This article was downloaded by: [New York University] On: 11 May 2015, At: 21:27 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of the American College of Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uacn20
Hypothesis: etiology of atherosclerosis and osteoporosis: are imbalances in the calciferol endocrine system implicated? a
a
J Moon , B Bandy & A J Davison
a
a
Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada. Published online: 02 Sep 2013.
To cite this article: J Moon, B Bandy & A J Davison (1992) Hypothesis: etiology of atherosclerosis and osteoporosis: are imbalances in the calciferol endocrine system implicated?, Journal of the American College of Nutrition, 11:5, 567-583, DOI: 10.1080/07315724.1992.10718263 To link to this article: http://dx.doi.org/10.1080/07315724.1992.10718263
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Hypothesis: Etiology of Atherosclerosis and Osteoporosis: Are Imbalances in the Calciferol Endocrine System Implicated? Jim Moon, PhD, FACN, Brian Bandy, PhD, and Allan J. Davison, PhD Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
Downloaded by [New York University] at 21:27 11 May 2015
Key words: vitamin D, pathological calcification, atherosclerosis, osteoporosis, osteomalacia, magnesium deficit, free radical, iron, calcium, nicotine, cholesterol Atherosclerosis and osteoporosis are currently considered unrelated diseases. Osteoporosis involves bone calcium (Ca) loss and predominantly affects females after menopause. Atherosclerosis is an illness predominantly affecting males, and is primarily characterized by abnormal lipid metabolism. However, pathological calcification of the arterial wall is an underlying feature of atherosclerosis. Ca homeostasis is thus important in atherosclerosis as well as in osteoporosis. Men also develop osteoporosis although at a later age than women, and, as osteoporosis progresses in women, there is an accompanying calcification of arteries leading to increased incidence of atherosclerosis in aging women. Thus, during old age, both atherosclerosis and osteoporosis are prevalent in both males and females. The dramatic increase in atherosclerosis among women as they develop osteoporosis suggests that the two illnesses may be more closely related than previously realized. The use of vitamin D as a food supplement coincides with epidemic onsets of atherosclerosis and osteoporosis, and excess vitamin D induces both conditions in humans and laboratory animals. These observations suggest a role for chronic vitamin D excess in the etiology of the two illnesses. Magnesium (Mg) deficiency, nicotine, and high dietary cholesterol are contributing factors that accentuate adverse effects of vitamin D. Abbreviations: Ca = calcium, 7-DHC = 7-dehydrocholesterol, l,25(OH)2D = 1,25-dihydroxyvitamin D, Fe = iron, FDA = Food and Drug Administration, 25-OHD = 25-hydroxyvitamin D, IHD = ischemie heart disease, Mg = magne sium, RDA = recommended dietary allowance, RNI = recommended nutrient intake, UV = ultraviolet
INTRODUCTION
factors in atherosclerosis, IHD, and osteoporosis. Atherosclerosis is a disease of abnormal lipid metabo lism. Calcification of the arterial internal elastic lamina is part of the pathological process [3-15], and precedes for mation of intimai lipid plaques by about a decade [3,4]. Calcifications of iliac and internal carotid arteries are observed in infancy, before the appearance of fatty streaks [16,17]. Calcific diseases include atherosclerosis, calcific valvular sclerosis, calcific tendonitis, apatite deposition osteoarthritis, tympanosclerosis, calcinosis cutis, tumour calcification, dental plaque, and dysfunctional calcification occurring in implanted cardiovascular devices, artificial hearts, and intrauterine contraceptive devices [18,19]. This manuscript is presented in four parts. Initially, we consider the role of soft tissue calcification in atheroscle-
With advancing age, levels of Ca in bone decrease, and deposition of Ca in soft tissues increases. Untoward con sequences include: osteoporosis, atherosclerosis, cerebral arteriosclerosis, arthritis, and kidney stones. The identifi cation of risk factors for ischemie heart disease (IHD) has led to the hope that modification of these risk factors could prevent or reduce its incidence. However, intervention programs have had little success in preventing or reducing overall mortality from IHD [1]. A similar circumstance is found with osteoporosis, since only combined therapy using estrogens and Ca slows down progressive bone Ca loss in postmenopausal women [2]. Further advances seem contingent upon new concepts regarding possible causative
Addressreprintrequests to Jim Moon, PhD, School of Kinesiology, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada. Journal of the American College of Nutrition, Vol. 11, No. 5, 567-583 (1992) Published by the American College of Nutrition 567
Vitamin D in Atherosclerosis and Osteoporosis rosis. This is followed by a discussion of the epidemiology of atherosclerosis in relation to abnormal Ca metabolism. The third section considers atherosclerosis and osteopo rosis as concurrent expressions of abnormal calciferol en docrinology. The concluding section contains a discussion of the problem of achieving appropriate calciferol hormone balance.
CONTRIBUTIONS OF CALCIFICATION TO ATHEROSCLEROSIS
Downloaded by [New York University] at 21:27 11 May 2015
Calcifying Proteins of Atherosclerotic Plaques The calcification that occurs in atherosclerosis is char acterized by calcification of matrix vesicles by a "seeding" or nucleating mechanism similar to that occurring in bone calcification [20,21]. It is invariably associated with a zone of lipid accumulation [21]. A unique γ-carboxyglutamic acid-containing protein has been isolated from calcified atherosclerotic plaques, and named "atherocalcin" [22, 23]. The vitamin K-dependent bone protein, osteocalcin, is another of the γ-carboxyglutamic acid-containing pro teins in calcified atherosclerotic plaque [23]. A proteolipid calcification "nucleator" [24], along with a Ca-acidic phospholipid-phosphate complex are present [25], supporting the suggestion that aortic tissue calcifies through mecha nisms similar to those involved in bone mineralization. A peptide containing histidinoalanine crosslinks is important in the calcification process [26]. Understanding the roles of the proteins involved in calcification is a prerequisite to understanding the pathogenesis of atherosclerosis. Chemical Composition of the Mineral Deposits The chemical composition of atherosclerotic mineral deposits has been well studied. The deposits are composed of Ca and phosphate, with some Mg, iron (Fe), and other trace mineral constituents [27-32]. The microcrystalline deposit materials are heterogeneous, and can be repre sented chemically as carbonate-substituted apatite [30, 31]. The mechanism for the formation of cardiovascular deposits reportedly proceeds through hydrolysis of octacalcium phosphate precursor [31]. Ca Channel Blockers Protect Against Atherosclerosis and IHD Support for a role for Ca in atherosclerosis comes from observations that inhibitors of arterial Ca deposition (diphosphonates) and Ca antagonists (e.g., nifedipine, verapamil, kiltiazem, and nilvadipine), which do not affect abnormal blood lipid levels, attenuate the development of experimental atherosclerosis [33-37]. It has been suggested
568
that Ca channel blockers exert some of their actions by protecting against aortic Ca deposition [37]. In addition, during an ischemie attack, there is a massive influx of Ca into cardiac cells, accompanied by mitochondrial accu mulation of Ca [38]. This indicates defective membrane function as an early feature of ischemie injury. Ca channel blockers may be beneficial in preventing Ca influx. Mg is a natural Ca channel blocker [39], and therefore exerts a beneficial effect in preventing pathological arterial calcifi cation. Vitamin D Induces Phospholipid Incorporation into Biomembranes Since the discovery of protein induction by 1,25-dihydroxyvitamin D [l,25(OH)2D], it has become generally accepted that vitamin D's mode of action is similar to that of the steroid hormones [40]. These hormones enter the cell where they are bound to a cytosolic carrier protein and transported to the cell nucleus where they induce synthesis of ribonucleic acid, which then directs synthesis of new proteins. Ca-binding protein is one of the proteins induced by 1,25(OH)2D3, and this is believed to be a factor involved in translocation of Ca across the lumen of the intestine [40]. However, another mechanism by which vitamin D controls cell Ca flux has been suggested that is independent of de novo protein synthesis [41-46]. Rasmussen et al [4143] demonstrated that 1,25(OH)2D3 enhances the synthesis of phosphatidylcholine in enterocytes independent of new protein synthesis. There is a close correlation in the timecourse of change after l,25(OH)2D3 treatment between incorporation of unsaturated fats into the brush border phosphatidylcholine fraction and the Ca-transport prop erties of the membrane [41-43]. Holmes et al [44] and Kummerow [45,46] have exten sively studied the effects on Ca translocation of inser tion of partially oxidized derivatives of cholesterol [25hydroxycholesterol and 25-hydroxyvitamin D (25-OHD)] in vitro into liposomes. Ca uptake is more rapid in the presence of the partially oxidized derivatives than in the presence of cholesterol alone [44-46], suggesting that per turbation of membranes by the polar 25-hydroxy group plays a role in increasing membrane permeability to Ca ions. Cytotoxic and atherogenic effects of oxysterols have been reviewed [47,48]. l,25(OH)2D regulates intracellular ionized Ca in colonocytes by mechanisms involving mem brane phosphatidylinositol breakdown, and release of intracellar stored Ca; vitamin D deficiency abolishes this effect [49]. Vitamin D Excess Causes Arterial Calcification The calciferol endocrine system, like all endocrine sys tems, must be carefully balanced. Any factor which causes
VOL. 11, NO. 5
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D in Atherosclerosis and Osteoporosis an imbalance in an endocrine system may result in pa thology. Insufficient exposure to solar ultraviolet (UV) rays results in a deficiency of calciferol, producing rickets or osteomalacia [50,51]. Excess calciferol is a well-docu mented cause of cardiovascular, renal, and skeletal damage among humans poisoned during megavitamin D therapy [52-61], among hyperreactive infants that received excess vitamin D during routine fortification of foods [62-71], and in laboratory animals [72-88]. Skeletal damage from excess vitamin D, in both humans and animals, can be either hypercalcification or rarefaction of bone. Cardiovas cular damage is primarily calcine with lipids surrounding the zone of calcification.
ing may contribute to progression of the disease. When nicotine (which by itself was harmless) was added to a harmless diet containing vitamin D and cholesterol, the animals progressively developed lethal calcific lesions charactersitic of chronic hypervitaminosis D, indicating that nicotine activates the arterial calcifying actions of vitamin D. Liu et al [84], using rhesus monkeys, similarly demon strated that the three vasotoxic factors (dietary hypercholesterolemia, hypervitaminosis D2, and nicotinism), when administered singly, did not produce advanced atheroscle rotic lesions. However, when combined, major changes simulating human atherosclerosis could be readily in duced.
