Do bisphosphonates and RANKL inhibitors alter the progression of coronary artery calcification? A systematic review.

Objectives: To determine whether bisphosphonates and NF-κB ligand (RANKL) inhibitors delay coronary artery calcification (CAC).

Design: A systematic review was conducted.

Data Sources: MEDLINE, EMBASE and CENTRAL.

Eligibility Criteria: Longitudinal studies investigating CAC progression in adults (>18 years) taking either a bisphosphonate or denosumab compared with those who did not.

Data Extraction And Synthesis: Study and participant characteristics, and primary outcome ( ∆ CAC from baseline to follow-up) were extracted. The Risk Of Bias In Non-Randomised Studies-of Interventions (ROBINS-I) and Risk-of-Bias Tool for Randomised Trials (RoB2) tools were used to assess the risk of bias for observational and randomised controlled trials (RCTs), respectively. Outcome measures were reported.

Results: Four observational studies and one RCT (n=377) were included. Three studies solely reported the effect of bisphosphonates on ∆ CAC; one study (n=56) demonstrated a statistically significant CAC reduction in the intervention group (-372 mm/year) compared with control (+159 mm/year) (p<0.01). One study (n=14) demonstrated a difference in ∆ CAC between intervention (+880 mm/year) versus control (+2220 mm/year), however, no p value comparing groups was reported. One study (n=115) found no statistically significant difference between intervention and control.One study (n=42) exclusively investigated the effect of RANKL on ∆ CAC; there was a statistically significant reduction in CAC at 6-month follow-up between intervention (-133±124 modified Agatston unit (AU)) and control (+188±72 modified AU), p=0.03.One study (n=150) compared both bisphosphonates and denosumab to control and found no statistically significant difference between either intervention group and control over 24 months. Meta-analysis was not performed due to limited, heterogeneous studies.

Conclusions: There is insufficient evidence supporting the correlation between bisphosphonate or RANKL inhibitor use and CAC progression. Further research is warranted.