Osteoporosis: Risk Factors, Prevention, and Treatment
by Hans R. Larsen, MSc ChE
Osteoporosis is entirely preventable, but vitamin K2 is the key.Osteoporosis is characterized by a decrease in bone mass and density, causing bones to become fragile and increasing the risk of fractures. In the United States 26% of women 65 years or older, and more than 50% of women 85 years or older have osteoporosis. Over 1.5 million fractures, requiring about 500,000 hospitalizations and costing the health care system about 12 billion dollars, occur every year as a result of osteoporosis. Men are not immune to osteoporosis, but the incidence is significantly lower than among women. It is estimated that 1 in 3 women and 1 in 10 men now aged 55 years or older are destined to develop osteoporosis within their lifetime.
Most commonly osteoporosis-related fractures occur at the wrist, spine, or hip. To better understand the risk factors for osteoporosis and to suggest ways of preventing and treating the disease, it is necessary to first gain a broad understanding of the process of bone formation.
Bones consist of a matrix of hydroxyapatite (calcium phosphate) and other minerals embedded in a cross-linked collagen matrix. The formation and maintenance of the bone structure is an ongoing, dynamic process. Up until the age of about 30 years the process involves mainly bone formation, but after this bone formation and bone resorption develop a delicate balance, which if bone resorption becomes dominant can lead to osteopenia (a forerunner of osteoporosis) and osteoporosis. There are two main types of cells involved in the process - osteoblasts, which promote the formation of new bone structure by increasing calcium content, and osteoclasts, which promote the resorption (demineralization of old bone) by releasing calcium into the blood circulation. Bone formation and resorption are also known as bone remodelling and take place continuously in the entire skeleton. The concentration of calcium in the blood is maintained within very narrow limits using the bone structure as a reservoir. The hormone calcitonin promotes the transfer of calcium into the bones, while parathyroid hormone (PTH) promotes the release of calcium from the bones.
Vitamin D is important in controlling PTH level with a deficiency leading to higher PTH concentration and subsequent demineralization. There is some evidence that an estrogen deficiency makes the osteoclasts more sensitive to PTH. Vitamin K is important in the synthesis of the gamma-carboxylated protein, osteocalcin. A deficiency of osteocalcin is associated with impaired bone formation (remineralization). Calcium, magnesium, boron, zinc, and strontium are all important constituents of the bone matrix with calcium being needed in the greatest amount.
DIAGNOSISOsteoporosis and its "warning sign", osteopenia, are diagnosed using a special x-ray technique called DEXA scanning (Dual Energy X-ray Absorptiometry). The scanning is painless and takes about 30 minutes. It measures the amount of minerals in the bones of the forearm, hip, and spine. The resulting number is called bone mineral density (BMD) and is used to determine if a patient has osteopenia or osteoporosis. The BMDs obtained for a particular patient are compared to average BMDs obtained in normal young adults of the same sex. Thus, if the patient's BMD is within one standard deviation of the mean for young adults he/she is considered to have normal BMD. If the BMD is between 1 and 2.5 standard deviations below that of young adults, the patient would be classified as having osteopenia. If the patient's BMD is more than 2.5 standard deviations below the young adult, then the diagnosis is osteoporosis. For most BMD tests, a decrease of one standard deviation below normal corresponds to a 10-12% decrease in bone density.
Although DEXA scanning provides useful information about bone mass, the results are not necessarily indicative of bone strength, which depends on both bone density and microscopic bone structure (rarely evaluated except in specific research projects).
RISK FACTORS AND PREVENTIONAlthough the all-important risk factor of age cannot be changed at time of diagnosis, there are several risk factors, which can indeed be modified so as to reduce the risk of osteopenia and its progression to osteoporosis. Among the more important of these are:
Certain medications (steroids such as prednisone, thyroid medications such as levothyroxine, antidepressants, and warfarin) have also been implicated as risk factors as have several diseases and disorders, notably celiac disease (sprue), elevated homocysteine levels, and hyperparathyroidism. There is also some evidence that a rapid heart rate is associated with osteoporosis in older women.
There is some evidence that whole-body vibration exercise using a Galileo or Power-Plate machine can lessen osteoporosis-associated chronic back pain; however, there is no indication that it increases BMD when used in conjunction with alendronate.
Vitamin D and Calcium
The connection between vitamin D deficiency and osteoporosis was first reported by Meryl LeBoff and colleagues at Brigham and Women's Hospital in Boston. Their 1999 study found that 50% of women admitted with acute osteoporosis-related hip fracture were vitamin D deficient. They suggested that supplementation with vitamin D and accompanying suppression of PTH may reduce future fracture risk and help the healing of existing fractures. They concluded that vitamin D deficiency among the elderly is entirely preventable and recommended supplementation with calcium and 800 IU/day of vitamin D.
Australian researchers have observed that vitamin D deficiency is also a major cause of osteoporosis and hip fractures among men. Their study involved 41 men (60 years and older) who were admitted with hip fractures. Known risk factors for osteoporosis and hip fracture were determined and compared to those of two control groups - one a group of 41 inpatients, the other a group of 41 outpatients all without hip fractures and aged 60 years or older. The researchers found that men in the hip fracture group had significantly lower blood levels of vitamin D (25-hydroxyvitamin D) than did men in the control group. Sixty-three per cent of the men in the hip fracture group had a subclinical vitamin D deficiency (<50 nmol/L serum 25- hydroxyvitamin D) as compared to only 25 per cent in the control group. The researchers also noted that men with hip fractures and hospital in-patients had lower levels of calcium and testosterone than did the out-patient controls. About 89 per cent of the men with hip fractures and the in-patients were diagnosed with hypogonadism (low testosterone levels). The researchers conclude that a vitamin D deficiency is a major cause of hip fractures in elderly men.