Vitamin D, Cholesterol, and Nicotine Act Synergistically in the Induction of Experimental Atherosclerosis
Yitamin D Excess and Mg Deficit Act Synergistically to Induce Arterial Calcification in Laboratory Animals
Since laboratory experiments have demonstrated that either high cholesterol or high vitamin D diets can produce atherosclerosis in animals, and that the two factors accen tuate one another in this capacity, it has been asked what other factors may act synergistically with these. At least two other factors have been identified: nicotine and Mg deficit. Hass et al [75] tried for several years to produce an arterial disease having the characteristics of human atheroarteriosclerosis (calcific medial degeneration, fibrocellular intimai proliferation and intimai atheromatous accumulation with subsequent degenerative reactions). The closest approximation resulted from moderate hyper vitaminosis D and mild hyperlipemic hypercholesteremia in rabbits. However, due to an inability to fully simulate patterns observed in humans, Hass et al [75] added nic otine to their atherogenic diet. Nicotine was chosen due to its adrenergic actions and because excessive cigarette smok-
Mg deficiency, like vitamin D excess, induces calcifi cations of arteries and kidneys [89-93]. Interrelationships of vitamin D and Mg are complex, entailing interactions with Ca, phosphate, fluoride, parathyroid hormone, calcitonin, and estrogen [89-93] (Figs. 1, 2 and 3). Marginal Mg intake is prevalent in North America [91,92]. Mg has been considered the principal cardioprotective factor found in drinking water [91]. Mg deficiency and vitamin D excess mutually accentuate the deleterious effects of one another on soft tissue calcifications [90,92,93]. Mg deficiency interferes with vitamin D utilization [93]. One form of rickets fails to respond to vitamin D until dietary Mg is increased [94,95]. Paradoxically, hypomagnesemia may result from either hyper- or hypovitaminosis D. Hypervitaminosis D increases urinary Mg, increasing Mg requirements [92]. Vitamin D deficiency decreases Mg absorption and therefore also increases Mg requirements [93]. Increasing dietary Mg decreases the
V I T A M I N
D E
-► DECREASED INTESTINAL Hg ABSORPTION -► DECREASED VITAHIN D UTILIZATION-^— ■>- HYPOCALCEMIA L D L - C H O L - < HYPERTENSION A R T E R I A L SPASMS "^ (DIET Ca) OSTEOPENIA ■
Ca>
I E N C Y
Fig. 1. Vitamin D and magnesium [93].
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
569
Vitamin D in Atherosclerosis and Osteoporosis INTENSIFICATION
PROTECTION Renal Calculi
t
V I T A M
Calcium Phosphate Fluoride
N
Fat Sodium
D Nicotine
M A G N E S
Hypercalciuria Hypercalcemia
1 Platelet Aggregation Hyperlipemia Hypertension Subcetlular Damage Athero, Arteriosclerosis Myocardial Infarction
U M
Vitamin E Vitamin C ß-Carotene Potassium
Downloaded by [New York University] at 21:27 11 May 2015
Fig. 2. Intensifying and protective factors in vitamin Dinduced pathology. Adapted from [93, 133, 134].
atherosclerosis induced in swine by hypervitaminosis D [96]. The mechanisms by which Mg deficiency accentuates pathological calcification are not fully understood, but undoubtedly Ca channel blocking by Mg is involved [39]. Vitamin D Excess and Mg Deficit Result in Abnormal Lipid Metabolism as Encountered in Atherosclerosis Much of the vitamin D fed to domestic animals (as a growth hormone) concentrates in fat stores of the animals, making animal fat a source of vitamin D [97]. Fats (by accumulating and sequestering vitamin D) affect vitamin D metabolism, and vitamin D affects lipid metabolism. Vitamin D has been implicated as a hypercholesterolemic agent: in infantile hypercalcemia [68,71,98]; among farm ers ingesting vitamin D preparations (estimated 700-2500 IU/day) [99,100]; and among adults with atherosclerosis
\
PTH -
Increased osteoclast activity
\
Chronic vitamin D excess
Decreased bone Ca & Mg
Mg deficit
/
Nicotine and other adrenergic agents
OSTEOPOROSIS PATHOLOGICAL CALCIFICATION / OF SOFT TISSUES
High hemodynamic load
/
Free radical generation
Cholesterol; saturated fats
*
Subcellular damage and tissue injury
Mg deficit and/or vitamin D excess
ADVANCED ATHEROSCLEROSIS
Fig. 3. The deleterious cycle of vitamin D excess, magnesium deficit, tissue injury, and pathological calcification.
570
EPIDEMIOLOGICAL ASPECTS OF ATHEROSCLEROSIS MAY BE CLARIFIED BY CONSIDERING EXCESS VITAMIN D INGESTION AS AN ETIOLOGIC FACTOR A number of epidemiological findings regarding athero sclerosis are not explained by contemporary theories, but are clarified by the concept that disturbed calciferol endo crinology resulting in a calcific disease is an important underlying factor in the etiology of atherosclerosis and IHD. Concurrent Origins of the Epidemic in Canada, the United States, England, and Wales Coincide with Increasing Use of Vitamin D and Decreasing Dietary Mg
Elevated 1,25(OH)2-D1
Low dietary Ca
[101,102]. In a study of rats, on the other hand, serum cholesterol levels were lowered by vitamin D2 ingestion, while liver cholesterol levels were dramatically elevated [103]. Ingestion of l,25(OH)2D stimulated a fourfold in crease in 7,8-didehydrocholesterol levels in rat skin, but did not affect skin or serum cholesterol levels [104]. The degree of atherosclerosis in laboratory animals fed high fat diets is intensified by Mg deficiency and dimin ished by higher than usual amounts of Mg [93]. Mg deficiency increases the ratio of low density lipoproteins to high density lipoproteins, and Mg supplementation de creases this ratio [105]. In a clinical test Mg replacement therapy provided for 47 patients with IHD and acute myocardial infarction confirmed results in laboratory ani mals [106]. The beneficial effects of intravenously admin istered Mg to correct arrhythmia in acute myocardial infarction has been reviewed [107,108].
Confusion regarding the time of origin of the present epidemic of atherosclerosis and IHD was clarified by An derson [109-113]. Anderson and Halliday [113] point out that the sex differential can be used to trace development of the modern epidemic in males, since the male/female death rate is relatively unaffected by changes in diagnostic accuracy, medical fashion, and statistical classification. Male and female death rates were similar until the mid19208. Since then, the male/female predominance in creased steadily until 1970 in Canada, the United States, England, and Wales [112]. The curative effect of cod liver oil in rickets was docu mented by Hess and Unger in 1917 [114]. By 1923 the importation offish liver oil in the United States was about 500,000 gallons, and increased to over 2.8 million gallons in 1930 [97]. The use of UV-irradiated milk was intro duced in the United States in 1924 [115]. Information is
VOL. 11, NO. 5
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D in Atherosclerosis and Osteoporosis not available regarding how much vitamin D was delivered in UV-treated milk. The manufacture of vitamins D2 and D3 increased from 35 lb in 1948 to 14,000 lb in 1972 [40,97]. In 1970 vitamin D2 was added to baked goods, breakfast cereals, pasta and rice dishes, fats and oils, milk and milk products, meat and poultry products, sauces, nonalcoholic beverages, dairy product analogs, candy bars, multivitamin supplements, and baby formulas [116]. Vi tamin supplements containing up to 25,000 IU of vitamin D in a single pill were sold in health food stores, and supplements containing 2,000 IU were common [117]. Although the Food and Drug Administration (FDA) issued orders to reduce the amount of vitamin D in flour, cereals, and over-the-counter vitamin supplements, the FDA does not have the staff to monitor the amount of vitamin D in food and supplements. Health and Welfare Canada is in much the same predicament. For instance, since 1970 there has been a regulation that vitamin D fortified milk should be analyzed for vitamin D at least twice a year. In British Columbia the first laboratory to analyze for vitamin D was set up in 1989. Along with this excessive delivery of vitamin D, there has also been a continually declining intake of Mg due to Mg-deficient artificial fertilizers and many processing pro cedures which decrease food Mg content [91]. Thus the epidemic of IHD in North America directly parallels both the increasing use of vitamin D and the decreasing avail ability of dietary Mg, two major factors that act synergistically to induce calcifications of arteries and kidneys. The Decreasing Incidence in Death From IHD in North America Coincides with Decreased Delivery of Vitamin D In the 1970s the death rate from IHD in the United States began to decrease [118-120]. In Alameda County, CA, after adjustment for age, sex, race, and baseline IHD conditions and symptoms, there was a 45% decline in the 9-year odds ratio of IHD mortality between two cohorts taken to be representative in 1965 and 1974 [120]. Ad justment for cohort differences in the following IHD risk factors did not explain the decline: smoking status, leisure time physical activity, self-assessed physical activity, alco hol consumption, body mass index, or social network participation; neither did adjustment for measures of ed ucation, preventive medical care, availability of a regular physician or clinic, health insurance coverage, number of physician visits during the last 12 months, or occupation [120]. In the late 1960s the FDA began considering legislation to limit amounts of vitamin D delivered to the US popu lation. By 1972 the current regulations went into effect which limit foods to which vitamin D may be added: milk, baby foods, and multivitamin supplements [117]. The
maximum permissible level of vitamin D in over-thecounter supplements is now 400 IU in the label-recom mended daily intake [117]. Canada has adopted similar regulations. In Canada, margarine is fortified (660IU/100 g), and in both Canada and the United States some break fast cereals contain added vitamin D. Thus, there has been a dramatic decrease in vitamin D consumption in North America since 1970, which coincides with the decreasing incidence in death from IHD. Blacks are Less Sensitive Than Whites to Vitamin D Toxicity, and Are Relatively Protected from Atherosclerosis In 1965, Eggen et al [7] reported an increased incidence of calcification and atherosclerotic degeneration in arteries of whites as compared to blacks in New Orleans, based on 1,243 consecutive necropsies of whites and blacks aged 30-69 years [7]. This finding was confirmed in all locations studied in the International Atherosclerosis Project [121], which assessed the extent of atherosclerotic plaque forma tion in 23,000 autopsy cases from 19 location-race groups. Cases with diseases known to be associated with more severe atherosclerosis, such as coronary artery disease, stroke, hypertension, and diabetes were excluded since the purpose of the study was to determine the extent of ath erosclerotic lesions for predicting occurrence in the general population. This is in contrast to mortality from heart disease, since blacks have higher heart disease death rates [122], due to the higher death rates among blacks from hypertension and cardiovascular diseases of an unspecified nature [123]. Strong [121] stated: "The existence of large differences in average extent of atherosclerosis among white populations and among Negro populations suggests that environmental conditions may be important deter minants of the prevalence and extent of atherosclerotic lesions. Conditions that might be considered include ha bitual diet, physical activity, cigarette smoking, stress, and other factors." Perhaps one environmental condition influencing this difference is vitamin D. Dark-skinned infants are more susceptible to rickets than are fair-skinned infants, due to lower vitamin D biosynthesis on exposure to UV rays [114,115]. Similarly, dark-skinned infants are less suscep tible to toxic effects of vitamin D than are fair-skinned infants [68,71 ]. It is likely that dark-skinned adults are also less susceptible to vitamin D toxicity, although no infor mation is presently available. The rate of decline in ageadjusted heart disease deaths from 1968-1975 among women and blacks has been half that of white men [123], consistent with an attenuated effect of vitamin D in blacks and premenopausal women.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
571
