Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment, by Dr. Mildred S. Seelig

Magnesium Research (1990) 3,3, 197-215 REVIEW ARTICLE

Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment

Mildred S. Seelig

Community and Preventive Medicine, New York Medical College, Valhalla, New York; American College of Nutrition, Wilmington, N. Carolina, USA.

Go to figures and tables for this article.

Summary: Prophylactic treatment of postmenopausal osteoporosis with oestrogen and calcium, often in combination, disregards the likelihood that an excess of each agent may increase magnesium requirements and decrease serum Mg levels. Relative or absolute Mg deficiency, which is likely in the Occident where the Mg intake is commonly marginal, can militate against optimal therapeutic bone response, Mg being important for normal bone structure, and can increase the risk of adverse effects. Although oestrogen has cardiovascular protective effects (expressed by the lower incidence of heart disease in premenopausal women than in men, and also in postmenopausal women given low dosage oestrogen replacement treatment), high dosage oestrogen oral contraceptives have caused increased intravascular blood clotting with resultant thromboembolic cardio- and cerebrovascular accidents. This might be contributed to by the oestrogen-mediated shift of circulating Mg to soft and hard tissues, which in persons with marginal Mg intakes may lead to suboptimal serum levels. If the commonly recommended dietary Ca/Mg ratio of 2/1 is exceeded (and it can reach as much as 4/l in countries with low to marginal Mg intakes), relative or absolute Mg deficiency may result, and this may increase the risk of intravascular coagulation, since blood clotting is enhanced by high Ca/Mg ratios. Mechanisms by which Ca activates the various steps in blood coagulation that are also stimulated by oestrogen are considered here, as are the multifaceted roles of Mg that favourably affect blood coagulation and fibrinolysis, through its activities in lipoprotein and prostanoid metabolism.

Key words: Alcoholic, bone structure, calcium therapy, Ca/Mg ratio, combination therapy, diabetic, intravascular coagulation, malabsorption, Mg deficiency, Mg lipoproteins, Mg requirements, oestrogen therapy, osteoporosis prophylaxis, postmenopausal, prostanoids.

Introduction

Far less appreciated than calcium in the treatment or prevention of osteoporosis is the importance of magnesium. Osteoporotic bone has subnormal Mg content, such as is found in Mg deficiency. Many factors interact in the vulnerability to relative or absolute Mg deficiency of those prone to the development of osteoporosis. Low Mg intake, decreased Mg absorption, and hormonal changes that influence the distribution of magnesium and its effects on vitamin D metabolism are major factors in the elderly. In post-menopausal women, among whom are found most of the cases of osteoporosis, loss of oestrogen — which affects distribution of both Ca and Mg — is the predominant factor. The marginal Mg content of many Western diets can be contributory. Other conditions in which osteoporosis has developed, such as chronic alcoholism, disease- or therapy-induced Mg malabsorption or renal wasting, and poorly controlled diabetes mellitus increase Mg deficiency, the latter by increasing urinary Mg output and decreasing its tissue uptake. Since Mg deficiency causes changes in bone structure, the effect on Mg of agents used in prevention and treatment of osteoporosis should be considered. Oestrogen replacement delays onset and retards progression of postmenopausal osteoporosis, partly by antagonizing mobilization of both Ca and Mg by parathyroid hormone (PTH). The effect of oestrogen in lowering serum Mg by shifting Mg to soft tissues and bone could be implicated in the thromboembolic side effects of high doses of synthetic oestrogens. Since many of the steps in coagulation are Ca-dependent and are antagonized by Mg, might an increase in the serum Ca/Mg ratio in persons whose diets are low or marginal in Mg favour intravascular coagulation? Would adding Mg to oestrogen-Ca treatment of osteoporosis decrease that possibility?

Factors that increase magnesium inadequacy in those at risk of osteoporosis

Dietary magnesium deficiency
Mg intakes below the USA recommended daily allowance (RDA) of 300 mg/day are common^1-12. Yet such an intake is below the recommendable daily intake of 6 mg/kg.day^1,4,7-10. It has been customary to advise a dietary Ca/Mg ratio of 2/1, but with the frequently advised intake of 1200 mg/day of Ca or more for the elderly, the ratio may be at least 4/1. Excess of fat, sugar, phosphates, Ca, and vitamin D can each increase Mg requirements, and can lead to relative Mg deficiency^1,4-7. The elderly, who are prone to involutional osteoporosis, often have reduced food intake^13,14, impaired intestinal Mg absorption^15,16, and increased urinary Mg excretion¹⁷ — factors that increase the likelihood of Mg deficiency. Their hormonal changes can contribute to Mg loss¹⁴ (Fig. 1).

