Renal Bone Disease

Kidney International (1999) 56, S46–S51; doi:10.1046/j.1523-1755.1999.07305.x

New analogs of vitamin D3

Eduardo Slatopolsky, Adriana Dusso and Alex Brown

Renal Division, Washington University School of Medicine, St. Louis, Missouri

Correspondence: Eduardo Slatopolsky, M.D., Washington University School of Medicine, Renal Division, 660 South Euclid Ave., St. Louis, Missouri 63110, USA.

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Abstract

New analogs of vitamin D3. Calcitriol, the most active metabolite of vitamin D, controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone (PTH). However, because of its potent effects on intestinal calcium absorption and bone mobilization, calcitriol treatment can induce hypercalcemia, often precluding its use at therapeutic doses. Hyperphosphatemia is also a persistent problem among patients undergoing chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol. Several pharmaceutical companies were able to modify the side-chain of the 1,25(OH)2D3, allowing some of these new analogs to retain the action on the parathyroid glands while decreasing their hypercalcemic and hyperphosphatemic effects. The structure-activity relationship for ligand-mediated transcriptional regulation has been studied in detail. In some analogs the serum binding protein (DBP) plays a key role in determining the pharmacokinetics of the vitamin D compound. The affinity to DBP for 22-oxacalcitriol (OCT), an analog of calcitriol for the treatment of secondary hyperparathryoidism, is approximately 300–400 times lower than that of calcitriol and the analog is rapidly cleared from the circulation. The mechanisms for the selectivity of 19-nor-1,25(OH)2D2 (paricalcitol) (Zemplar®) another analog of calcitriol, is clearly different from OCT. Although the mechanisms of action is not completely known, it does appear that paricalcitol down-regulates the VDR in the intestine. It is likely that the unique biological profiles of vitamin D analogs in vivo are due to multiple mechanisms. Understanding the molecular basis of the analog selectivity will not only provide an explanation for their unique actions but allow intelligent design of more effective analogs in the future.

Keywords:

calcitriol, hypercalcimia, hyperphosphatemia, paricalcitol, parathyroid hormone

The vitamin D hormone calcitriol (1,25(OH)2D3), the most active metabolite of vitamin D, controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone (PTH)1,2,3,4,5. Because of its effects in PTH suppression, 1,25(OH)2D3 has been successfully used in the treatment of secondary hyperparathyroidism which almost always accompanies chronic renal failure6,7,8. The efficacy of intravenously administered 1,25(OH)2D3 in suppressing PTH levels in patient with secondary hyperparathyroidism is well established. However, because of its potent effects on intestinal calcium absorption and bone calcium mobilization, 1,25(OH)2D3 treatment can induce hypercalcemia, often precluding the use of therapeutic doses. Hyperphosphatemia is also a persistent problem among patients undergoing chronic hemodialysis and can be aggravated by therapeutic doses of 1,25(OH)2D39,10. The use of large doses of calcium carbonate or acetate to control phosphate absorption only increases the risk of hypercalcemia resulting from 1,25(OH)2D3 therapy11,12,13. Therefore an analog of 1,25(OH)2D3 that retains the therapeutic effects on PTH levels but has only minor impacts on calcium and phosphate metabolism would be an ideal tool for the treatment of secondary hyperparathyroidism.

The biological actions of calcitriol are mediated by the nuclear vitamin D receptor (VDR). Upon binding 1,25(OH)2D3, the VDR undergoes a conformational change and forms a complex with a retinoid X receptor (RXR). The VDR/RXR complex binds to specific sequences in target genes and may increase or decrease the rate of gene transcription Figure 1. At present, there is evidence for only a single form of the VDR. Thus, the same VDR mediates both the calcemic actions and the nonclassical, potentially therapeutic actions of calcitriol.

Figure 1.
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Transcriptional control of gene expression by 1,25(OH)2D3. The diagram shows the key steps involved in transcriptional regulation of 1,25(OH)2D3: (1) Ligand binding to the vitamin D receptor (VDR); (2) heterodimerization of VDR with retinoid X receptor (RXR); (3) binding of the VDR/RXR complex to the vitamin D response element; and (4) recruitment of components of the RNA polymerase II (Pol II) complex, including direct interactions with captivators (CoA) and transcriptional factor IIB (B). (Reproduced with permission from20).

