Effects of zoledronic acid on two rare cases of X-linked early-onset osteoporosis due to PLS3 mutations:a 3-year follow-up and literature review

SUN Zhi-xing; MA Ming-sheng; QIU Zheng-qing

doi:10.3969/j.issn.2095-252X.2025.08.005

Abstract：Objective To assess the 3-year efficacy of zoledronic acid(ZOL)infusion on X-linked early-onset osteoporosis due to PLS3 mutations.Methods Two rare cases diagnosed as PLS3-related idiopathic juvenile osteoporosis(IJO)in the department of pediatrics of Peking Union Medical College Hospital(PUMCH)from January 2016 to December 2020 were included.ZOL treatment was given once a year with a duration of 2 years,while short-term and long-term adverse events were recorded at each visit.Bone mineral density(BMD)at the lumbar spine(LS)and femur neck were measured by dual energy X-ray absorptiometry using software for children at baseline and every 6 to 12 months during ZOL treatment.Subjective improvement of vertebral compression fracture(VCF)was assessed by performing quantitative vertebral morphometry and calculating concavity index on lateral spine radiographs,while objective improvement of VCF was assessed via children's semiquantitative sensation on back pain.Further fractures(if any)since ZOL treatment were also recorded.Meanwhile,English and Chinese databases were retrieved to have a review on clinical features,genetic abnormalities,and bisphosphonates'effects of PLS3-related IJO.Results Two boys,with a past history of recurrent limb fractures and intermittent low back discomfort at the age of 4 and 8 years old respectively,were described.They had low BMDs at the LS of 0.409-0.534 g/cm2(L1-4 Z-score<-2.0)and and shared severe VCFs in the thoracic and lumbar vertebrae.Serum concentrations of calcium,phosphate,magnesium,creatinine,ALP,25-hydroxy vitamin D3,thyroxine,PTH,and sex-hormones were within normal age-specific ranges.The patients also had normal levels of urinary(24 h)free cortisol,urinary(24 h)electrolytes,and serum immunofixation electrophoresis.The PLS3 pathogenic variants were identified in both patients using whole exome sequencing and Sanger validation.One patient presented an acute-phase reaction within one days after the first infusion of ZOL with the highest body temperature of 37.7℃.No other adverse effect such as headache,peripheral edema,chest pain,or nausea was observed.During the 36-month follow-up,LS-BMD began to increase after 12-month treatment and reached normal after 12 to 18-month treatment.The concavity index of patients was raised by 13.5%,25.2%,and 32.9%after 1-year,2-year,and 3-year treatment of ZOL,respectively,suggesting a 3-year subjective improvement rate of VCF of 100%(2/2).The 3-year objective remission rate of VCF was 100%(2/2).There was one new-occurred fracture at 1-year follow-up of ZOL treatment,and no further fracture events thereafter.Conclusions Zoledronic acid infusion is a safe and effective treatment for PLS3-related IJO,with satisfying 3-year effects.