Magnesium deficiency and decreased bone magnesium in osteoporosis
Markedly increased retention of Mg after a parenteral Mg load — one of the most reliable tests for Mg deficiency ^9,18-20 has been found in postmenopausal patients with osteoporosis^21,22. A study of Mg levels in serum and bone biopsy specimens of 10 elderly women (68.9 ± 6 years) with osteoporosis, compared with serum Mg of age-matched women free of bone disease and with necropsy bone of women who had died suddenly, showed marginally low serum Mg in the controls (1.74 mEq/litre) and low Mg (1.64 mEq/ litre) in the osteoporotic women²³. The bone Mg of the osteoporotic women (1.54 ± 0.29 mg/g) was lower than that of sudden death victims (1.75 ± 0.25)²³.

There was Mg malabsorption in 12 of 20 postmenopausal osteoporotics¹⁵. Loss of trabecular bone (in which the bone crystals are abnormal^21,24) is associated with decreased trabecular bone Mg in postmenopausal and senile osteoporosis^15,21,22,24, in alcohol-associated osteoporosis²⁵, and in diabetics^21,26. The abnormalities were not seen in oestrogen-treated women²¹. Patients with non-alcoholic cirrhosis (without osteoporosis) had low Mg in bone cortex rather than in trabecular bone.²⁷

The acidity of bone extracellular fluid has been postulated to fall when Mg deficiency depresses the Mg-dependent ATPase H⁺-H⁺ pump in osteocytes.²⁸ It is suggested that, as a result of lowered pH of the bone extracellular fluid, octacalcium phosphate formation in bone falls, although resorption proceeds — a possible way in which long term Mg deficiency may lead to osteoporosis²⁸.

Conditions that increase magnesium needs, associated with osteoporosis
Magnesium malabsorption and renal wasting — Magnesium deficiency, manifested by low bone Mg and low bone Mg/Ca ratios, as well as by negative Mg balance, has been detected in patients with sprue, steatorrhea, inflammatory bowel disease, intestinal resections, and genetic isolated Mg malabsorption^29-36. Malabsorption was associated with slight generalized bone thinning in a 67-year-old man with malabsorption³², and with evidence of demineralization in a black 56-year-old woman³⁶. Vertebral osteoporosis was seen in a young man with Mg deficiency secondary to intestinal resection³⁰. Juvenile osteoporosis has been reported in Barrter's syndrome, a genetic renal Mg wasting condition³⁷. Mg malabsorption¹⁵ and renal Mg wasting³⁸ have been diagnosed in postmenopausal osteoporosis.

Alcoholism — Alcoholics' poor food intake, and their malabsorption, in addition to the increase of urinary Mg output caused by, alcohol, even when consumed in moderate amounts^39-41, can cause severe enough Mg deficiency to cause overt signs: Mg-responsive tremors, hallucinations, convulsions, and arrhythmias^41-43. Chronic Mg deficiency of alcoholism⁹ may contribute to development of osteoporosis²⁵.

Pregnancy — Pregnancy increases the need for both Mg and Ca, because of both fetal and maternal requirements^5,44; osteoporosis can he a risk among women who have had multiple pregnancies. In such women, repeated drains on Mg, as well as on Ca, may contribute to hyperparathyroidism of pregnancy (see below) which is so common as to be termed 'physiological'^5,45, and which mobilizes bone minerals,

Diabetes mellitus — Diabetes mellitus is a disease that is characterized by Mg depletion, caused by complex mechanisms⁹. The extent of the Mg loss in diabetics is related to the severity of the disease. Osteoporosis is not infrequent in insulin-dependent diabetics^21,46. Severe hypomagnesaemia has long been associated with decompensated diabetes⁴⁷. Less profound reductions in serum Mg have been demonstrated in juvenile diabetics^48,49. Contributory to the Mg deficiency of diabetes mellitus is glycosuria, which increases Mg output in the urine even in normal subjects given glucose loads^41-50. Insulin is important in cellular uptake of Mg^51,52; in its long term inadequacy or with refractoriness to its activity, diminished tissue Mg — including that of bone — is likely.