Vitamin D in Atherosclerosis and Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D Increases Body Fe Stores and This Can Initiate Free Radical Damage in Atherosclerosis Initially it was believed that the lower incidence of IHD among females might be due to estrogens, however, exog enous estrogen worsens the prognosis for men who have had myocardial infarction [124]. The Framingham study found that the onset of cardiovascular disease in women is not strictly age-dependent but is coupled with the cessation of menses [125]. The incidence of cardiovascular disease increases within 2 years after menopause. Women acquire IHD later than men, but develop the disease at a greater rate. The Framingham investigators expressed their per plexity at these findings [125]: We can only speculate as to the reasons for the postmenopausal increase in coronary heart disease inci dence The specification, when it is forthcoming, must account for the fact that surgical menopause without removal of the ovaries apparently leads to the same jump in risk noted with bilateral oophorectomy (plus hysterectomy) Somewhere in this tantalizing mystery may lie a lesson of profound importance in understanding the genesis and course of this disease, perhaps in men as well as in women. As Gordon et al [125] and Sullivan [126] stated, any viable hypothesis should consider why women over a broad age range suffer the same risk of IHD increase when they stop menstruating for any reason. The gender difference in stored Fe has been proposed as an explanation of the gender difference in IHD [126]. An increase in stored Fe is coupled directly with cessation of menses, whether by natural menopause, hysterectomy, or oophorectomy [124]. In affluent societies males tend to accumulate Fe with age, and traces of Fe invariably occur in calcified lesions of atherosclerotic plaques [27-32]. If this hypothesis is correct, menstruating women in affluent societies may be protected by the same factor that protects men in underdeveloped countries, that is, lower Fe stores [126]. Vitamin D increases Fe absorption. In chicks fed a low Ca diet, vitamin D elevated the amount of Fe in blood, liver and bone when the Fe was given orally, indicating an increase in Fe absorption under the influence of vitamin D [127]. In human infants a significant association of Fe deficiency with poor vitamin D status has been reported [128]. The low overall incidence, and lack of a high male/ female ratio in the death rate from cardiovascular disease in underdeveloped countries where vitamin D is not added to the food supply and where dietary Fe is comparatively low may, in part, be due to the lack of vitamin D in foods. This concept is a logical extension of the "tissue injury hypothesis" of atherogenesis [129], in which tissue injury triggers calcification at the site of injury [88]. Oxidative modifications of low-density lipoproteins increase their atherogenicity [130]. Free radical generation has been sug
572
gested as a mechanism of induction of tissue damage and low-density lipoprotein oxidation observed in atheroscle rosis [ 131 ]. Fe that is not tightly bound to internal chelating agents such as hemoglobin, transferrin, or ferritin, is avail able for free radical generation [131]. Thus, Fe deposited in atherosclerotic plaques may be available for free radical generation and accentuation of tissue damage, resulting in a vicious cycle of further Ca and Fe accumulations, to which the calcification increased by oxysterols contributes [47,48]. Epidemiology of Vitamin D Excess in Atherosclerosis and IHD is Inconclusive Although the relationship between vitamin D ingestion and IHD has not been thoroughly investigated, underde veloped countries (where vitamin D is not used as a food additive) generally have a low incidence compared to those countries that use vitamin D (Table 1, Fig. 4). Countries where the greatest amounts of vitamin D are used tend to have the highest heart disease death rates. For instance, from 1950-1969 in a 26-country survey, the age-adjusted death rate for heart disease among men in the US was around 700/100,000 population, second only to Finland [ 132]. Canada was among the seven countries with highest age-adjusted heart disease death rates with around 600 deaths/100,000 population. This time period represents the time of maximal vitamin D delivery in the US and Canada. During the same time period England/Wales and Ireland had a heart disease death rate among males less than 500/100,000 population. During 1969-1970 the heart disease death rate began to decrease in the US and Canada while in England/Wales and Ireland there was a continuing slow increase so that presently the heart disease death rate is similar in the US, Canada, England/Wales, and Ireland (a little over 500/100,000 population) [132]. Holmes and Kummerow [97], Peng and Taylor [133], and Moon [134] have reviewed the suggested role of vitamin D in athero sclerosis. Knox [135] found a positive correlation between vita min D ingestion and death from IHD. Linden [136] con ducted an epidemiological study in Tr0mso, Norway, which indicated an association between ingestion of vita min D and IHD; approximately 30 /ig (1200IU) of vitamin D/d correlated with increased incidence of heart attacks. On the other hand, in the Trgmso Heart Study, Vik et al [137] analyzed deep-frozen serum samples from 30 myocardial infarction patients. These were compared with 60 age- and sex-matched controls who had serum samples taken in the same month as the patients. No difference in 25-OHD was observed [137]. Another study of 16 myo cardial infarct patients in Heidelberg, West Germany, sim ilarly found no difference in circulating 25-OHD between patients and controls [138].
VOL. 11, NO. 5
Vitamin D in Atherosclerosis and Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
ARE OSTEOPOROSIS AND ATHEROSCLEROSIS RELATED? The widely accepted concept that vitamin D is "good for bones" is derived from the impressive effect of the hormone (or prohormone) in preventing and curing rick ets. The information herein presented considers vitamin D, and other hormonally active metabolic products of vitamin D, as an integrated endocrine system that regulates aging of the skeleton, cardiovascular system, and kidneys. There can be little doubt that calciferol hormone bal ance is important throughout life. As with other steroid hormones, there is natural variation during life. Circulating levels of l,25(OH)2D3 reach a peak shortly after birth [139], decrease, peak again during the adolescent growth spurt [140], and decrease once more. Interfering with the natural course of events by artificially maintaining elevated levels during a period when levels would otherwise be decreasing may have adverse effects. Since excess vitamin D induces cardiovascular and skeletal effects similar to atherosclerosis and osteoporosis in both laboratory animals [72-88] and humans [52-71], we must ask if osteoporosis as well as atherosclerosis might, in part, be due to imbal ances in the calciferol endocrine system induced by life long, low-level excesses of vitamin D. Distinguishing Osteomalacia from Osteoporosis Albright et al [141] defined postmenopausal osteopo rosis as a clinical entity in 1941. Since then this disorder has been identified very commonly in the elderly, espe cially in North America. A few years after peak adult bone
400 g00
Cardiac Deaths
C o u n t r y / V i t D Intake
Fig. 4. Vitamin D intake in relation to femoral neck fracture rate among women, and heart disease death rate among men (data plotted from Table 1). Using these data, femoral neck fracture among women and heart disease death rate among men are significantly correlated (r = 0.634; p < 0.05).
mass is attained, age-related bone loss begins [142], occur ring regardless of sex, race, occupation, economic devel opment, geographical location, historical epoch, or dietary habits [142-144]. In men the rate of cortical bone loss is about 0.3% of peak adult bone mass/year, and trabecular bone loss is slightly greater [142]. In women the average rate of loss is about 1 % of peak adult bone mass/year for both cortical and trabecular bone, with acceleration for
Table 1. Vitamin D Intake,1 Rates for Fracture of the Proximal Femur,2 and Death Rates for Heart Disease3 Heart disease
Fractures Country
VitD Female
Canada USA Sweden UK Neth4 Finland Israel Yugo4 Singapore Hong Kong Bantu
++++ ++++ + + + + + No
No No No
200 101.6 87.2 63.1 51.1 49.9 69.9 39.2 15.3 31.3 5.3
Male 50 50.5 38.2 29.3 28.5 27.4 42.8 37.9 26.5 27.2 5.6
F/M 4 2.01 2.75 2.15 1.80 1.78 1.63 1.03 0.58 1.15 0.94
Male 650 700 340 520 370 780 450 320 200 83 Low
Female 200 190 100 150 100 200 200 200 100 37 Low
M/F 3.25 3.7 3.4 3.5 3.7 3.9 2.25 1.6 2 2.2
1
Vitamin D ingestion is estimated for Canada [ 193], the US and Great Britain [ 154]. Each plus represents approximately 50 IU/day. Plusses are used rather than fig or IU, to indicate the uncertainty regarding how much vitamin D is actually being delivered. 2 Rates for fractures of the proximal femur are cases/100,000 population/year. Populations were age-adjusted to the US population in 1970 [159], except those for Canada, which are age-adjusted to the Manitoba population [161]. 3 Death rates for heart disease are estimated for the time period, 1965-1969 (to precede the sharp decline in heart disease death rate in the US and Canada), and are expressed as deaths/100,000 population [132]. Hong Kong and Singapore heart disease death rates are for 1968 and were age-standardized for ages 40-69 [203]. A low incidence of atherosclerosis is reported among Bantus [121]. 4 Neth = Netherlands; Yugo = Yugoslavia.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
573
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D in Atherosclerosis and Osteoporosis about 5 years after menopause, and a lower rate both earlier and later [142]. Over their lifetimes, women may lose about 35% of their cortical bone and 50% of their trabecular bone, whereas men lose about two-thirds of these amounts [142,144]. In osteomalacia, osteoid-covered surfaces and abnormal calcification fronts are observed, whereas in osteoporosis bone mass is decreased [51,115,144-152]. Osteomalacia has many causes, including diet, lack of sunshine exposure, drug use, and exposure to metals such as lead, cadmium, and aluminum. Administration of vitamin D or one of the more active metabolites of vitamin D is frequently effective in treating osteomalacia [144-147]. On the other hand, osteoporosis is generally resistant to vitamin D therapy, and is not considered to be due to vitamin D deficiency [144,145]. Fracture of the femoral neck is a common measure of both osteomalacia and osteoporosis [144-152]. In the United Kingdom, osteomalacia with resultant femoral neck fractures is common. Aaron et al [148,149] found the incidence of osteomalacia to vary with season in a series of 134 iliac-crest biopsies from unselected cases of fracture of the proximal femur. The highest incidence of abnormal calcification fronts (43%) was observed in Feb ruary-April, and the lowest (15%) in August-October. The highest frequence of abnormal osteoid-covered surfaces (47%) was observed in April-June and the lowest ( 13%) in October-December. The overall frequency of osteomalacia in femoral neck fracture cases in Leeds was estimated to be about 37% [148]. There are low circulating levels of 25-OHD in elderly women in Great Britain [153] and among elderly Irish people [154]. However, low circulating levels of 25-OHD are not always indicative of osteomalacia [155]. More sophisticated methods of detecting osteomalacia and eval uating calciferol hormone status are being developed [156]. Contrary to the circumstance in Great Britain and Ireland, osteoporosis is considered the most frequent cause of femoral neck fracture in North America [144,147,157160]. Melton et al [157,158] have assessed the risk of hip fracture based on bone mineral density and age among women in Rochester, MN. Hip fractures were uncommon among women with femoral bone density > 1.0 g/cm2, with frequency increasing as bone density declined below this level [157]. In countries where osteoporosis is com mon, and which have a high incidence of femoral neck fractures, there is a high ratio of female/male femoral neck fractures [159]. This has been used as an epidemiological tool to trace the origins of the osteoporosis epidemic [159,160] much as the male/female death rate from IHD has been used to trace the epidemic of atherosclerosis [109113].
