title: Effects of denosumab on bone turnover markers in postmenopausal osteoporosis.
abstract: Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab-treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C-telopeptide of type I collagen [CTX] and tartrate-resistant acid phosphatise [TRACP-5b]) and bone formation (serum procollagen type I N-terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab-treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab-treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = -0.24 to -0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.
authors.affiliation: National Institute for Health Research Bone Biomedical Research Unit, University of Sheffield, Sheffield, United Kingdom. r.eastell@sheffield.ac.uk
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Andreas
authors.initials: A
authors.lastname: Grauer
authors.forename: Stepan
authors.initials: S
authors.lastname: Kutilek
authors.forename: Cesar
authors.initials: C
authors.lastname: Libanati
authors.forename: Michael R
authors.initials: MR
authors.lastname: McClung
authors.forename: Ian R
authors.initials: IR
authors.lastname: Reid
authors.forename: Heinrich
authors.initials: H
authors.lastname: Resch
authors.forename: Ethel
authors.initials: E
authors.lastname: Siris
authors.forename: Daniel
authors.initials: D
authors.lastname: Uebelhart
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang
authors.forename: Georges
authors.initials: G
authors.lastname: Weryha
authors.forename: Steve R
authors.initials: SR
authors.lastname: Cummings
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects*; D024042:Collagen Type I / Q000097:blood; D000069448:Denosumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000097:blood; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000097:blood; D011347:Procollagen / Q000097:blood; D053245:RANK Ligand / Q000494:pharmacology* / Q000627:therapeutic use*; D012016:Reference Values; D018709:Statistics, Nonparametric; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D007527:Isoenzymes; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D053245:RANK Ligand; C052929:collagen type I trimeric cross-linked peptide; C047202:procollagen Type I N-terminal peptide; D000069448:Denosumab; D000469:Alkaline Phosphatase; C000605510:ACP5 protein, human; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase