Vitamin D in Bone Disease

Symposium on Pediatric Nephrology

Vitamin D in Bone Disease Michael E. Norman, M.D.*

VITAMIN D METABOLISM This article deals with vitamin D therapy of selected metabolic bone diseases including vitamin D deficiency and those disorders that occur in the setting of renal tubular dysfunction or chronic renal (glomerular) insufficiency. However, in 1982 the term vitamin D does not refer only to the naturally occurring parent compounds ergocalciferol (D 2 ) and ~holecalciferol (D,); a series of synthetic compounds (dihydrotachysterol, 1a-hydroxyvitamin D,) and the naturally occurring metabolites (25-hydroxyvitamin 0 3 , 24,25dihydroxyvitamin 0 3 , 1,25-dihydroxyvitamin 0 3 ) have also become available to treat the diseases that will be discussed. An explosion of.new knowledge about vitamin D metabolism over the past decade has led to the advances in vitamin D therapy alluded to above. Much of this new information is based on the availability of tritiated vitami1,1 D compounds possessing high specific activity, which has permitted ready identification of various metabolic pathways. The reader is referred to the recent and excellent reviews of vitamin D metabolism for more details. 30• 93 In order to understand the rationale for the newer vitamin D therapies, a brief synopsis of this new information is in order. The steps in vitamin D metabolism are briefly outlined in Figures 1 to 3. Vitamin D 3 is formed in the skin from 7-dehydrocholesterol under the influence of ultraviolet light (Fig. 1). It is transported to the liver bound to a plasma protein (D-binding protein, DBP), where it is then hydroxylated in the 25 position by hepatic microsomes to 25-hydroxyvitamin D 3• Vitamin D 2 and D 3 , derived from plant and animal tissues respectively, undergo ingestion, absorption in the small intestine, and transport via the intestinal lymphatics to the liver (Fig. 2). Therefore, the liver has two sources of vitamin D substrate to produce 25-hydroxyvitamin D. When either pathway is intact and fully operative, vitamin D deficiency rarely occurs. The liver metabolite is then transported to the kidney bound to DBP, where it undergoes !-hydroxylation in proximal cortical tubular cells to the biologically active form of vitamin D, 1,25dihydroxyvitamin D 3 (Fig. 3). Subsequent metabolism of 1,25-dihydroxyvitamin D 3 occurs, but the products do not have proven functions in man. 25-Hydroxyvitamin D 3 may also be hydroxylated in the 24 or 26 positions. Whereas 25,26 dihydroxyvitamin *Director, Division of Nephrology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Supported in part by the Upjohn Company, Roxane Laboratories, Inc., and a grant from the National Institutes of Health, No. 19278.

Pediatrics Clinics of North America-Vol. 29, No.4, August 1982

947

948

MICHAEL

7-Dehydrocho leste'rol

E.

NORMAN

Pre-Vitamin [h

Vitamin 03

~ Plasma DBP

!

Liver

25-hydroxylase

25-0HD,

Figure 1. Vitamin D metabolism-!.

II.

EJ (Cholecalciferol)

Vitamin D2

* D2, 03 in man

25-hydroxyl ase

0 3 only in fowl

25-0HD

Figure 2.

Ill.

I

KIDNEY

*

Vitamin D metabolism-II.

I Vitamin 0 3 25 ,26(0H)D 3

1\1\11)

26-hydro~/ Y

25-0HD 3 -26,23 lactone

24-R hydroxylase 124,25(0H) 2 D3

I

kidney. gut, cartilage . ,

Calcitroic Acid

y

y.

1

I

I

1>

hydroxylase

e~

S1de-cha1n ox1dat10n r-~-----, . 1 ,25(0H),D 3 . gut

\\I

24-R hydroxylase 1 ,24,25(0H},D 3 kidney, gut, cartilage

Figure 3. Vitamin D metabolism-III.

Nameless Metabolite

949

VITAMIN D IN BONE DISEASE

Table 1. Vitamin D Metabolism*

COMPOUND

Da 25(0H)Da 24,25(0HhDa 1,25(0HhD3

PLASMA

PROBABLE

ESTIMATED

CONCENTRATION

TURNOVER RATE

PRODUCTION

(J.LG/L)

(T 1/2-DAYS)

(J.LG/DAY)

0.5-2 5--50 1-3 0.02-0.04

5--20 15-40 0.5-2

40 10 1.0 0.4

*Adapted from Kanis eta!. 54

D 3 is not biologically active, 24,25-dihydroxyvitamin D 3 is active in vitro and in vivo under certain defined conditions, as will be discussed below. The three vitamin D metabolites which have been clinically employed in metabolic bone diseases are denoted by the boxes (Fig. 3). 1,25-Dihydroxyvitamin D 3 promotes intestinal absorption of calcium and phosphorus, bone resorption of calcium, and renal reabsorption of calcium in vitro and in vivo. It is defined as the biologically active form of vitamin D because it is the only vitamin D metabolite that performs these functions at physiologic concentrations. Vitamin D itself, as well as 25-hydroxyvitamin D 3 and probably 24,25-dihydroxyvitamin D 3 , can mimic most if not all of the actions of 1,25-dihydroxyvitamin D 3 , but only at pharmacologic concentrations. Although it is now known that organs other than the kidney (such as the placenta105 ) can produce 1,25-dihydroxyvitamin D 3 , the kidney is the major site of synthesis regulating vitamin homeostasis in man. The production of 1,25-dihydroxyvitamin D 3 is believed to be under relatively tight control and is influenced by a number of factors. Hypocalcemia may directly stimulate the renal !-hydroxylase enzyme, but is believed to exert its major effect on 1,25-dihydroxyvitamin D 3 synthesis by stimulation of parathyroid hormone (PTH) secretion. 65 Similarly, hypophosphatemia stimulates production of 1,25-dihydroxyvitamin D 3 in man, 42 although it is not clear if the intracellular concentration of phosphate in renal tubular cells is also important in regulating 1,25-dihydroxyvitamin D 3 synthesis. Plasma levels of 1,25-dihydroxyvitamin D 3 in man show no seasonal variation in response to varying exposure to sunlight; such variation does exist for 25- and 24,25dihydroxyvitamin D 3 , with the highest levels noted in the summer and early fall months. Finally, renal production of 1,25-dihydroxyvitamin D 3 is probably not substratedependent except under conditions of marked elevations in circulating 25-hydroxyvitamin D 3 •66 The salient features of vitamin D metabolism as it is currently understood are summarized in Table 1.54 What is important to note for the discussion that follows is the rapid turnover of 1,25-dihydroxyvitamin D 3 and its very low plasma concentrations when compared to the other compounds. Of equal importance to any discussion of vitamin D therapy in metabolic bone diseases is what is not known or remains controversial about vitamin D metabolism at the present time. 1. The pharmacokinetics of vitamin D metabolism are just now beginning to be understood. It would appear that the rapid production and turnover of 1,25-dihydroxyvitamin D 3 make single plasma determinations oflimited value in any given individual. 57 What is more, recent evidence suggests marked oscillations of this metabolite during repeated measurements over a 24-hour period. 72 2. It has been suggested but not proved tilat 1,25-dihydroxyvitamin D 341 and 24,25dihydroxyvitamin D 322 directly inhibit PTH secretion in states of secondary hyperparathyroidism. 3. There is as yet no convincing evidence that 1,25-dihydroxyvitamin D 3 or any other vitamin D metabolite has a direct mineralizing effect on bone in normals or in vitamin D-deficient-resistant man. 4. It is not clear whether 25-hydroxyvitamin D 3 or 24,25-dihydroxyvitamin D 3 exert tileir own unique biologic actions in man such as the stimulation of bone mineralization99 or tiley merely mimic tilose actions of 1,25-dihydroxyvitamin D 3 • 5. Finally, it has been suggested but not proved that physiologic concentrations

MICHAEL E. NORMAN

950

of 25- and/or 24,25-dihydroxyvitamin D 3 may exert a permissive effect on the bone healing actions of 1,25-dihydroxyvitamin D 3 in certain disease states. 56 The known and possible biologic actions of the D vitamins are summarized in Figure 4.