Interrelations between magnesium and calcium

High calcium intake with marginal or low magnesium intake

To compensate for the loss of Ca from osteoporotic bone, oral treatment with Ca and vitamin D as a calcaemic agent is common, without taking into consideration the effect of these agents on Mg requirements, or the importance of Mg in maintaining normal bone matrix⁵. High dietary Ca/Mg ratios interfere with Mg absorption, partially because Ca and Mg share a common intestinal absorption pathway^34,53,54. Vitamin D favours Ca over Mg absorption⁵⁵. Metabolic studies have shown interference by high dietary Ca with Mg retention of normal young women¹, and of patients with osteopathies (Fig. 2)^34,56,57. Moderately high Ca intake (1270 to 2360 mg/day) had little effect on the Mg balance of elderly men⁵⁸. Similarly, addition of 900 mg Ca/day to young men's diets containing 700 mg Ca had little effect on Mg balance⁵⁹. However, even though the Mg balance was not affected by up to 2 g/day of Ca in normal young men, their plasma Mg levels fell⁶⁰.

Effect of magnesium supplementation on hypocalcaemia

Persons subject to osteoporosis who have low Mg dietary intakes are prone to low serum levels of both cations. Raising Mg intake increases Ca absorption in normal young men on adequate Ca intake⁶¹. The restoration by parenteral or oral Mg treatment of responsiveness to vitamin D and parathyroid hormone (PTH) (see below) is important in Mg-deficient patients. It corrects hypocalcaemia as well as hypomagnesaemia^31,33,55.

Interrelation of magnesium with parathyroid hormone — Low Ca levels, despite adequate dietary Ca, may result from Mg deficiency, as well as from Ca deficiency. It has long been known that hypocalcaemia can be a manifestation of severe Mg deficiency in adults^{30-33,47,62,63}, as well as in infants^{30-33,47,62,63}, with convulsive hypocalcaemia responsive to Mg but not to Ca^5,64,65. Their refractoriness to calcaemic therapy is caused by impaired release of PTH and target organ (bone and kidneys) resistance to PTH^66-71. However, early or less severe Mg deficiency increases PTH secretion, which increases bone mineral mobilization not only of Ca but of Mg in vitro⁶⁸ and in vivo in humans^36,63,69. Studies of adults with hypocalcaemia secondary to Mg deficiency showed that most had both impaired PTH secretion and end organ resistance to PTH^69-71. Mg is required for activity of adenylate cyclase in parathyroid tissue⁷², in kidney⁷³, and in bone⁷⁴. That enzyme converts ATP to cyclic AMP (cAMP)⁷⁵, which is needed for PTH secretion⁶⁹. Defective cAMP generation may thus be responsible for both target organ resistance to PTH and for its impaired secretion in severe Mg deficiency^69-71.

Vitamin D interrelations with magnesium — Vitamin D deficiency impairs not only Ca absorption, but that of Mg^53,76,77. Formation of the active hormonal metabolites of vitamin D partially depends on enzymes that are Mg-dependent^78,79. Thus the Mg status affects the calcaemic response to vitamin D treatment of osteoporotic patients. Hypocalcaemic patients with Mg deficiency have not reresponded to the addition of vitamin D to Ca therapy in refractory hypoparathyroidism⁸⁰, in malabsorption or alcoholism⁸¹, or in refractory rickets^82-24 until Mg was provided. It is important to note that the provision of excess Ca or vitamin D and phosphate without correction of a Mg deficit can cause bone to be hypermineralized and brittle⁵. The effect of acute Mg deficiency on production of the active vitamin D metabolites is inconsistent, possibly due to the biphasic effect of Mg on the 1-α-hydroxylase activity^85,86. Both normal and low lelevels of the vitamin D metabolites have been found in Mg-deficient patients treated with vitamin D^87,88. Prolonged (up to 20 days) Mg administration, sufficient to raise the level of PTH (t(the trophic hormone for a-hydroxylation), has raised low levels of calcitriol and serum Ca⁸⁸.

