Refer to: Jacobs MD: Vitamin D deficient states-Pathophysiology and treatment-Medical Staff Conference, University of California, San Francisco. West J Med 131:305-312, Oct 1979

Vitamin

D

Medical Staf Conference

Deficient States

Pathophysiology and Treatment These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Professor of Medicine, and James L. Naughton, Assistant Professor of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.

DR. SMITH: * At Moffitt Hospital, it has been traditional at the end of the academic year for us to ask the Chief Medical Residents to present Medical Grand Rounds. This permits us to express publicly our deep appreciation for the remarkable leadership they have brought to our patient care and learning programs. Dr. Mark D. Jacobs will discuss the topic of vitamin D deficient states. DR. JACOBS:t Over the last decade, there have been exciting advances in our understanding of vitamin D metabolism. Rather than a vitamin, which functions as a coenzyme biochemically, vitamin D is a steroid hormone, more accurately a prohormone, which undergoes a series of enzymatic activation steps before influencing mineral homeostasis. Each step is subject to important controls and may be impaired by one or more disease processes. Pathologic processes involving such varied organ systems as the liver, kidneys, parathyroids, gastrointestinal tract, adrenals and ovaries may have profound effects on calcium and bone through abormalities in vitamin D metabolism. As medical advances have per*Lloyd H. Smith, Jr., MD, Professor and Chairman, Department of Medicine. -,Mark D. Jacobs, MD, Chief Medical Resident at the time of this Grand Rounds. He is now on the faculty of the medical school at Brown University, Providence, Rhode Island.

mitted longer survival in patients with serious illnesses involving these organs, the importance of diagnosis and treatment of associated bone disease increases. This paper will review the pathophysiology of defects in vitamin D metabolism, viewed as vitamin D deficient states, and outline our current understanding of their treatment. The primary functions of vitamin D are (1) maintenance of normal serum calcium and phosphorus, (2) bone and epiphyseal mineralization and (3) prevention of myopathy. In order to carry out these functions, vitamin D acts upon intestine, kidney and bone, and cooperates with parathyroid hormone in a complex regulatory system' (Figure 1). Humans have two main sources of vitamin D2 (Figure 2); the most important is the skin, where 7-dehydrocholesterol undergoes photolysis, upon exposure to the ultraviolet component of sunlight, to form cholecalciferol (D,). In normal persons, adequate sunlight and sufficient dietary calcium and phosphorus will prevent the development of rickets or osteomalacia. This bone disease is the hallmark of the vitamin D deficient state, and is characterized by an increase in the volume of unmineralized osteoid, resulting in pain, weakness, deformity and fracture.4 This type of deficiency disease was prevalent during the Industrial RevoTHE WESTERN JOURNAL OF MEDICINE

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VITAMIN D DEFICIENT STATES

lution, when air pollution and indoor confinement severely restricted exposure to sunlight.3 Today, we can be independent of the sun for vitamin D because of adequate dietary sources. As little as 400 IU per day in growing children, and 100 IU per day in adults, will prevent deficiency. Although D3 is naturally found in butter, eggs and cod liver oil, our most reliable sources are foods such as bread and milk (400 IU per quart) which are fortified with D, (ergocalciferol). This compound is easily manufactured by the ultraviolet irradiation of ergosterol from yeast and fungi. D2 and D, are essentially of equal potency,2 and from this point the terms are used interchangeably. Dietary vitamin D mixes with micelles and is absorbed in the proximal small bowel. Bound to a specific transport globulin, it reaches the liver where calciferol-25-hydroxylase converts it to 25-

Kidney Figure 1.-Sites of vitamin D action (reproduced with permission from DeLuca H and Arch Intern Med1).

hydroxy vitamin D (25-OH-D3, calcifediol). This reaction is loosely controlled but seems to be inhibited in states of excess vitamin D stores. 25OH-D3 is the major form in the circulation and a large percentage undergoes enterohepatic cycling. The level of 25-OH-D3 is mainly a function of intake (sunlight and diet) balanced against loss (degradation, enterohepatic losses, proteinuria) and therefore its determination is important in making the diagnosis of deficiency or intoxication.2