VITAMIN D METABOLISM IN RENAL DISEASES Much of our knowledge about alterations in vitamin D metabolism in renal diseases comes from the measurement of plasma levels of 25-, 24,25- and 1,25-dihydroxyvitamin D in adult73 and pediatric20 patients, notwithstanding the limitations of this approach as noted above. What appears certain is that the renal production of 1,25-dihydroxyvitamin D 3 and its consequent plasma level are directly correlated with functioning renal mass 106 and its physiologic expression as glomerular filtration rate (GFR). 20• 23• 51 • 78 When GFR falls below 40 to 50 ml!min/1.73 M 2 , plasma levels of 1,25-dihydroxyvitamin D 3 begin to decline, and a state of relative vitamin D deficiency occurs. Plasma levels of 25-hydroxyvitamin D 3 are maintained in the normal range in renal failure, provided there is an ample source of the substrate vitamin D (skin or diet), hepatic metabolism is undisturbed, and there is no heavy proteinuria. 55 Plasma 24,25-dihydroxyvitamin D 3 also correlates with GFR, much in the same fashion as 1,25-dihydroxyvitamin D 3 • 48 • 107 What is not clear is when an absolute deficiency of either 24,25- or 1,25-dihydroxyvitamin D 3 occurs in the course of chronic renal failure. Such deficiencies are observed when patients actually reach end-stage renal failure and require dialysis. However, prior to this point, absolute vitamin D deficiency is difficult to assess from plasma levels because normal ranges for these metabolites are still being established. What is interesting but unexplained in renal failure is the loss of the normal reciprocal relationship that exists between 24,25- and 1,25-dihydroxyvitamin D 3 ; 30 • 93 those stimuli which normally increase 1,25-dihydroxyvitamin D 3 production suppress 24,25-dihydroxyvitamin production and vice versa. It should also be noted that the seasonal variations in plasma 25- and 24,25-dihydroxyvitamin D 3 levels noted in normal man are preserved when chronic renal failure supervenes."0 It has been suggested that 1,25-dihydroxyvitamin D 3 production can be stimulated in renal failure by the mass action effect of markedly elevated 25-hydroxyvitamin D 3 levels consequent to therapy with this agent. 66 • 109 Our own studies in this regard provide no evidence to support this contention, either acutely or after several years of 25-hydroxyvitamin D 3 therapy. 102 On the other hand, preservation of the role of phosphate deficiency in stimulating production of 1,25-dihydroxyvitamin D 3 may be maintained in chronic renal failure; a recent study reported that a phosphate-restricted diet was associated with a rise in plasma 1,25-dihydroxyvitamin D 3 and a fall in PTH

Concentr-ation

Agent Vitamin D

~

[pharmacologic]a.-

25(0H)D

~

{pharmacologic]

1 ,25(0H)zo

~

[physiologic]

24,25(0H)zD ~

Test System Calcium, phosphorus (out)

f

Calcium resorption {bone) ? Ca 1ci urn, phosphorus, re-

absorption (kidney)

[pharmacologic]

? Suppression of PTH release

T

Test Species

~~n~tions

In Vitro

•

In Vivo

• -

~

Animal (chicken, rat, doq)

Man Norma 1

Disease

Figure 4.

Biologic activity of the D vitamins.

VITAMIN DIN BONE DISEASE

951

levels in children with chronic renal failure. 81 It is intriguing to note that these changes were noted without a coincidental fall in serum phosphorus. Studies correlating vitamin D metabolite levels with bone histomorphometry suggest that low 25-34 and 24,25-dihydroxyvitamin D 3 levels correlate best with osteomalacia/3 and low 1,25-dihydroxyvitamin D 3 correlates best with osteitis fibrosa (e.g., secondary hyperparathyroidism)Y However, the finding of apparently normal plasma 1,25-dihydroxyvitamin D 3 levels in patients with osteomalacia with or without associated renal failure 83 does not necessarily imply that this metabolite plays no role in bone mineralization. Rather, it may suggest that a critical ratio of 1,25-dihyroxyvitamin D 3 to 25- and/or 24,25-dihydroxyvitamin D 3 is needed to remineralize osteomalacic bone. Current knowlege about vitamin D metabolite levels in chronic renal failure is summarized in Table 2.

WHY IS VITAMIN D THERAPY NECESSARY TO TREAT METABOLIC BONE DISEASES IN CHILDREN? Historical Observations The association of lack of dietary vitamin D and sunlight deprivation with clinical and radiologic rickets has been known for many years. That this occurs usually in the setting of adequate dietary intake of calcium and phosphorus is now readily appreciated, indicating that vitamin D plays a unique role in maintaining a growing skeleton. 45 Further proof comes from the rapid healing that occurs when physiologic replacement doses of vitamin D are administered to vitamin D-deficient humans. More recent observations provide an additional rationale for the use of vitamin D in a variety of metabolic bone diseases. These observations include demonstration of abnormalities in organ processes that are known to participate in the normal pathways of vitamin D metabolism, such as fat malabsorption by the small intestine, altered 25hydroxylation of vitamin D by the liver, impaired renal !-hydroxylation, and target organ resistance to 1,25-dihydroxyvitamin D 3 • The relationships between metabolic pathways for vitamin D and discrete deficiencies or abnormalities in these pathways leading to specific diseases are outlined in Table 3. Finally, recent development of vitamin D assays has permitted documentation of deficiencies of each of the three major metabolities in various disease states, which suggests the need for replacement therapy.

General Considerations and Assessment of Therapeutic Efficacy Except in the case of simple lack of vitamin D, successful therapy of the metabolic bone diseases usually requires adjunctive therapies to vitamin D, including supplemental calcium, phosphorus, and alkali. Most of the disorders require pharmacologic doses of vitamin D to heal the bones. In each disease, estimates of therapeutic efficacy must be balanced against risks of toxicity, particularly vitamin D intoxication with hypercalcemia. Indeed, the major initial impetus for employing 1,25-dihydroxyvitamin D 3 and its synthetic congener, la-hydroxyvitamin D 3 , in the treatment of renal metabolic bone disease was their very short half-life, which made intoxication a relatively brief event when it was encountered. In children one major and unique goal of therapy with vitamin D in any metabolic bone disease is relief of skeletal symptoms and improvement in linear growth. Correction of hypocalcemia, hypophosphatemia, elevated alkaline phosphatase, and secondary hyperparathyroidism is the biochemical objective. Radiographic healing of rickets and both radiographic and histologic healing of osteomalacia and osteitis fibrosa are fundamental to the assessment of vitamin D efficacy in all of these disorders. Normalization of vitamin D profiles in plasma is often but not always associated with correction of the other abnormalities. This may result from the need to maintain supraphysiologic levels of the vitamin D metabolites in order to effect sustained skeletal repair in several of these disorders.

