Early-onset osteoporosis (EOOP) is rare but causes significant morbidity from recurrent fractures. Over 17% of cases are associated with a genetic cause. We report an index case of a 73-year-old man with a lifelong history of low-trauma fractures, beginning at age 4. By age 19, he had sustained five clavicular and upper-limb fractures, followed by three vertebral fractures at age 22 and multiple long-bone fractures later in adulthood.

Examination showed joint hypermobility and increased skin elasticity, without blue sclerae, high-arched palate, chestwall deformity, dental or digital abnormalities. Investigations excluded secondary causes. Initial DXA (age 40) showed low Z-score of -4.5 at lumbar spine and -2.8 at femoral neck. HR-pQCT demonstrated reduced bone strength, markedly reduced cortical and trabecular volumetric density and increased cortical porosity.

A strong multigenerational family history of osteoporosis and fractures was present. His daughter sustained postpartum vertebral fractures, and grandson developed childhood lower-limb fractures. Testing of the patient and grandson confirmed a hemizygous PLS3 c.994_995del.p(Asp332*) pathogenic variant.

He received oral bisphosphonates for approximately 20 years, followed by denosumab for 5 years. He has remained fracture-free past six years, with stable BMD in the osteopenia range. Given prolonged antiresorptive exposure, teriparatide was commenced, with the aim of consolidating treatment following anabolic therapy.

PLS3-related X-linked dominant osteoporosis typically affects males more severely, with variable phenotypes in heterozygous females. Loss-of-function mutation disrupts intracellular actin cytoskeleton regulation. This case highlights the importance of early genetic testing in EOOP to diagnose monogenic bone disease, guide timely fracture-prevention treatment and genetic counselling.