574
Why does the incidence of atherosclerosis, accompa nying osteoporosis, progress so rapidly among women after menopause? Whey do men have a lower incidence of osteoporosis? Why are blacks less susceptible to both os teoporosis and atherosclerosis than Caucasians? These im portant questions can be answered on the basis that vita min D excess results in imbalanced calciferol endocrinol ogy which is responsible for both décalcification of bone and concomitant increased calcification of arteries that occurs among postmenopausal women and aging men in developed countries. What evidence supports this concept? 1. Osteoporosis began its epidemic upsurge in Rochester, MN (and presumably in North America in general), in the late 1920s [159,160], at approximately the same time that IHD was becoming epidemic [ 109-113], coin cident with increasing use of vitamin D and decreasing availability of Mg. 2. Elderly people in North American countries where vitamin D delivery is high have elevated serum 25OHD [153] (Fig. 5), accompanied by the highest inci dence of osteoporosis [157-161] (Table 1, Fig. 4). 3. Blacks are more resistant than fair-skinned people to osteoporosis [143,162] and atherosclerosis [121], and are also more resistant to the toxic effects of vitamin D [68,71]. Another reason for the difference in bonewasting disease is thought to be the greater bone mass of blacks [162]. 4. In Great Britain and Ireland, osteomalacia with accom panying low circulating levels of 25-OHD is prevalent, while its occurrence in North America is considered uncommon [146-152]. This is attributed to both lower exposure of elderly people in Great Britain and Ireland
,.·'
«U.S.A
60 DENMARKφ O
E CANADA»
c
9. 40 -
/
X
o m
.··'
.·'
/
·
u.s.A
_ DUBLIN
O
0I
1 1 1 1 100 200 300 400 MEAN VITAMIN D INTAKE IU/DAY Fig. 5. Relationship between vitamin D intake and serum 25OHD in elderly groups from different countries. Multiple points for United States, Dublin, and Great Britain represent values found in different studies [154].
VOL. 11, NO. 5
Vitamin D in Atherosclerosis and Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
to solar UV rays, and lower consumption of vitamin D than in North American countries [145-154] (Table 1, Fig. 4). 5. In countries where vitamin D was routinely used and added to the food supply in the 1960s and 1970s (United States, Canada, Finland, Israel, Great Britain), osteoporosis was of epidemic proportions, and the fe male/male hip fracture rate was greater than one, ap proaching two in most cases [159] (Table 1, Fig. 4). 6. In countries where vitamin D was not added to the food supply in the 1960s to 1970s (Hong Kong, Yugo slavia, Singapore, South African Bantu), incidence of hip fracture was much lower than in those where vita min D was routinely added to food, and female/male hip fracture rate was close to unity [159] (Table 1, Fig. 4). l,25(OH) 2 D Stimulates Bone Ca Resorption Although rickets in experimental animals may be cured by vitamin D treatment, it is also possible to induce rickets in animals by feeding excessive levels of vitamin D [163]. Bone Ca mobilization is apparently the source of hypercalcemia observed in animals and humans given excessive vitamin D [164]. In a woman who had received large overdoses of vitamin D during a 10-year period, defective bone mineralization was observed, in association with hypercalcemia, hyperphosphatemia, and raised serum con centrations of vitamin D metabolites [165]. The osteodystrophy of vitamin D excess in this patient was similar to that seen among cattle poisoned by 1,25(OH)2D3 in certain plants in South America [166,167]. Thus, vitamin D can either cure rickets and osteomalacia, or, in excess, cause bone Ca wasting. In tissue culture l,25(OH)2D is a potent stimulator of bone résorption [168]. In vivo studies in chicks and rats have also demonstrated bone Ca mobilization by l,25(OH)2D [169]. Administration of l,25(OH)2D to healthy men eating low Ca diets elevated serum levels of the hormone accompanied by increased bone Ca résorp tion [170]. Schwartzman and Frank [171] found enhanced bone résorption in osteoporosis patients undergoing treat ment with la,25(OH)2D3. Spencer et al [169] found marked increases in urinary Ca during vitamin D treat ment (10,000, 25,000, and 50,000 IU/day) of alcoholosteoporosis in middle-aged males. Nordin et al [173] studied six different treatment regimens on 95 postmenopausal women with unequivocably wedged or compressed vertebrae. Vitamin D (10,000-50,000 IU/day) and l,25(OH)2D3 (1-2 Mg/day) resulted in increased bone Ca résorption [173]. Mazess and co-workers found reduced bone mass associated with high circulating levels of la,25(OH)2D3 among female Aleutian islanders aged 4075 [174].
Thus, increased levels of l,25(OH)2D induce bone Ca loss in humans [170-173], with associated decreased bone density [174]. Studies of serum l,25(OH)2D among frac ture patients have been inconclusive. For example, Gal lagher et al [175] reported slight (but significant) subnor mal circulating levels of l,25(OH)2D in osteoporotics, whereas Haussler et al [176] found no difference in 25 crush fracture patients compared to 21 normal agematched controls. Mechanism of Increased Bone Ca Loss Induced by l,25(OH) 2 D As mentioned, one of the surprising findings of the Framingham Study was the fact that IHD increases among women with the cessation of menses, and that this increase is not due to cessation of estrogen production [124-126]. Why do estrogens protect bone from osteoporotic degen eration [2], but fail to protect arteries from atherosclerotic degeneration [124-126]? Differentiation of committed stem cells to monocytes, macrophages, and osteoclasts is stimulated by l,25(OH)2D [176]. The osteoclasts increase bone Ca mobilization. Estrogens may exert their beneficial effects on bone by blocking l,25(OH)2D stimulation of osteoclastogenesis [176]. Since men continue to secrete low levels of estrogens throughout life, they are relatively protected from the dramatic decrease in estrogen produc tion that accompanies menopause among women. It is thus possible that redistribution of Ca resulting from cal ciferol endocrine imbalance results in concurrent décalci fication of bone accompanied by pathological calcification of arteries and soft tissues that is prevalent in countries where vitamin D is routinely added to food. Paulson et al [177] studied the effects of several analogs of l,25(OH)2D on bone résorption in vitro. These analogs have been shown to be ten times more potent than l,25(OH)2D in stimulating differentiation of HL-60 cells to monocyte phenotype. Some of these potent analogs failed to induce higher bone Ca résorption than l,25(OH)2D. The failure of all of the analogs to show higher bone resorbing activity than l,25(OH)2D was inter preted to suggest that the mechanism of l,25(OH)2Dinduced bone résorption may not involve stimulation of monocyte cell differentiation [177]. Although the mechanism of increased bone Ca résorp tion induced by l,25(OH)2D has not been resolved, it would appear that men are relatively protected from osteoclastic effects of vitamin D by continuous low-level estro gen secretion throughout life. Ca is redistributed from bone to arteries among men also, but the effect occurs slowly over a lifetime, rather than acutely following cessation of estrogen secretion as occurs among women following men opause.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
575
Vitamin D in Atherosclerosis and Osteoporosis Mg Deficit in Relation to Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
Decreased trabecular bone Mg [178-180], Mg malab sorption [181], renal Mg wasting [ 182], and low serum Mg [183] have been found in postmenopausal osteoporosis. Lowering of serum Mg induced by estrogen (which shifts Mg to soft tissues and bone) has been suggested as a cause of thromboembolic side effects of high doses of synthetic estrogen [184]. Ca and Mg share a common intestinal absorption pathway, with vitamin D favoring Ca over Mg [185]. Since Ca-dependent steps of blood coagulation are antagonized by Mg, addition of Mg to estrogen-Ca treat ment of osteoporosis has been recommended [184]. The significance of interrelations between vitamin D and Mg in regard to bone disease requires further study.
BALANCING THE VITAMIN DENDOCRINE SYSTEM The information here reviewed suggests that: 1. Atherosclerosis is a calcific disease to which vitamin D excess may contribute. 2. Osteoporosis accompanied by elevated levels of circu lating 25-OHD (>30 ng/ml) is prevalent in the US and Canada. 3. The frequency of osteoporosis in England is unknown, but probably contributes to the incidence of femoral neck fractures [143,145,149]. 4. Osteomalacia accompanied by low circulating levels of 25-OHD (
Journal of the American College of Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uacn20
Hypothesis: etiology of atherosclerosis and osteoporosis: are imbalances in the calciferol endocrine system implicated? a
a
J Moon , B Bandy & A J Davison
a
a
Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada. Published online: 02 Sep 2013.