tC I:J1 ~

Table 2. Vitamin D Metabolite Levels in Chronic Renal Failure METABOLITE

25(0H)D

BLOOD LEVEL

Normal

Reduced 1,25(0H)D

24,25(0H)D

REFERENCES

20,23,48, 73,107

6,77

Normal (GFR > 50 mllmin/ 1.73 M 2 )

20,23,80,107

Reduced (GFR < 50 mllmin/ 1.73 M 2 )

20,23,80,107

Normal

Low

43,47,96

48,78,101,107

COMMENTS

1. Seasonal fluctuations persist. 2. Direct correlation with vitamin D therapy, sunlight exposure, protein intake, and serum 24,25(0H) 2 D (controversial). 3. Inverse correlation with urinary protein losses and histologic osteomalacia. 4. No correlation with serum 1,25(0H)eD. 1. Levels related to type of renal disease (lower if renal tubular mass decreased or obstructive uropathy than if glomerulonephritis). 2. 'Threshold effect": at or below a GFR of 35-45 ml/min/1.73 M 2 , 1,25(0HhD correlates with GFR. 3. Inverse correlation with serum phosphorus, ? dietary phosphorus intake; PTH and histologic osteitis fibrosa. 4. No correlation with serum 25(0H)D.

1. 2. 3. 4.

Seasonal fluctuations persist. Unequivocally low in hemodialyzed and anephric patients. Direct correlations with serum 25(0H)D (controversial). Inverse correlation with urinary protein losses and histologic osteomalacia.

a:: n :I: > t'l r

t:%1

z0

:>0 ~

~

953

VITAMIN D IN BONE DISEASE

Table 3. Abnormalities in Vitamin D Metabolism in Metabolic Bone Disease METABOLIC PATHWAY

DEFICIENCY OR ABNORMALITY

1. Skin: Photoconversion of 7-dehydrocholesterol to vitamin D 3; transport via blood (Dbinding protein) to liver 2. Diet: Ingestion of vitamin D 2 or D 3; small bowel absorption; transport via lymphatics 3. Liver: 25-hydroxylation by the liver cell microsomes; enterohepatic circulation; transport to the kidney of 25(0H)D3

L D deficiency: Insufficient sunlight exposure

4. Kidney: !-hydroxylation and 24-hydroxylation by tubular cells; circulation of 1,25(0HhD3 and 24,25(0HhD 3

5. Target Organs: gut absorption, bone resorption, and renal reabsorption of calcium via 1,25(0HhD3 (receptor-dependent)

2. D deficiency: Dietary deficiency or malabsorption 3. Abnormal metabolism: Increased production of inactive metabolites by anticonvulsant-mediated enzyme induction; impaired enterohepatic circulation from primary biliary disease 4. Abnormal metabolism: a. reduced glomerular filtration rate (renal mass): deficient production in chronic renal failure [1,25 and 24,25(0HhD3] b. normal glomerular filtration rate: ? deficient production in familial hypophosphatemic rickets and Fanconi syndrome [1,25(0HhD3]; deficient production in Type I vitamin D dependency [1,25(0HhD3] 5. Receptor deficiency or "block": a. Type II vitamin D dependency b. uremia

VITAMIN D DEFICIENCY Nutritional vitamin D deficiency is the oldest and most completely characterized of the metabolic bone diseases. Despite the widespread use of dairy products fortified with vitamin D and multivitamin preparations, this disease remains a major pediatric health problem. Vitamin D-deficiency rickets is not merely confined to Third World countries, as recent reports would indicate. 3 • 4 Factors contributing to the resurgence of this disease include limited exposure to sunlight, especially in dark-skinned people, 46 and dietary exclusion of vitamin D. A detailed clinical description of this disease is found in Harrison and Harrison. 45 Occasionally, in far advanced untreated vitamin D deficiency, the major biochemical and radiographic findings are those of secondary hyperparathyroidism, including osteitis fibrosa, aminoaciduria, and bicarbonaturia with metabolic acidosis. This disease is simply and effectively treated by the administration of slightly supraphysiologic replacement doses of vitamin D 2 (1,000 to 2,000 IU/day); healing of rickets and normalization of serum phosphate and calcium will occur over several weeks to months. However, in order to effect more rapid recovery and thereby differentiate vitamin D deficiency from the other rickets syndromes, larger oral daily doses of vitamin D 2 may be given (12,000 to 16,000 IU). Some authors advocate the short-term administration of massive doses ofD 2 (600,000 IU given once or 100,000 IU in 6 divided doses), which effects very rapid clinical and laboratory improvement with a surprisingly minimal risk of toxicity. 45 Current literature suggests that there is no advantage in

954

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substituting 1,25-dihydroxyvitamin D 3 for vitamin D 2 in this disorder, even though plasma 1,25-dihydroxyvitamin D levels may be reduced in the face of hypocalcemia, hypophosphatemia, and elevated PTH. 19 In malabsorptive states, no true vitamin D resistance exists, but impaired absorption of vitamin D results from a structural abnormality in the small bowel or a deficiency of bile salts .. Most children respond to the daily administration of vitamin D 2 in doses that are 10 to 20 times the physiologic dose (Table 4). In both uncomplicated nutritional D deficiency and malabsorption, therapy causes serum calcium and phosphorus levels to rise and alkaline phosphatase levels to fall promptly and in parallel. Catch-up growth and healing of the rickets may take considerably longer; the length of time required for the bones to heal appears to correlate with the duration and severity of the deficiency state before therapy is begun. If a state of D deficiency persists during the vulnerable first year or two of life, the child may not demonstrate full catch-up growth consequent to treatment. Abnormal liver function can lead to clinically evident vitamin D deficiency by one of two general mechanisms: (1) the effects of anticonvulsant drugs on hepatic metabolism of vitamin D; or (2) structural disease of the liver and/or biliary tract leading either to impaired 25-hydroxylation of vitamin D or impaired enterohepatic circulation of 25-hydroxyvitamin D. Phenobarbital and phenytoin are both known to induce liver enzymes and accelerate the production of polar vitamin D metabolites, which undergo glucuronidation and are then excreted into the bile. These compounds apparently are biologically inactive and the net result of this process is a reduced hepatic formation of the active metabolite, 25-hydroxyvitamin D 3 , and a lowered plasma level of this compound in most patients. 44 25-Hydroxyvitamin D is the major circulating form of vitamin D in man, so a reduced plasma level signals a state of vitamin D deficiency. Because these patients do not absorb calcium, often demonstrate poor growth, show osteopenia and rickets on xray, and have secondary hyperparathyroidism, it was anticipated that they would also be deficient in circulating 1,25-dihydroxyvitamin D 3 • Recent studies have shown that such is not the case. 50 Therefore, some other mechanism must be involved to explain the clinical and biochemical abnormalities noted in these patients. It may be that the anticonvulsant drugs themselves have a direct effect on intestinal calcium transport. 45 It may be that a critical level of circulating 25- or 24,25-dihydroxyvitamin D 3 is required to permit 1,25-dihydroxyvitamin D 3 to affect intestinal calcium absorption and bone resorption. Finally, since only a small percentage of children receiving long-term anticonvulsants develop biochemical or clinical evidence of vitamin D deficiency, 62 other environmental factors such as limited exposure to sunlight and poor nutrition almost certainly play a role in causing rickets. To prevent the development of rickets, children receiving long-term anticonvulsant therapy should probably receive maintenance doses of vitamin D 2 that are two to three times normal (e.g., 800 to 1200 IU per day). The optimal treatment of anticonvulsant-induced osteomalacia should be 25hydroxyvitamin D 3 , but this agent has just recently been released by the Food and Drug Administration and is approved only for the treatment of renal osteodystrophy in adult dialysis patients. Current recommendations are to administer vitamin D 2 in starting doses of 4000 to 8000 IU. Any patients receiving long-term anticonvulsant drugs, but especially those with clinically

