Romosozumab is effective in patients with variants in LRP5, LRP6, or WNT1

Romosozumab has proven efficacy in postmenopausal osteoporosis, but data in LRP5/6 or WNT1 variant carriers are scarce. In 33 patient-years of women carrying such variants, romosozumab improved BMD and bone formation more than antiresorptives or no treatment. These findings suggest romosozumab as a potential therapy for genetically defined bone loss.

The sclerostin inhibitor romosozumab is an osteoanabolic drug that enhances the canonical Wnt-β-catenin pathway. While its efficacy in postmenopausal osteoporosis is known, clinical data on the use of romosozumab in patients with variants in the LRP5, LRP6, or WNT1 gene affecting this pathway remain limited.

We present clinical routine data of 33 patient-years in 27 postmenopausal women with heterozygous deleterious or established risk alleles variants (ACMG class 2-5) in the LRP5/6 or WNT1 gene, using dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and laboratory parameters. Among these, 12 were treated with vitamin D and calcium only (NoT), 11 with antiresorptive therapy (AR), and 10 with romosozumab (ROMO).

Patients treated with romosozumab showed significantly greater gains in areal bone mineral density (aBMD) compared to others (lumbar spine-NoT = -0.12% ± 5.02%, AR = + 3.97% ± 4.71%, ROMO = + 15.74% ± 7.63%, p < 0.001 for ROMO vs. AR and vs. NoT). This was accompanied by an increase in trabecular bone density and mass in the tibia, as well as elevated bone formation markers such as bone alkaline phosphatase after 6 months (AR = -3.36 µg/L ± 8.044 µg/L vs. ROMO = + 3.08 µg/L ± 2.21 µg/L, p = 0.026). Our findings indicate that romosozumab is effective in patients with heterozygous variants in the LRP5/6 or WNT1 gene. Here, romosozumab was superior to established antiresorptive treatments.

Thus, romosozumab might be a specific treatment for these patients. However, further studies are needed with larger patient cohorts and in particular with regard to biallelic loss-of-function variants in the LRP 5/6 or WNT1 gene.