Novel, Selective Vitamin D Analog Suppresses Parathyroid Hormone in Uremic Animals and Postmenopausal Women

Abstract

Background: The use of 1α-hydroxylated vitamin D therapy to control secondary hyperparathyroidism in renal failure patients has been a success story, culminating with the demonstration of increased life expectancy in patients treated with these compounds. However, hypercalcemic episodes have been a recurrent problem with these therapies and have resulted in the added use of calcium mimetics. Clearly there is good reason to search for improved vitamin D therapy. In our inventory of vitamin D compounds, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) surfaced as a potential candidate. This was based on its preferential localization in the parathyroid gland and a clear suppression of serum parathyroid hormone (PTH) levels without a change in serum calcium in a clinical trial in postmenopausal women. Methods: 2MD has now been tested in the rat 5/6-nephrectomy model of renal failure, and in postmenopausal women to determine if it can suppress serum PTH at doses that do not elevate serum calcium and serum phosphorus concentrations. Results: Daily oral treatment of uremic rats on 2.5 ng/bw/day of 2MD dramatically suppressed PTH without a change in serum calcium or serum phosphorus. Further, PTH was suppressed in postmenopausal women after only 3 daily oral doses of 2MD that continued for 4 weeks with no change in serum calcium or serum phosphorus. Conclusion: These results coupled with a pharmacokinetic half-life of ~24 h suggest that 2MD given either daily or at the time of dialysis may be a superior therapy for secondary hyperparathyroidism in chronic renal failure patients.

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

“…In this study 2MD suppressed serum PTH levels dose-dependently without elevating serum calcium levels at the lowest dose of 220 ng/day. Recently a dose-finding study with 2MD in postmenopausal women confirmed the PTH suppressive effects of 2MD without calcemic side effects (509). A distribution study performed in rats showed that radioactive 2MD was accumulated in the classical target tissues of vitamin D (bone, intestine) but was most strongly localized in the thyroid/parathyroid (509).…”

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“…31,32 This would suggest that, in the absence of CsA or tacrolimus, 2AMD or 2MD may have a wider therapeutic window. In previous studies, 19,20 2MD was shown to suppress PTH in uremic rats, postmenopausal women, and hemodialysis patients with SHPT. The latter finding was from a dosing trial in which patients received oral 2MD 3 times weekly for 4 weeks and the effective dose range was 330 to 770 ng/dose (or 131-330 ng/day), which is equivalent to 2 to 4.7 ng/kg, assuming patient weight of 70 kg.…”

“…The effects of 2AMD at 4 different doses were compared to 2MD at 5 ng/kg in the CsA model, a concentration known to be effective in other measures of renal function. 19,20 Induction of nephrotoxicity was evident in our CsA model, as shown by histologic changes (including increased tubular atrophy and interstitial cellularity) and by significant rises in BUN, increased collagen, fibronectin and vimentin content, and decreased body weight. Testing a range of 2AMD dose regimens allowed us to identify an optimal therapeutic dose and allowed important assessments of the possible effects of a range of relevant doses.…”

“…15 Novel selective analogs of 1,25(OH)2D3, such as 2-methylene-19-nor-(20S)-1α,25-dihydroxivitamin D 3 (2MD), are known to be hyperactive vitamin D receptor agonists. 18,19 The 2MD analog has been shown to decrease PTH at doses that do not increase serum calcium or phosphorus levels in a uremic rat model of SHPT and in a cohort of postmenopausal women. 19 20 This was more recently confirmed in a double-blind, placebo-controlled trial that included dialysis patients who were previously administered a calcimimetic.…”

“…18,19 The 2MD analog has been shown to decrease PTH at doses that do not increase serum calcium or phosphorus levels in a uremic rat model of SHPT and in a cohort of postmenopausal women. 19 20 This was more recently confirmed in a double-blind, placebo-controlled trial that included dialysis patients who were previously administered a calcimimetic. 21 In this study, we report the effects of 2α-methyl-19-nor-(20S)-1α,25-dihydroxyvitamin D 3 (2AMD), an analog structurally similar to 2MD, on its ability to protect rat kidneys from cyclosporine (CsA)-induced nephrotoxicity.…”