van Velsen Evert F S, Wijnen Mark, Muradin Galied S R, Zillikens M Carola
Department of Internal Medicine, Erasmus Medical Center, University Medical Center, 3015 CE, Rotterdam, the Netherlands.
Erasmus MC Bone Center, Erasmus Medical Center, University Medical Center, 3015 CE, Rotterdam, the Netherlands.
JCEM Case Rep. 2024 Dec 26;3(1):luae238. doi: 10.1210/jcemcr/luae238. eCollection 2025 Jan.
A defect in the canonical Wnt-β-catenin pathway may lead to reduced bone strength and increased fracture risk. Sclerostin is a key inhibitor of this pathway by binding to low-density lipoprotein (LDL) receptor-related protein , thereby reducing bone formation. The effectiveness of romosozumab, a human monoclonal antibody that binds sclerostin and prevents this inhibitory effect, has been questioned in patients with inactivating genetic variants in or . We present a 67-year-old woman with severe osteoporosis with 4 grade 2 vertebral fractures due to a heterozygous pathogenic variant in . She was treated with romosozumab for 1 year, after which a routine follow-up spine x-ray revealed 5 new vertebral fractures, despite a strong increase in bone mineral density (BMD) (lumbar spine [LS] + 58%; femur neck [FN] + 23%), although overestimated at LS because of the vertebral fractures. This suggests that in patients with loss-of-function variants, romosozumab is able to increase BMD. However, it is unclear whether the progressive vertebral fractures are due to the severe osteoporosis in relation to the start of romosozumab or a diminished responsiveness related to her variant. Further evaluation is needed on the effect of romosozumab on BMD and fracture outcomes in patients with a likely defective receptor.
经典Wnt-β-连环蛋白信号通路的缺陷可能导致骨强度降低和骨折风险增加。硬化蛋白是该信号通路的关键抑制剂，它通过与低密度脂蛋白（LDL）受体相关蛋白结合，从而减少骨形成。对于携带或基因失活变异的患者，一种能结合硬化蛋白并阻止这种抑制作用的人源单克隆抗体——罗莫单抗的有效性受到了质疑。我们报告了一名67岁患有严重骨质疏松症的女性，由于基因杂合致病变异导致4处2级椎体骨折。她接受了1年的罗莫单抗治疗，之后常规随访脊柱X光片显示出现了5处新的椎体骨折，尽管骨密度（BMD）大幅增加（腰椎[LS]增加58%；股骨颈[FN]增加23%），不过由于椎体骨折，腰椎处的骨密度增加可能存在高估。这表明对于携带功能丧失变异的患者，罗莫单抗能够增加骨密度。然而，目前尚不清楚椎体骨折进展是由于开始使用罗莫单抗时就存在的严重骨质疏松，还是与她的基因变异相关的反应性降低。对于罗莫单抗对可能存在受体缺陷的患者的骨密度和骨折结局的影响，还需要进一步评估。