25-OH-D3 can be further hydroxylated in the 1,24, or 26 positions. The 1a-hydroxylase enzyme resides exclusively in the renal tubules and is the most important control step in mineral homeostasis. Production of 1,25-(OH)2D3 from 25-OHD, is tightly controlled by parathyroid hormone (PTH), phosphate and its own levels. 1,25-(OH)2 D3 is the most potent vitamin D metabolite which raises serum calcium and is the only naturally occurring form that, in physiologic amounts, can maintain normal serum calcium despite nephrectomy or parathyroidectomy. In fulfilling the modern concept of hormonal regulatory systems, 1,25-(OH),2D3 is synthesized exclusively in the kidney, affects target sites in the intestine, bone and kidney, and is under tight regulatory feedback inhibition5 (Figure 3). Hypocalcemia causes the parathyroid glands to secrete parathyroid hormone, which stimulates the 1-hydroxylase to synthesize 1,25-(OH) 2D3 and which suppresses the alternate 24-hydroxylase

DIETARY D3

Uv

S SKIN

PORTAL CIRCULATION

-, BLOOD

-

"

HO

7-DEHYDROCHOLESTEROL

CHOLECALCIFEROL (D3)

Figure 2.-Sources of vitamin D and its hepatic conversion to 25-OH-D3 (reproduced with permission from Favus M and Med Clin North Amer2).

306

OCTOBER 1979 * 131

KIDNEY

2IDNEY' -2S E 2-OR O

STORAGE

* 4

ENTEROHEPATIC CULAT1N

INTESTINE

VITAMIN D DEFICIENT STATES

pathway. 1,25-(OH)2D3 increases intestinal calcium absorption, and, in concert with PTH, enhances calcium reclamation in the kidney and mobilization of calcium from bone. Extra phosphate that is mobilized is excreted through the inhibitory effect of PTH on tubular phosphate reabsorption. As serum calcium normalizes, PTH falls and 24hydroxylation of 25-OH-D3 is stimulated. Hypophosphatemia directly stimulates the synthesis of 1,25-(OH)2D3, which increases intestinal phosphate absorption and, in the absence of PTH, enhances renal phosphate reabsorption.2 INCREASED Pi REQUIREMENT

INCREASED Co REQUIREMENT

SERUM Pi

SERUM Co

PARATHYROID GLANDS

t PTH

-?

_ 1,25-(OH)2 D3-- PHYSIOLOGIC

25-OH-D3F

FUNCTION

t

INTESTINE BONE

+r-

24, 25-(OH)2D3

Figure 3.-Regulatory pathway of vitamin D metabolism-maintenance of normal serum calcium and phosphate by feedback control (reproduced with permission from Favus M and Med Clin North Amer2).

r

Steroid Mode of Actiod Structurally 1,25-(OH)2D3 resembles other steroid hormones with its complex ring structure separating key hydroxyl groups. In the intestine, 1,25-(OH)2D3 enters the intestinal cell and binds to a specific cytosol receptor. This hormonereceptor complex migrates to the nucleus where it interacts with nuclear chromatin, activates the expression of a section of deoxyribonucleic acid (DNA) and directs the synthesis of a new calcium binding protein which is believed to participate in the intestinal uptake of calcium.2 Consequences of vitamin D deficiency are (1) osteomalacia due to inadequate concentration of calcium and phosphate at mineralization sites and lack of some direct but as yet undefined effect of vitamin D on bone, (2) hypocalcemia and negative calcium balance secondary to intestinal mal-

absorption, (3) secondary hyperparathyroidism with hypophosphatemia, (4) proximal muscle weakness which may be secondary to elevated PTH, hypophosphatemia or lack of direct effect of vitamin D. Clinically, osteomalacia4 is characterized by bone pain, particularly of the spine, ribs, pelvis and upper femurs, which is made worse by effort and direct pressure. Patients may limp or waddle as a result of weakness and

Normal (10. 1). (23)t (6. O)tt

Serum Ca Serumn PTH

Serumii Pi Seru m 25-OH-D3 (34)t "p

I

Progressive Depletion 25-OH-D3

Serum Ca (7.4) A Serum PTH (115) YSerumPi (2.5)

DldHydroxylase

Stagem 25-OH-D3 ( 8. 0) (severe rickets)

VI. 25-(OH) D32

Stage.' 25-OH-D3 (16.0)

(moderate rickets)

r

Aserum ca

(9.

