Denosumab treatment for juvenile Paget's disease: results from two adult patients with osteoprotegerin deficiency ("Balkan" mutation in the TNFRSF11B gene).

Context: Most patients with juvenile Paget's disease (JPD) have homozygous loss-of-function mutations in the TNFRSF11B gene resulting in osteoprotegerin deficiency. Because recombinant osteoprotegerin is not available for clinical use, an alternative therapeutic approach could be denosumab, which acts on the same pathway.

Main Objective: The aim was to study the effect of denosumab on bone turnover markers in two adult patients with JPD ("Balkan" mutation) previously treated with calcitonin and bisphosphonates.

Setting: The study was conducted at two tertiary hospitals in Greece.

Patients: Patient 1 (a 36-year-old woman) developed a severe and long-term hypocalcemia after a single dose (3.5 mg) of zoledronic acid. Her bone disease remained active despite treatment. Patient 2 (a 67-year-old man) had satisfactorily controlled bone disease with only intermittent risedronate treatment during the last 10 years, but suffered from progressive loss of hearing and vision. Low doses (20-40 mg) of denosumab every 3-6 months were administered in both patients.

Results: Bone markers (including total and bone-specific alkaline phosphatase, procollagen I N-terminal peptide, and osteocalcin) were reduced to normal levels in both patients, with nadir observed 2-4 months after each denosumab injection. Retinal and hearing involvement remained unchanged, but patient 2 developed a rapid progression of cataract in the right eye.

Conclusions: Low-dose denosumab every 3-6 months for about 2 years in two patients with JPD successfully controlled their bone disease. The long-term effect of denosumab on the nonskeletal complications remains to be elucidated.