r

~

z

Table 4. Vitamin D Preparations

Physiologic Dose1 (J.Lg/day) Pharmacologic Dose2 (J.Lg/ day or J.Lgikg!day) Onset of Maximal Effect (Days) Dosage Forms (J.Lg)

t:l

DIHYDRO-

25-HYDROXY-

1,25-DIHYDROXY-

VITAMIN D2

TACHYSTEROL

VITAMIN D 3

VITAMIN Da

10 200--600

20

5

125-400

1-2

0.5 .015-.050

30

15

15

3

Liquid: 200 J.Lg/ml in a 60 ml bottle (Drisdol) Capsules: 1,250 J.Lg (Drisdol) Tablets: 1,250 J.Lg (Calciferol) Injection: 12,500 J.Lg in sesame

oil

Liquid: 250 J.Lg/ml (Hytakerol); 1,000 J.Lg/ml (DHT) Capsules: 125 J.Lg (Hytakerol) Tablets: 200 J.Lg, 400 J.Lg (DHT)

Tablets: 20 J.L 50 J.Lg

Comments

give liquid or capsules once a day; give injection as a depot once a month

give once a day

give once a day

Commercial N arne

Calciferol (Kremers-Urban) Drisdol (Winthrop)

Hytakerol (Winthrop) Dihydrotachysterol or DHT (Roxane)

Calderol (Upjohn)

z t:C 0

zt%J

S?

"'t%J ~

t%J

Tablets: 0.25 J.Lg

give in two divided doses

Rocaltrol (Roche)

'Conversion Table; 1 J.Lg Vitamin D 2 = 40 IU of activity 1000 J.Lg (1 mg) D 2 = 40,000 IU of activity 1000 J.Lg (1 mg) DHT = 120,000 IU of activity 2 Starting dose for renal osteodystrophy or vitamin D-resistant syndromes. Doses for vitamin D 2 and DHT are given as a range, the dose depending on age and size; doses for 25-hydroxyvitamin D 3 and 1,25-dihydroxyvitamin D 3 are given in J.Lg/kg/day.

co

CJ1 CJ1

956

MICHAEL

E.

NORMAN

evident bone disease, should receive periodic checks of blood calcium and phosphorus and, if available, measurements of plasma 25-hydroxyvitamin 0 3 • * Single measurements of alkaline phosphatase are not particularly sensitive for bone disease in children treated with anticonvulsants, because of the uncertain contribution of the hepatic isoenzyme to the total blood level. Serial determinations are more useful in this regard. Structural liver disease such as primary biliary cirrhosis may result in severely compromised liver function, leading to hypocalcemia, osteopenia on radiographs, and/or clinical and radiographic rickets. 63 25~Hydroxyvitamin D levels are often but not always reduced, 56 probably as a result of interruption of the enterohepatic circulation of this metabolite. 2 Circulating 1,25-dihydroxyvitamin D levels are normal, but 24,25-dihydroxyvitamin 0 3 levels are reduced. 56 Therefore, the bone disease encountered in patients with severe liver disease is not the result of a deficiency of any particular vitamin D metabolite. Therapy with vitamin D is as indicated for patients receiving anticonvulsants.

VITAMIN D THERAPY OF METABOLIC BONE DISEASES INVOLVING THE RENAL TUBULE This review is not meant to be comprehensive but will focus on the renal metabolic bone diseases most frequently encountered in pediatric practice. These disorders are divided into two major groups. Primary phosphate deficiency disorders include familial hypophosphatemic rickets and idiopathic or secondary (cystinosis, Lowe's syndrome, etc.) Fanconi syndrome. Primary vitamin D deficiency disorders include lack of vitamin D (absence of sunshine, dietary deficiency, malabsorption), abnormal liver metabolism (primary liver or biliary disease, anticonvulsant drugs), and abnormal renal metabolism (vitamin D dependency, Types I, II; chronic renal insufficiency, renal osteodystrophy). Not included are diseases such as the renal tubular acidoses, the therapy of which does not usually require vitamin D. For details of the clinical and radiologic changes encountered in these disorders, the reader is referred to the excellent monograph by Harrison and Harrison. 45 The clinical manifestations of the renal metabolic bone diseases are protean and include listlessness, apathy, irritability, pallor, diaphoresis, failure to thrive (height and weight), hypotonia, muscle weakness, hyporeflexia or arreflexia, "pot belly," regression of or failure to achieve normal motor milestones (sit, stand, walk), joint hypermobility, tetany, stridor, seizures, craniotabes, frontal bossing, skull asymmetry, rachitic rosary, Harrison's grooves, kyphosis, kyphoscoliosis, genu varum, genu valgum, waddling gait, joint swelling, bone pain, and pathologic fractures. The signs and symptoms depend on such factors as the age of the child, whether or not he or she is walking, the severity of the mineral derangements, the degree of secondary hyperparathyroidism, and associated abnormalities such as malnutrition. *This assay is becoming more widely available through a number of commercial laboratories.

VITAMIN DIN BONE DISEASE

957

Although hypocalcemia, hypophosphatemia, or both are reliable markers for most of the disorders listed above (except chronic renal failure in which hyperphosphatemia is the rule), the levels of these mineral ions do not necessarily correlate with the degree of the radiologic or histologic changes, especially in chronic renal failure. Elevated serum alkaline phosphatase for age is the rule in renal metabolic bone disease. However, the changes in alkaline phosphatase occasioned by vitamin D therapy are by no means uniform and assume different interpretations under different clinical settings. For example, in chronic renal failure with severe secondary hyperparathyroidism, bone turnover in general and osteoblastic activity (e.g., bone formation) in particular are increased. It is, of course, the osteoblasts which produce bone-derived alkaline phosphatase. With therapy of the hyperparathyroidism by vitamin D, a fall in alkaline phosphatase signals a positive therapeutic response. On the other hand, if there is histologic osteomalacia with low bone formation and bone turnover, as may occur in some patients with renal phosphate wasting and osteodystrophy, successful therapy is marked by a rise in alkaline phosphatase, as bone formation increases. Finally, alkaline phosphatase is not a useful guide to follow in assessing therapeutic responses to vitamin D in patients receiving anticonvulsants or who have primary liver or biliary tract disease. This is because of the uncertain contribution of the hepatic isoenzyme of alkaline phosphatase to the total serum pool. Hyperparathyroidism as reflected by an elevated serum PTH usually correlates with radiographic changes of osteitis fibrosa and the histologic pattern of an increased osteoclast resorption surface and marrow fibrosis. 74 • 88 It should be noted that there is a continuing controversy over the appropriate PTH assay to select in working up and following a child with renal metabolic bone diseases. 10 This author generally prefers the use of the C-terminal assay in pediatric patients, because of the larger body of published data with which to compare individual patient results. It is the serial rather than the single measurement of PTH that yields the most useful information. In addition, there are now clinically available two sensitive and accurate assays of PTH function which rely upon the renal response to increased circulating levels of the hormone. 10 Histologic osteomalacia has no reliable biochemical and/or radiologic correlates in renal metabolic bone disease, unless there is actively growing bone. Under the latter circumstances, rickets is the hallmark of a mineralizing defect. 5 8 In the relatively new field of quantitative and dynamic bone histology known as bone histomorphometry, osteomalacia of trabecular bone obtained by a percutaneous iliac bone biopsy is best diagnosed by finding an impaired mineralization rate coupled with an excess of osteoid. 58 To determine the mineralization rate, it is necessary to administer two short courses of tetracycline 1 to 2 weeks apart before the bone biopsy. Tetracycline is taken up by actively mineralizing bone and appears as a fluorescent label of the mineralization front.

