Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

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Journal of Bone and Mineral Research

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Generalized arterial calcification (AC) of infancy (GACI) is the autosomal recessive disorder caused by deactivating mutations within the gene for ectonucleotide pyrophosphatase phosphodiesterase-1 (ENPP1). ENPP1 on osteoblasts, chondrocytes, and vascular smooth muscle cells hydrolyzes nucleotide triphosphates to nucleotide monophosphates and inorganic pyrophosphate (PPi). PPi potently inhibits mineralization. In GACI, low extracellular levels of PPi promote hydroxyapatite crystal deposition in elastic fibers of arteries. Untreated, ~ 85% of patients die by age six months from cardiac ischemia and congestive heart failure. Etidronate (EHDP), the bisphosphonate (BP), inhibits bone resorption but can mimic PPi blocking mineralization. During EHDP treatment for GACI, AC can resolve and does not recur with cessation of treatment. Skeletal disease is not a feature of GACI, although rickets can develop from EHDP therapy.

We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC resolved during infancy after five months of EHDP therapy, but joint calcifications, seen in GACI, had progressed. He was receiving 200 mg/day of EHDP and had odynodysphagia, opioid-controlled body pain, facial asymmetry, plagiocephaly, proptosis, joint calcifications and contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal although serum osteocalcin was low and he had markedly elevated serum levels of creatine kinase (brain isoform) and TRAP-5b consistent with osteopetrosis (OPT). Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, widened physes with metaphyseal osteosclerosis, “tongues” of radiolucency, along with cupping and fraying, and long-bone bowing. Radiographic features of BP-induced OPT included femoral Erlenmeyer flask deformity and osteosclerosis (lumbar spine DXA z-score +5.7). ENPP1 mutation analysis revealed a missense mutation (c.653A>T, p.Asp218Val) that reduced catalytic efficiency to 17% of normal. After stopping EHDP, he improved quickly with remarkable healing of his rachitic skeleton and decreased joint calcifications.

Our patient with GACI had profound, but rapidly reversible, inhibition of skeletal mineralization along with paradoxical calcifications near joints from high-dose EHDP therapy. Although EHDP is life-saving in GACI, surveillance for toxicity is important.

doi: 10.1002/jbmr.1752


ectopic calcification, hypophosphatasia, osteopetrosis, bisphosphonate, pyrophosphate, testicular microlithiasis


Chemistry | Medicine and Health Sciences

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