The significance of interrelations between vitamin D and Mg as regards bone disease requires further study. An important effect of meeting the increased Mg requirement of baby pigs treated with high dosage vitamin D was that of significantly increasing bone elasticity, which resulted in some increased resistance to breakage⁷⁶ (Fig. 3).

Interrelations of oestrogen with PTH, vitamin D, and magnesium

Oestrogen treatment; antagonism of PTH

Prolonged replacement oestrogen therapy, preferably with low dose conjugated oestrogens (Premarin), alternating with a progestin, is useful in prophylactic and therapeutic treatment of postmenopausal osteoporosis — whether associated with spontaneous or iatrogenic cessation of oestrogen secretion^89-98. Inferential evidence that hyperparathyroidism is a factor in postmenopausal osteoporosis is its increased frequency at and after the menopause^99,100, and its greater severity in hyper- than in hypoparathyroid women¹⁰¹. Oestrogen antagonizes PTH-induced bone resorption in vitro^102,103, and bone of ovariectomized rats is more sensitive to PTH — as measured by Ca and hydroxyproline content and decreased bone thickness¹⁰⁴. Loss of oestrogen at menopause causes negative Ca balance, and greater bone responsiveness to the Ca-mobilizing effect of PTH, and decreased formation of calcitriol¹⁰⁵. These findings, and the evidence that oestrogen inhibits the bone-resorbing effect of PTH^101,106, support the clinical use of oestrogen in osteoporosis. It is possible that the loss of the protective effect of oestrogen on bone — mediated both by its effects on PTH release and PTH-induced demineralization — is the cause of postmenopausal osteoporosis. Both of these effects may be influenced by the effects of oestrogen on Mg^5,107.

Oestrogen effect on vitamin D metabolism — role of

The evidence, from metabolic balance studies, that young women retain Mg better on marginal Mg intakes than do young men has suggested that the effect of oestrogen on Mg might contribute to their greater resistance to arterial and cardiac disease^1,4,5,107. There are some data indicating shift of blood Mg to tissues under the influence of oestrogen: soft tissue^108,113 and bone^114-116 (Table 1). Circulating Mg levels are higher in young men than in young women, particularly when oestrogen levels are highest, such as during ovulation or during oral contraceptive use^115-128, and when pregnant (see below). Oestrogen-induced lowering of serum Mg is not associated with increased urinary Mg output or decreased Mg absorption, which supports the premise that oestrogen shifts Mg to tissues. After the menopause, women lose more Mg in their urine than do young women, whether or not they are taking oral contraceptives^126-128(Fig. 4). Oestrogen/progestogen treatment can reduce Mg loss and may thereby be beneficial in postmenopausal osteoporosis^127-129.

Even when corrected for haemodilution, serum Mg is lower in pregnant than in non-pregnant women^5,130-132. During pregnancy, meeting fetal Mg needs is the major factor in predisposing to maternal Mg deficiency, but the high oestrogen levels probably contribute to the fall in serum Mg early in pregnancy. Magnesium deficiency has been implicated in the pathogenesis of pre-eclampsia^5,44,134-138, in part through increased blood coagulation^135-138.

Oestrogen effect on vitamin D metabolism — role of magnesium

Low calcitriol levels, and low activity of enzymes involved in its formation, are associated with old age and with involutional osteoporosis^139-144, but the response of the disease to its administration is inconsistent¹⁴³. The need for more parathyroid stimulation for normal vitamin D metabolism by women with osteoporosis, and the lesser response of the elderly to calcitriol¹⁴⁴, has been correlated with possible Mg deficiency¹⁴⁵. The level of calcitriol has been raised during physiologically increased oestrogen, for example during pregnancy¹⁴⁶, and during use of oestrogen¹⁴⁷. It has been suggested that impaired activation of 1-α-hydroxylase might be responsible for the oestrogen deficiency-induced decreased formation of the active vitamin D metabolite¹⁴⁸. On the grounds that low levels of the active form of vitamin D were found in Mg deficiency⁸⁷, and that oestrogen increases Mg retention (see above), it is suggested that the increase in calcitriol formation caused by oestrogen might mediated by increased tissue Mg.

Worth exploring is the relationship to osteoporosis of the lower serum Mg and decreased urinary Mg loss by women on oestrogen therapy in comparison with those not so treated. Does this reflect a shift to bone, as in rats^113-116? Does increased urinary Mg of postmenopausal women reflect their inability to retain Mg? It has been noted that low trabecular bone Mg, and abnormal bone crystals, seen in pelvic crest biopsies of osteoporotic patients are not present in post-menopausal women receiving oestrogen²¹.