Familial Hypophosphatemic Rickets Familial hypophosphatemic or vitamin D-resistant rickets is by far the most common renal metabolic bone disease without renal failure, if one excludes simple vitamin D deficiency. It was first described by Albright in

958

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a child with hypophosphatemia and rickets, whose bones healed only after massive doses of vitamin D were administered.' It has subsequently been characterized clinically as a rachitic disorder with a variable onset in infancy and childhood, retardation of linear growth, renal phosphate wasting in the face of hypophosphatemia, normocalcemia, and unresponsiveness to doses of vitamin D that would cure simple D deficiency. 45 It is inherited as a sexlinked dominant disorder or may occur as a sporadic mutation. Clinical and radiographic findings tend to be most pronounced in the lower extremities. The hallmark of the disease is hypophosphatemia that persists throughout the 24-hour cycle, masking the diurnal variation in serum phosphate seen in normal individuals. The degree of hypophosphatemia does not parallel the degree of bone disease. Most investigators agree that there is a specific and discrete tubular transport defect for phosphate in this disease, involving proximal renal tubular reabsorption and small intestinal absorption. 94 There may also be an exaggerated phosphaturic response to PTH. 97 Progress in our understanding of this aspect of the pathogenesis has been aided by studies of the X-linked hypophosphatemic (Hyp) mouse, a model for this disease. 35 Nonetheless, caution in applying this information to man is necessary because normal phosphate metabolism in the mouse is very different from that of man. What remains controversial about the pathogenesis of familial hypophosphatemic rickets is whether or not there is an associated defect in vitamin D metabolism. This hypothesis has been suggested because some patients fail to produce "normal'' amounts of 1,25-dihydroxyvitamin D 3 in response to a hypophosphatemic stimulus leading to inappropriate plasma levels of this metabolite. Most investigators report that serum 1,25-dihydroxyvitamin D levels are eitherlow 18· 85·95 or inappropriately low-normaP2 for the level of serum phosphate. Others report normal 1,25-dihydroxyvitamin D levels in untreated patients, arguing against a defect in D metabolism. 29 Other theories to explain the apparent abnormality in vitamin D metabolism are an increased catabolism 18 or an abnormal osteoblast response to vitamin D. 40 There is general agreement that the key to therapy is early recognition and treatment to preserve linear growth and prevent progressive bone deformities. Large doses of vitamin D itself (25,000 to 50,000 IU) have healed rickets and improved linear growth, although there is no appreciable change in serum phosphate or in renal phosphate wasting. At these doses of vitamin D, the incidence of hypercalcemia is high with its attendant risk of renal damage. 85 Phosphate supplements alone (1.0 to 4.0 gm per day in 4 to 6 divided doses) will also improve the clinical and radiographic abnormalities and raise serum phosphate levels. The risk of giving phosphate alone is the development of hypocalcemia and secondary hyperparathyroidism which is not a typical feature of the untreated patient. 40·85 Thus, most investigators now favor a combination of vitamin D and phosphate supplements, with excellent results reported in relief of symptoms, improvement in linear growth velocity, rise in serum phosphate, radiographic healing of the rickets,13·40·85 and improvements in the mineralization defect.4° Curiously, this therapy does not reverse the phosphate transport defect. Because of their potency and rapid turnover, 1,25-dihydroxyvitamin D/3 • 40 or 1a-dihydroxyvitamin 0 385 are now favored over ergocalciferol or DHT as the vitamin D

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VITAMIN DIN BONE DISEASE

agents of choice in familial hypophosphatemic rickets. Starting doses are dependent on age and size, but usually range from 15 to 50 ng per kg per day or a total dose of 0.25 to 2.0 flog per day (see Table 4). Corresponding doses of phosphate are 0.5 to 3.0 gm given as a solution (Neutra-Phos K solution, 1 gm of phosphorus and 57 mEq of potassium per 300 ml), a capsule (Neutra-Phos capsule, 250 mg), or a tablet (K-phos Neutra, 250 mg). In addition to following yearly growth velocities, serum chemistries, and radiographs as guides to therapeutic efficacy, Rasmussen et al. suggest serial measurements of the fractional excretion of calcium as an early marker of impending vitamin D toxicity85 and nephrogenous cyclic-AMP in the urine as a marker of hyperparathyroidism. 10• 85 Fractional excretion of calcium is calculated from simultaneous measurements of serum and urine creatinine and urine calcium on a "spot" urine: Fee = a

[UcJ [Uc,_.,]

X

Sc,_., (normal values, < 0.150)

Fanconi Syndrome The Fanconi syndrome is a heterogeneous group of disorders characterized by transport defects for phosphate, glucose, amino acids, and bicarbonate in the proximal renal tubule. 90 It may be idiopathic or secondary to inborn errors of metabolism such as cystinosis, Lowe's syndrome, galactosemia, and so forth. The metabolic bone disease that ensues is believed to result from a combination of renal phosphate wasting leading to hypophosphatemia and renal bicarbonate wasting leading to metabolic acidosis. Large doses of vitamin D will not only improve growth and heal rickets, but may actually improve calcium59 and phosphate 60 • 90 balance in this disorder. The mechanisms by which this occurs remains speculative but include: (1) increased calcium absorption by the small intestine; (2) an increased phosphate absorption by the small intestine; (3) blunting of the PTH-mediated renal phosphaturia; and (4) overcoming a primary defect in the production of 1,25dihydroxyvitamin D 3 • 9 • 59 Optimal therapy probably consists of a combination of phosphate supplementation and large doses of vitamin D, given as ergocalciferol or DHT (Table 4). However, for the reasons outlined in the section on familial hypophosphatemic rickets, the more potent metabolite, 1,25-dihydroxyvitamin D 3 or lu-hydroxyvitamin D 3 , may be preferred ~md has yielded encouraging results in preliminary reports. 59 An important ancillary therapy is provision of supplemental alkali, given as a combination of sodium and potassium bicarbonate or citrate, 45 the latter to counter renal potassium losses.