It is clear that vitamin D deficiency, irrespective of calcium status, is a critical risk factor for osteoporosis and associated bone fractures. Thus, it is fortunate that several clinical trials have concluded that vitamin D supplementation is effective in fracture prevention. Researchers at Harvard School of Public Health, after evaluating 14 reliable studies of oral vitamin D supplementation, concluded that daily supplementation with 700-800 IU of vitamin D reduced hip fracture risk by 26% and overall non-vertebral fracture rate by 23%. No benefit was observed with a daily dose of 400 IU (current RDA for women under the age of 70 years).
A group of researchers at Harvard Medical School studied over 72,000 postmenopausal nurses for 18 years and found that those whose daily vitamin D intake exceeded 500 IU had a 37% lower risk of hip fracture than did women whose intake was less than 140 IU/day. They found no benefit of a high daily intake of milk or calcium on its own. The researchers point out that about 60% of the women in the survey had vitamin D intakes below those recommended by the Food and Nutrition Board (400 IU for women between the ages of 51 and 70 years and 600 IU for women older than 70 years). They also point out that the amount of vitamin-D produced by exposure to sunlight decreases significantly with age (due to thinning of the skin) and the use of sunscreens. They further suggest that the reason why milk showed no significant protective effect may be due to its content of vitamin A which recently has come under scrutiny in regard to its possible role as a negative factor in bone health. The researchers conclude that women should ensure an adequate daily intake of vitamin D either through the use of supplements or through increased consumption of fish such as salmon or sardines.
The importance of daily supplementation with vitamin D is becoming increasingly clear. A team of American and Swiss researchers recently concluded that a daily intake of at least 1000 IU is required in order to achieve reasonable protection against the risk of osteoporosis, fractures, falls, and colon cancer. They suggest that an increase in the current RDA is warranted. Dr. Reinhold Vieth and colleagues of the University of Toronto go even further. They found that 62% of supposedly healthy Canadians were deficient in vitamin D and that a daily intake of 4000 IU (100 micrograms/day) was needed to bring their level of 25(OH)D, the active metabolite of vitamin D, to the desirable level of 75 nmol/L. The researchers conclude that 4000 IU/day of vitamin D3 is a safe and desirable intake, but very specifically caution that their findings regarding vitamin D3 (cholecalciferol) cannot be applied to the synthetic version of vitamin D2 (ergocalciferol), the form most often used in North America. Vitamin D2 is far more toxic than vitamin D3 and produces unique metabolites not generated by D3. The researchers are very "down" on vitamin D2 and say, "It is an anachronism to regard vitamin D2 as a vitamin."
An adequate intake of calcium is clearly essential in achieving and maintaining sufficient bone mass due to the simple fact that calcium, in the form of hydroxyapatite, constitutes the major part of the bone structure. In combination with vitamin D it is effective in preventing bone loss and fractures. Ten years ago French researchers discovered that daily supplementation with 1200 mg of calcium and 800 IU of vitamin D3 (cholecalciferol) for 3 years reduced the number of hip fractures in a group of 3270 elderly women by 23%. The researches also noted that the bone density in calcium/vitamin D supplemented women increased by 2.7% over an 18-month period, while it decreased by 4.6% in the placebo group. Since 1996 several other studies have verified the benefits of supplementation with calcium and vitamin D. In 1998 researchers at Johns Hopkins Medical School concluded that, "Optimal intakes of both calcium and vitamin D are relatively cost-effective, safe, and easily implemented approaches to maintain existing bone mass and assist in the prevention of fractures."
Dutch researchers report that 1000-1200 mg/day of calcium (elemental) plus 800 IU/day of vitamin D is effective in the prevention and treatment of osteoporosis. German researchers, after evaluating several randomized, prospective, placebo-controlled clinical trials, conclude that supplementation with 800-1500 mg/day of calcium plus 400-1200 IU/day of vitamin D reduces the risk of falls and fall-related fractures in the elderly. Indeed, the evidence that supplementation with calcium and vitamin D is beneficial in preventing and treating osteoporosis is incontrovertible.
It is, however, becoming increasing clear that a supposedly adequate calcium intake does not guarantee the absence of osteoporosis. The calcium must not only be ingested, it must also be absorbed and its excretion minimized. In other words, it is not the calcium intake per se that is important, but rather how much of it is actually retained in the body. Researchers at the University of Pittsburgh have found that the intake of fat and fiber significantly influences calcium absorption. Their study involved 142 healthy pre-menopausal white women who had enrolled in the Women's Healthy Lifestyle Project in 1995-96. The women had blood samples drawn three hours after consuming apple juice containing labeled (isotope) calcium. The blood samples were analyzed for calcium, 1,25 dihydroxyvitamin D (the active from of vitamin D), and PTH. The researchers found that about 35% (17-58%) of the labeled calcium had been absorbed. It was clear that women with a higher fat intake and a lower intake of fiber absorbed significantly more calcium than did women with less fat and more fiber in their diet. Women with high blood levels of vitamin D also showed increased absorption while women who consumed alcohol had decreased absorption. There is also some indication that a higher total calcium intake is associated with a lower rate of absorption. The researchers caution that it may only be certain types of fiber (eg. wheat bran) that inhibit calcium absorption. Fiber found in green leafy vegetables such as kale, broccoli, and bok choy may not be detrimental to absorption. They found no indication that genetic differences among the women were in any way related to calcium absorption. The researchers express the hope that their findings will encourage a second look at the current standard recommendation to emphasize a low-fat, high-fiber diet.