Magnesium deficiency-associated thromboses; mechanisms

Magnesium/calcium in blood coagulation
That Ca activates blood clotting, and that Mg antagonizes this effect, has been known since 1944; it was assumed to result from competitive inhibition by Mg of Ca-dependent conversion of prothrombin to thrombin¹⁴⁹. Since then, the need for Ca by many steps leading to fibrin formation and polymerization in clot formation^150,151 has been further defined. Review of published evidence on counteraction by Mg of Ca-stimulated steps in coagulation focused on the effect of Mg on prothrombin and Factors V, VII, and IX, as well as on its enhancement of fibrinolysis¹⁵² (Table 2). Mg stabilizes fibrinogen and decreases fibrin formation; it also increases fibrinolysis¹⁵⁹. Mg also slows thrombin generation, both in vitro and in vivo^152,153.

Platelet aggregation requires both Mg and Ca, but is largely Ca-dependent. In vitro studies have yielded conflicting results as to the effect of Mg on platelet structure and function; at low, but not at higher than physiological concentrations, the Ca/Mg ratio is an important determinant154,155. When Ca was missing or low in concentration, Mg inhibited aggregation^151,155-161. Addition of Mg to blood samples has reduced ADP-induced platelet clumping. It has been suggested that Ca is required for aggregation and Mg is required to maintain the shape of platelets and for deaggregation. Serotonin, the release of which from aggregating platelets is dependent on Ca and inhibited by Mg^162-164, accelerates divalent cation-induced platelet clumping¹⁶⁵. Mg is released from platelet granules¹⁶⁵; it inhibits both further platelet release reactions¹⁵⁴ and steps in blood coagulation (Table 2) by competitive inhibition of Ca. Mg deficiency increases serotonin release from platelets^166,167. Serotonin-induced vascular muscle contraction is also inhibited by Mg^168,169.

Experimental magnesium deficiency

Partial thromboplastin and thrombin clotting times were significantly shortened in Mg-deficient calves, but their prothrombin time, their platelet counts, and platelet aggregation were unaffected¹⁷⁰. Hypercoagulability of blood of Mg-deficient rats, produced by feeding diets rich in saturated fat to animals (see below), decreased coagulation time and increased prothrombin consumption and could be prevented by adding Mg to the diet^171,172.

Prostacyclin and thromboxane — There is some evidence that Mg deficiency inhibits synthesis of prostacyclin (a vasodilating, anti-platelet-aggregating, anti-hypertensive prostaglandin^173-176), and increases release of thromboxane A2 and B2 (TXB2), which are vasoconstrictive, pro-aggregating prostaglandins^175-176 from platelet aggregates. It has been hypothesized that the accelerated platelet clumping produced by platelet-active collagen (as a model of the bared subendothelial collagen of damaged vascular intima) in Mg-deficient lambs was mediated by diminished production of prostacyclin¹⁷⁷.

The release of increased amounts of arachidonic acid, the precursor of prostanoids, from thymocytes of Mg-deficient rats¹⁷⁸ led to study of the effect of Mg deficiency on these derivatives of phospholipid metabolism in blood¹⁷⁹. Prostacyclin, as measured by its stable metabolite 6-keto-PGFa1, was increased two-fold; PgE2 was increased threefold, but TXB2 was increased more than 10-fold. These increases were attributed to increased Ca levels in Mg-deficient rats, since the enzyme responsible for liberation of arachidonic acid is Ca-activated phospholipase A2¹⁸⁰. The depression of cyclic AMP seen in Mg deficiency may also participate directly in the markedly increased TXB2 synthesis of Mg deficiency, since cyclic AMP inhibits TXB2 production by platelets¹⁸¹. Fatty acid metabolism is altered in Mg deficiency^182-188, with arachidonic acid production diminished as a result of slowed conversion of linoleic acid to arachidonic acid^188,189, a finding pertinent to the role of prostanoids in blood coagulation.

Dietary Mg depletion of humans has recently been shown to increase platelet aggregation and TXB2 release, effects that were reversed by Mg infusion¹⁸⁹. A nine-fold increase in serum TXB2 was seen in a marathon runner immediately after racing, when his serum Mg was lowest (1.07 mEq/litre), as compared with the pre-race value¹⁹⁰.