Vitamin D-Dependent Rickets It was predictable that our new knowledge of the pathways of vitamin D metabolism would lead to the discovery of the pathogenesis of an unusual form of severe rickets occurring in infancy, which is unresponsive to doses of vitamin D far in excess of the physiologic requirements. 82 This disease, known as vitamin-D-dependency or pseudodeficiency rickets, is of two types. Type I is an autosomal recessive disorder that results from a failure of renal !-hydroxylation of 25-hydroxyvitamin D 3 , leading to an absolute

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deficiency of circulating 1,25-dihydroxyvitamin 0 3 •61 The clinical picture is one of severe hypocalcemia and hypophosphatemia with secondary hyperparathyroidism that is fully responsive to physiologic (replacement) doses of 1,25-dihydroxyvitamin D 3 or 1a-hydroxyvitamin 0 3 •38• 86 Thus, 0.5 1-Lg of 1,25dihydroxyvitamin D 3 is equivalent to 40,000 IU of vitamin D 2 in healing power! Long-term treatment studies have revealed that the requirements for vitamin D vary according to the degree of the 1-hydroxylase defect (e.g., genetic factors), the severity of the secondary hyperparathyroidism, and the degree of growth retardation. 5 Type II was initially reported in a young woman with the phenotypic features of Type I but a normal plasma level of 1,25-dihydroxyvitamin D and resistance to physiologic doses of this agent.u Subsequent studies confirmed these observations and expanded the clinical pattern to include kindreds in whom there were ·other abnormalities such as alopecia. 89 It has now been shown that this disease is due to a specific defect in the receptors for 1,25dihydroxyvitamin 0 3 •61 This has resulted in the need for massive doses of this metabolite, sufficient to raise plasma 1,25-dihydroxyvitamin D levels 5 to 100 times normal to restore normocalcemia and normophosphatemia and heal rickets!

RENAL OSTEODYSTROPHY Clinical Features Renal osteodystrophy is a syndrome, not a specific disease, that results from chronic renal failure of varying etiologies. Generally, the more severe the renal failure and the corresponding reduction in GFR, the more frequent and severe the renal osteodystrophy. Historically and by convention, renal osteodystrophy has been defined and classified on the basis of radiographs of the skeleton. Abnormalities include osteopenia or generalized demineralization, rickets, osteitis fibrosa (such as in secondary hyperparathyroidism), and osteosclerosis. The latter is more frequently seen in adults and refers to alternating bands of hyperdense and hypodense bone typically noted in the vertebrae. The clinical features may include bone pain, pathologic fractures, slipped epiphyses, bone deformities, and an abnormal gait. However, the hallmark of renal osteodystrophy in children is impaired linear growth, leading to short stature. It is this feature that differentiates them from adults with comparable degrees of chronic renal failure. While there is good correlation between the presence of renal rickets and short stature, 100 disturbances of growth in chronic renal failure are multifactorial, and are probably due as much to an impaired dietary intake of essential nutrients as to renal osteodystrophy. 7 • 100 Growth retardation in these children is present in both static and dynamic (e.g., growth velocity) measurements, and is both relative when factored for chronologie age and absolute when factored by skeletal (bone) age. The chemical picture of renal osteodystrophy varies, but in the classic and untreated case, there is hypocalcemia, hyperphosphatemia, and elevated alkaline phosphatase for age. Circulating PTH (usually measured by a Cterminal assay) is invariably elevated, reflecting an increased concentration

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of both active hormone and inactive metabolites that are normally cleared by the kidney. A recently developed technique for obtaining specimens of trabecular bone from the anterior iliac wing or the iliac crest by a percutaneous procedure has permitted the definitive histologic classification of renal osteodystrophy by qualitative and quantitative techniques. Abnormalities are of three general types: (I) osteomalacia characterized by an excess of osteoid and a defect in the rate of mineralization of osteoid; (2) osteitis fibrosa which reflects the effects of excess PTH and consists of an increased osteoclast resorption surface and endosteal fibrosis; and (3) a mixed picture of both osteomalacia and osteitis fibrosa. 75 We believe that, at the present time, histologic classification of renal osteodystrophy is important in selecting the right form(s) of vitamin D therapy for individual patients (see below). As previously noted, elevated PTH levels correlate well with radiographic and histologic evidence of secondary hyperparathyroidism. Renal rickets, on the other hand, is different from the rickets seen in patients with normal glomerular filtration. It is not due simply to a mineralization defect resulting from vitamin D deficiency, but reflects changes produced by secondary hyperparathyroidism occurring at the metaphyseal ends of long bones. 74 Moreover, we now know that osteomalacia secondary to a mineralizing defect can occur in trabecular bone, in the absence of rickets and secondary hyperparathyroidism. Despite this observation, there are no reliable clinical or biochemical abnormalities which can predict osteomalacia short of a bone biopsy. Renal osteodystrophy occurs more frequently in children than in adults, probably because new bone growth is particularly sensitive to the changes in vitamin D, phosphate, and parathyroid metabolism occasioned by chronic renal failure. In addition, bone turnover and remodelling is much more rapid in children than in adults, and this is more visibly disturbed by chonic renal failure. Reliable statistics on the incidence of renal osteodystrophy were unavailable until chronic renal failure was no longer considered an untreatable and therefore a fatal condition in children. An important paper on this subject appeared in 1972 when Fine and associates reported their experience with renal osteodystrophy in 38 children receiving hemodialysis in preparation for renal transplantation. 36 Almost one-half of these children met the radiographic criteria for renal qsteodystrophy, a figure 11/2 to 2 times that reported for adults. An important observation made by this group and subsequently confirmed by us 75 was that the frequency and severity of renal osteodystrophy were greatest when chronic renal failure occurred very early in life, persisted for many years prior to therapy for the bone disease, and was the result of congenital nephropathies and obstrucive uropathies, as opposed to the glomerulonephridites. The former diseases tend to damage tubular and interstitial tissues out of proportion to glomerular injury. Also, in children with congenital nephropathies and obstructive uropathies, chronic renal failure tends to persist for long periods of time before endstage renal failure ensues and dialysis is begun. Initial studies of renal osteodystrophy in children focused on clinicial characterization and therapy of patients on hemodialysis, for the syndrome was more severe and disabling in this population. Recently, attention has

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focused on early diagnosis of renal osteodystrophy during the course of mild to moderate chronic renal insufficiency and therapies to prevent the emergency of clinically overt bone disease. 49· 75 When in the course of chronic renal failure renal osteodystrophy is found to occur depends in part on what diagnostic tools are available to detect it. Radiographs of the hands using high-grade industrial x-ray film and analysis under magnification will reveal increased bone resorption as an early feature of secondary hyperparathyroidism.45 The relatively new technique of photon absorptiometry may reveal decreased mineral content of cortical bone in patients who are totally asymptomatic and who have normal serum chemistries. 16 When the GFR falls below 45 to 50 ml/min/1.73 M2 , secondary hyperparathyroidism invariably occurs in patients with congenital nephropathies or obstructive uropathies, as evidenced by a rise in PTH levels when compared to appropriate controls. 75

Pathogenesis In order to understand the rationale for administering vitamin D or one of its metabolites to children with renal osteodystrophy, a brief reivew of the pathogenesis is appropriate (Fig. 5). As chronic renal failure advances, hypocalcemia develops as the consequence of two separate but interrelated events. First, the kidney loses its ability to maintain phosphate homeostasis as the filtered load of phosphate falls, and hyperphosphatemia occurs. Serum calcium falls in a reciprocal but as yet poorly understood manner, and PTH secretion is stimulated, Initially, this restores mineral homeostasis but at the expense of an elevated PTH level. Eventually this adaptive mechanism fails and the effects of secondary hyperparathyroidism begin to appear. Normally, bone remodelling requires the orderly resorption of calcium and phosphorus from "old bone" in order to effect mineralization of "new" osteoid. This activity is mediated by the coordinated action ofPTH and 1,25-dihydroxyvitamin D 3 • As already noted, plasma 1,25-dihydroxyvitamin D levels fall with advancing renal failure. In the face of a relative or absolute deficiency of circulating 1,25-dihydroxyvitamin D, excessive PTH will effect bone resorption but in a disorderly and pathologic manner. Second, the impaired production of 1,25-dihydroxyvitamin D 3 leads to impaired intestinal absorption of calcium which also contributes to hypocalcemia. It is possible, but not proved, that the metabolic acidosis so commonly observed in chronic renal failure may further impair bioactivation of 1,25-dihydroxyvitamin D 3 from whatever functioning renal tissue is present. 27 Whether or not the uremic state itself or a deficiency of 1,25-dihydroxyvitamin D 3 directly impairs bone mineralization remains a matter of conjecture, but either mechanism would help to explain the presence of predominant osteomalacia noted in some patients. 75 Indeed, the classic theory of rickets, which holds that a decreased intestinal absorption of calcium and phosphorus leads to a fall in the ion product (Ca + + x HP0 4 - -) and reduced mineralization of osteoid matrix, does not hold in renal failure, where phosphate retention is the rule and the ion product remains normal. The observation that vitamin D therapy can improve the mineralization defect in renal osteodystrophy without changing the ion product has been the major basis for believing that vitamin D exerts a direct effect on bone. 33

