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Old May 31st, 1988, 21:00
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1988. Vitamin D and Osteoporosis

Heston TF: Vitamin D and osteoporosis.

Osteoporosis is a progressive bone disease resulting from the diminution and restructuring of skeletal mass. The bone trabeculae are dominantly affected; a lowering bone density along with a restructuring of the trabecular architecture lead to weakened bones susceptible to fracture. Bone pain is common even when no fracturing takes place. The trabeculae in osteoporosis tend to thicken, even though the haversian and marrow spaces are enlarged. Bones in the forearm, spine, and hip are usually the most debilitated. Over a lifetime, Caucasian females lose about 35% of their peak cortical bone and 50% of their trabecular bone (1).

Elderly, white Caucasian females are at the highest risk for osteoporosis. Of all Caucasian women over 60, anywhere from 5% to 30% are afflicted, and it may result, directly or indirectly, in the death of a significant number of them. Of the approximately 1.2 million fractures due to osteoporosis, from 10% to 20% are fatal, usually due to bed rest pneumonia or lung blood clots. 50% of the survivors need long-term institutionalization. Of women over 45, osteoporosis is more common than heart attacks, strokes, diabetes, rheumatoid arthritis, or breast cancer. Treating osteoporosis in the United States costs anywhere from three to six billion dollars per year because of the great many people it affects. As with most diseases, prevention is best--curing the disease is enormously more difficult. Fortunately, intensive research into osteoporosis has given us measures to take now that will decrease our chances of getting it later in life. Proper vitamin D consumption throughout the life cycle remains a crucial factor in the prevention of osteoporosis.

Vitamin D helps regulate calcium absorption, transport, and storage so calcium homeostasis is maintained. The exact mechanism of vitamin D's role is unclear, and constantly under revision. The active form is thought to act directly upon the brush border of the gut, causing molecular reorganization that promotes calcium diffusion into the cell. In chicks, 1,25 dihydroxy vitamin D (1,25-OH(2)D), the biologically active form of vitamin D, increases the phosphocholine (PC) content of the brush border concomitantly with a modification of the PC acyl chains, which together increase the fluidity of the membrane. 1,25-OH(2)D also acts like a steroid hormone: after entering the cell, a high-affinity receptor binds to it, takes it to the cell nucleus where it associates with a genome (thought to be determined by histone proteins), activates specific genes which cause the transcription of messenger ribonucleic acid coded to produce calcium binding protein (CaBP), which results in an increased translation and the subsequent production of CaBP. This CaBP transports the calcium through the cell cytoplasm to a sodium dependent calcium pump that excretes calcium ions into the plasma.

Vitamin D also is thought to affect this calcium-sodium pump (2). The mitochondria and alkaline phosphatase also have a role in this process. The mitochondria may serve as shuttle organelles for the CaBP-Ca complex; alkaline phosphatase appears at increased levels with vitamin D stimulation. Phosphate absorption also is facilitated by vitamin D. In addition to promoting calcium absorption into the body, vitamin D can promote either mineralization of the bone or bone resorption. Bones are the chief storage site of calcium- approximately 99% of the body's calcium is found in the bones. In the bone, 1,25-OH(2)D stimulates the production of a bone gamma carboxyglutamic acid protein, a CaBP that requires vitamin K for a crucial carboxylation. This protein is thought to be osteocalcin. Vitamin D activated bone resorption is thought to occur by stimulation of the lymphoblasts to convert into lymphocyte T cells, which cause osteoclast formation. Vitamin D acts to promote the synthesis and maturation of bone collagen as well. Vitamin D also acts on the kidneys, muscles, and various other sites in the body. In the kidneys, it helps modulate calcium resorption to maintain calcium homeostasis. It helps maintain the integrity of muscles, and has some antitumor activity.

In addition to vitamin D, many other factors are involved in the progression of osteoporosis, and interact intimately with vitamin D. Calcium remains one of the most important factors. Consuming enough calcium in the diet in addition to the right amount of vitamin D remains one of the most likely ways to prevent osteoporosis-chronic calcium deficiency has been strongly linked to the disease. Epidemiologic studies have shown rural residents whose diets are rich in dairy products suffer less from the symptoms of osteoporosis than others who consume smaller amounts of calcium (3).