YSerum PTH (65 ySerum Pi (2. .7)

Yserumca (8.5)

Stage I

(19.0) 25-OH-D3 Aserum PTH (89) (mild X Serum Pi (5.5) rickets)

IMHydroxylase

* t tt

"'-1, 25-(OH)2 D3

t

mg/dl Al eq/ml (GP IM)

mg/dl ng/ml

Figure 4.-Stages of vitamin D deficiency-laboratory and bone findings (reproduced with permission from Arnaud S and publisher7). THE WESTERN JOURNAL OF MEDICINE

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VITAMIN D DEFICIENT STATES

pain. Long-standing deficiency causes such bone undermineralization and softening that skeletal deformities result. Associated laboratory findings depend on the stage of disease7 (Figure 4): In stage I, there are slightly low levels of 25-OH-D3, low serum calcium, low normal serum phosphorus, elevated PTH (mild rickets). In stage II the 25-OH-D3 levels are moderately low, and PTH returns serum calcium to normal through stimulation of 1,25-(OH) 2D3 formation, but increases renal phosphate excretion. As serum calcium levels return to normal, PTH falls (moderate rickets). In stage III there are very low 25-OH-D, levels and low 1,25-(OH)2D3 levels, intestinal calcium malabsorption and bone resistance to PTH, hypocalcemia, hypophosphatemia and high PTH (severe rickets). Elevation of bone alkaline phosphatase and low urinary calcium may also be found. Roentgenographic findings are primarily those of osteopenia, which is nonspecific and attributable to loss of bone mineral content. However, at least 30 percent of bone must be lost before osteopenia is apparent by the usual radiographic techniques. Osteomalacia may cause an indistinct, coarse appearance of bone trabeculae, but the radiographic hallmarks are Looser zones (pseudofractures) which are radiolucent bands found at the periosteal surface of ribs, pubic rami, scapulae and proximal ends of long bones. These represent stress fractures which heal poorly due to the mineralization defect; they may light up on bone scan and be mistaken for metastatic lesions. Subperiosteal resorption due to secondary hyperparathyroidism may also be present. Although there are more sensitive means of detecting bone loss, such as photon absorption densitometry, bone biopsy remains the most sensitive and specific means of diagnosing osteomalacia. After tetracycline labeling, histologically one sees an increase in osteoid volume with a decrease in the percentage of osteoid surface showing tetracycline fluorescence (the active mineralization front). Findings can be confirmed by the demonstration of low 25-OH-D3 levels.4

Gastrointestinal Disease The most common causes of simple vitamin D deficiency in the United States today are gastrointestinal disease. These have in common either primary malabsorption of dietary vitamin D or interruption of the enterohepatic circulation of 25-OH-D3 with increased gastrointestinal 308