From this brief review of the pathogenesis ofrenal osteodystrophy, three important features of the treatment program should be obvious: (1) administration of normal amounts of elemental calcium in the diet and with the aid of supplements if necessary (normal amounts range from 0.5 to 1.5 gm per day depending on the age and size of the child); (2) control of serum

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VITAMIN D IN BONE DISEASE

Hyperparathyt-oidism

Impaired Mineralization

.,~.

Figure 5.

Pathogenetic factors in renal osteodystrophy.

phosphate in the normal range with the use of phosphate binders; 98 and (3) control of metabolic acidosis with appropriate doses of alkali. 14

Vitamin D Therapy Although the spectrum of renal osteodystrophy varies widely in published reports, disturbances in vitamin D metabolism are invariably present and play an important role in pathogenesis. However, the requirement for pharmacologic doses of vitamin D in any of its currently available forms suggests more a picture of vitamin D resistance than vitamin D deficiency from a simple lack of the precursor or one of its metabolites. Recent attention has focused on 1,25-dihydroxyvitamin D 3 because it is produced by the kidney, it is the most potent biologically active vitamin D compound in promoting intestinal calcium absorption and bone resorption, and it is deficient in the plasma of patients with advanced renal failure. However, as will be discussed below, the other D vitamins have been employed in renal osteodystrophy, and in many cases mimic the beneficial effects of 1,25dihydroxyvitamin D 3 • The major differences between these other D vitamins and 1,25-dihydroxyvitamin D 3 are the doses required to achieve therapeutic efficacy based on relative potencies and the frequency and duration of episodes of hypercalcemia. The general goals of therapy with vitamin D in renal osteodystrophy are: (1) to increase intestinal absorption of calcium and phosphorus to normal; (2) to restore a normal calcemic response of the skeleton to PTH in the control of serum calcium; (3) to reduce secondary hyperparathyroidism; and (4) to restore normal and orderly mineralization of osteoid. Vitamin D and DHT. Vitamin D has been sporadically employed in the treatment of renal osteodystrophy for several decades, but it was not until 1961 that the first systematic observations of the effects of vitamin D in renal osteodystrophy were reported. 31 In that report, Dent et al. detailed

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their experience with 0 and dihydrotachysterol, which was the synthetic product of irradiated ergosterol, now known as OHT. Although all of the children reported in this study went on to die of end-stage renal failure, treatment with vitamin 0 provided marked relief of symptoms, improvements in calcium balance and radiographic abnormalities, and a lowering of elevated serum phosphate. Subsequent to that classic report, OHT supplanted vitamin 0 as the vitamin 0 agent of choice in renal osteodystrophy. This was based partly on the knowledge that OHT required only 25-hydroxylation by the liver to 25-hydroxy OHT to become biologically active in man, thus bypassing renal metabolism. For obvious reasons, this was an attractive characteristic of a drug intended for use in chronic renal failure! In addition, OHT had a shorter half-life than vitamin 0, ensuring a shorter period of hypercalcemia if too large a dose was administered. Subsequent studies primarily in hemodialyzed adults 26• 57 and children 68 but occasionally in nondialyzed patients 104 confirmed the efficacy and relative safety of OHT. It remains the vitamin 0 agent of choice in juvenile renal osteodystrophy at the present time, although no controlled studies of its use in this condition have been reported. 1,25-Dihydroxyvitamin D 3 and la-Hydroxyvitamin D 3 • A voluminous literature has accumulated regarding the treatment of renal osteodystrophy with 1,25-dihydroxyvitamin 0 3 or its synthetic congener, 1a-hydroxyvitamin 0 3 • It was natural that this agent should be tried for the reasons cited above. There is, nonetheless, no consensus among investigators in this field about when and how to use these metabolites in renal osteodystrophy. The primary reason for this continuing uncertainty relates to two observations: (1) the marked degree of variability in their efficacy in published reports, and (2) the absence of long-term, randomized controlled trials comparing 1,25dihydroxyvitamin 0 3 with OHT and 25-hydroxyvitamin 0 3 in carefully matched patients. Early studies focused on adults undergoing hemodialysis and confirmed the potent effects of 1,25-dihydroxyvitamin 0 3 or 1a-hydroxyvitamin 0 3 in promoting intestinal calcium absorption, raising serum calcium, healing osteitis fibrosa on radiographs, and reducing alkaline phosphatase. These studies have been recently summarized in an excellent review. 71 PTH levels also fell in these patients, though not to normal. An unanswered question in these early studies, which is still not resolved today, is whether the fall in PTH was a direct effect of 1,25-dihydroxyvitamin 0 3 on the parathyroid gland or was mediated through the elevations in serum calcium. In children who had not responded satisfactorily to vitamin 0, Chan et al. 15 and Chesney et al. 17 have recently reported favorable effects on linear growth and growth velocity, serum chemistries, secondary hyperparathyroidism, and mineralization of cortical bone. Full catchup growth did not occur, especially in the children whose chronic renal failure and osteodystrophy began very early in life. 17 Subsequent studies employing sequential bone biopsies confirmed suspected healing of osteitis fibrosa, 8 • 69 especially in patients with the mixed lesion, and at least one report demonstrated a definite beneficial effect of 1,25-dihydroxyvitamin 0 3 on adult osteomalacia. 5 9 However, others suggested that 1,25-dihydroxyvitamin 0 3 would only improve mineralization in the face of "normal" circulating levels of 25- and/or 24,25-dihydroxyvitamin 0 3 •22•53 The published effects of 1,25-dihydroxyvitamin 0 3 on renal osteodystrophy

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Table 5.

