Bisphosphonate-Induced Osteopetrosis: Novel Bone Modeling Defects, Metaphyseal Osteopenia, and Osteosclerosis Fractures After Drug Exposure Ceases

Abstract

ABSTRACT:In 2003, we reported on a 12-yr-old boy who had developed osteopetrosis (OPT) while receiving pamidronate (PMD) for idiopathic bone pain and enigmatic elevation in circulating bone alkaline phosphatase. Now 17 yr of age, he was re-evaluated 6.5 yr after PMD exposure stopped. Our patient described less bone pain but further limb fractures. His growth plates were fused, yet hyperphosphatasemia persisted. Radiographs documented interval fractures of a metacarpal, an osteosclerotic distal radius, and a dense diaphyseal segment of an ulna where a "chalkstick" break remained incompletely healed after 2 yr. There was new L 4 spondylolysis, and previous L 5 spondylolysis had caused spondylolisthesis. Modeling disturbances of OPT persisted, but partial recovery was shown by metaphyseal surfaces with a unique concave shape. Metaphyseal osteosclerosis had remodeled imperfectly to become focal areas of dense, diaphyseal bone. Newer metaphyseal bone was unexpectedly osteopenic, especially in his distal femurs where cortices were thin and a paucity of trabeculae was documented by CT. Femoral necks had become short and wide with an abnormal contour. A "bone-within-bone" configuration was now present throughout his skeleton. In vertebrae, endplates were thin, and trabecular osteopenia was present central and peripheral to the bands of osteosclerosis. BMD Z-scores assessed by DXA had decreased into the normal range in his spine, hip, and whole body. Iliac crest biopsy showed active bone formation, with much less accumulated primary spongiosa than during the PMD infusions. Osteoclasts that had been dysmorphic, round cells without polarization and off of bone surfaces were now unremarkable in number, location, and appearance. In conclusion, bisphosphonate toxicity during childhood can impair skeletal modeling and remodeling with structural changes that evolve and carry into adult life.

Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schönberg disease (Chloride Channel 7 Deficiency Osteopetrosis) among the sclerosing bone disorders

“…In 2 unrelated children referred with pamidronate-induced OPT (Fig. 5C, D), serum LDH and AST were not elevated (8,18) (data not shown). Two unrelated infants at St Louis Children's Hospital with severe autosomal recessive (''malignant'') OPT due to compound heterozygous TGIRG1 mutations had serum LDH levels that were elevated at 677 and 1235 U/L (normal 130 to 400 U/L for ages 1 month to 5 years); however, LDH isoenzyme quantitation was not performed because myelophthisic marrow AE2 SD mean from 5 pediatric patients with nonosteosclerotic bone disorders and normal serum total LDH and AST levels.…”

“…Indeed, our reported patient referred with pamidronate (PMD)-induced OPT (8) had increases in serum TRACP-5b and BB-CK 1½ years after PMD exposure stopped (8) but not 6 years later when his osteoclasts resumed functioning. (18) His serum LDH and AST levels were normal at both time points. (8,18) On referral, our second (unpublished) patient with PMD-induced OPT (Fig.…”

“…Although a slight serum LDH elevation of 611 IU/L (normal 300 to 600 IU/L) was observed in Kenney-Caffey disease (n ¼ 1), levels otherwise were normal in the remaining 40 Shriners patients representing progressive osseous heteroplasia (19) (2), Lenz-Majewski syndrome (1), dysosteosclerosis (20) (1), bisphosphonate-induced osteopetrosis (8,18) (2), osteopathia striata with cranial sclerosis (1), polycystic osteosclerosis with hypercalcemia (21) (1), Camurati-Engelmann disease (1), osteopoikilosis including Buschke-Ollendorff syn- , bowing, and pseudofractures (short arrow) present also in the posterior ribs and every extremity long bone (C). There was vertebral body endplate sclerosis, anterior compression fractures of the lower thoracic and upper lumbar spine, and spondylolysis in keeping with OPT (8) (arrow) (D).…”

Complications of pamidronate therapy in paediatric osteoporosis

“…The regimens have varied based mainly on the ease of administration, convenience and age of the patient. Complications of bisphosphonate therapy are well reported in adults and children mainly for the treatment of malignancy and malignant hypercalcaemia, where high doses of up to 3 mg/kg/day are used [19][20][21]. These include fever, symptomatic hypocalcaemia, renal and ophthalmic toxicity [8,20,21].…”

An atypical subtrochanteric femoral fracture from pycnodysostosis: A lesson from nature

“…(10) Atypical subtrochanteric femoral fractures, as seen in our patient, have been described previously in pycnodysostosis, (11)(12)(13) osteopetrosis, (14,15) and hypophosphatasia, (16,17) but recent case series demonstrate a potential association between similar fractures and bisphosphonate use. (18)(19)(20) A review of over 14,000 women from bisphosphonate trials, however, found the occurrence of these fractures to be rare. (21) It is possible that there is a genetic predisposition to atypical subtrochanteric fractures, and polymorphisms of the gene encoding cathepsin K could be such a candidate gene.…”