A subgroup of the osteoporotic female population of the United States has undoubtedly incurred their disease due to calcium deficiency. Calcium repletion, through dietary measures or supplements, has been shown to be of value in stabilizing their osteoporosis. More importantly, calcium intake may provide significant prophylaxis for osteoporosis, particularly in the teenage and early 20's female age groups. Calcium is safe (in the absence of kidney stones), relatively inexpensive, and logistically simple to take. Its usage in the female population appears quite reasonable at this time (4).

Many other dietary factors play crucial roles in osteoporosis. Excess dietary phosphorus is antagonistic to calcium absorption because as serum phosphorus increases, levels of 1,25-OH(2)D decrease (leading to lower calcium absorption). High dietary phosphorus also speeds up the age related increase in parathyroid hormone (PTH) levels. Aluminum and magnesium based antacids increase calcium excretion (high dietary aluminum also is correlated with Alzheimer's disease). In addition, cigarettes, alcohol, caffeine, and salt all have negative effects upon calcium absorption. Oxalate containing foods, such as cocoa, soybeans, kale and spinach decrease calcium absorption. Diets high in fiber lead to diminished absorption. Hexaphophoenositol, found in bran and wheat meal, lowers absorption. Several drugs promote osteoporosis: Dilantin and other anticonvulsants; tetracycline antibiotics; and cortisol and cortisol analogues. Stress and a lowered acid secretion in the gut further encourage the progression of osteoporosis. Lysine and arginine increase calcium absorption, but in general, high dietary protein is discouraged because it leads to increased calcium excretion. Vitamin C and lactose increase absorption. While in childhood and pregnancy calcium absorption is up to 75% and greater, adults usually absorb only 30% to 60%- this percentage is highly dependent upon the other factors discussed above (5). Magnesium, zinc, manganese, and fluoride are important dietary factors, but their modes of action have not as yet been clearly defined. Meeting the recommended daily allowance (for the minerals that have an RDA) is the best that can be suggested at this time.

Exercise is important in the development and prevention of osteoporosis. Like vitamin D, either too much or too little can lead to osteoporosis. A high body mass and weight-bearing exercise both tend to increase the bone density. Bone density peaks in the 20's for most people, and it is speculated that high peak densities will delay the onset of osteoporosis. Exercise at a young age therefore has a large impact upon the subsequent development of osteoporosis. Even moderate exercise by elderly, osteoporotic patients seems to help prevent morbidity. Females must be aware of their menstrual cycle. Excess exercise may lead to amenorrhea, and in such cases will promote the onset of osteoporosis, most likely due to the change in hormone levels. Amenorrheics tend to have low circulating estrogen levels similar in some ways to the changes that occur after menopause. They have an altered metabolism. Amenorrhea afflicts females mainly in weight-bearing disciplines: it affects up to 50% of competitive runners, 44% of ballet dancers, and 25% of noncompetitive runners, but only 12% of swimmers and cyclists. The reason for this has not been explained. Amenorrheic runners consume unusually low energy diets (with proportionally low levels of calcium and vitamin D) for their level of exercise, probably due to both physiological and psychological factors. Compounded with altered hormone levels and a light body mass, this diet leads to an early onset of osteoporosis (6).

Estrogen perhaps is the most important factor in this complex disease. It is speculated that estrogen decreases the sensitivity of the skeleton to PTH, which promotes calcium resorption from the bones. As age increases, levels of PTH also increase and the ability of the kidneys to hydroxylate 25-OHD to 1,25-OH(2)D decreases. The levels of 1,25-OH(2)D decrease about 50% with aging. Lower levels of estrogen after menopause make this these changes cause greater bone resorption.

