Endocrine Abstracts

In the ARCH study¹, romosozumab was compared with an active comparator, alendronate. Unexpectedly, an imbalance in adjudicated serious cardiovascular AEs was observed during the first year of the study, triggering numerous discussions among experts and giving rise to hypotheses regarding the mechanism leading to such a difference. However, it should be noted that an even lower cardiovascular risk in high-dose romosozumab treatment as compared to placebo was reported in a meta-analysis². In addition, a recent systematic review and meta-analysis showed no increase in cardiovascular risk with regard to stroke, atrial fibrillation, heart failure, coronary artery disease, and cardiovascular death individually while, however, increasing the risk for the composite of four-point major adverse cardiovascular events³. Given that these results were not completely conclusive³, a comparative trial between romosozumab and antiresorptive agents is needed to shed further light on this question. In conclusion, he difference in rates of cardiovascular events between romosozumab and alendronate seen in ARCH could be attributable to a possible cardioprotective effect of alendronate or could also represent a chance finding⁴. However, a recent genome-wide association study meta-analysis using Mendelian randomization in 33.961 European individuals provided genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 diabetes mellitus, myocardial infarction, and the extent of cardiovascular disease⁵. Thus, there is a need to develop strategies to mitigate potential AEs associated with romosozumab treatment on atherosclerosis and its related risk factors.

Highlights: • The role of wnt signalling in atherogenesis raises the possibility that the wnt inhibitor, sclerostin, provides a natural defence to this process, and that anti-sclerostin antibodies might increase the risk of atherosclerosis and associated conditions such as CVD.

• Randomised controlled trials of treatment with the anti-sclerostin antibody, romosozumab, have yielded conflicting evidence with respect to possible adverse effects of sclerostin inhibition on CVD risk.

• Three Mendelian randomisation (MR) studies have examined effects of sclerostin lowering on CVD outcomes. Concordant findings were seen in two studies, comprising an effect of sclerostin lowering on increased risk of MI and type II diabetes mellitus. One study also suggested that sclerostin lowering increases coronary artery calcification.

Triangulation of evidence from different sources provides some suggestion that sclerostin lowering increases MI risk, supporting the need for CVD risk assessment when considering treatment with romosozumab.

References: 1. Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, Maddox J, Fan M, Meisner PD, Grauer A (2017) Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 377(15):1417–1427. https://doi.org/10.1056/NEJMoa1708322.

2. Kaveh S, Hosseinifard H, Ghadimi N, Vojdanian M, Aryankhesal A (2020) Efficacy and safety of romosozumab in treatment for low bone mineral density: a systematic review and meta-analysis. Clin Rheumatol 39(11):3261–3276. https://doi.org/10.1007/s10067-020-04948-1.

3. Lv F, Cai X, Yang W, Gao L, Chen L, Wu J, Ji L (2020) Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: systematic review and meta- analysis. Bone 130:115121. https://doi.org/10.1016/j.bone.2019.115121.

4. Cummings SR, McCulloch C (2020) Explanations for the difference in rates of cardiovascular events in a trial of alendronate and romosozumab. Osteoporos Int 31(6):1019–1021. https://doi.org/10.1007/s00198-020-05379-z.

5. Zheng J, Wheeler E, Pietzner M, Andlauer TFM, Yau MS, Hartley AE, Brumpton BM, Rasheed H, Kemp JP, Frysz M, Robinson J, Reppe S, Prijatelj V, Gautvik KM, Falk L, Maerz W, Gergei I, Peyser PA, Kavousi M, de Vries PS, Miller CL, Bos M, van der Laan SW, Malhotra R, Herrmann M, Scharnagl H, Kleber M, Dedoussis G, Zeggini E, Nethander M, Ohlsson C, Lorentzon M, Wareham N, Langenberg C, Holmes MV, Davey Smith G, Tobias JH (2023) Lowering of circulating sclerostin may increase risk of atherosclerosis and its risk factors: evidence from a genome-wide association meta-analysis followed by mendelian randomization. Arthritis Rheumatol 75(10):1781–1792. https://doi.org/10.1002/art.42538.