To cite this article: J Moon, B Bandy & A J Davison (1992) Hypothesis: etiology of atherosclerosis and osteoporosis: are imbalances in the calciferol endocrine system implicated?, Journal of the American College of Nutrition, 11:5, 567-583, DOI: 10.1080/07315724.1992.10718263 To link to this article: http://dx.doi.org/10.1080/07315724.1992.10718263
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Hypothesis: Etiology of Atherosclerosis and Osteoporosis: Are Imbalances in the Calciferol Endocrine System Implicated? Jim Moon, PhD, FACN, Brian Bandy, PhD, and Allan J. Davison, PhD Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
Downloaded by [New York University] at 21:27 11 May 2015
Key words: vitamin D, pathological calcification, atherosclerosis, osteoporosis, osteomalacia, magnesium deficit, free radical, iron, calcium, nicotine, cholesterol Atherosclerosis and osteoporosis are currently considered unrelated diseases. Osteoporosis involves bone calcium (Ca) loss and predominantly affects females after menopause. Atherosclerosis is an illness predominantly affecting males, and is primarily characterized by abnormal lipid metabolism. However, pathological calcification of the arterial wall is an underlying feature of atherosclerosis. Ca homeostasis is thus important in atherosclerosis as well as in osteoporosis. Men also develop osteoporosis although at a later age than women, and, as osteoporosis progresses in women, there is an accompanying calcification of arteries leading to increased incidence of atherosclerosis in aging women. Thus, during old age, both atherosclerosis and osteoporosis are prevalent in both males and females. The dramatic increase in atherosclerosis among women as they develop osteoporosis suggests that the two illnesses may be more closely related than previously realized. The use of vitamin D as a food supplement coincides with epidemic onsets of atherosclerosis and osteoporosis, and excess vitamin D induces both conditions in humans and laboratory animals. These observations suggest a role for chronic vitamin D excess in the etiology of the two illnesses. Magnesium (Mg) deficiency, nicotine, and high dietary cholesterol are contributing factors that accentuate adverse effects of vitamin D. Abbreviations: Ca = calcium, 7-DHC = 7-dehydrocholesterol, l,25(OH)2D = 1,25-dihydroxyvitamin D, Fe = iron, FDA = Food and Drug Administration, 25-OHD = 25-hydroxyvitamin D, IHD = ischemie heart disease, Mg = magne sium, RDA = recommended dietary allowance, RNI = recommended nutrient intake, UV = ultraviolet
INTRODUCTION
factors in atherosclerosis, IHD, and osteoporosis. Atherosclerosis is a disease of abnormal lipid metabo lism. Calcification of the arterial internal elastic lamina is part of the pathological process [3-15], and precedes for mation of intimai lipid plaques by about a decade [3,4]. Calcifications of iliac and internal carotid arteries are observed in infancy, before the appearance of fatty streaks [16,17]. Calcific diseases include atherosclerosis, calcific valvular sclerosis, calcific tendonitis, apatite deposition osteoarthritis, tympanosclerosis, calcinosis cutis, tumour calcification, dental plaque, and dysfunctional calcification occurring in implanted cardiovascular devices, artificial hearts, and intrauterine contraceptive devices [18,19]. This manuscript is presented in four parts. Initially, we consider the role of soft tissue calcification in atheroscle-
With advancing age, levels of Ca in bone decrease, and deposition of Ca in soft tissues increases. Untoward con sequences include: osteoporosis, atherosclerosis, cerebral arteriosclerosis, arthritis, and kidney stones. The identifi cation of risk factors for ischemie heart disease (IHD) has led to the hope that modification of these risk factors could prevent or reduce its incidence. However, intervention programs have had little success in preventing or reducing overall mortality from IHD [1]. A similar circumstance is found with osteoporosis, since only combined therapy using estrogens and Ca slows down progressive bone Ca loss in postmenopausal women [2]. Further advances seem contingent upon new concepts regarding possible causative
Addressreprintrequests to Jim Moon, PhD, School of Kinesiology, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada. Journal of the American College of Nutrition, Vol. 11, No. 5, 567-583 (1992) Published by the American College of Nutrition 567
Vitamin D in Atherosclerosis and Osteoporosis rosis. This is followed by a discussion of the epidemiology of atherosclerosis in relation to abnormal Ca metabolism. The third section considers atherosclerosis and osteopo rosis as concurrent expressions of abnormal calciferol en docrinology. The concluding section contains a discussion of the problem of achieving appropriate calciferol hormone balance.
CONTRIBUTIONS OF CALCIFICATION TO ATHEROSCLEROSIS
Downloaded by [New York University] at 21:27 11 May 2015
Calcifying Proteins of Atherosclerotic Plaques The calcification that occurs in atherosclerosis is char acterized by calcification of matrix vesicles by a "seeding" or nucleating mechanism similar to that occurring in bone calcification [20,21]. It is invariably associated with a zone of lipid accumulation [21]. A unique γ-carboxyglutamic acid-containing protein has been isolated from calcified atherosclerotic plaques, and named "atherocalcin" [22, 23]. The vitamin K-dependent bone protein, osteocalcin, is another of the γ-carboxyglutamic acid-containing pro teins in calcified atherosclerotic plaque [23]. A proteolipid calcification "nucleator" [24], along with a Ca-acidic phospholipid-phosphate complex are present [25], supporting the suggestion that aortic tissue calcifies through mecha nisms similar to those involved in bone mineralization. A peptide containing histidinoalanine crosslinks is important in the calcification process [26]. Understanding the roles of the proteins involved in calcification is a prerequisite to understanding the pathogenesis of atherosclerosis. Chemical Composition of the Mineral Deposits The chemical composition of atherosclerotic mineral deposits has been well studied. The deposits are composed of Ca and phosphate, with some Mg, iron (Fe), and other trace mineral constituents [27-32]. The microcrystalline deposit materials are heterogeneous, and can be repre sented chemically as carbonate-substituted apatite [30, 31]. The mechanism for the formation of cardiovascular deposits reportedly proceeds through hydrolysis of octacalcium phosphate precursor [31]. Ca Channel Blockers Protect Against Atherosclerosis and IHD Support for a role for Ca in atherosclerosis comes from observations that inhibitors of arterial Ca deposition (diphosphonates) and Ca antagonists (e.g., nifedipine, verapamil, kiltiazem, and nilvadipine), which do not affect abnormal blood lipid levels, attenuate the development of experimental atherosclerosis [33-37]. It has been suggested
568
that Ca channel blockers exert some of their actions by protecting against aortic Ca deposition [37]. In addition, during an ischemie attack, there is a massive influx of Ca into cardiac cells, accompanied by mitochondrial accu mulation of Ca [38]. This indicates defective membrane function as an early feature of ischemie injury. Ca channel blockers may be beneficial in preventing Ca influx. Mg is a natural Ca channel blocker [39], and therefore exerts a beneficial effect in preventing pathological arterial calcifi cation. Vitamin D Induces Phospholipid Incorporation into Biomembranes Since the discovery of protein induction by 1,25-dihydroxyvitamin D [l,25(OH)2D], it has become generally accepted that vitamin D's mode of action is similar to that of the steroid hormones [40]. These hormones enter the cell where they are bound to a cytosolic carrier protein and transported to the cell nucleus where they induce synthesis of ribonucleic acid, which then directs synthesis of new proteins. Ca-binding protein is one of the proteins induced by 1,25(OH)2D3, and this is believed to be a factor involved in translocation of Ca across the lumen of the intestine [40]. However, another mechanism by which vitamin D controls cell Ca flux has been suggested that is independent of de novo protein synthesis [41-46]. Rasmussen et al [4143] demonstrated that 1,25(OH)2D3 enhances the synthesis of phosphatidylcholine in enterocytes independent of new protein synthesis. There is a close correlation in the timecourse of change after l,25(OH)2D3 treatment between incorporation of unsaturated fats into the brush border phosphatidylcholine fraction and the Ca-transport prop erties of the membrane [41-43]. Holmes et al [44] and Kummerow [45,46] have exten sively studied the effects on Ca translocation of inser tion of partially oxidized derivatives of cholesterol [25hydroxycholesterol and 25-hydroxyvitamin D (25-OHD)] in vitro into liposomes. Ca uptake is more rapid in the presence of the partially oxidized derivatives than in the presence of cholesterol alone [44-46], suggesting that per turbation of membranes by the polar 25-hydroxy group plays a role in increasing membrane permeability to Ca ions. Cytotoxic and atherogenic effects of oxysterols have been reviewed [47,48]. l,25(OH)2D regulates intracellular ionized Ca in colonocytes by mechanisms involving mem brane phosphatidylinositol breakdown, and release of intracellar stored Ca; vitamin D deficiency abolishes this effect [49]. Vitamin D Excess Causes Arterial Calcification The calciferol endocrine system, like all endocrine sys tems, must be carefully balanced. Any factor which causes
VOL. 11, NO. 5
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D in Atherosclerosis and Osteoporosis an imbalance in an endocrine system may result in pa thology. Insufficient exposure to solar ultraviolet (UV) rays results in a deficiency of calciferol, producing rickets or osteomalacia [50,51]. Excess calciferol is a well-docu mented cause of cardiovascular, renal, and skeletal damage among humans poisoned during megavitamin D therapy [52-61], among hyperreactive infants that received excess vitamin D during routine fortification of foods [62-71], and in laboratory animals [72-88]. Skeletal damage from excess vitamin D, in both humans and animals, can be either hypercalcification or rarefaction of bone. Cardiovas cular damage is primarily calcine with lipids surrounding the zone of calcification.
ing may contribute to progression of the disease. When nicotine (which by itself was harmless) was added to a harmless diet containing vitamin D and cholesterol, the animals progressively developed lethal calcific lesions charactersitic of chronic hypervitaminosis D, indicating that nicotine activates the arterial calcifying actions of vitamin D. Liu et al [84], using rhesus monkeys, similarly demon strated that the three vasotoxic factors (dietary hypercholesterolemia, hypervitaminosis D2, and nicotinism), when administered singly, did not produce advanced atheroscle rotic lesions. However, when combined, major changes simulating human atherosclerosis could be readily in duced.