Full figure and legend (22K)

The novel aspect of these analogs is their differential actions, compared to 1,25(OH)2D3in vivo. In fact, as these analogs have a relatively high affinity for the vitamin D receptor, it is not unexpected that they are able to mimic many of the actions of 1,25(OH)2D3in vivo. The unique feature of the therapeutically useful analogs is the ability to efficiently support some but not all 1,25(OH)2D3 associate activities. Most commonly, the analogs display decreased potency in enhancing intestinal absorption or bone mobilization of calcium and phosphorus. In some cases, the analogs have a relatively high calcemic effect, but tend to produce even higher activities in other specific cells or tissues. The selectivity is not always cell or tissue specific, but can be gene or process specific within the same tissue.

The structure-activity relationship for ligand-mediated transcriptional regulation has been studied in detail. The A-ring structure is most crucial, especially the hydroxyl groups, for binding to the VDR. Modification of the D-ring or side chain does not greatly affect VDR binding, but can influence biological potency by altering the pharmacokinetics or catabolism. Analogs can also produce distinct conformational changes in the VDR that may produce gene-specific actions. A combination of structural modifications can produce analogs with diverse biological profiles.

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MECHANISMS FOR ANALOG SELECTIVITY

In the past 10 years several laboratories have studied the potential mechanisms involved in the selectivity of vitamin D analogs14. The apparent tissue specificity for the action of analogs can be attributed to several potential mechanisms including 1) altered DBP affinity; 2) association with other serum carriers including lipoproteins; 3) altered cellular uptake; 4) accumulation of active metabolites within the cell; 5) different rates of catabolic inactivation; 6) differential activation of the nongenomic pathway via a distinct membrane-bound receptor (mVDR); 7) altered binding to the nuclear VDR leading to changes (increases or decreases) in 8) VDR-RXR heterodimerization, 9) DNA binding of the VDR-RXR complex, and 10) formation of the preinitiation complex14 Figure 2. Thus, differences in intracellular metabolism, pharmacokinetics, nongenomic activities, and interactions with the VDR may provide potential explanations for the in vivo selectivity of any analog. Likely, more than one of these mechanisms contribute to the unique in vivo activity profile of each analog.

Figure 2.
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Potential sites of differential action of 1,25(OH)2D3 and analogs. The possible stems in the vitamin D activation pathways at which differences in vitamin D analog action could lead to selective activities in vivo are shown. The steps diagramed include: (1) DBP affinity (2) interaction with other serum proteins including lipoproteins (3) cellular uptake (4) conversion to active metabolism (5) catabolic inactivation (6) activation of the nongenomic pathway through a putative membrane vitamin D receptor (mVDR) (7) interaction with the nuclear vitamin D receptor (VDR) (8) formation of the VDR-RXR complex (9) binding of the activated complex to DNA and (10) formation of the preinitiation complex with RNA polymerase II. (Reproduced with permission from14).

Full figure and legend (33K)

The serum vitamin D binding protein (DBP) plays a key role in determining the pharmacokinetics of the vitamin D compound. This protein binds all the natural vitamin D metabolites and thereby greatly enhances the circulating half-life, but at the same time it reduces their uptake by the target tissue. Many of the side-chain–modified analogs have lower DBP affinity than 1,25(OH)2D3 which increases their clearance rate but allows them to be more accessible to the target cells. The affinity of 22-oxacalcitriol (OCT), one such analog, is approximately 300–400 times lower than that of 1,25(OH)2D3 and the analog is rapidly cleared from the circulation15,16,17. At the same time, the tissue uptake of OCT is greater, but more transient, than that of 1,25(OH)2D317,18. The short residence time of OCT in the intestine and bone produces only transient increases in calcium absorption and bone mobilization18. However, the same pulse of OCT in the parathyroid glands elicits a prolonged suppression of PTH, probably due to the longer half-life of this response.