The rate of excretion of calcium is also an important factor in determining its effectiveness in osteoporosis prevention. Dr. Christopher Nordin of Australia's Institute of Medical and Veterinary Science points out that is not the total calcium intake which determines bone strength (density), but rather the difference between what is taken in and what is excreted. Research has shown that for each gram of animal protein consumed one milligram of calcium is lost in the urine. This means that a 40-gram reduction in animal protein intake reduces the urinary calcium loss by 40 mg which, in turn, corresponds to a reduction in calcium requirements of 200 mg (assuming an absorption of 20%). A reduction in sodium (salt) intake of 2.3 grams also reduces urinary calcium loss by 40 mg lowering requirements by another 200 mg. So a person with a low intake of protein and salt might have half the calcium requirements of a person eating a typical North American diet. This and the fact that developing countries generally get more sunshine (vitamin D) than developed countries go a long way towards explaining the difference in the incidence of osteoporosis and bone fractures between different cultures and individuals. Dr. Nordin concludes that there is no single, universal calcium requirement, only a requirement linked to the intake of other nutrients especially animal protein and sodium.
Dairy products like milk, cheese and yogurt are the richest sources of calcium followed by collards, spinach, beans, sardines and canned salmon. There is some indication that milk may not be an optimum source of calcium for older people. Researchers at the Boston University School of Medicine have studied the effectiveness of various sources of supplemental calcium in preventing bone loss in older women. Their study involved 60 postmenopausal women aged 65 years or older who did not suffer from osteoporosis and whose daily calcium intake from their regular diet was less than 800 mg/day. The women were randomly assigned to three groups. Group 1 supplemented with four 8-ounce glasses of vitamin D-fortified milk per day, group 2 took a 500 mg calcium carbonate supplement twice a day with meals, and group 3 took a placebo twice a day with meals. Bone density measurements of the spine (L2-L4) and thighbone (greater trochanter[GT]) were done at six-month intervals for a two-year period. After two years women in the placebo group (average daily calcium intake was 683 mg) had lost an average of 3% of their baseline bone mineral density in the trochanter area. This loss occurred exclusively during the winter months. Women in the milk group had an average daily calcium intake of 1028 mg and lost 1.5% of their bone density in the GT area. Women who supplemented with calcium carbonate tablets increased their daily intake to 1633 mg and suffered no bone loss in the GT area. The women in the supplement group also increased the bone density in their spine and femoral neck area by about 3%, while the placebo group women lost about 0.3%, and the milk group about 1.8%. The researchers conclude that 1000 mg/day of supplemental calcium is required in order to prevent bone loss in older women living in northern latitudes. They also point out that an adequate vitamin D intake (600-700 IU/day) is essential in order to prevent bone loss during the winter.
Other researchers, however, have found that calcium is equally well absorbed from skim milk, calcium-fortified orange juice, and calcium carbonate tablets. The most commonly used calcium supplements are calcium carbonate and calcium citrate. A comprehensive study comparing the bioavailability of calcium carbonate and calcium citrate found that calcium citrate was consistently better absorbed whether taken on an empty stomach or with a meal.[25} Other research has shown that calcium carbonate is extremely poorly absorbed by people with low stomach acid even if taken with meals. Inasmuch as low stomach acid (achlorhydria) is a common condition among older people, calcium citrate, calcium malate or calcium fumarate are all much better choices than calcium carbonate. Natural oyster shell calcium, dolomite, and bone-meal products should be avoided due to the potential for lead contamination and poor absorbability.
As an added bonus, supplementation with vitamin D and calcium has also been found to reduce systolic blood pressure by about 10%. Calcium citrate supplementation is also effective in reducing LDL cholesterol (the "bad" kind) and increase HDL cholesterol (the "good" kind").
In any case, there would seem to be little advantage in consuming more than the RDA (1200 mg/day) of calcium and a great advantage in ensuring that this intake is accompanied by a vitamin D3 intake of at least 1000 IU/day. Low-fat dairy products contain as much calcium per serving as do high-fat products. Calcium supplements should be taken in divided doses of 500 mg or less and preferably between meals except for calcium carbonate, which must be taken with meals because of its poor absorption. Calcium citrate is the preferred supplement for older people or individuals with inadequate stomach acid production. A daily calcium intake of up to 2000 mg appears to be safe for most individuals. Antacid medications containing aluminum significantly increase the loss of calcium through the urine, as does a diet high in animal protein and salt.
