Bone microarchitecture and strength in men and women with <i>PLS3</i> gene variants assessed with HR-pQCT

X-linked osteoporosis, caused by PLS3 genetic variants, is a rare bone disease, clinically affecting mainly men. Limited data are available on bone microarchitecture and genotype-phenotype correlations in this disease. Our aims were to assess bone microarchitecture and strength in adults with PLS3 variants using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to explore differences in the phenotype from HR-pQCT between PLS3 variants. HR-pQCT scans were obtained from the distal radius and tibia of 13 men and 3 women with PLS3 variants. Results were compared with age- and sex-matched controls from a normative dataset from literature and expressed as Z-scores. Median age was 46 yr for men and 48 yr for women. In men, total bone area was large (median Z-score: 1.33 radius; 1.46 tibia) due to a large trabecular area (+1.73 radius; +1.87 tibia), while the cortical area was small (-2.61 radius; -2.84 tibia). Total volumetric bone mineral density (BMD) was low due to low trabecular (-3.46 radius; -3.37 tibia) and cortical BMD (-2.87 radius; -2.26 tibia). Regarding bone microarchitecture, the largest deviations were found in trabecular number (-2.18 radius; -1.64 tibia), trabecular separation (+2.32 radius; +1.65 tibia), and cortical thickness (-2.99 radius; -2.46 tibia), whereas trabecular thickness and cortical porosity were normal (-0.36 and -0.58 radius; 0.09 and -0.79 tibia). Additionally, failure load was low (-2.39 radius; -2.2 tibia). Results in the women deviated less from normative data. Men with frameshift/nonsense variants seemed to have more deviant trabecular and cortical microarchitecture and strength, at both scan locations, than those with missense/in-frame insertion variants. In conclusion, HR-pQCT provides valuable insights into bone area, BMD, microarchitecture, and strength in adults with PLS3 variants and can be used to explore genotype-phenotype relationships. Longitudinal analyses in larger groups are needed to study the natural course of the disease and treatment effects.