Effects of 1,25(0H)2 D 3 on Renal Osteodystrophy

PARAMETER

PRE-THERAPY

Growth Velocity Serum calcium Serum Pi Serum alkaline phosphatase Serum parathyroid hormone Calcium absorption Calcium resorption X-rays Bone mineral content Bone biopsy

Decreased Decreased Normal to Increased Increased Increased Decreased Decreased Osteitis fibrosa Osteomalacia (Rickets) Decreased Osteitis fibrosa Osteomalacia

POST-THERAPY

Increased Increased Variable Variable Decreased Increased Increased Healing Healing Increased Healing Variable

are summarized in Table 5. The doses of 1,25-dihydroxyvitamin D 3 and 1uhydroxyvitamin D 3 required to produce therapeutic responses were virtually identical. With increasing reports of bone biopsies in renal osteodystrophy, the histologic heterogeneity of this disorder began to emerge. For example, in addition to osteomalacia, osteitis fibrosa, and the mixed lesion, a peculiar form of dialysis bone disease emerged, characterized by almost pure osteomalacia with low bone turnover, normal to slightly elevated serum calcium, normal PTH, and marked sensitivity to the toxic (i.e., hypercalcemic) effects of 1,25-dihydroxyvitamin D 3 without any positive therapeutic response. 24 This syndrome, known as "dialysis osteomalacia," is now known to be related to aluminum toxicity from aluminum in dialysis water, chronic ingestion of aluminum antacid preparations, or a combination of these factors. 24 A comprehensive review of the literature suggests that the decision to employ 1,25-dihydroxyvitamin D 3 in renal osteodystrophy include the considerations outlined in Table 6, and that it be made in consultation with a pediatric nephrologist. 25-Hydroxyvitamin D 3 • 1,25-Dihydroxyvitamin D 3 was not the only vitamin D metabolite being tested in renal osteodystrophy in the early to Table 6.

1,25(0H)2 D 3 Treatment of Renal Osteodystrophy

Indications Symptomatic bone disease (pain, fractures, deformities) Hypocalcemia Hyperparathyroidism X-ray and!or bone biopsy evidence of osteitis fibrosa

Factors Influencing Therapeutic Response Dose of calcitriol Duration of therapy Degree of hyperparathyroidism Calcium intake Serum levels of 25(0H)D and 24,25(0H)zD Histologic pattern on bone biopsy

, Contraindications Normal to elevated serum calcium Uncontrolled hyperphosphatemia Normal serum PTH and!or absence of osteitis fibrosa Bone biopsy evidence of predominant osteomalacia

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mid 1970's. 25-Hydroxyvitamin D, was much less expensive and more widely available for experimental studies. In pharmacologic doses, it was shown to promote intestinal calcium absorption in uremic man92 but was only 1:400 as potent as 1,25-dihydroxyvitamin D,25 as compared to a 1:125 ratio of potency in normal man. Subsequently, in 1976, 25-hydroxyvitamin D, was shown to exert a favorable effect on both secondary hyperparathyroidism and osteomalacia in adults 103 and children 108 undergoing chronic hemodialysis. Since then, several reports in adults 39• 87• 91 and children64 have confirmed these earlier observations, and emphasized a particularly beneficial effect on the osteomalacia component of renal osteodystrophy when compared to 1,25- or la-hydroxyvitamin D,. 37 Our own studies in children with mild to moderate chronic renal failure and early renal osteodystrophy reveal that 25-hydroxyvitamin D 3 is a remarkably safe and effective metabolite when administered over long periods. It improves linear growth, and often but not always heals both osteitis fibrosa and osteomalacia with a more pronounced effect in the latter lesion. 76 Three questions naturally arise from these· observations: does 25-hydroxyvitamin D, exert its therapeutic effects (1) by conversion to 1,25dihydroxyvitamin D, or 24,25-dihydroxyvitamin D 3 by residual renal tissue; (2) by stimulation of extrarenal synthesis of 1,25-dihydroxyvitamin D 3 ; or (3) by displacement of 1,25-dihydroxyvitamin D 3 from its natural receptor because of its high concentration in the small intestine, at the bone-fluid interface, and so forth. Alternatively, does 25-hydroxyvitamin D, exert its own unique biologic effects in chronic renal failure distinct from 1,25dihydroxyvitamin D,? Recent studies in vitamin D-deficient osteomalacic adults suggest that this latter hypothesis may in fact be correct. 84 24,25-Dihydroxyvitamin D,. At the present time, there are insufficient data available on the therapeutic effects of 24,25-dihydroxyvitamin D, in renal osteodystrophy to recommend its use. Controlled clinical trials comparing this metabolite with the other metabolites previously discussed, and combining 24,25-dihydroxyvitamin D 3 with 1,25-dihydroxyvitamin D 3 , are currently under way. The observations upon which these trials are based include the following: 24,25-dihydroxyvitamin D 3 (1) promotes intestinal calcium absorption; 52 (2) stimulates bone formation; 79 (3) directly inhibits PTH secretion; 12 and (4) is reduced in the plasma of uremic patients, 48• 78 • 101• 107 but may be required in normal concentrations to enhance the actions of 1,25dihydroxyvitamin D 3 •

VITAMIN D TOXICITY The only recognized toxicity of any vitamin D preparation is hypercalcemia, which may or may not be symptomatic. Symptoms include abdominal pain, vomiting, polyuria, headaches, hypertension, and seizures. Most pertinent to this review are the effects resulting from metastatic calcification with particular reference to the kidney. Acute hypercalcemia has potential renovascular effects that can sharply reduce the glomerular filtration rate, while acute or chronic hypercalcemia may cause nephrocalcinosis and/or nephrolithiasis, also reducing renal function. 45 It is not known if the vitamin D

VITAMIN D IN BONE DISEASE

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metabolites can exert a direct adverse effect on renal function. A controversy currently exists in the literature with particular reference to 1,25-dihydroxyvitamin 0 3 • Some authors report accelerated deterioration in the glomerular filtration rate21 while others deny it. 70 At issue are the methods employed to assess the glomerular filration rate, and the frequency of measurements over time. In addition, in order to properly assess the specific effects of vitamin D on renal function in renal osteodystrophy, it is necessary to keep serum calcium, phosphorus, and PTH constant during the periods of observation. This has not always been done in the published studies. Finally, it is well recognized that previously stable chronic renal failure in children often enters a stage of accelerated deterioration to end-stage renal failure when puberty commences, quite independent of any vitamin D therapy. Notwithstanding the controversies over the renal toxicity of the D vitamins, it is quite clear that a major practical advantage of 1,25-dihydroxyvitamin 0 3 or 1a-hydroxyvitamin 0 3 over all of the other vitamin D compounds is the very rapid turnover. This results in only transient episodes of hypercalcemia when toxicity occurs, providing the drug is stopped promptly.

GOALS FOR FUTURE STUDY It is this author's opinion that the goals for future studies of vitamin D therapy for metabolic bone diseases can best be achieved by controlled clinical trials, especially with respect to renal osteodystrophy. Questions that need answering include: (1) When in the course of chronic renal failure should a vitamin D agent be given? (2) How should therapeutic efficacy be assessed? Will serial measurements of plasma levels of vitamin D metabolites correlate with clinical and laboratory improvements? (3) What is the best metabolite or combination of metabolites to administer in a particular (histologic) subtype of renal osteodystrophy?

CURRENT RECOMMENDATIONS No review of this type should end without a set of treatment guidelines for the practicing pediatrician. In applying a "state of the art" knowledge of vitamin D metabolism in health and in metabolic bone diseases to the vitamin D therapy of these diseases, the author offers the following recommendations: (1) Vitamin D deficiency states should be treated with the appropriate doses of vitamin D itself. (2) Familial hypophosphatemic rickets should be treated with a combination of phosphate and large doses of vitamin D or DHT. Use of 1,25-dihydroxyvitamin 0 3 should be reserved for patients unresponsive to D or DHT, and administered in conjunction with a physician expert in this field. Alternatively, initial therapy with this metabolite should be administered after the appropriate consultation is obtained. (3) Children with Fanconi' s syndrome and vitamin D dependency should be treated in conjunction with an expert. (4) Children with renal osteodystrophy should be treated with DHT. If one of the vitamin D metabolites is being contemplated, consultation with a pediatric nephrologist is in order.

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