Bone Abstracts

Background: Pamidronate is FDA approved only in adults. It is frequently used off-label in the treatment of pediatric bone diseases, such as osteogenesis imperfecta, juvenile osteoporosis, and osteopenia in nonambulatory patients with cerebral palsy. The use of pamidronate in these conditions is relatively common, but there may be more to be understood about its role in other rare pediatric bone diseases.

Presenting problem: Jansen’s Metaphyseal Chondrodysplasia (JMC) is an ultra-rare, autosomal-dominant, skeletal dysplasia caused by activating mutations in the PTH/PTHRP receptor PTHR1. It is characterized by severe hypercalcemia, hypophosphatemia, decreased TRP, normal/elevated levels of 1,25-dihydroxyvitamin D3, and very low levels of PTH or PTH-related peptide (PTHrP). While bisphosphonates are an established treatment of hypercalcemia for other conditions, its use in JMC is more uncertain. However, it is posited that bisphosphonates may reduce hypercalcemia, hypercalciuria, nephrocalcinosis, and decrease bone turnover in patients with JMC. Generalized arterial calcification of infancy (GACI) is an ultra-rare, autosomal recessive disorder with high infantile mortality, characterized by calcifications of large and medium vessels, leading to arterial stenosis and decreased vascular elasticity. Inactivating mutations in the ENPP gene lead to decreased levels of inorganic pyrophosphate, an inhibitor of hydroxyapatite-crystal deposition in blood vessels. Less commonly, mutations in ABCC6 lead to ectopic tissue calcification in the skin and arterial blood vessels, but the mechanism is unknown. In patients with GACI, it is posited that bisphosphonates, which are analogs of inorganic pyrophosphate, interfere with hydroxyapatite crystal formation, inhibit further calcium deposition of existing lesions, and decrease bone turnover.

Clinical management: One patient with JMC and three patients with GACI were treated with IV pamidronate, initial dose of 0.5 mg/kg per dose ×3 consecutive days, then 1–1.5 mg/kg per dose at varying intervals. The patient with JMC had control of his hypercalcemia, improved mobility, and decreased pain. Patients with GACI were simultaneously treated with oral acetazolamide, and had normalization of serum calcium, and reduction or complete resolution of their vascular calcification.

Discussion: Because these disorders are ultra-rare, it is unlikely that randomized, controlled trials of bisphosphonate therapy will be undertaken, which makes case reports of efficacy of this treatment in these disorders vitally important.

Disclosure: The authors declared no competing interests.