Interrelations of fat intake, hyperlipaemia and coagulability — High fat intakes, in experimental Mg deficiency, increases Mg requirements, as expressed by the anti-coagulative and cardiovasculo-protective effects of adding Mg to thrombogenic, hyperlipidaemic, or infarctoid diets^{3,5,6,171,172,191-207}. Experimental Mg deficiency has long been known to affect serum lipoproteins^191-199. Mechanisms involved in Mg/lipid interrelations, as they affect coagulation and vascular disease, are being elucidated^182-187. Mg deficiency of weanling rats has caused hypertriglyceridaemia with increases in very low density lipoproteins (VLDL), and low density lipoprotein (LDL) fractions, with increased cholesterol in those fractions, but decreased cholesterol in the high density lipoproteins (HDL)^{182,l84-l87,202-204} (Fig. 5). Defective triglyceride removal from the blood in Mg-deficient rats¹⁸³ is associated with reduction of plasma lecithin cholesteryl acyl-transferase (Fig. 6), and of lipoprotein1ipase^203-206.

Magnesium deficiency-associated thromboses; clinical aspects and treatment

Marginal clinical magnesium deficiency

Patients with latent tetany of marginal Mg deficiency have developed thromboses and emboli; new events were prevented by Mg supplements, and recurred when supplements were discontinued^122,207-211.

Postoperative; magnesium anaesthetics

An early study showed that blood taken from surgical patients, who had been anaesthetized with an Mg-containing preparation, clotted but then liquefied completely within 2 hours; blood of such patients at autopsy 12 hours after death was liquid^212,213. Because there were no cases of phlebothrombosis or emboli among 120 survivors of major surgery so anaesthetized, the investigator undertook clinical trials of the presumed thrombolytic effect of Mg. Patients with deep vein phlebothrombosis responded to parenteral Mg therapy; oral Mg therapy was prescribed prophylactically, with resultant decreased platelet aggregation and inconsistent thrombolysis. In a confirmatory study of the improved recovery of patients with thrombophlebitis or phlebothrombosis, treated with intramuscular or oral Mg (providing 80 mg/ampoule and 50 mg/tablet), blood coagulation indices (clot formation, prothrombin times, antithrombin) were unaffected, but fibrinolysis increased substantially²¹⁴.

Pregnancy-associated thrombotic disease
Pregnancy and puerperium — Pulmonary embolism is a major cause of death during pregnancy and the puerperium²¹⁵, which suggests that the naturally high oestrogen secretion at that time increases intravascular coagulation. Comparison of incidence of postpartum phlebothrombosis treated with parenteral Mg, followed by oral Mg (200 mg three times/day for 3-10 days postpartum), provided after delivery, was compared with the phlebitic events during a prior year in which that regimen was not followed. Those treated with Mg exhibited substantial reduction in postpartum thrombosis, after spontaneous or operative delivery (Table 5)²¹⁶.

Pre-eclampsia and eclampsia — Hypercoagulability of blood has been associated with pre-eclampsia and eclampsia, and with associated placental abnormalities^{5,134-138,217-219}. Abnormalities that increase the risk of thrombosis in eclampsia include decreased plasminogen activation and decreased fibrinolysis, with resultant decreased thrombolytic potential. Also found were lowered platelet counts — which suggests their consumption as a result of intravascular coagulation²¹⁸. (See above for interaction with prostanoids.)

Parenteral magnesium treatment of eclampsia; anticoagulant effect — Hypomagnesaemia, which is characteristic of pre-eclampsia and eclampsia before renal failure, is associated with comparable increases in coagulation (see above). Administration of pharmacological amounts of Mg is the time-honoured means of treatment of eclamptic convulsions and hypertension^5,220,221. It is used as a drug, but much of it is retained^134,220 — suggesting repair of underlying Mg deficiency. That the effect of Mg in eclampsia may also entail its antithrombotic effect was postulated on the basis of the rapid reduction of markedly increased platelet adhesiveness after intramuscular Mg in eclamptic women, and the combination of many factors that predispose to Mg deficiency in pregnancy^135-138. When Mg deficiency produced eclampsia with glomerular microthrombi and decreased lowered platelet counts in pregnant ewes, the theory was extended to encompass the lowered prostacyclin/TXB2 ratio seen both with pregnancy and Mg deficiency^137,138 (Fig. 7).