Vitamin D, Cholesterol, and Nicotine Act Synergistically in the Induction of Experimental Atherosclerosis
Yitamin D Excess and Mg Deficit Act Synergistically to Induce Arterial Calcification in Laboratory Animals
Since laboratory experiments have demonstrated that either high cholesterol or high vitamin D diets can produce atherosclerosis in animals, and that the two factors accen tuate one another in this capacity, it has been asked what other factors may act synergistically with these. At least two other factors have been identified: nicotine and Mg deficit. Hass et al [75] tried for several years to produce an arterial disease having the characteristics of human atheroarteriosclerosis (calcific medial degeneration, fibrocellular intimai proliferation and intimai atheromatous accumulation with subsequent degenerative reactions). The closest approximation resulted from moderate hyper vitaminosis D and mild hyperlipemic hypercholesteremia in rabbits. However, due to an inability to fully simulate patterns observed in humans, Hass et al [75] added nic otine to their atherogenic diet. Nicotine was chosen due to its adrenergic actions and because excessive cigarette smok-
Mg deficiency, like vitamin D excess, induces calcifi cations of arteries and kidneys [89-93]. Interrelationships of vitamin D and Mg are complex, entailing interactions with Ca, phosphate, fluoride, parathyroid hormone, calcitonin, and estrogen [89-93] (Figs. 1, 2 and 3). Marginal Mg intake is prevalent in North America [91,92]. Mg has been considered the principal cardioprotective factor found in drinking water [91]. Mg deficiency and vitamin D excess mutually accentuate the deleterious effects of one another on soft tissue calcifications [90,92,93]. Mg deficiency interferes with vitamin D utilization [93]. One form of rickets fails to respond to vitamin D until dietary Mg is increased [94,95]. Paradoxically, hypomagnesemia may result from either hyper- or hypovitaminosis D. Hypervitaminosis D increases urinary Mg, increasing Mg requirements [92]. Vitamin D deficiency decreases Mg absorption and therefore also increases Mg requirements [93]. Increasing dietary Mg decreases the
V I T A M I N
D E
-► DECREASED INTESTINAL Hg ABSORPTION -► DECREASED VITAHIN D UTILIZATION-^— ■>- HYPOCALCEMIA L D L - C H O L - < HYPERTENSION A R T E R I A L SPASMS "^ (DIET Ca) OSTEOPENIA ■
Ca>
I E N C Y
Fig. 1. Vitamin D and magnesium [93].
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
569
Vitamin D in Atherosclerosis and Osteoporosis INTENSIFICATION
PROTECTION Renal Calculi
t
V I T A M
Calcium Phosphate Fluoride
N
Fat Sodium
D Nicotine
M A G N E S
Hypercalciuria Hypercalcemia
1 Platelet Aggregation Hyperlipemia Hypertension Subcetlular Damage Athero, Arteriosclerosis Myocardial Infarction
U M
Vitamin E Vitamin C ß-Carotene Potassium
Downloaded by [New York University] at 21:27 11 May 2015
Fig. 2. Intensifying and protective factors in vitamin Dinduced pathology. Adapted from [93, 133, 134].
atherosclerosis induced in swine by hypervitaminosis D [96]. The mechanisms by which Mg deficiency accentuates pathological calcification are not fully understood, but undoubtedly Ca channel blocking by Mg is involved [39]. Vitamin D Excess and Mg Deficit Result in Abnormal Lipid Metabolism as Encountered in Atherosclerosis Much of the vitamin D fed to domestic animals (as a growth hormone) concentrates in fat stores of the animals, making animal fat a source of vitamin D [97]. Fats (by accumulating and sequestering vitamin D) affect vitamin D metabolism, and vitamin D affects lipid metabolism. Vitamin D has been implicated as a hypercholesterolemic agent: in infantile hypercalcemia [68,71,98]; among farm ers ingesting vitamin D preparations (estimated 700-2500 IU/day) [99,100]; and among adults with atherosclerosis
\
PTH -
Increased osteoclast activity
\
Chronic vitamin D excess
Decreased bone Ca & Mg
Mg deficit
/
Nicotine and other adrenergic agents
OSTEOPOROSIS PATHOLOGICAL CALCIFICATION / OF SOFT TISSUES
High hemodynamic load
/
Free radical generation
Cholesterol; saturated fats
*
Subcellular damage and tissue injury
Mg deficit and/or vitamin D excess
ADVANCED ATHEROSCLEROSIS
Fig. 3. The deleterious cycle of vitamin D excess, magnesium deficit, tissue injury, and pathological calcification.
570
EPIDEMIOLOGICAL ASPECTS OF ATHEROSCLEROSIS MAY BE CLARIFIED BY CONSIDERING EXCESS VITAMIN D INGESTION AS AN ETIOLOGIC FACTOR A number of epidemiological findings regarding athero sclerosis are not explained by contemporary theories, but are clarified by the concept that disturbed calciferol endo crinology resulting in a calcific disease is an important underlying factor in the etiology of atherosclerosis and IHD. Concurrent Origins of the Epidemic in Canada, the United States, England, and Wales Coincide with Increasing Use of Vitamin D and Decreasing Dietary Mg
Elevated 1,25(OH)2-D1
Low dietary Ca
[101,102]. In a study of rats, on the other hand, serum cholesterol levels were lowered by vitamin D2 ingestion, while liver cholesterol levels were dramatically elevated [103]. Ingestion of l,25(OH)2D stimulated a fourfold in crease in 7,8-didehydrocholesterol levels in rat skin, but did not affect skin or serum cholesterol levels [104]. The degree of atherosclerosis in laboratory animals fed high fat diets is intensified by Mg deficiency and dimin ished by higher than usual amounts of Mg [93]. Mg deficiency increases the ratio of low density lipoproteins to high density lipoproteins, and Mg supplementation de creases this ratio [105]. In a clinical test Mg replacement therapy provided for 47 patients with IHD and acute myocardial infarction confirmed results in laboratory ani mals [106]. The beneficial effects of intravenously admin istered Mg to correct arrhythmia in acute myocardial infarction has been reviewed [107,108].
Confusion regarding the time of origin of the present epidemic of atherosclerosis and IHD was clarified by An derson [109-113]. Anderson and Halliday [113] point out that the sex differential can be used to trace development of the modern epidemic in males, since the male/female death rate is relatively unaffected by changes in diagnostic accuracy, medical fashion, and statistical classification. Male and female death rates were similar until the mid19208. Since then, the male/female predominance in creased steadily until 1970 in Canada, the United States, England, and Wales [112]. The curative effect of cod liver oil in rickets was docu mented by Hess and Unger in 1917 [114]. By 1923 the importation offish liver oil in the United States was about 500,000 gallons, and increased to over 2.8 million gallons in 1930 [97]. The use of UV-irradiated milk was intro duced in the United States in 1924 [115]. Information is
VOL. 11, NO. 5
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D in Atherosclerosis and Osteoporosis not available regarding how much vitamin D was delivered in UV-treated milk. The manufacture of vitamins D2 and D3 increased from 35 lb in 1948 to 14,000 lb in 1972 [40,97]. In 1970 vitamin D2 was added to baked goods, breakfast cereals, pasta and rice dishes, fats and oils, milk and milk products, meat and poultry products, sauces, nonalcoholic beverages, dairy product analogs, candy bars, multivitamin supplements, and baby formulas [116]. Vi tamin supplements containing up to 25,000 IU of vitamin D in a single pill were sold in health food stores, and supplements containing 2,000 IU were common [117]. Although the Food and Drug Administration (FDA) issued orders to reduce the amount of vitamin D in flour, cereals, and over-the-counter vitamin supplements, the FDA does not have the staff to monitor the amount of vitamin D in food and supplements. Health and Welfare Canada is in much the same predicament. For instance, since 1970 there has been a regulation that vitamin D fortified milk should be analyzed for vitamin D at least twice a year. In British Columbia the first laboratory to analyze for vitamin D was set up in 1989. Along with this excessive delivery of vitamin D, there has also been a continually declining intake of Mg due to Mg-deficient artificial fertilizers and many processing pro cedures which decrease food Mg content [91]. Thus the epidemic of IHD in North America directly parallels both the increasing use of vitamin D and the decreasing avail ability of dietary Mg, two major factors that act synergistically to induce calcifications of arteries and kidneys. The Decreasing Incidence in Death From IHD in North America Coincides with Decreased Delivery of Vitamin D In the 1970s the death rate from IHD in the United States began to decrease [118-120]. In Alameda County, CA, after adjustment for age, sex, race, and baseline IHD conditions and symptoms, there was a 45% decline in the 9-year odds ratio of IHD mortality between two cohorts taken to be representative in 1965 and 1974 [120]. Ad justment for cohort differences in the following IHD risk factors did not explain the decline: smoking status, leisure time physical activity, self-assessed physical activity, alco hol consumption, body mass index, or social network participation; neither did adjustment for measures of ed ucation, preventive medical care, availability of a regular physician or clinic, health insurance coverage, number of physician visits during the last 12 months, or occupation [120]. In the late 1960s the FDA began considering legislation to limit amounts of vitamin D delivered to the US popu lation. By 1972 the current regulations went into effect which limit foods to which vitamin D may be added: milk, baby foods, and multivitamin supplements [117]. The
maximum permissible level of vitamin D in over-thecounter supplements is now 400 IU in the label-recom mended daily intake [117]. Canada has adopted similar regulations. In Canada, margarine is fortified (660IU/100 g), and in both Canada and the United States some break fast cereals contain added vitamin D. Thus, there has been a dramatic decrease in vitamin D consumption in North America since 1970, which coincides with the decreasing incidence in death from IHD. Blacks are Less Sensitive Than Whites to Vitamin D Toxicity, and Are Relatively Protected from Atherosclerosis In 1965, Eggen et al [7] reported an increased incidence of calcification and atherosclerotic degeneration in arteries of whites as compared to blacks in New Orleans, based on 1,243 consecutive necropsies of whites and blacks aged 30-69 years [7]. This finding was confirmed in all locations studied in the International Atherosclerosis Project [121], which assessed the extent of atherosclerotic plaque forma tion in 23,000 autopsy cases from 19 location-race groups. Cases with diseases known to be associated with more severe atherosclerosis, such as coronary artery disease, stroke, hypertension, and diabetes were excluded since the purpose of the study was to determine the extent of ath erosclerotic lesions for predicting occurrence in the general population. This is in contrast to mortality from heart disease, since blacks have higher heart disease death rates [122], due to the higher death rates among blacks from hypertension and cardiovascular diseases of an unspecified nature [123]. Strong [121] stated: "The existence of large differences in average extent of atherosclerosis among white populations and among Negro populations suggests that environmental conditions may be important deter minants of the prevalence and extent of atherosclerotic lesions. Conditions that might be considered include ha bitual diet, physical activity, cigarette smoking, stress, and other factors." Perhaps one environmental condition influencing this difference is vitamin D. Dark-skinned infants are more susceptible to rickets than are fair-skinned infants, due to lower vitamin D biosynthesis on exposure to UV rays [114,115]. Similarly, dark-skinned infants are less suscep tible to toxic effects of vitamin D than are fair-skinned infants [68,71 ]. It is likely that dark-skinned adults are also less susceptible to vitamin D toxicity, although no infor mation is presently available. The rate of decline in ageadjusted heart disease deaths from 1968-1975 among women and blacks has been half that of white men [123], consistent with an attenuated effect of vitamin D in blacks and premenopausal women.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
571
