title: RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk.
abstract: Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with bone mineral density (BMD). The osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2363 postmenopausal women with osteoporosis (1142 placebo, 1221 DMAb), selected from 7808 participants in the FREEDOM trial (3906 placebo, 3902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semiquantitative method from lateral spine X-rays. Change in AC score from baseline to 12 (n = 1377), 24 (n = 1231), and 36 months (n = 1045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score >0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60-90), 88% were white, and 77% had AC score >0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.
authors.affiliation: Institute for Aging Research, Hebrew Senior Life and Harvard Medical School, Boston, MA, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Samelson
authors.forename: Paul D
authors.initials: PD
authors.lastname: Miller
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Nadia S
authors.initials: NS
authors.lastname: Daizadeh
authors.forename: Luanda
authors.initials: L
authors.lastname: Grazette
authors.forename: Mary S
authors.initials: MS
authors.lastname: Anthony
authors.forename: Ogo
authors.initials: O
authors.lastname: Egbuna
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang
authors.forename: Suresh R
authors.initials: SR
authors.lastname: Siddhanti
authors.forename: Angela M
authors.initials: AM
authors.lastname: Cheung
authors.forename: Nathalie
authors.initials: N
authors.lastname: Franchimont
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D001018:Aortic Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000069448:Denosumab; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D061205:Vascular Calcification / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000069448:Denosumab
keywords: AORTIC CALCIFICATION; CARDIOVASCULAR; DENOSUMAB; OSTEOPOROSIS; RANKL/OPG