OCTOBER 1979 * 131

* 4

losses.4 The prevalence of osteomalacia in gastrointestinal disease is often not appreciated and therefore is underdiagnosed. After a mean of seven years following subtotal gastrectomy, there is a 25 percent incidence of bone disease which is often asymptomatic and suggested only by the finding of an elevated bone alkaline phosphatase. Although 25-OH-D3 levels are low, the relative contributions of malabsorption and decreased dietary intake remain to be determined.9"°0 Malabsorption states8'1' interfere with bile salt, micelle-mediated absorption and enterohepatic recycling of the fat soluble forms of vitamin D. Diseases such as gluten-sensitive enteropathy,12 regional enteritis,'3 ileojejunal bypass'4 or pancreatic insufficiency have a high incidence of subclinical osteomalacia and low 25-OH-D3 levels. Hepatic diseases such as Laennec cirrhosis or primary biliary cirrhosis cause vitamin D malabsorption secondary to bile salt deficiency, although hepatic parenchymal levels of 25-hydroxylase have not been determined. Therapy with 5,000 to 10,000 IU per day of ergocalciferol (D2) given orally is generally sufficient, but occasionally parenteral therapy is required.8 Peak increase in 25-OH-D3 levels may take one to three weeks, and levels should be monitored. Calcifediol (25-OH-D3) may be available soon, and has the advantages of rapid onset and shorter half-life. Increased excretion of 25-OH-D3 may occur through the gastrointestinal tract due to binding of bile salts by cholestyramine therapy.18 The nephrotic syndrome is associated with hypocalcemia, impaired intestinal calcium absorption, secondary hyperparathyroidism and low 25-OHD. levels, due to losses of vitamin D binding globulin in urine.19 Anticonvulsant therapy,20 particularly with diphenylhydantoin and phenobarbital, has been associated with hypocalcemia and osteomalacia. Plasma 25-OH-D3 levels are low,21 presumably secondary to increased degradation by hepatic microsomal enzymes induced by these drugs. Lack of exposure to sunlight by patients in hospitals or other institutions may also contribute. However, 1,25-(OH),DD3 levels are normal.2 This finding suggests the importance of other 25-OHD, derivatives in the maintenance of normal bone. A direct effect of these drugs on bone also cannot be excluded. Fortunately, 2,000 to 4,000 IU per day of D, given orally is effective therapy; the role of prophylaxis needs further study.

VITAMIN D DEFICIENT STATES TABLE 1.-Comparison of Vitamin D Preparations in Hypoparathyroid States*

I2

25-OH-D3

Daily dose in hypoparathyroidism (ug) ........ 750-3,000 50-200 Relative potency ........ 1 15 Time to restore normocalcemia (weeks) ...... 4-8 24 Time to reach maximum effect (weeks) ......... ?4-10 ?5-20 Persistence after cessation (weeks) .............. 6-18 4-12

EARLY RENAL FAILURE

1,25-

V

(0H)2D3

0.5-2.0 1,500

-

t[Po4]4

LOSS OF NEPHRONS

(-)

\

b

.

(+

(4) 1,25-(O1H)2D3

NL

( + ) Intestinal I \Calcium

NL

-

%-I \

½-I

-I

Absorption

h-1

D2 = ergocalciferol 25-OH-D3 = calcifediol 1,25-(OH) 2D3 = calcitriol

KIDNEY---r------(+) ;[Ca++]

NL

*Reproduced with permission from Frame B.4

The Cushing syndrome is an important cause of osteopenia,22 with notable loss of trabecular bone resulting in characteristic vertebral compression and rib fractures. Patients at greatest risk for corticosteroid-induced osteopenia include children, the elderly (especially women) and patients with immobilizing rheumatic disorders.24 Corticosteroids appear to decrease bone formation by a direct suppression of osteoblastic bone collagen synthesis; they increase bone resorption indirectly, through secondary hyperparathyroidism, by causing a dose-related malabsorption of intestinal calcium. Alternate day administration of prednisone or daily doses of less than 10 mg have no significant effect on calcium absorption. However, daily doses in excess of 15 mg result in a proportionate decrease in 25-OH-D3 levels and calcium malabsorption.25 Furthermore, in rats it has been shown that high dose corticosteroids decrease 1, 25-(OH)2D3 levels, although these measurements have not been made in humans. High doses of D2 and 25-OH-D3, but physiologic doses of 1,25(OH) 2D3 will correct the disturbance, suggesting 1-a-hydroxylase suppression in humans.24 The role of vitamin D therapy in patients receiving high doses of corticosteroids has not yet been established in large clinical studies.