A decreased prostacyclin/TXB2 ratio has been implicated in the pathogenesis of toxaemias of pregnancy²²². The relationship of the Mg deficiency of eclampsia to this change in prostanoids was suggested soon thereafter^138,223,224. The inhibitory effect of Mg on both platelet aggregation and hypertension in toxaemias of pregnancy has been attributed to its stimulation of prostacyclin production²²³. That the anti-hypertensive effect of Mg might be mediated by prostacyclin was suggested by the increase in prostacyclin production induced by Mg infusion of normal subjects²²⁵.

Migraine, oestrogen and prostacyclin/TBX2 — Of particular interest as regards interrelations of oestrogen with Mg is the strong association of migraine with eclampsia1^136,226,227; eclampsia was 220 times more prevalent in pre-eclamptics with histories of migraine than in those without. Migraine was found 2.5 times as often in patients with pre-eclampsia before the 34th week of pregnancy as it was in those with normal pregnancy²²⁸. Favourable results have been reported in 80% of 3000 women given 200 mg/day of Mg for the prophylaxis of eclampsia and migraine when they were taking oral contraceptives or were pregnant^136,226.

Support for the premise that Mg deficiency is involved in the pathogenesis of migraine derives from its higher incidence among those prone to hypomagnesaemia, and relates it with association of the effect of Mg on prostanoids and thrombogenesis^136,226,229 (Fig.7). Several specific interrelationships of vascular factors that seem to be involved in migraine²³⁰ that pertain to Mg deserve mention. Prostaglandin metabolism has been correlated with migraine (see above for Mg and prostanoids). Increased serotonin release from platelets²³¹, which occurs in migraine²³² may contribute to cerebral vasospasm; it is enhanced by Ca and inhibited by Mg^162-165. Ca channel blockers are effective in prophylaxis of migraine²³³; Mg has been proposed as a physiological Ca channel blocker²³⁴, on which basis Mg treatment was proposed for migraine²³⁵.

Myocardial infarction, coronary artery disease; cerebral Thrombosis
Blood coagulation, fat intake, hyperlipaemia, and magnesium requirements — Increased platelet adhesiveness has long been recognized in ischaemic heart disease²³⁶, and is known to be intensified by hyperlipaemia due to high intake of saturated fatty acids^237-240 and that found in clinical arteriothrombotic disease²⁴¹.

Magnesium treatment in ischaemic heart disease; effects on lipoproteins — Reported as long ago as the adverse effects of saturated fats on blood coagulation in patients with ischaemic heart disease was the favourable response to (uncontrolled) Mg treatment of several hundred patients with ischaemic heart disease (IHD), with and without recent myocardial infarction^242,243. Their reduction in angina, in association with lowered serum β-lipoproteins, persisted as long as the Mg treatment was maintained, but rose when it was discontinued. Clinical confirmation was provided in another series of patients, who experienced clinical improvement on similar treatment with MgSO₄ (2 ml 50%,, intramuscularly every 5 d for 12 injections): marked reduction β-lipoproteins occurred, with no change in α-lipoproteins^244,245(Table 6).

Effects on coagulation and fibrinolysis of magnesium treatment of ischaemic heart disease — In the foregoing uncontrolled study of the anti-anginal efficacy AMg, and the lowering of β-lipoproteins of patients with ischaemic heart disease by intramuscular Mg, it was found that Mg markedly reduced the increased plasmin inhibition, and functioned synergistically with heparin in management of patients who had suffered recent myocardial infarction^244,245. In another study, platelet adhesiveness was studied in 25 patients within 48 h of myocardial infarction and was found to be markedly increased; their mean serum Mg on the third day was marginally low (1.7 mEq/litre), versus a control nor mal mean of 2.36 (Table 7)²⁴⁵. There is increasing clinical evidence that Mg deficiency predisposes to clinical cardiovascular disease, including myocardial infarction^5,20,247-254 and that Mg treatment improves the post-infarction course by reducing risk of arrhythmias^{5,234,249,250-252,255-263}.