The mechanisms for the selectivity of 19-nor 1,25(OH)2D2 (paricalcitol) (Zemplar®), another analog of calcitriol, are clearly different from OCT. The DBP affinity of paricalcitol is nearly the same as that of 1,25(OH)2D3; therefore its clearance rate and time course of tissue localization are similar to those of 1,25(OH)2D3. The mechanisms responsible for the action of paricalcitol are not known, but it does appear that paricalcitol down regulates the VDR in the intestine19.

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SELECTIVE VITAMIN D ANALOGS FOR SECONDARY HYPERPARATHYROIDISM

The development of analogs for the treatment of secondary hyperparathyroidism involves a series of evaluations. The first criterion was that the analog retained reasonably high affinity for the vitamin D receptor. As we described above this will require the presence of an hydroxyl group at the 1 alpha position. The second criterion was that the analog had substantially less calcemic activity than 1,25(OH)2D3. Despite high VDR affinities many analogs have greatly reduced abilities to raise serum calcium. For example, the diminished calcemic action of 19-nor 1,25(OH)2D2 cannot really be attributed to decreased binding to the VDR20.

The third criterion was the ability to suppress PTH secretion not only in vitro but also in vivo, since some of these analogs that are very effective in vitro are rapidly metabolized in vivo and are unable to suppress secondary hyperparathyroidism. Currently there is substantial experimental and clinical evidence with 2 analogs, 22-oxacalcitriol (OCT) and 19-nor 1,25(OH)2D2 (paricalcitol, Zemplar®). In addition there is clinical information in regard to 1alpha-(OH)D221.

Figure 3 depicts the structure of 1,25(OH)2D3 and several vitamin D analogs with important therapeutic application. 1,25(OH)2D3 inhibits cell proliferation and promotes cell differentiation. However, its use in conditions like psoriasis is limited by its calcemic activity. Calcipotriol on the other hand, was found to induce terminal differentiation of cultured keratinocytes as potently as 1,25(OH)2D3 but it was more than 200 times less potent in raising serum and urinary calcium in normal rats when given orally or intraperitoneally22. A series of analogs has been tested experimentally in the clinical arena for the suppression of secondary hyperparathyroidism. One of these compounds, 22-oxacalcitriol (OCT), is made in Japan by Chugai Laboratories. It differs from 1,25(OH)2D3 solely by the substitution of an oxygen atom for the methylene group at carbon 22 Figure 3. OCT can inhibit pre pro PTH mRNA levels in vivo as effectively as 1,25(OH)2D323. In contrast OCT is less calcemic than 1,25(OH)2D3 in normal mice24 and rats23.

Figure 3.
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Chemical structure of calcitriol and several vitamin D analogs. (Reproduced with permission from20).

Full figure and legend (29K)

Furthermore, unpublished studies presented by Akisawa et al in the renal osteodystrophy satellite symposium of the International Society of Nephrology Meeting in Iguazu Falls, Australia (May 7–10, 1999), clearly demonstrated the capability of this drug to suppress secondary hyperparathyroidism in patients with advanced renal failure with minor changes in serum calcium. Thus, although more studies are necessary to completely assess the effectiveness of the drug, this analog apparently has a significant therapeutic advantage over 1,25(OH)2D3 in the control of secondary hyperparathyroidism without inducing severe hypercalcemia and hyperphosphatemia as observed with the administration of 1,25(OH)2D3.

Results obtained during a small clinical trial with 1alpha-hydroxyvitamin D2 have recently been published21. In this study, patients with moderate or severe secondary hyperparathyroidism received the vitamin D analog at a dose of 4 mug daily or three times per week following dialysis. During the study the mean drop in serum PTH levels was slightly more than 50%. Serum calcium levels rose slightly from 8.8 plusminus 0.18 to 9.5 plusminus 0.21 mg/dL (P < 0.01). 1alpha-hydroxyvitamin D2 (Hectoral) has recently been approved for oral treatment of secondary hyperparathyroidism.