It is commonly believed that a high calcium intake increases the risk of forming kidney stones. Researchers at the Universities of Michigan and Arkansas, however, provide convincing proof that this contention is wrong and that a high dietary intake of calcium actually reduces the risk of stone formation. Their study involved 1309 women aged between 20 and 92 years. The women's intake of calcium, oxalate-containing foods, and ascorbic acid was estimated using the National Cancer Institute Food Frequency Questionnaire. The women resided in three different communities where the calcium content of the water supply varied between 15 mg/mL and 375 mg/mL. Analysis of the collected data showed that women with medically diagnosed kidney stones (44 out of 1309 or 3.4 per cent) had an average intake of 843 mg/day of calcium from food, supplements, and water while women without a history of kidney stones had an average intake of 1070 mg/day. The main difference in calcium intake was associated with food intake rather than with water or supplement intake. There was no significant difference in total fluid intake or intake of oxalate-rich foods between women who had kidney stones and those who had not. Neither was there any association between the intake of ascorbic acid (vitamin-C) and the risk of kidney stones. Bone mineral density and incidence of fractures were no different between women with or without kidney stones when the data was adjusted for age, body mass index, and calcium, oxalate and ascorbic acid intake. The researchers speculate that a high calcium diet may be protective because the calcium binds to the oxalate in the intestines and thereby prevents it from reaching the kidneys. They conclude that increasing the intake of dietary calcium may be protective against kidney stones and that an increased dietary calcium intake is not associated with a greater risk of forming renal stones.
Italian researchers have confirmed that a normal calcium intake does not increase the risk of kidney stones in men. Their randomized clinical trial included 120 men with a history of kidney stones (idiopathic hypercalciuria). Sixty of the men were assigned to a low-calcium diet (avoidance of milk, yogurt and cheese) while the other sixty were assigned to a normal calcium diet that was low in animal protein (52 grams/day max.) and salt.
After five years 23 of the men in the low-calcium diet group had experienced a recurrence of kidney stones as compared to only 12 men in the normal calcium diet group. Thus the men in the low-calcium group had twice the risk of recurrence than did the men in the normal calcium, low protein and low salt group. Says Dr. David Bushinsky of the University of Rochester, "Physicians should no longer prescribe a low-calcium diet to prevent recurrent nephrolithiasis in patients with idiopathic hypercalciuria".[30,31]
Researchers at the Pitie-Salpetriere Medical School found that ingestion of as little as 0.5 liters (18 oz) of calcium-rich mineral water (Vittel) has an immediate and profound effect on the prevention of bone loss. Their experiment involved 12 healthy young men who participated in a series of tests designed to compare the effects of a natural mineral water containing 345 mg/L of elemental calcium with that of a mineral water containing only 10 mg/L. The study participants (after an overnight fast) drank 0.5 liters of either of the two mineral waters and then had blood and urine samples collected for the next four hours. The ingestion of the calcium- rich water significantly inhibited the secretion of parathyroid hormone after one hour and the effect was still evident after four hours. The blood level of type 1 collagen cross-linked C- telopeptide (CTx) also declined markedly after drinking the calcium-rich water. Low levels of parathyroid hormone and CTx are both beneficial in that they are associated with a reduction in bone loss (resorption). The researchers conclude that drinking calcium-rich mineral water throughout the day will not only ensure an adequate water intake, but will also help to preserve bone mass.
A clinical trial in Israel showed that postmenopausal women suffering from osteoporosis could stop further bone loss by supplementing with 250-750 mg/day of magnesium for two years. Some (8%) of the treated women even experienced a significant increase in trabecular bone density. Untreated controls lost bone mass at the rate of 1% a year. Another experiment in Czechoslovakia found that 65% of women who supplemented with 1500 to 3000 mg of magnesium lactate daily for two years completely got rid of the pain and stopped further development of deformities of the vertebrae. Other studies have shown that magnesium is helpful in the treatment of cardiac arrhythmias and that an adequate intake helps prevent atherosclerosis.
Legumes, tofu, seeds, nuts, whole grains, and green leafy vegetables are good sources of magnesium. Magnesium glycinate (chelated magnesium) is the most bioavailable and best tolerated supplement. Magnesium citrate is also highly available, but may cause loose stools. The common form of magnesium used in supplements, magnesium oxide, is essentially useless in that only about 4% of the ingested amount is actually absorbed.
In a recent trial involving 5091 postmenopausal women with osteoporosis, hip fracture was reduced by 36% and vertebral fracture by 39%. This trial also clearly demonstrated the beneficial effect of strontium on BMD. Increases of 8.2% at the femoral neck and 9.8% at total hip were observed in women treated for 3 years. A recent Cochrane review concluded that strontium ranelate is effective in both prevention and treatment of osteoporosis. Doses used in the trials ranged from 125 - 1000 mg/day for prevention to 500 - 2000 mg/day for treatment of existing osteoporosis. A 37% reduction in vertebral fractures and a 14% reduction in non-vertebral fractures were demonstrated over a 2-year period with 2 grams/day of strontium ranelate (containing 700 mg of elemental strontium).
It is not clear why strontium has such a beneficial effect on bone health, but it has recently been reported that commercial foods grown on fields using synthetic fertilizers, pesticides, and herbicides have appreciably lower levels of strontium than their organic food counterparts. Although recent studies have focused on the use of strontium ranelate, previous studies have found the following forms of organically-bound strontium to be equally effective - strontium gluconate, strontium carbonate, strontium lactate, and strontium chloride.
Strontium ranelate was developed in France and unfortunately, is not available in North America.