Increasing serum Mg only to 2.1 mEq before partial occlusion (by suture) of coronary arteries of animals markedly diminished platelet aggregation at the site of injury and distal to it²⁶⁴. This suggests that Mg treatment in ischaemic heart disease might protect against thrombosis formation on atherosclerotic arteries and microthrombi associated with arteriospasms²⁶⁴. The anti-arrhythmic effect of Mg is implicated in the improved survival of post-myocardial infarction patients treated with Mg infusions; its anti thrombotic effect may also participate.

Cardiovascular protection by oestrogen
The lower cardiovascular disease death rate in pre menopausal women than in men suggests that oestrogen has a protective effect. It is proposed that this effect might be mediated by the improvement in Mg retention caused by oestrogen^1,3,5,107. Experimental animals treated with oestrogen^265,266, and pregnant animals with high oestrogen levels, have increased resistance to induced arterial and cardiac damage^267-269. Epidemiological studies showing either no effect on²⁷⁰ or lowered coronary disease risk of elderly women receiving replacement low dosage oestrogens^271-275 support the premise that oestrogen is protective against cardiovascular lesions.

Thrombophlebitis on high dose synthetic oestrogens — However, high levels of oestrogen have been reported to have been associated with intravascular coagulation⁵. Men treated with oestrogens for prostatic carcinoma had more thrombosis-associated cardiac disease than those not so treated²⁷⁶, although the degree of atherosclerosis seems not to have been affected²⁷⁷. The venous thrombophlebitic events in women on high dosage oestrogen-containing oral contraceptives^278-280 (Fig. 8), and in women given oestrogens to inhibit lactation^281,282, led to study of the increased coagulation caused by oestrogens. The synthetic oestrogens, especially in high doses, but not the conjugated oestrogens (in lower doses), shorten prothrombin time²⁸³, increase prothrombin consumption²⁸⁴, and increase platelet adhesiveness^284,285. In low doses they exert little or no effect²⁸⁶. Premarin showed no significant increase of clotting tendency in women given 1.25 mg/d for a month²⁸⁷. An epidemiological study has shown no increased risk of stroke in postmenopausal women on low dose replacement oestrogen²⁸⁸.

High dose oestrogen-induced thrombophlebitis; due to lower ed serum magnesium? — It has been hypothesized that high dose oestrogens increase the risk of thromboembolism and phlebothrombosis as a result of oestrogen induced shift of circulating Mg to tissues, lowering serum Mg levels^115,289. The recent report that oral contraceptive users who smoke have increased plate let aggregation and decreased prostacyclin levels²⁹⁰, and the interrelationships of Mg with prostacyclins (see above), provide more insight into additional mechanisms by which oestrogen may affect blood coagulation through its effects on Mg. It has been advised that during any long term oestrogen therapy the Mg status should be monitored and deficits corrected to reduce the risk of phlebothrombosis^9,122,211.

Conclusions

This correlation of multiple interrelations among the factors that increase the likelihood of development of osteoporosis, and among the treatments of that disease (that currently emphasize administration of oestrogen and Ca), calls attention to the mechanisms by which such combination therapy may increase Mg requirements. Patients who take enough Ca supplements to exceed the commonly recommended Ca/Mg ratio of 2/I, especially in those with the marginal Mg dietary intake that is common in the developed world, may develop relative or absolute Mg deficiency, with suboptimal serum Mg levels. Combined Ca and oestrogen treatment of such patients might lower serum Mg, thereby increasing the risk of intravascular coagulation. Postmenopausal women who are treated with low dose replacement oestrogen to prevent or slow osteoporosis are not considered to be at risk of thromboembolic events such as have been associated with use of high dosage synthetic oestrogens. Ca activates many steps in blood coagulation; Ca supple mentation, in conjunction with oestrogen, might con tribute to an increased possibility of intravascular blood clotting. Mg counteracts some of the Ca- activated steps in blood coagulation, and even has some fibrinolytic activity. Furthermore, it has been shown to participate in activities that may function to correct the lipid and prostanoid abnormalities associated with Mg deficiency and that increase the risk of thrombosis. Thus Mg supplementation is suggested to reduce the risk of intravascular coagulation, and possibly to improve the anti-osteoporotic therapeutic effect.

References

1 Seelig, M.S. (1964): The requirement of magnesium by the normal adult. Summary and analysis of published data. Am. J. Clin. Nutr. 14, 342-390.

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