Hypoparathyroidism The syndrome of hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, neuromuscular irritability and tetany. The two major categories, hypoparathyroid (hormonopenic) and pseudohypoparathyroid (hormonoplethoric),25 have in common malfunction of the calcium sensing arm of the homeostatic mechanism and reduction of 1,25-(OH)2D3 synthesis.2 Past attempts at correction of hypocalcemia with

BONE Resorption

a

PTIH r

I

iOSTEITIS FIBROSAI

_I

_______ Figure 5.-Pathophysiology of osteodystrophy in early renal failure (glomerular filtration rate greater than 30 ml per minute): Solid lines (-) are direct consequences of nephron loss; dotted lines (---) are compensatory pathways. NL=normal levels.

pharmacologic doses of ergocalciferol (D2) or dihydrotachysterol have been unsatisfactory and fraught with the hazard of prolonged toxicity26 (Table 1). However, physiologic doses of 1,25(OH) 2D3 (calcitriol) or la-OH-D2 have successfully increased intestinal calcium absorption and returned serum-ionized calcium to normal levels.27-29 In the more common hormonopenic state, 1,25-(OH) 2D3 deficiency is proportional to the degree of PTH deficiency and hyperphosphatemia, so vigorous efforts should be made to achieve normal serum phosphate levels through the use of phosphate binding gels. Chronic Renal Failure Although renal osteodystrophy has long been known to be a complication of chronic renal failure, it has emerged as a serious problem only recently, with prolonged patient survival made possible by dialysis. The pathogenesis of bone disease in renal failure is complex and multifactorial, but it can be best understood in terms of defects in mineral homeostasis involving PTH and a deficiency of vitamin D.2'30 According to the Bricker-Slatopolsky hypotheSiS,30,31 one of the earliest and central abnormalities of renal failure is the decreased ability of the kidney to excrete phosphorus adequately (Figure 5). A loss of nephrons results in a rise in serum THE WESTERN JOURNAL OF MEDICINE

309

VITAMIN D DEFICIENT STATES

LATE RENAL FAILURE

fP04 no PTH

24,25-(OH)2D3 LOSS OF NEPHRONS

*(-4 X-1--I

t[Po4] I4

+

\

1,25-(OH)2D3

i24,25-(OH)2D3 (-)I

4

\

* *inc increased1,25-D3 25-OH*D3 low 1,25-D3 A

BoneMineralization

-~OSTEOMALACIA

iPO4 t PTH

f Intestinal Absorption

1,25-(OH)2D3

f Renal Reabsorption * Bone Resorption * Intestinal Absorption

Figure 7.-Control point of 25-OH-D3 metabolism and proposed consequences on calcium metabolism: Hypocalcemia (elevated parathyroid hormone levels) or hypophosphatemia favors 1,25-(OH)2D3 formation. Repleted state favors 24,25-(OH)2D3.

Intestinal

Calcium Absorption

[ Co++]

KIDNEY BONE Resorption

HI

t PTI*H

_ _.

I

OSTEITIS FIBROSA __ _ __ _ _ _ __ _ _

_ _

Figure 6.-Pathophysiology of osteodystrophy of late renal failure (glomerular filtration rate less than 30 ml per minute): Solid lines (-) are direct consequences of nephron loss; dotted lines (----) are compensatory pathways and -* indicate blocked pathways.

phosphate, a fall in ionized calcium and, consequently, an elevation of serum PTH levels at glomerular filtration rates of 60 to 80 ml per minute. At this stage, hyperparathyroidism without osteomalacia is usually found on bone biopsy.32 Elevated PTH acts to bring serum calcium levels to within normal limits by increasing tubular phosphate excretion as well as maintaining normal serum 1,25-(OH)2D3 levels30'33 and, hence, adequate intestinal calcium absorption and bone mobilization. The next phase34 of renal osteodystrophy develops at a glomerular filtration rate below 30 ml per minute, as nephron loss and phosphate retention reduce synthesis of 1,25-(OH),D3 and the remaining tubules can no longer excrete the phosphate load despite elevated PTH levels (Figure 6). Low circulating 1,25-D3 levels result in bone resistance to PTH and intestinal malabsorption of calcium, the hallmarks of the vitamin D resistant state of uremia. Hypocalcemia is further aggravated by poor dietary intake and decreased sunlight exposure, contributing to vitamin D deficiency.2'3 However, the renal osteodystrophy of end-stage renal failure is more than just osteomalacia superimposed on osteitis fibrosa; there are poorly understood effects of toxins on protein collagen metabolism as well as very high PTH levels which contribute to the findings of osteoporosis and osteosclerosis.34 Therapy with physiologic doses of 1,25-(OH)2

