Bone Abstracts

Juvenile Paget’s disease (JPD) is an extremely rare, yet painful and debilitating bone disease with onset occurring during early childhood. JPD can be caused by loss of function of osteoprotegerin, resulting in subsequent osteoclast stimulation via the activated receptor activator of nuclear factor-kappa B (RANK) pathway. Increased bone turnover and a lack of bone modelling lead to severe deformities, frequent fractures, short stature and loss of hearing.

The treatment of JPD is challenging and has previously been based on either calcitonin or cyclic administration of bisphosphonates. However, with the development of denosumab, a RANK-ligand antibody, a treatment targeting pathophysiology in JPD may be available.

We report clinical and biochemical effects of denosumab treatment on an 8-year-old girl with a severe form of JPD. The patient is the second child of healthy, consanguineous parents of Turkish descent. Genetic analysis revealed a novel homozygous mutation in the osteoprotegerin gene TNFRSF11B:c. (2T>G); (2T>G), which results in a methionine to arginine exchange at position one of exon 1, presumably resulting in the loss of the start codon and therefore a significant loss of functional osteoprotegerin protein. Osteoprotegerin levels in serum were diminished in the patient (0.7 pmol/l, normal range 1.69–3.6 pmol/l) and within the lower normal range in mother and father.

Before starting the denosumab treatment regimen, the patient had been treated for 3.5 years with i.v. pamidronate. However, with an intensified pamidronate treatment bone turnover markers stayed elevated and the girl suffered from frequent bone pain and pathological fractures.

The administration of denosumab resulted in a prompt improvement of disease control. Bone pain ceased on the day of the injection and N-telopeptide and desoxypyridinoline levels in urine decreased the same day. Alkaline phosphatase levels dropped within the normal range and remained at normal levels for 5 months following the final dose of denosumab.

However, concomitantly with the first injection, severe hypocalcemia developed, for which the patient was hospitalized and i.v. calcium substitution was required for a total of 13 days. Calcium demand remained high (900 mg/day) for the 6 weeks following the injection. A second dose of denosumab was well tolerated and markers of bone turnover stayed within the normal range. With ongoing calcium supplementation a sudden but severe hypercalcemia developed 6 weeks after the second dose of denosumab. At that time denosumab was discontinued despite the clinical improvement and pamidronate treatment was commenced.

In summary, denosumab appears to be significantly effective for osteoclast inhibition for the treatment of JPD. However, severe hypocalcemia and possibly hypercalcemia later on are side effect for which close patient monitoring is required.