We have done extensive work with 19-nor-1,25(OH)2D225. This analog has the carbon-28 and the double bond at the carbon-22 that are characteristics of the vitamin D2 compounds, but it lacks the carbon-19 and the exocyclic double bond found in all natural vitamin D metabolites Figure 3. We demonstrated that 19-nor-1,25(OH)2D2 suppresses parathyroid hormone secretion in primary cultures of bovine parathyroid cells as potently as 1,25(OH)2D3. In addition, this compound can suppress pre pro PTH messenger RNA and PTH secretion without inducing hypercalcemia or hyperphosphatemia Figure 4. Daily administration of 19-nor 1,25(OH)2D2 to parathyroidectomized rats fed either a calcium- or a phosphorus-deficient diet for 9 days produced smaller increases in plasma calcium and phosphorus than 1,25(OH)2D3. Dose–response studies demonstrated that 19-nor-1,25(OH)2D2 is approximately 10 times less active than 1,25(OH)2D3 in mobilizing calcium and phosphorus from bone26. Moreover, in contrast to 1,25(OH)2D3 that up regulates the VDR in the intestine, 19-nor 1,25(OH)2D2 has the opposite effect19.

Figure 4.
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The effects of 19-nor-1,25(OH)2D2 on serum PTH in normal and uremic rats. All three doses of 19-nor-1,25(OH)2D2 (8, 25, and 75 ng) produced a significant decrease in circulating PTH levels. However, none increased ionized calcium levels. *, P < 0.01; †, P < 0.02. filled square, pretreatment values; square, posttreatment values. (Reproduced with permission from25).

Full figure and legend (30K)

The efficacy of 19-nor-1,25(OH)2D2 in renal failure patients was demonstrated in a recent study27 in 78 patients; placebo was given to approximately one-third of the patients, and 19-nor-1,25(OH)2D2 was administered to two-thirds of the patients. The dose was initially 0.04 mug and rose to an average of 0.12 mug/kg during the course of the seven week study. Serum PTH levels dropped an average of approximately 60% Figure 5 with only a slight increase in serum calcium from 9.24 plusminus 0.12–9.56 plusminus 0.15 dl Figure 6. There were only seven significant episodes of hypercalcemia out of 414 determinations. However, in these patients the PTH concentrations had decreased to very low levels, <100 pg/ml. Thus, the hypercalcemia likely was induced by an excessive administration of this analog. Since physicians have learned that a PTH of 300 pg/ml usually is accompanied by normal bone histology, in this study the physicians should have decreased the dose of 19-nor-1,25(OH)2D2 when they observed such a major decrease in the levels of serum PTH. Presumably, this would have further reduced incidence of hypercalcemia.

Figure 5.
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Changes in the levels of intact PTH expressed as a percentage of change from baseline values during the study period in placebo-treated (circle) and paricalcitol-treated (filled circle) groups. The bars depict the doses of paricalcitol that increase according to protocol. (Reproduced with permission from27).

Full figure and legend (21K)

Figure 6.
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The values for normalize serum calcium (upper lines) and serum phosphorus (lower lines) during the 12 weeks of study in placebo (circle) and paricalcitol (filled circle) groups.*P < 0.05. (Reproduced with permission from27).

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CONCLUSION

The predominant form of selectivity observed is that the analog has a much lower calcemic and phosphatemic activity than expected on the basis of nuclear VDR affinity and apparent high activity in vitro. Many of these analogs have been found to have low affinity for DBP and are therefore more rapidly cleared from the circulation, but at the same time they may be more accessible to target tissues. Pharmacokinetic changes may explain most of the differences in activity found with 22-oxacalcitriol compared to 1,25(OH)2D3. The rate of intracellular catabolism can vary with cell type and may produce tissue-specific effects of the analogs. Vitamin D analogs may also induce different conformational changes in the VDR upon binding26, which could influence transactivation on a gene-specific basis by altering VDR interactions with other components of the transcriptional complex or specific DNA elements. It is likely that the unique biological profiles of vitamin D analogs in vivo are due to multiple mechanisms. Understanding the molecular basis of the analog selectivity will not only provide an explanation for their unique actions but allow intelligent design of more effective analogs in the future.

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References

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