Novel, selective vitamin D analog suppresses parathyroid hormone in uremic animals and postmenopausal women.
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.


CONCLUSIONS
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.
Department of Biochemistry, University of Wisconsin-Madison, and Deltanoid Pharmaceuticals, Inc.,Madison, Wisc., USA.
Julia B
JB
Zella
Lori A
LA
Plum
David R
DR
Plowchalk
Michael
M
Potochoiba
Margaret
M
Clagett-Dame
Hector F
HF
DeLuca
D000818:Animals; D050071:Bone Density Conservation Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy / Q000209:etiology; D008297:Male; D010280:Parathyroid Glands / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood*; D010758:Phosphorus / Q000097:blood; D017698:Postmenopause / Q000097:blood / Q000187:drug effects*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000150:complications; D014511:Uremia
C468519:2-methylene-1,25-dihydroxy-19-norvitamin D3; D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone; D010758:Phosphorus; D002117:Calcitriol; D002118:Calcium