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OCTOBER 1979 * 131

* 4

D3 (calcitriol, 0.5 mg per day) or la-OH-D3 (1 to 2 /g per day)35-39 has resulted in remarkable correction of biochemical abnormalities, with increased intestinal calcium absorption, normal levels of serum calcium and fall of PTH levels. Because of the short half-life of 1,25-(OH)2D3, the risk of vitamin D intoxication is much less than that of pharmacological doses of D2 (Table 1). Episodes of hypercalcemia resolved in days rather than months. In addition, there was impressive clinical resolution of disabling bone pain and muscle weakness. However, serial bone biopsy studies showed improvement predominantly of the osteitis fibrosa component of bone disease, with much less effect on the osteomalacia. This unexpected finding cast serious doubts on whether 1,25-(OH) 2D3 could account for all the biologic effects of vitamin D. Although nephrectomy abolishes synthesis of 1, 25-(OH)2D3, evidence of osteomalacia does not develop in all anephric patients.40 In some patients, low 25-OH-D3 levels seemed to correlate with osteomalacia.4' In direct comparison of therapy with -25-OH-D3 (calcifediol), 1,25-(OH)2D3 or 1 a-OH-D3 in patients with simple vitamin D deficient osteomal.acia42 or renal osteodystrophy,43 25-OH-D3 was clearly superior in promoting bone mineralization. Also supraphysiologic 25-OH-D3 has been shown to improve intestinal calcium absorption, raise serum calcium, lower alkaline phosphatase and PTH, and improve both symptoms and histology of osteomalacia in patients on dialysis.34'44 This effect required levels of 25-OHD3 to be six times greater than normal; if hypercalcemia developed, it resolved in half a week to three weeks after withdrawal of the drug. Which metabolite of 25-OH-D3 is responsible for proper bone mineralization is a key question in vitamin D research today. There is accumulating evidence that 24,25-(OH)2D3 or some other 25-OH-D3 metabolite may be important in the

VITAMIN D DEFICIENT STATES TABLE 2.-Optimal Therapy for Renal OsteodystrophyEarly Renal Failure (Glomerular filtration rate greater than 30 ml per minute) Dietary phosphate binders Insure adequate calcium and protein intake ? low dose vitamin D Late Renal Failure (Glomerular filtration rate less than 30 ml per minute) Vigorous use of phosphate binders, especially before vitamin D therapy; monitor parathyroid hormone levels Dialysis against bath of 6 to 8 mg per dl of free calcium Adequate protein and calcium intake (1 gm per day

elemental calcium) Vitamin D metabolite therapy-25-OH-D3 or 1,25(OH)2D3 or both Sunlight and exercise

process of bone mineralization6 (Figure 7). 24, 25-(OH)2D5 is synthesized in both kidney and intestine,' and has been shown to increase intestinal calcium absorption while decreasing the serum concentrations of calcium and phosphorus. 24,25-(OH),2D8 is preferred in the repleted state to promote normal bone mineralization and the synthesis of hydroxyapatite (Caj0[PO4]6[OH]2). Animal studies have shown there to be a potent antirachitic effect of 24,25-(OH) 2D8 and have even suggested a cooperative role with 1,25(OH),2D3 in the normal mineralization process.'6 Further studies in humans will determine if 24, 25- (OH)2D8 is necessary for bone mineralization in patients with chronic renal failure. The therapeutic approach to renal osteodystrophy is outlined in Table 2.

Postmenopausal Osteoporosis Approximately 1 million fractures per year occur in American women over the age of 45, of which some 700,000 are related to osteoporosis.47 Fractures are a significant cause of morbidity and mortality in the geriatric population. The fullblown syndrome of back pain, skeletal fractures and loss of height is, however, seen in only 25 percent of those with decreased skeletal mass.'8"9 Although the onset of osteoporosis and menopause are temporally related, as first pointed out by Albright,50 the syndrome does not develop in all postmenopausal women. Other important factors are (1) age, (2) race (greater in whites), (3) skeletal mass at maturity, (4) physical activity, (5) nutrition (calcium intake, lactose intolerance), (6) vitamin D status and (7) hormonal status (estrogens). 48,5152 Abnormalities found in women with osteo-