It is a well-established fact that the incidence of hip fractures is exceptionally high in Sweden and Norway. Researchers at the Uppsala University in Sweden believe that an excessive intake of vitamin A may be involved. Vitamin-A intake is traditionally higher in the Nordic countries where cod liver oil is commonly taken as a supplement and margarine and milk are often fortified with both vitamins A and D. The researchers studied a group of 175 women (aged 28 to 74 years) and found that their bone density (measured in the spine and thigh bone) correlated with their vitamin A intake. Women with an average daily intake of more than 7500 IU (1.5 mg) were found to have a 10 per cent lower bone mineral density in the thighbone (femoral neck) and a 14 per cent lower density in the lumbar spine. This relationship held true even after correcting for numerous other factors related to bone density such as smoking, physical activity level, menopausal status, calcium and vitamin D intake, etc. The researchers also evaluated the correlation between vitamin A intake and hip fracture in a group of 247 women with hip fracture and 873 age-matched controls (40 to 76 years of age). They found that the risk of hip fracture was twice as high among women who consumed more than 7500 IU/day as among women consuming 2500 IU/day (0.5 mg) or less. They point out that animal studies have shown that excessive vitamin A intakes are correlated with accelerated bone resorption and spontaneous fractures and conclude that an excessive dietary intake of vitamin A is associated with osteoporosis in humans.
Blood serum level of vitamin B12 is difficult to measure accurately, so instead of measuring cobalamin level, many studies measure the level of methylmalonic acid (MMA). MMA is a precursor to metabolic reactions controlled by cobalamin, so if its level is abnormally high, then the level of cobalamin is abnormally low. The normal blood level of vitamin B12 ranges between 200 and 600 picogram/mL (148-443 picomol/L). A MMA level greater than 271 nmol/L indicates a vitamin B12 deficiency. The classical vitamin B12 deficiency disease is pernicious anemia, a serious disease characterized by large, immature red blood cells.
Vitamin B12 is important in DNA synthesis and may affect bone formation. It has been linked to osteoblastic activity in clinical studies and cell culture. A 1992 study involving a group of postmenopausal women in Rochester, Minnesota reported an almost 2-fold increase in the risk of hip and spine fractures, and an almost 3-fold increase in wrist fractures among women with pernicious anemia when compared to normal controls. More recently, researchers at the University of California (SF) found that women with low serum vitamin B12 levels (below 280 pg/mL) lost bone mass in the hip more rapidly than did women with B12 levels above 280 pg/mL (1.6% loss/year vs. 0.2% loss/year).
The Framingham Offspring Osteoporosis Study (1996-2001) examined the relationship between plasma vitamin B12 status and BMD in 2576 adults. The conclusion was that men with low plasma vitamin B12 levels had significant lower BMD at the hip, while women with low levels had significantly lower BMD at the spine. The Framingham researchers conclude that low vitamin B12 status may be a risk factor for low BMD.
The association between low vitamin B12 status and inferior BMD is not limited to the older generation. A Dutch study observed that vitamin B12 levels were significantly lower and MMA levels significantly higher in adolescents with low BMD.
The amount of vitamin B12 actually needed by the body is very small, probably only about 2 micrograms or 2 millionth of a gram/day. Unfortunately, vitamin B12 is not absorbed very well so much larger amounts need to be supplied through the diet or supplementation. The richest dietary sources of vitamin B12 are liver, especially lamb's liver, and kidneys. Eggs, cheese and some species of fish also supply small amounts, but vegetables and fruits are very poor sources. Several surveys have shown that most strict, long-term vegetarians are vitamin B12 deficient. Many elderly people are also deficient because their production of the intrinsic factor needed to absorb the vitamin from the small intestine decline rapidly with age.
Fortunately, oral supplementation with vitamin B12 is safe, efficient and inexpensive. Most multi-vitamin pills contain 100-200 microgram of the cyanocobalamin form of B-12. This must be converted to methylcobalamin or adenosylcobalamin before it can be used by the body. The actual absorption of B12 is also a problem with supplements. Swallowing 500 micrograms of cyanocobalamin can result in absorption of as little as 1.8 microgram so most multivitamins do not provide an adequate daily intake. The best approach is to dissolve a sublingual tablet of methylcobalamin (1000 micrograms) under the tongue every day. That will be sufficient to maintain adequate body stores. However, if a deficiency is actually present then 2000 microgram/day for one month is recommended followed by 1000 microgram/day. Some physicians still maintain that monthly injections of vitamin B12 is required to maintain adequate levels in the elderly and in patients with a diagnosed deficiency. There is however, no scientific evidence supporting the notion that injections are more effective than sublingual supplementation.
The main role of vitamin K is to act as a cofactor for the conversion of glutamate into gamma-carboxyglutamate, which, in turn, is involved in the synthesis of osteocalcin, the hormone that promotes bone formation. Several epidemiological studies have concluded that a vitamin K deficiency causes reductions in bone mineral density and increased the risk of fractures.
Other studies have shown that a high intake of vitamin K is associated with a substantially reduced risk of hip fracture and that a daily intake below 109 micrograms/day is associated with an increased risk.[66,67] Several studies have also concluded that supplementation with a combination of vitamin K1, vitamin D3, and calcium is highly effective in increasing BMD.[68,69] Dutch researchers treated 188 postmenopausal women for 3 years with supplements (calcium, magnesium, zinc, vitamin D3, and vitamin K1) and found that the annual rate of bone loss decreased by 35 to 40%.
