Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density.
Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.
Bone
Henry G
HG
Michigan Bone and Mineral Clinic, Detroit, MI 48236, USA. hgbone.md@att.net
McClung
Michael R
MR
Roux
Christian
C
Recker
Robert R
RR
Eisman
John A
JA
Verbruggen
Nadia
N
Hustad
Carolyn M
CM
DaSilva
Carolyn
C
Santora
Arthur C
AC
Ince
B Avery
BA
D000368:Aged; D000369:Aged, 80 and over; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000378:metabolism; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000473:pathology
D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; D056657:Cathepsin K; C527128:odanacatib