porosis include increased rate of bone loss, decreased intestinal calcium absorption, slight hyperphosphatemia, normal or low PTH, fasting hypercalciuria, lower mean 1,25-(OH),2D8 levels and lower mean estrogen levels.53'54 These findings, including the vitamin D abnormalities, are best explained by the model of Heaney.55 He proposed that primary estrogen deficiency resulted in increased skeletal resorption because of increased sensitivity to the effects of PTH. This increased mobilization of bone results in transient elevation of serum calcium, suppression of PTH, decreased 1,25-(OH),2D8 levels and, hence, both decreased calcium absorption from intestine and loss of calcium through the kidney. Overall, there is negative calcium balance due to preferential mobilization of bone reserves, and secondary suppression of the PTH and vitamin D homeostatic mechanism. Treatment with estrogen will raise 1,25- (OH)2 D5, increase intestinal calcium absorption and prevent further bone loss without reversing the osteopenic state.'8 56-59 Modest doses of D2 or physiologic doses of 1,25-(OH)2D3 will correct intestinal calcium malabsorption and decrease bone resorption.54 60'6' However, the combination of sodium fluoride, calcium and vitamin D will stimulate bone formation and increase bone mass.02 Since estrogens may carry an increased risk of endometrial carcinoma,68 and fluoride causes pronounced gastrointestinal side-effects as well as possible abnormal bone histology, no current therapy for the established disease is ideal.48'64 The best approach is preventive: ensure adequate sunlight, exercise, calcium intakle and physiologic vitamin D 'supplementation. In considering estrogen therapy one must weigh the relative risk of fracture versus the possible development of cancer. Further study is required to define the roles of fluoride, calcitonin and vitamin D metabolites. REFERENCES 1. DeLuca H: Vitamin D metabolism and function. Arch Intern Med 138:836-847, 1978 2. Favus M: Vitamin D physiology and some clinical aspects of the vitamin D endocrine system. Med Clin of North Amer 62: 1291-1317, 1978 3. Haussler M, McCain T: Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med 297:974-983, 1041-1050, 1977 4. Frame B, Parfitt A: Osteomalacia-Current concepts. Ann Intern Med 89:966-982, 1978 5. DeLuca H: Vitamin D endocrinology. Ann Intern Med 85: 367-377, 1976 6. Kanis J, Heyman G, Russell R, et al: Biological effects of 24,25-dihydroxycholecalciferol in man, In Norman AW, Schaefer K, Coburn JW, et al (Eds): Vitamin D: Biochemical, Chemical, and Clinical Aspects Related to Calcium Metabolism-Proceedings of Third Workshop on Vitamin D, Asilomar, Pacific Grove, CA, Jan 1977. Berlin, de Gruyter, 1977, pp 793-795