It is likely that between 200 and 500 micrograms/day of dietary vitamin K may be required for optimal gamma-carboxylation of osteocalcin. Unfortunately, relatively few people achieve such high intakes from their diet. Thus, it is fortunate that available evidence regarding relative bioavailabilities suggests that 100 micrograms/day of vitamin K in the form of supplements is equivalent to 200 - 500 micrograms/day obtained from the diet. Vitamin K has a very wide safety range. No adverse effects or hazards have ever been associated with supplementation with natural vitamin K.
DIET AND LIFESTYLEThere are several diet and lifestyle factors, which can have a profound effect on the risk of developing osteoporosis.
Researchers at the University of California believe that the explosive growth in osteoporosis and hip fractures is caused by an over-acidic diet. They point out that the modern western diet contains lots of grains, cheese, bread, and meat which all produce acid in the body. In order to neutralize this acid overload the body, if necessary, pulls carbonates, phosphates, and ammonia out of the bones, eventually leaving them fragile and porous. The researchers point out that countries with a diet high in meat, cheese, and fish have 40 times as many hip fractures as some Asian countries where fruits and vegetables are the mainstay and cheese and meat are seldom eaten. A recent study involving American women found that those who ate the most acid-producing diet had four times as many hip fractures as those on the least acid-producing diets. Another study found that potassium bicarbonate is very effective in neutralizing the effects of high-acid diets. The researchers recommend that people go easy on cheese (very acid forming), meat and grains and instead increase their intake of fruits and vegetables. They also suggest that avoiding an acid-forming diet may actually be more important than ensuring an adequate calcium intake.
Researchers at Tufts University have discovered that the effect of protein intake on bone mass is highly dependent on the concurrent intake of calcium and vitamin D. Their study involved 342 healthy men and women aged 65 years or older who participated in a three-year, randomized, placebo-controlled trial of calcium and vitamin D supplementation. The calcium group received 500 mg of calcium citrate maleate and 700 IU (17.5 micrograms) of vitamin D daily in the form of supplements. The average total daily calcium intake in the supplement group was 1346 mg/day as compared to 871 mg/day in the control group. The average total protein intake was 79 grams/day varying between 14 and 20 per cent of total energy intake. Plant protein intake was about 5 per cent of energy. Bone mineral density (BMD) was measured every six months at the femoral neck, spine and total body. At the end of the three-year supplementation period the researchers observed that the BMD for total body and femoral neck had increased significantly amongst those in the calcium/vitamin D supplement group who had the highest intake of protein (greater than 20 per cent of total energy on average). BMD in total body and femoral neck decreased in the placebo group irrespective of protein intake. The researchers conclude that a high protein intake is associated with an increase in BMD provided it is accompanied by supplementation with calcium citrate maleate and vitamin D.[74,75]
Thus, it would seem that a moderate to high protein diet is not detrimental if accompanied by supplementation with calcium, vitamin D, and potassium bicarbonate.
Elevated Resting Heart Rate
ASSOCIATED DISEASES AND CONDITIONSHyperhomocysteinemia
Hyperhomocysteinemia is characterized by elevated blood levels of the amino acid homocysteine. High homocysteine levels have been implicated as a risk factor for atherosclerosis and stroke. The "official" normal blood level range for homocysteine is 5 - 15 micromol/L. However, there is increasing evidence that this upper level may be too high and that a maximum level of 7 micromol/L for people under 60 years of age and a maximum level of 12 micromol/L for those over the age of 60 years may be more appropriate. There is evidence that a high homocysteine level is associated with increased osteoclast activity (loss of bone minerals. It is also becoming clear that high homocysteine levels are associated with an increased risk of osteoporosis and osteoporotic fractures.
It has long been established that homocysteine levels and status of folic acid, vitamin B6 and vitamin B12 are closely linked. A study of 1550 men and women participating in the National Health Nutrition Examination Survey (NHANES) found that participants with a homocysteine level of 20 micromol/L or higher had significantly lower BMD (measured at the hip with DEXA scan) than did those with a serum level less than 10 micromol/L. NHANES researchers conclude that a low serum vitamin B12 level, a high level of homocysteine, and a high level of methylmalonic acid are all independent risk factors for osteoporosis. They found no association between folate levels (serum and red blood cell) and BMD or osteoporosis risk.
In contrast, Norwegian researchers found a correlation between low folate levels and low BMD (in women only) and also confirmed a strong correlation between high homocysteine levels and low BMD in women only. The Norwegian researchers found no association with vitamin B12 levels.
British researchers have also concluded that a low serum folate level is a significant risk factor for osteoporosis with vitamin B6 and vitamin B12 having a lesser effect. Korean researchers believe that homocysteine activates osteoclast formation through the generation of reactive oxygen species (free radicals) and that this activation and its resulting loss of bone mass can be prevented by supplementation with antioxidants such as N-acetylcysteine.
It is clear that a high homocysteine level is a significant risk factor for low BMD, osteopenia, and osteoporosis. There is also evidence that low levels of folic acid and vitamin B12 (correlates with high levels of methylmalonic acid) are associated with an increased risk. Fortunately, oral supplementation with folic acid (400-800 micrograms/day), vitamin B6 (50 mg/day), and vitamin B12 (1000 micrograms/day as sublingual methylcobalamin) will not only raise the levels of these vitamins, but will also result in a substantial reduction in homocysteine level.