Patients on TPN, amenorrheic women, castration patients, and especially Caucasian females are at the highest risk for osteoporosis, especially in light of current dietary practices. Dietary calcium levels are still below recommended levels throughout the life cycle (although progress has been made in recent years), as is dietary magnesium and zinc. In a Western United States survey of 2451 adults, less than 9% supplemented their diet with calcium, even though approximately 50% had inadequate calcium intakes. This is surprising since 66.6% took supplements, and calcium is one of the most glaring deficiencies in the American diet (10). Whether or not women are getting enough vitamin D is harder to gauge due to varying amounts of sunlight exposure. Still, in 1985 the percentage of women 19-50 who drank milk (the major source of vitamin D in the American diet) daily was only about 51%, while soft-drink consumption (which promotes poor calcium absorption) was 54%. Eggs, one of the other few sources of vitamin D, are being consumed less and less, down 18% from 1977 (7). In Ireland, 47% of the institutionalized elderly women had a subclinical vitamin D deficiency; 91.3% of the group that did not take supplements had some kind of vitamin or mineral deficiency and 64.3% of the supplement users also were deficient (8). In the United Kingdom vitamin D was identified as one of the few nutrients consumed by pregnant and lactating mothers at levels below recommended (9). In a recent survey of the elderly in France, no one surveyed consumed greater than 200 IU/d of vitamin D (50% of the USRDA). Greater than 60% of hip fracture patients are deficient in vitamin D, and studies indicate that patients with osteonecrosis of the femoral head have significantly lower serum levels of vitamin D metabolites.

The treatment of osteoporosis is complicated and constantly being updated. Early identification of high-risk patients is encouraged. A short-term gonadotropin-releasing hormone-antagonist test may be helpful to identify patients at risk for rapid calcium loss after castration or spontaneous menopause. Exercise, supplementary calcium, and estrogen therapy in selected postmenopausal women may be prescribed. Immobilization devices may be necessary for severe pain or fracture, but they should be minimized as constant exercise is vital for healthy bones. 2 glasses of milk per day along with large doses of supplementary calcium carbonate (in excess of 2 grams of elemental calcium or 4.8 grams of calcium carbonate) are well tolerated by most patients. If constipation is a problem, taking magnesium with the calcium may prove to be beneficial. An initial dosage regimen of 25,000 to 50,000 IU of vitamin D 2 times per week for the 1st 4 to 6 weeks then daily usage of a 1000 IU supplement is recommended. Sunlight exposure and UV irradiation of independent patients should be encouraged, but among the institutionalized, UV irradiation has been shown to be impractical while a vitamin D supplement is highly effective. For milder cases, supplementation with 1-1.5 grams of calcium may be all that's necessary, but with more severe or progressive disease, women may be given conjugated estrogen 0.625 to 1.25 mg/d. For 5 consecutive days of each month, the women should not take any estrogen to prevent uterine endometrial hyperplasia. A progestin such as medroxyprogesterone acetate may also be given for the last 10 days of this cycle at 10 mg/d to lower the risk of endometrial cancer. This progestin, however, may do more harm than good by causing withdrawal bleeding, promoting unfavorable serum lipid values, and increasing the risk of coronary and cerebrovascular thrombosis. Some women may be unable to take estrogen due to its side effects or other contraindications. They may benefit by 100 IU/d of salmon calcitonin taken by subcutaneous injection. Men are not given estrogen, but benefit by calcium supplementation at similar levels. Urinary calcium levels of less than 100 mg/d indicate decreased calcium absorption, and patients with these lab values may benefit from 50,000 IU/d of vitamin D. Sodium fluoride at 50 mg/d taken with calcium appears to also increase bone mass, but this use of sodium fluoride has not yet been approved by the FDA.

Other treatments being researched could ultimately be more effective than the above recommendations. Metabolites of vitamin D, such as 1,25-OH(2)D may be more beneficial as supplements in osteoporosis therapy due to decreased renal function of the patients. High dose clomiphene citrate therapy appears to be nearly as effective as conjugated estrogens for conservation of urinary calcium, yet does not cause endometrial proliferation or withdrawal bleeding after progesterone therapy. In juvenile osteoporosis, extended therapy with calcitonin, anabolic steroids, active forms of vitamin D3, calcium agents, physiotherapy and exercise has shown promise.

REFERENCES

1. Riggs B: Involutional osteoporosis. N Eng J Med 1986;314:1676-1684.

2. Wasserman RH, Fuller CS: Calcium transport proteins, calcium absorption, and vitamin D. Ann Rev Physio 1983;45:375-390.

