Bisphosphonate-Induced Osteopetrosis
Authors: Michael P. Whyte, Deborah Wenkert, Karen L. Clements, William H. McAlister, Steven Mumm
Journal: New England Journal of Medicine (2003)

isphosphonates, synthetic analogues of inorganic pyrophosphate, potently inhibit skeletal resorption by suppressing the recruitment and activity of osteoclasts and shortening their life span. 1 Consequently, several bisphosphonates were developed to treat hypercalcemia (associated with cancer), osteoporosis, and Paget's disease of bone and are used for additional disorders in adults. 1 Increasingly, bisphosphonates are being administered to children [2][3][4] and have been reported to improve clinical outcomes and augment bone mass in conditions such as osteogenesis imperfecta, 5 juvenile osteoporosis, 2 and fibrous dysplasia, 6 although controlled studies of these compounds in children are lacking. 3,4,7Genetic defects that abrogate the action of osteoclasts cause osteopetrosis, which is characterized by dense, poorly formed, and brittle skeletal tissue. 8Acquired osteopetrosis, or marble bone disease, could therefore result from treatment with bisphosphonates during growth.Here, we document a case of drug-induced osteopetrosis.A 12-year-old white boy, referred to us for unexplained skeletal pains and markedly elevated serum alkaline phosphatase activity, first began to limp as a result of left-hip discomfort after unobserved playground trauma at the age of 5 years.The symptoms subsequently became intermittent but intensified and included pain deep in the left thigh and leg.A finding of hyperphosphatasemia (alkaline phosphatase level, approximately 1400 U per liter; normal level, <350), reflecting bone alkaline phosphatase, prompted a biochemical assessment of mineral homeostasis, skeletal radiography and scintigraphy, and magnetic resonance imaging.Only possible synovitis of the left hip was identified.Nevertheless, the child's condition improved little with analgesics and nonsteroidal antiinflammatory drugs.At six years of age, his right distal radius healed uneventfully after substantial trauma; however, his fingertips also reportedly broke after a minor injury.At 7 1 ⁄ 2 years of age, the results of dual-energy x-ray absorptiometry were interpreted as showing low density of the lumbar spine, although the z score was ¡1.0.Extensive investigations included tests for osteogenesis imperfecta, lysosomal storage diseases, rheumatologic diseases, mitochondrial-gene defects, and aminoaciduria, all of which were negative.The results of karyotyping and electromyography with nerve-conduction velocity were normal.Bone antiresorptive therapy was begun with intranasal salmon calcitonin daily for one month to treat "idiopathic hyperphosphatasia," yet urinary excretion of total hydroxyproline was 58 mg per day (442 µmol per day; normal level, 23 to 77 mg [175 to 587 µmol] per day), and the serum osteocalcin level was 12 ng per milliliter (normal level, 18 to 24), reflecting no acceleration of skeletal turnover.The boy's pain diminished, but serum alkaline phosphatase activity did not decrease.Soon after, discomfort provoked by exercise intensified and included his right lower limb.At 7 3 ⁄ 4 years of age, his antiresorptive treatment was changed to pamidronate (Aredia, Novartis).Initially, a dose of 10 mg (0.37 mg per kilogram of body weight) infused intravenously on three consecutive days seemed to diminish the intensity, duration, and b case report