Preliminary research suggests it might slow cyclooxygenase (COX)-2 production (De Pascual-Teresa et al, 2004).

Inflammation is known to be associated with increased levels of lipid peroxides and free radicals, which are generated by the liver as well as by inflamed tissues in the body. Animals fed curcumin showed decreased levels of lipid peroxides and subsequent reduction in the processes of inflammation. One study showed curcumin to be eight times more powerful that vitamin E in preventing lipid peroxidation. Taken in-group arrangements such as with vitamin C, curcuminoids are three times as potent in neutralizing free-radical molecules.

In summary, the antioxidant mechanisms of curcuminoids may include one or more of the following interactions: They may intervene in oxidative attacks to restrict or prevent them from happening; scavenge or neutralize free radicals; and break the oxidative chain reaction caused by free radicals.

Anti-Inflammatory Effects

Curcuminoids inhibit enzymes, which participate in the synthesis of inflammatory substances in the body. The natural anti-inflammatory activity of curcuminoids is comparable in strength to steroidal drugs, and such non-steroidal drugs as indomethacin and phenylbutazone, which have dangerous side effects.

Inflammation results from a complex series of actions and/or reactions triggered by the body's immunological response to tissue damage. This damage may be caused by physical traumas including various diseases and surgery. Moderate inflammation is necessary for the healing process; however, continuous inflammation leads to chronic conditions like arthritis and its associated pain. In a double blind, controlled study, three groups of patients received either curcumin (400 mg), the anti-inflammatory prescription drug phenylbutazone (100 mg), or a placebo (250 mg of lactose powder) three times daily for five consecutive days after surgery. They had been admitted for either a hernia condition or an accumulation of fluid in the scrotum. The results: curcumin was just as effective as phenylbutazone in reducing post-operative inflammation.

Curcuminoids prevent the synthesis of several inflammatory prostaglandins and leukotrienes. When the anti-inflammatory properties of curcumin were tested in a double blind clinical trial in patients with rheumatoid arthritis, curcumin produced significant improvement in all patients, and again the therapeutic effects were comparable to those obtained with phenylbutazone. The studies described here were undertaken to determine the in vivo efficacy of well-characterized curcuminoid-containing turmeric extracts in the prevention or treatment of arthritis using streptococcal cell wall (SCW)-induced arthritis, a well-described animal model of rheumatoid arthritis (RA). Arthritic index, a clinical measure of joint swelling, was used as the primary endpoint for assessing the effect of extracts on joint inflammation. An essential oil-depleted turmeric fraction containing 41% of the three major curcuminoids was efficacious in preventing joint inflammation when treatment was started before, but not after, the onset of joint inflammation. A commercial sample containing 94% of the three major curcuminoids was more potent in preventing arthritis than the essential oil-depleted turmeric fraction when compared by total curcuminoid dose per body weight. In conclusion, these data document the in vivo anti-arthritic efficacy of an essential oil-depleted turmeric fraction and suggest that the three major curcuminoids are responsible for this anti-arthritic effect (De Pascual-Teresa et al, 2004) & (J Nat Prod. 2006).

Strontium

Strontium is a bone-seeking mineral incorporated by ionic substitution for calcium onto the crystal surface of bone (Dahl et al., 2001). In the test-tube (in vitro), strontium inhibits the activity of osteoclasts, bone cells that break down bone, or “resorb” bone as part of the normal bone remodelling process (Baron & Tsouderos, 2002). The effect of strontium, in the form of strontium citrate (a salt of strontium and ranelic acid), was studied in monkeys over a six-month period. Strontium altered the remodelling of bone in the monkeys, resulting in decreased bone resorption with a concomitant maintenance of bone formation. A trend toward increased volume of osteoid, the organic matrix of bone, was observed, although this was not associated with defects in bone mineralization (Buehler et al., 2001). In another animal study, monkeys fed strontium at high doses for six weeks showed a marked increase in bone strontium content. No harmful effects on bone mineral chemistry or structure occurred (Boivin et al., 1996). At low doses, strontium has been shown to increase the number of bone forming sites in thighbones of adult rats, without adverse effects on the mineral content of bone or mineralization of the organic bone matrix (Grynpas et al., 1996). Strontium was shown to reverse bone loss induced by oestrogen deficiency in rats (Marie et al., 1993).

Clinical Trials

Human clinical trials have examined the effect of strontium on bone in postmenopausal women. In the dose-ranging (Phase 2) PREVOS trial, women in early menopause were administered strontium citrate or a placebo for two years. Strontium citrate was given at daily doses of 125 mg, 500 mg or 1 gram. (Total weight of compound; strontium plus ranelic acid). Compared to women in the placebo group, who lost bone, women on strontium at the 1 gram dose showed statistically significant increases in bone mineral density (BMD) of the hip, thigh and lumbar spine. Biochemical markers of bone formation, such as serum alkaline phosphatase, increased. No effect on markers of bone resorption was observed, leading to the conclusion that strontium citrate, at the 1-gram daily dose, increased bone formation without decreasing bone resorption proportionally. It was concluded that 1 gram per day is the minimum effective daily dose of strontium citrate in these women (Reginster et al., 2002).

In another Phase 2 trial (STRATOS trial), 353 postmenopausal women with osteoporosis, who had experienced at least one spinal fracture, took strontium citrate for two years at daily doses of 500 mg, 1 gram or 2 grams. Women on the 2-gram dose showed a significantly greater increase in lumbar spine BMD than those on placebo. The number of subjects who had new spinal deformities was significantly reduced (Meunier et al., 2002). As in the PREVOS trial, serum levels of alkaline phosphatase, a marker of bone formation, increased, while markers of bone resorption (breakdown) decreased. The overall conclusion is that the minimum effective daily dose of strontium citrate (whole compound) is 1 gram in early postmenopausal non-osteoporotic women and 2 grams in postmenopausal women with osteoporosis (Reginster & Meunier, 2003).

Phase 3 efficacy studies on strontium citrate have been conducted on 1649 subjects in 12 countries. These studies began with an open-run (non-controlled study period in which subjects took calcium and vitamin D supplements to normalize their blood levels of these nutrients (Meunier & Reginster, 2003). Following this, two parallel groups were administered 2 grams daily of strontium citrate or placebo for 3-years. The subjects continued to take calcium and vitamin D during the study. In subjects on strontium citrate, BMD increased in the lumbar vertebrae by 14.4 percent and in the thighbone by 8.3 percent. The number and risk of vertebral fractures decreased (Meunier et al., 2004).

Strontium ranelate was well tolerated in the trials discussed above. The incidence of adverse events in subjects on strontium ranelate was statistically equivalent to the placebo groups, and no negative effects on haematology and other biochemical parameters have been observed.

In view of the fact that subjects on the strontium trials also took calcium, and in some cases vitamin D, to maintain normal blood levels of these nutrients, it is important to ensure calcium and vitamin D intakes are adequate when supplementing with strontium. This is underscored by earlier research on animals suggesting that increasing the intake of strontium via diet may demineralize bone when calcium is deficient (Grynpas & Marie, 1990). In rats with chronic kidney failure, strontium has been shown to cause osteomalacia, a condition in which bone is softened due to lack of mineral content. For this reason, people on kidney dialysis should not use strontium supplements (Schrooten et al., 1998).

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