Animals lacking the gene for osteoprotegerin, a decoy receptor that inhibits RANKL, have increased vascular calcification, suggesting that the RANK/RANKL pathway may play a role in this process. Denosumab (DMAb), a fully human mAb that inhibits RANKL, reduced fracture risk in the FREEDOM trial of postmenopausal women with osteoporosis (Cummings et al, N Engl J Med 2009;361:756). Here we report the effects of DMAb on vascular calcification in a subset of women from the FREEDOM trial at high risk for cardiovascular events.
A total of 7,868 postmenopausal women aged 60 to 90 years with osteoporosis were randomized to receive placebo (Pbo) or DMAb 60 mg Q6M for 3 years. In a sub-study, 2,363 subjects (1,142 Pbo, 1,221 DMAb) at high risk for cardiovascular events were identified by baseline risk factors, according to the modified RUTH criteria used in the MORE study (Keech et al, Curr Med Res Opin 2005;21:135). Using lateral lumbar spine x-rays taken at baseline, 12, 24, and 36 months, aortic calcification was scored from 0 to 3 for anterior and posterior aortic segments adjacent to L1-L4 as described in the Framingham Heart Study (Kauppila et al, Atherosclerosis 1997;132:245). Total aortic calcification severity scores were calculated by summing the 8 individual scores. Total scores could range from 0 to 24, with lower scores representing less aortic calcification. Baseline cardiovascular risk factors were similar between treatment groups with the most frequent being age ≥ 70 years (91%), hypertension (83%), and high cholesterol (65%). Aortic calcification severity scores and change from baseline in aortic calcification severity scores were similar for the Pbo and DMAb groups at all time points assessed. In conclusion, these findings suggest that the slight progression in severity of aortic calcification did not differ between Pbo and DMAb groups over 3 years of treatment in postmenopausal women with osteoporosis considered at high risk for cardiovascular events.