Vitamin D in Atherosclerosis and Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D Increases Body Fe Stores and This Can Initiate Free Radical Damage in Atherosclerosis Initially it was believed that the lower incidence of IHD among females might be due to estrogens, however, exog enous estrogen worsens the prognosis for men who have had myocardial infarction [124]. The Framingham study found that the onset of cardiovascular disease in women is not strictly age-dependent but is coupled with the cessation of menses [125]. The incidence of cardiovascular disease increases within 2 years after menopause. Women acquire IHD later than men, but develop the disease at a greater rate. The Framingham investigators expressed their per plexity at these findings [125]: We can only speculate as to the reasons for the postmenopausal increase in coronary heart disease inci dence The specification, when it is forthcoming, must account for the fact that surgical menopause without removal of the ovaries apparently leads to the same jump in risk noted with bilateral oophorectomy (plus hysterectomy) Somewhere in this tantalizing mystery may lie a lesson of profound importance in understanding the genesis and course of this disease, perhaps in men as well as in women. As Gordon et al [125] and Sullivan [126] stated, any viable hypothesis should consider why women over a broad age range suffer the same risk of IHD increase when they stop menstruating for any reason. The gender difference in stored Fe has been proposed as an explanation of the gender difference in IHD [126]. An increase in stored Fe is coupled directly with cessation of menses, whether by natural menopause, hysterectomy, or oophorectomy [124]. In affluent societies males tend to accumulate Fe with age, and traces of Fe invariably occur in calcified lesions of atherosclerotic plaques [27-32]. If this hypothesis is correct, menstruating women in affluent societies may be protected by the same factor that protects men in underdeveloped countries, that is, lower Fe stores [126]. Vitamin D increases Fe absorption. In chicks fed a low Ca diet, vitamin D elevated the amount of Fe in blood, liver and bone when the Fe was given orally, indicating an increase in Fe absorption under the influence of vitamin D [127]. In human infants a significant association of Fe deficiency with poor vitamin D status has been reported [128]. The low overall incidence, and lack of a high male/ female ratio in the death rate from cardiovascular disease in underdeveloped countries where vitamin D is not added to the food supply and where dietary Fe is comparatively low may, in part, be due to the lack of vitamin D in foods. This concept is a logical extension of the "tissue injury hypothesis" of atherogenesis [129], in which tissue injury triggers calcification at the site of injury [88]. Oxidative modifications of low-density lipoproteins increase their atherogenicity [130]. Free radical generation has been sug
572
gested as a mechanism of induction of tissue damage and low-density lipoprotein oxidation observed in atheroscle rosis [ 131 ]. Fe that is not tightly bound to internal chelating agents such as hemoglobin, transferrin, or ferritin, is avail able for free radical generation [131]. Thus, Fe deposited in atherosclerotic plaques may be available for free radical generation and accentuation of tissue damage, resulting in a vicious cycle of further Ca and Fe accumulations, to which the calcification increased by oxysterols contributes [47,48]. Epidemiology of Vitamin D Excess in Atherosclerosis and IHD is Inconclusive Although the relationship between vitamin D ingestion and IHD has not been thoroughly investigated, underde veloped countries (where vitamin D is not used as a food additive) generally have a low incidence compared to those countries that use vitamin D (Table 1, Fig. 4). Countries where the greatest amounts of vitamin D are used tend to have the highest heart disease death rates. For instance, from 1950-1969 in a 26-country survey, the age-adjusted death rate for heart disease among men in the US was around 700/100,000 population, second only to Finland [ 132]. Canada was among the seven countries with highest age-adjusted heart disease death rates with around 600 deaths/100,000 population. This time period represents the time of maximal vitamin D delivery in the US and Canada. During the same time period England/Wales and Ireland had a heart disease death rate among males less than 500/100,000 population. During 1969-1970 the heart disease death rate began to decrease in the US and Canada while in England/Wales and Ireland there was a continuing slow increase so that presently the heart disease death rate is similar in the US, Canada, England/Wales, and Ireland (a little over 500/100,000 population) [132]. Holmes and Kummerow [97], Peng and Taylor [133], and Moon [134] have reviewed the suggested role of vitamin D in athero sclerosis. Knox [135] found a positive correlation between vita min D ingestion and death from IHD. Linden [136] con ducted an epidemiological study in Tr0mso, Norway, which indicated an association between ingestion of vita min D and IHD; approximately 30 /ig (1200IU) of vitamin D/d correlated with increased incidence of heart attacks. On the other hand, in the Trgmso Heart Study, Vik et al [137] analyzed deep-frozen serum samples from 30 myocardial infarction patients. These were compared with 60 age- and sex-matched controls who had serum samples taken in the same month as the patients. No difference in 25-OHD was observed [137]. Another study of 16 myo cardial infarct patients in Heidelberg, West Germany, sim ilarly found no difference in circulating 25-OHD between patients and controls [138].
VOL. 11, NO. 5
Vitamin D in Atherosclerosis and Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
ARE OSTEOPOROSIS AND ATHEROSCLEROSIS RELATED? The widely accepted concept that vitamin D is "good for bones" is derived from the impressive effect of the hormone (or prohormone) in preventing and curing rick ets. The information herein presented considers vitamin D, and other hormonally active metabolic products of vitamin D, as an integrated endocrine system that regulates aging of the skeleton, cardiovascular system, and kidneys. There can be little doubt that calciferol hormone bal ance is important throughout life. As with other steroid hormones, there is natural variation during life. Circulating levels of l,25(OH)2D3 reach a peak shortly after birth [139], decrease, peak again during the adolescent growth spurt [140], and decrease once more. Interfering with the natural course of events by artificially maintaining elevated levels during a period when levels would otherwise be decreasing may have adverse effects. Since excess vitamin D induces cardiovascular and skeletal effects similar to atherosclerosis and osteoporosis in both laboratory animals [72-88] and humans [52-71], we must ask if osteoporosis as well as atherosclerosis might, in part, be due to imbal ances in the calciferol endocrine system induced by life long, low-level excesses of vitamin D. Distinguishing Osteomalacia from Osteoporosis Albright et al [141] defined postmenopausal osteopo rosis as a clinical entity in 1941. Since then this disorder has been identified very commonly in the elderly, espe cially in North America. A few years after peak adult bone
400 g00
Cardiac Deaths
C o u n t r y / V i t D Intake
Fig. 4. Vitamin D intake in relation to femoral neck fracture rate among women, and heart disease death rate among men (data plotted from Table 1). Using these data, femoral neck fracture among women and heart disease death rate among men are significantly correlated (r = 0.634; p < 0.05).
mass is attained, age-related bone loss begins [142], occur ring regardless of sex, race, occupation, economic devel opment, geographical location, historical epoch, or dietary habits [142-144]. In men the rate of cortical bone loss is about 0.3% of peak adult bone mass/year, and trabecular bone loss is slightly greater [142]. In women the average rate of loss is about 1 % of peak adult bone mass/year for both cortical and trabecular bone, with acceleration for
Table 1. Vitamin D Intake,1 Rates for Fracture of the Proximal Femur,2 and Death Rates for Heart Disease3 Heart disease
Fractures Country
VitD Female
Canada USA Sweden UK Neth4 Finland Israel Yugo4 Singapore Hong Kong Bantu
++++ ++++ + + + + + No
No No No
200 101.6 87.2 63.1 51.1 49.9 69.9 39.2 15.3 31.3 5.3
Male 50 50.5 38.2 29.3 28.5 27.4 42.8 37.9 26.5 27.2 5.6
F/M 4 2.01 2.75 2.15 1.80 1.78 1.63 1.03 0.58 1.15 0.94
Male 650 700 340 520 370 780 450 320 200 83 Low
Female 200 190 100 150 100 200 200 200 100 37 Low
M/F 3.25 3.7 3.4 3.5 3.7 3.9 2.25 1.6 2 2.2
1
Vitamin D ingestion is estimated for Canada [ 193], the US and Great Britain [ 154]. Each plus represents approximately 50 IU/day. Plusses are used rather than fig or IU, to indicate the uncertainty regarding how much vitamin D is actually being delivered. 2 Rates for fractures of the proximal femur are cases/100,000 population/year. Populations were age-adjusted to the US population in 1970 [159], except those for Canada, which are age-adjusted to the Manitoba population [161]. 3 Death rates for heart disease are estimated for the time period, 1965-1969 (to precede the sharp decline in heart disease death rate in the US and Canada), and are expressed as deaths/100,000 population [132]. Hong Kong and Singapore heart disease death rates are for 1968 and were age-standardized for ages 40-69 [203]. A low incidence of atherosclerosis is reported among Bantus [121]. 4 Neth = Netherlands; Yugo = Yugoslavia.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
573
Downloaded by [New York University] at 21:27 11 May 2015
Vitamin D in Atherosclerosis and Osteoporosis about 5 years after menopause, and a lower rate both earlier and later [142]. Over their lifetimes, women may lose about 35% of their cortical bone and 50% of their trabecular bone, whereas men lose about two-thirds of these amounts [142,144]. In osteomalacia, osteoid-covered surfaces and abnormal calcification fronts are observed, whereas in osteoporosis bone mass is decreased [51,115,144-152]. Osteomalacia has many causes, including diet, lack of sunshine exposure, drug use, and exposure to metals such as lead, cadmium, and aluminum. Administration of vitamin D or one of the more active metabolites of vitamin D is frequently effective in treating osteomalacia [144-147]. On the other hand, osteoporosis is generally resistant to vitamin D therapy, and is not considered to be due to vitamin D deficiency [144,145]. Fracture of the femoral neck is a common measure of both osteomalacia and osteoporosis [144-152]. In the United Kingdom, osteomalacia with resultant femoral neck fractures is common. Aaron et al [148,149] found the incidence of osteomalacia to vary with season in a series of 134 iliac-crest biopsies from unselected cases of fracture of the proximal femur. The highest incidence of abnormal calcification fronts (43%) was observed in Feb ruary-April, and the lowest (15%) in August-October. The highest frequence of abnormal osteoid-covered surfaces (47%) was observed in April-June and the lowest ( 13%) in October-December. The overall frequency of osteomalacia in femoral neck fracture cases in Leeds was estimated to be about 37% [148]. There are low circulating levels of 25-OHD in elderly women in Great Britain [153] and among elderly Irish people [154]. However, low circulating levels of 25-OHD are not always indicative of osteomalacia [155]. More sophisticated methods of detecting osteomalacia and eval uating calciferol hormone status are being developed [156]. Contrary to the circumstance in Great Britain and Ireland, osteoporosis is considered the most frequent cause of femoral neck fracture in North America [144,147,157160]. Melton et al [157,158] have assessed the risk of hip fracture based on bone mineral density and age among women in Rochester, MN. Hip fractures were uncommon among women with femoral bone density > 1.0 g/cm2, with frequency increasing as bone density declined below this level [157]. In countries where osteoporosis is com mon, and which have a high incidence of femoral neck fractures, there is a high ratio of female/male femoral neck fractures [159]. This has been used as an epidemiological tool to trace the origins of the osteoporosis epidemic [159,160] much as the male/female death rate from IHD has been used to trace the epidemic of atherosclerosis [109113].
