A 20-year-old woman with no medical history was referred to our hospital for evaluation and treatment of a 3-month history of worsening pain in the left ankle. Physical examination revealed no remarkable findings except tenderness on the anterior aspect of her left ankle. All laboratory data were within the reference ranges. Radiographs showed multiple discontiguous osteolytic lesions in the bones of the left lower extremity (femur, patella, tibia, and talus). The spotty lytic lesions were ill-circumscribed and lacked marginal sclerosis. Some were accompanied by thinning and ballooning of the bone cortexes. The lesion at the distal end of the tibia extended beyond the epiphyseal plate and eroded the subchondral bone; this lesion was considered to be the cause of her ankle pain. On ankle magnetic resonance imaging, the spotty lesions showed isointensity to the muscles on T1-weighted images, mild hyperintensity on T2-weighted images, and homogeneous enhancement by gadolinium administration. On fluorodeoxyglucose positron emission tomography (FDG-PET), all of the intraosseous spotty lesions in the left lower extremity were FDG-avid with a maximum standardized uptake value (SUV) of 15.95; no such lesions were present in the soft tissues. Based on the findings from the imaging studies, the differential diagnoses of the multiple bone lesions included bone metastasis, hematological malignancies such as malignant lymphoma and multiple myeloma, and vascular tumors. Curettage of the lesion in the distal tibia and artificial bone grafting were performed for pain relief and histological diagnosis. While waiting for the definitive diagnosis, progressive bone absorption at all of the lesions and worsening lower limb pain occurred over 1 month. The preliminary pathology report suggested a non-hematological neoplasm composed of spindle cells and osteoclast-like giant cells, which led to a clinical diagnosis of bone metastases from a solid cancer despite the fact that no lesion suspicious of primary cancer was present. Based on the clinical diagnosis of bone metastasis, monthly administration of denosumab (120 mg) was initiated. The final pathological report demonstrated proliferation of spindle cells and epithelioid cells with eosinophilic cytoplasm. The tumor cells were immunohistochemically positive for keratin (AE1/AE3), CD31, ERG, and FOSB, which led to the diagnosis of PMHE. Because her limb pain gradually improved after denosumab administration, the monthly denosumab treatment was continued. After 1 year of denosumab treatment, the drug was administered at longer intervals of up to 6 months. The drug was discontinued 4 years after its initiation. Although the spotty lesions remained, a plain radiograph showed no increase in the size of the lesions or the surrounding marked marginal scleroses. On FDG-PET, the lesions showed clearly decreased SUVs. Because denosumab treatment led to dramatic symptom improvement, the patient did not agree to undergo a second-look biopsy or curettage of the remaining lesions at the time of denosumab discontinuation. The patient developed no signs of new lesions or distant metastasis and agreed to continue undergoing active surveillance.