A very large Swedish study involving more than 13,000 individuals with celiac disease (and 65,000 controls) found that celiacs experienced twice the risk of hip fracture and a 40% greater risk of any fracture when compared to normal controls. Fortunately, at least two major studies have shown that adhering to a gluten-free diet can halt and even reverse celiac-associated bone loss. Argentinean researchers reported in 1997 that 3 years on a gluten-free diet results in an average one standard deviation increase in bone mass. Their study involved 25 celiac patients with osteopenia at the lumbar spine (72%) and other locations. The increase in bone mass was greater in premenopausal women than in postmenopausal women. Italian researchers carried out a study involving 86 newly-diagnosed celiac patients. At baseline, 34% of participants had normal BMD, 40% had osteopenia, and 26% had osteoporosis. After one year on a gluten-free diet, BMD had improved substantially. Another Italian study involving 40 newly-diagnosed celiac patients found that 20% of them had excessively high homocysteine levels as compared to an incidence of 6% in the non-celiac control group. Celiacs also exhibited folate deficiency more often than did control (42.5% vs. 8.3%). The Italian researchers also observed a strong correlation between high homocysteine levels and low levels of vitamin B12 and folic acid. A gluten-free diet normalized folate, vitamin B12, and homocysteine levels. This finding would tend to indicate that celiac disease can cause hyperhomocysteinemia.
DRUG-RELATED OSTEOPOROSISThyroid medications, prednisone, and warfarin have all been linked to an increased risk of osteoporosis.
French researchers report that a significant proportion of osteoporosis cases may be caused by the inappropriate use of thyroid hormones. Thyroid hormones are widely prescribed for older people and are among the drugs most prescribed to women in both Germany and the United States. The drugs can be used to either suppress an overactive thyroid gland or to bolster a failing one. The researchers evaluated the results of 33 clinical studies involving 1266 women and 95 men. They concluded that suppressive thyroid hormone therapy is associated with increased bone loss in postmenopausal women, but not in premenopausal women. Replacement therapy, on the other hand, was found to be associated with bone loss (spine and hip) in premenopausal women, but not in postmenopausal women. The researchers point out the over-treatment with thyroid hormones is common and that careful titration of the medication dose and close monitoring of blood levels of the hormones are required in order to avoid detrimental effects. They specifically caution against "overzealous or irrelevant" prescription of thyroid hormones.
There are several viable approaches to lessening this risk, but unfortunately these measures are not widely applied - at least not in the UK. A survey showed that only 14% of patients taking prednisone were given supplements or medications to avoid osteoporosis. Dr. Johannes Bijlsma, MD of the Utrecht University Hospital points out that supplementation with calcium and vitamin D can be quite effective in preventing osteoporosis. He recommends the following guidelines for corticosteroid treatment:
Postmenopausal women with very low bone density may also need to be treated with hormone replacement therapy or bisphosphonates, but Dr. Bijlsma is reluctant to recommend this option to all patients.
Researchers at the Medical College of Virginia have confirmed that supplementation with calcium and vitamin D can, to a large extent, counteract the negative effects of prednisone on BMD. Their randomized, double-blind, placebo-controlled trial involved 96 patients with rheumatoid arthritis, 65 of whom were receiving an average of 5.6 mg/day of prednisone. Half of the participants were given 1000 mg of elemental calcium (in the form of calcium carbonate) plus 500 IU of vitamin D daily in two divided doses - at breakfast and dinner. The other half was given placebo tablets. Calcium intake from food was about 900 mg/day for both groups. At then end of the two-year study the patients in the prednisone-treated placebo group had lost bone density in the lumbar spine and femur (thigh bone) at a rate of 2.0% and 0.9% per year respectively. In contrast, the patients taking the supplements had gained 0.75% and 0.85% per year respectively. No statistically significant changes in bone density were seen in patients not taking prednisone whether or not they took calcium and vitamin D. The researchers conclude that supplementing with 1000 mg/day of calcium (elemental) and 500 IU of vitamin D will prevent bone mineral loss in patients being treated with low doses of prednisone.[96,97]
Although this study did not find an increased risk of osteoporosis among female warfarin users, it is possible that an association still exists, but is masked by other, more important, risk factors such as loss of estrogen production after menopause. This hypothesis is supported by the recent finding by Australian researchers that children on long-term warfarin therapy also experience a marked reduction in bone density.
TREATMENT WITH PHARMACEUTICAL DRUGSConventional medical treatment of osteopenia and osteoporosis involves one or more of the following treatment protocols:
Hormone Replacement Therapy
The first bisphosphonate to be marketed was etidronate (Didronel, Didrocal), which is given in cycles of two weeks interspersed with 11 weeks of calcium carbonate supplementation. Etidronate is effective in increasing BMD in the spine (1% increase per year), but less effective in doing so at the hip.
Second generation bisphosphonates include alendronate (Fosamax), risedronate (Actonel), and zoledronate (Zometa). These newer drugs are taken continuously on a daily basis and should preferably be accompanied by supplementation with calcium and vitamin D.
Alendronate is significantly more effective than etidronate. A clinical trial involving medication with 10 mg/day of alendronate plus 500 mg of calcium found that the BMD in the lumbar spine increased by slightly more than 4% a year in the first and second years of treatment. This corresponds to an improvement of about 0.4 standard deviations. Alendronate is usually only prescribed for postmenopausal women whose BMD is more than 2.5 standard deviations below the young healthy norm and who have already suffered one or more fractures. It is not cost-effective for women with osteopenia. A recent study found that treating women with osteopenia with alendronate for 5 years would cost between $70,000 and $332,000 per quality-adjusted life-years gained. This essentially is saying that alendronate is not any more effective than no drug therapy in women with osteopenia.