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VITAMIN D DEFICIENT STATES 7. Arnaud S, Arnaud C, Bordier P, et al: The interrelationships between vitamin D and parathyroid hormone in disorders of mineral metabolism in man, In Norman AW, Schaefer K, Coburn JW, et al (Eds): Vitamin D and Problems Related to Uremic Bone Disease-Proceedings of Second Workshop on Vitamin D, Weisbaden, West Germany, Oct 1974. Berlin, de Gruyter, 1975, pp 397-410 8. Sitrin M, Meredith S, Rosenberg I: Vitamin D deficiency and bone disease in gastrointestinal disorders. Arch Intern Med 138: 886-888, 1978 9. Garrick R, Ireland A, Posen S: Bone abnormalities after gastric surgery. Ann Intern Med 75:221-225, 1971 10. Eddy R: Metabolic bone disease after gastrectomy. Am J Med 50:442-449, 1971 11. Stamp T: Intestinal absorption of 25-hydroxycholecalciferol. Lancet 2:121-123, 1974 12. Hepner G, Jowsey J, Arnaud C, et al: Osteomalacia and celiac disease. Amer J Med 65:1015-1020, 1978 13. Driscoll R, Meredith S, Wagonfeld J: Bone histology and vitamin D status in Crohn's disease-Assessment of vitamin D therapy. Gastroenterology 75:1051, 1977 14. Parfitt A, Mliller M, Frome B, et al: Metabolic bone disease after intestinal by-pass for treatment of obesity. Ann Intern Med 89:193-199, 1978 15. Long R, Wills M, Skinner R: Serum 25-hydroxy-vitamin D in untreated parenchymal and cholestatic liver disease. Lancet 2: 650-652, 1976 16. Hahn T, Avioli L: Hepatic bioactivation of vitamin D and clinical implications, In Norman AW, Schaefer K, Coburn JW, et al (Eds): Vtamin D: Biochemical, Chemical, and Clinical Aspects Related to Calcium Metabolism. Berlin, de Gruyter, 1977, pp 737-741 17. Hepatic osteodystrophy. Lancet 1:988-989, 1977 (Editorial) 18. Thompson W, Thompson G: Effect of cholestyramine on the absorption of vitamin D3 and calcium. Gut 10:717-722, 1969 19. Goldstein D, Yoshitake 0, Kurokawa K: Blood levels of 25-hydroxy-vitamin D in nephrotic syndrome. Ann Intern Med 87:664-647, 1977 20. Hahn T, Avioli L: Anticonvulsant osteomalacia. Arch Intern Med 135:997-100Q, 1975 21. Hahn T, Hendin B, Scharp C: Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 287:900-904, 1972 22. Hahn T: Corticosteroid-induced osteopenia. Arch Intern Med 138:882-885, 1978 23. Hahn T, Hahn B: Osteopenia in patients with rheumatic diseases-Principles of diagnosis and therapy. Semin Arthritis Rheum 6:165-188, 1976 24. Klein R, Arnaud S, Gallagher J, et al: Intestinal calcium absorption in exogenous hypercortisonism. J Clin Invest 60:253259, 1977 25. Nusynowitz M, Frame B, Kolb F: The spectrum of the hypoparathyroid states. Medicine 55:105-119, 1976 26. Avioli L: The therapeutic approach to hypoparathyroidism. Amer J Med 57:34-42, 1974 27. Russell R, Walton R, Smith R: 1,25-dihydroxycholecalciferol and la-hydroxycholecalciferol in hypoparathyroidism. Lancet 2: 14-17, 1974 28. Kooh S, Fraser D, DeLuca H, et al: Treatment of hypoparathyroidism and pseudohypoparathyroidism with metabolites of vitamin D-Evidence for impaired conversion of 25-hydroxyvitamin D to ia, 25-hydroxy-vitamin D. N Engl J Med 293:840844, 1975 29. Davies M, Taylor C, Hill L: 1,25-dihydroxycholecalciferol in hypoparathyroidism. Lancet 1:55-58, 1977 30. Slatopolsky E, Rutherford E, Hruska K, et al: How important is phosphate in the pathogenesis of renal osteodystrophy? Arch Intern Med 138:848-852, 1978 31. Bricker N, Slatopolsky E, Reiss E: Calcium, phosphorus, and bone in renal disease and transplantation. Arch Intern Med 123:543-553, 1969 32. Malluche H, Ritz E, Lange H, et al: Bone histology in incipient and advanced renal failure. Kidney Int 9:355-362, 1975 33. Slatopolsky E, Gray R, DeLuca H: Low serum levels of 1,25(OH)2D3 are not responsible for the development of secondary hyperparathyroidism in early renal failure, Fourth Workshop on Vitamin D. Berlin, Feb 1979, (abstract) 34. Bordier P, Marie P, Arnaud C: Evolution of renal osteodystrophy-Correlation of bone histomorphometry and serum and immunoreactive parathyroid hormone values before and after treatment with calcium carbonate or 25-hydroxycholecalciferol. Kidney Int, Suppl 2:102-112, 1975 35. Henderson R, Russell R, Ledingham, et al: Effects of 1,25dihydroxycholecalciferol on calcium absorption, muscle weakness, and bone disease in chronic renal failure. Lancet 1:379-384, 1974 36. Brickman A, Sherrard D, Jowsey J, et al: 1,25-dihydroxycholecalciferol-Effect on skeletal lesions and plasma parathyroid

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