3. Heston TF, Chesnut CH: Tab's really better now. The Daily of the University of Washington 1986;May 29:5.

4. Matkovic V, Kostial K, Simonovic I, Buzina R, Brodarec A, Nordin BEC: Bone status and fracture rates in two regions of Yugoslavia. Am J Clin Nutr 1979;32:540-549.

5. Avioli LV: Calcium and osteoporosis. Ann Rev Nutr 1984;4:471-491.

6. Nelson ME, Fisher EC, Catsos PD, Meredith CN, Turksoy RN, Evans WJ: Diet and bone status in amenorrheic runners. Am J Clin Nutr 1986;43:910-916.

7. United States Department of Agriculture: Nationwide food consumption survey. Continuing survey of food intakes by individuals. Women 19-50 years and their children 1-5 years. 1 day. Report No. 85-1. 1985.

8. Vir SC, Love AHG: Nutritional status of institutionalized and noninstitutionalized aged in Belfast, Northern Ireland. Am J of Clin Nutr 1979;32:1934-1947.

9. Black AE, Wiles SJ, Paul AA: The nutrient intakes of pregnant and lactating mothers of good socio-economic status in Cambridge, UK: some implications for recommended daily allowances of minor nutrients. Brit J Nutr 1986;56:59-72.

10. Schutz HG, Read M, Bendel R, Bhalla VS, Harrill I, Monagle JE, Sheehan ET, Bluebell BR: Food supplement usage in seven Western states. Am J Clin Nutr 1982;36:897-901.

SELECTED OTHER REFERENCES USED

A) Lips P, van Ginkel FC, Jongen MJM, Rubertus F, van der Vijgh WJF, Netelenbos JC: Determinants of vitamin D status in patients with hip fracture and in elderly control subjects. Am J Clin Nutr 1987;14:1005-10.

B) Abbasi R, Hodgen GD: Predicting the predisposition to osteoporosis. Gonadotropin-releasing hormone antagonist for acute estrogen deficiency test. JAMA 1986;255:1600-1604.

C) Bukhman AI, Zarubina NA, Kniazeva AP, Konnova EV, Dobracheva AD: [Hormone content of the blood in juvenile osteoporosis]. Probl Endokrinol (Mosk) 1987;33:13-17.

D) Chapuy MC, Chapuy P, Meunier PJ: Calcium and vitamin D supplements: effects on calcium metabolism in elderly people. Am J Clin Nutr 1987;46:324-328.

E) Inoue S, Igarashi M, Karube S, Oda H: Vitamin D3 metabolism in idiopathic osteonecrosis of femoral head. Nippon Seikeigeka Gakkai Zasshi 1987;61:659-666.

F) 6. Shike M, Shils ME, Heller A, Alcock N, Vigorita V, Brockman R, Holick MF: Bone disease in prolonged parenteral nutrition: osteopenia without mineralization defect. Am J Clin Nutr 1986;44:89-98.

G) Henry HL, Norman AW: Vitamin D: metabolism and biological functions. Ann Rev Nutr 1984;4:493-520.

H) Vitamin D status and vitamin K osteocalcin formation. Nutr Rev 1982;40:249.

I) Lips P, van Ginkel FC, Jongen MJM, et al: Determinants of vitamin D status in patients with hip fracture and in elderly control subjects. Am J Clin Nutr 1987;46:1005-1010.

J) Parfitt AM, Mathews CHE, Villanueva AR, Kleerekoper M, Frame B, Rao DS: Relationships between surface, volume, and thickness of iliac trabecular bonne in aging and in osteoporosis. J Clin Invest 1983;72:1396-1409.

K) Worthington-Roberts B (ed): Contemporary Developments in Nutrition. St. Louis, C.V. Mosby Co., 1981, chapters 6 and 8.

L) Linder MC (ed): Nutritional Biochemistry and Metabolism. New York, Elsevier, 1985, pp 110-115 and 141-146.

M) Morgan BLG: Nutrition Prescription. New York, Crown Publishers Inc., 1987, pp 234-241.

N) Berkow R (ed): The Merck Manual of Diagnosis and Therapy. Rahway (New Jersey), Merck Sharp and Dohme Research Laboratories, 1987, pp 924-928 and 1296-1297.
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