A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia.

Abstract

Vitamin D(3) analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC(50) = 7.1 +/- 1.6 nM) and induced osteocalcin promoter activity (EC(50) = 1.9 +/- 1.6 nM). VDRM2 was less potent in inducing Ca(2+) channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC(50) = 37 +/- 12 nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08 microg/kg per day. Hypercalcemia was observed at a dose of 4.6 microg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35-91]. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046 microg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23 microg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1-13, 3.2-7.7, and 3.5-6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential.

• Authors: Masahiko Sato, Jianliang Lu, Stephen Iturria, Keith R Stayrook, Lorri L Burris, Qing Qiang Zeng, Allen Schmidt, Robert J Barr, Chahrzad Montrose-Rafizadeh, Henry U Bryant, Yanfei L Ma
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 25 Issue 6 Pg. 1326-36 (Jun 2010) ISSN: 1523-4681 [Electronic] United States
• PMID: 20200930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 American Society for Bone and Mineral Research.

Chemical References

• Ligands
• Receptors, Calcitriol
• Retinoid X Receptors
• TRPV Cation Channels
• TRPV6 channel
• Osteocalcin
• Cholecalciferol
• Luciferases

Topics

• Animals
• Binding, Competitive (drug effects)
• Biological Assay
• Biomechanical Phenomena (drug effects)
• Bone Density (drug effects)
• Bone Diseases, Metabolic (complications, pathology)
• Bone and Bones (drug effects, pathology)
• Cholecalciferol (analogs & derivatives, pharmacology, therapeutic use)
• Female
• Humans
• Hypercalcemia (complications, drug therapy, pathology)
• Ligands
• Luciferases (metabolism)
• Osteocalcin (metabolism)
• Protein Multimerization (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcitriol (metabolism)
• Retinoid X Receptors (metabolism)
• TRPV Cation Channels (genetics)
• Transcriptional Activation (drug effects, genetics)
• Treatment Outcome