Bisphosphonates have, as do all pharmaceutical drugs, the potential for serious side effects, among them necrosis (rotting) of the jaw bone. Merck & Co, the manufacturer of Fosamax is currently facing several class action suits launched by Fosamax users who developed severe necrosis after undergoing dental work.
It is well known that both alendronate and naproxen, a popular non-steroidal anti-inflammatory drug (NSAID), can cause damage to the stomach lining including the actual development of stomach ulcers. Researchers at the Baylor College of Medicine have found that a combination of alendronate and naproxen is considerably more dangerous than either drug on its own. Their clinical trial involved 26 healthy volunteers (18 women and 8 men) between the ages of 30 and 50 years. The study participants were randomized to receive either 10 mg of alendronate once a day, 500 mg of naproxen twice a day or a combination of the two for a 14-day period. The presence of stomach lining damage was measured using videoendoscopy at the beginning and end of the test periods. The first test period was followed by a one-week wash-out period after which the participants were assigned to another regimen and so on until all the participants had tried all three regimens.
The researchers found that 10 mg/day of alendronate produced ulcers in 8 per cent of the participants, 500 mg of naproxen twice a day produced ulcers in 12 per cent, and 10 mg/day of alendronate plus 500 mg of naproxen twice a day produced ulcers in 38 per cent of the volunteers and significant side effects in 69 per cent. It is clear that alendronate and naproxen act synergistically in inducing stomach ulcers. The researchers conclude "it would appear prudent not to prescribe anti-inflammatory doses of traditional NSAIDs to patients receiving alendronate (and vice versa)."
It is possible that the gastrointestinal side effects of alendronate can be somewhat lessened by always taking the medication with a full glass of water and remaining in the upright position for at least an hour after taking it.
Selective Estrogen Receptor Modulators
As in the case of alendronate, raloxifene is not cost-effective in the treatment of osteopenia. A recent study concluded that 70-year-old women with osteopenia would gain 19 days of quality-adjusted life if treated with raloxifene for 5 years as compared to women treated with calcium/vitamin D plus weight-bearing exercise. This corresponds to a cost of $69,000 per quality-adjusted life year gained. Alendronate therapy resulted in a gain of 11 days of quality-adjusted life after treatment for 5 years.
Hot flushes and leg cramps are common side effects associated with raloxifene therapy, but the most serious adverse effect is a 3-fold increased risk of venous thromboembolism.[118,120] The best way of preventing venous thromboembolism is by daily supplementation with nattokinase (2000 - 4000 FU/day) and by wearing flight socks when travelling by air.
A major study published in the New England Journal of Medicine in 2004 concluded that supplementing with 2 grams/day of oral strontium ranelate reduced the risk of vertebral fractures by 50% in a group of 1649 postmenopausal women with low BMD.
In another study involving 5091 postmenopausal women with osteoporosis, hip fracture was reduced by 36% and vertebral fracture by 39%. This trial also clearly demonstrated the beneficial effect of strontium on BMD. Increases of 8.2% at the femoral neck and 9.8% at total hip were observed in women treated for 3 years. A recent Cochrane review concluded that strontium ranelate is effective in both prevention and treatment of osteoporosis. Doses used in the trials ranged from 125 to 1000 mg/day for prevention to 500 to 2000 mg/day for treatment of existing osteoporosis. A 37% reduction in vertebral fractures and a 14% reduction in non-vertebral fractures were demonstrated over a 2-year period with 2 grams/day of strontium ranelate (containing 700 mg of elemental strontium).
In addition to its many advantages in the treatment of osteopenia and osteoporosis, strontium ranelate is also remarkable in its lack of undesirable side effects. It does not, as may the bisphosphonates, cause rotting of the jaw bone or stomach ulcers, especially if used in combination with naproxen and perhaps other non-steroidal anti-inflammatory drugs (NSAIDs).
Although recent studies have focused on the use of strontium ranelate, previous studies have found the following forms of organically-bound strontium to be equally effective - strontium gluconate, strontium carbonate, strontium lactate, and strontium chloride.
Strontium ranelate was developed in France and, unfortunately, it not available in North America.
TREATMENT WITH NATURAL REMEDIESEssentially, all the natural remedies effective for prevention of osteopenia and osteoporosis are also effective in the treatment of these conditions. Thus, a natural treatment program would include several or all of the following supplements in the amounts indicated (NOTE: These dosages include amounts obtained from the diet and a daily multivitamin):
(1) Although clinical data on the effect of fish oils on the prevention and treatment of osteoporosis is scarce, there is now some indication that fish oil supplementation may increase BMD at the spine, at least in young men.[126,127] There is also some evidence that a low grade systemic inflammation may be involved in osteoporosis, in which case fish oils again would be highly beneficial.
To the best of my knowledge there is no indication that this supplementation program would interfere with the concomitant use of alendronate or raloxifene.
Before embarking on the supplementation program it would be desirable to establish a baseline with a DEXA scan and the following blood tests:
The results of these tests may help to pinpoint the reason for any excessive bone loss as well as gauging the effectiveness of the supplementation program.