574
Why does the incidence of atherosclerosis, accompa nying osteoporosis, progress so rapidly among women after menopause? Whey do men have a lower incidence of osteoporosis? Why are blacks less susceptible to both os teoporosis and atherosclerosis than Caucasians? These im portant questions can be answered on the basis that vita min D excess results in imbalanced calciferol endocrinol ogy which is responsible for both décalcification of bone and concomitant increased calcification of arteries that occurs among postmenopausal women and aging men in developed countries. What evidence supports this concept? 1. Osteoporosis began its epidemic upsurge in Rochester, MN (and presumably in North America in general), in the late 1920s [159,160], at approximately the same time that IHD was becoming epidemic [ 109-113], coin cident with increasing use of vitamin D and decreasing availability of Mg. 2. Elderly people in North American countries where vitamin D delivery is high have elevated serum 25OHD [153] (Fig. 5), accompanied by the highest inci dence of osteoporosis [157-161] (Table 1, Fig. 4). 3. Blacks are more resistant than fair-skinned people to osteoporosis [143,162] and atherosclerosis [121], and are also more resistant to the toxic effects of vitamin D [68,71]. Another reason for the difference in bonewasting disease is thought to be the greater bone mass of blacks [162]. 4. In Great Britain and Ireland, osteomalacia with accom panying low circulating levels of 25-OHD is prevalent, while its occurrence in North America is considered uncommon [146-152]. This is attributed to both lower exposure of elderly people in Great Britain and Ireland
,.·'
«U.S.A
60 DENMARKφ O
E CANADA»
c
9. 40 -
/
X
o m
.··'
.·'
/
·
u.s.A
_ DUBLIN
O
0I
1 1 1 1 100 200 300 400 MEAN VITAMIN D INTAKE IU/DAY Fig. 5. Relationship between vitamin D intake and serum 25OHD in elderly groups from different countries. Multiple points for United States, Dublin, and Great Britain represent values found in different studies [154].
VOL. 11, NO. 5
Vitamin D in Atherosclerosis and Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
to solar UV rays, and lower consumption of vitamin D than in North American countries [145-154] (Table 1, Fig. 4). 5. In countries where vitamin D was routinely used and added to the food supply in the 1960s and 1970s (United States, Canada, Finland, Israel, Great Britain), osteoporosis was of epidemic proportions, and the fe male/male hip fracture rate was greater than one, ap proaching two in most cases [159] (Table 1, Fig. 4). 6. In countries where vitamin D was not added to the food supply in the 1960s to 1970s (Hong Kong, Yugo slavia, Singapore, South African Bantu), incidence of hip fracture was much lower than in those where vita min D was routinely added to food, and female/male hip fracture rate was close to unity [159] (Table 1, Fig. 4). l,25(OH) 2 D Stimulates Bone Ca Resorption Although rickets in experimental animals may be cured by vitamin D treatment, it is also possible to induce rickets in animals by feeding excessive levels of vitamin D [163]. Bone Ca mobilization is apparently the source of hypercalcemia observed in animals and humans given excessive vitamin D [164]. In a woman who had received large overdoses of vitamin D during a 10-year period, defective bone mineralization was observed, in association with hypercalcemia, hyperphosphatemia, and raised serum con centrations of vitamin D metabolites [165]. The osteodystrophy of vitamin D excess in this patient was similar to that seen among cattle poisoned by 1,25(OH)2D3 in certain plants in South America [166,167]. Thus, vitamin D can either cure rickets and osteomalacia, or, in excess, cause bone Ca wasting. In tissue culture l,25(OH)2D is a potent stimulator of bone résorption [168]. In vivo studies in chicks and rats have also demonstrated bone Ca mobilization by l,25(OH)2D [169]. Administration of l,25(OH)2D to healthy men eating low Ca diets elevated serum levels of the hormone accompanied by increased bone Ca résorp tion [170]. Schwartzman and Frank [171] found enhanced bone résorption in osteoporosis patients undergoing treat ment with la,25(OH)2D3. Spencer et al [169] found marked increases in urinary Ca during vitamin D treat ment (10,000, 25,000, and 50,000 IU/day) of alcoholosteoporosis in middle-aged males. Nordin et al [173] studied six different treatment regimens on 95 postmenopausal women with unequivocably wedged or compressed vertebrae. Vitamin D (10,000-50,000 IU/day) and l,25(OH)2D3 (1-2 Mg/day) resulted in increased bone Ca résorption [173]. Mazess and co-workers found reduced bone mass associated with high circulating levels of la,25(OH)2D3 among female Aleutian islanders aged 4075 [174].
Thus, increased levels of l,25(OH)2D induce bone Ca loss in humans [170-173], with associated decreased bone density [174]. Studies of serum l,25(OH)2D among frac ture patients have been inconclusive. For example, Gal lagher et al [175] reported slight (but significant) subnor mal circulating levels of l,25(OH)2D in osteoporotics, whereas Haussler et al [176] found no difference in 25 crush fracture patients compared to 21 normal agematched controls. Mechanism of Increased Bone Ca Loss Induced by l,25(OH) 2 D As mentioned, one of the surprising findings of the Framingham Study was the fact that IHD increases among women with the cessation of menses, and that this increase is not due to cessation of estrogen production [124-126]. Why do estrogens protect bone from osteoporotic degen eration [2], but fail to protect arteries from atherosclerotic degeneration [124-126]? Differentiation of committed stem cells to monocytes, macrophages, and osteoclasts is stimulated by l,25(OH)2D [176]. The osteoclasts increase bone Ca mobilization. Estrogens may exert their beneficial effects on bone by blocking l,25(OH)2D stimulation of osteoclastogenesis [176]. Since men continue to secrete low levels of estrogens throughout life, they are relatively protected from the dramatic decrease in estrogen produc tion that accompanies menopause among women. It is thus possible that redistribution of Ca resulting from cal ciferol endocrine imbalance results in concurrent décalci fication of bone accompanied by pathological calcification of arteries and soft tissues that is prevalent in countries where vitamin D is routinely added to food. Paulson et al [177] studied the effects of several analogs of l,25(OH)2D on bone résorption in vitro. These analogs have been shown to be ten times more potent than l,25(OH)2D in stimulating differentiation of HL-60 cells to monocyte phenotype. Some of these potent analogs failed to induce higher bone Ca résorption than l,25(OH)2D. The failure of all of the analogs to show higher bone resorbing activity than l,25(OH)2D was inter preted to suggest that the mechanism of l,25(OH)2Dinduced bone résorption may not involve stimulation of monocyte cell differentiation [177]. Although the mechanism of increased bone Ca résorp tion induced by l,25(OH)2D has not been resolved, it would appear that men are relatively protected from osteoclastic effects of vitamin D by continuous low-level estro gen secretion throughout life. Ca is redistributed from bone to arteries among men also, but the effect occurs slowly over a lifetime, rather than acutely following cessation of estrogen secretion as occurs among women following men opause.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
575
Vitamin D in Atherosclerosis and Osteoporosis Mg Deficit in Relation to Osteoporosis
Downloaded by [New York University] at 21:27 11 May 2015
Decreased trabecular bone Mg [178-180], Mg malab sorption [181], renal Mg wasting [ 182], and low serum Mg [183] have been found in postmenopausal osteoporosis. Lowering of serum Mg induced by estrogen (which shifts Mg to soft tissues and bone) has been suggested as a cause of thromboembolic side effects of high doses of synthetic estrogen [184]. Ca and Mg share a common intestinal absorption pathway, with vitamin D favoring Ca over Mg [185]. Since Ca-dependent steps of blood coagulation are antagonized by Mg, addition of Mg to estrogen-Ca treat ment of osteoporosis has been recommended [184]. The significance of interrelations between vitamin D and Mg in regard to bone disease requires further study.
BALANCING THE VITAMIN DENDOCRINE SYSTEM The information here reviewed suggests that: 1. Atherosclerosis is a calcific disease to which vitamin D excess may contribute. 2. Osteoporosis accompanied by elevated levels of circu lating 25-OHD (>30 ng/ml) is prevalent in the US and Canada. 3. The frequency of osteoporosis in England is unknown, but probably contributes to the incidence of femoral neck fractures [143,145,149]. 4. Osteomalacia accompanied by low circulating levels of 25-OHD (
