Effectiveness of pamidronate as treatment of symptomatic osteonecrosis occurring in children treated for acute lymphoblastic leukemia.

BACKGROUND: Osteonecrosis (ON) is a severe complication of acute lymphoblastic leukemia (ALL) treatments. Recent studies suggest that bisphosphonates might reduce pain and loss of motor function in patients with ON. We assessed the effects of pamidronate compared to standard care in patients with symptomatic ON (sON) and studied whether steroids might be continued after diagnosis of ON in some patients. METHODS: We evaluated 17 patients with sON as complication of primary ALL treatment between 2000 and 2008. Fourteen patients were treated with pamidronate. Mobility and pain control were monitored in all patients. Affected joints were classified by magnetic resonance imaging (MRI) at ON diagnosis and after 6-72 months. RESULTS: Out of 220 patients with ALL, 17 (7.7%) patients developed sON. The median age at ALL diagnosis was 11 years (range: 2.7-16.6 years) and sON occurred a median of 13.4 months (range: 2.5-34 months) after ALL diagnosis. Affected joints were hip, knee and ankle. MRI scans showed 7 severe, 4 moderate, and 6 mild ON lesions. Fourteen patients showed improvement in pain (77% of patients) and motor function (59% of patients), even though corticoids were reintroduced in 4 patients. MRI demonstrated improvement, stability or worsening in 6, 3, and 5 cases, respectively. CONCLUSIONS: Pamidronate seems to be effective in the management of pain and motor function recovery in sON. Further studies are needed to provide evidence as to whether bisphosphonates can be recommended for the treatment or the prevention of ON in childhood ALL patients.

Low bone mass and high material bone density in two patients with Loeys-Dietz syndrome caused by transforming growth factor beta receptor 2 mutations.

Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by heterozygous mutations in the genes encoding transforming growth factor beta receptor 1 or 2 (TGFBR1 or TGFBR2). Although an association between LDS and osteoporosis has been reported, the skeletal phenotype regarding bone mass is not well characterized. Here, we report on two LDS patients with mutations in TGFBR2. Patient 1 was a 24-year-old man who had a total of three fractures involving the left radius, the left metacarpal, and the right femur. At the age of 14 years, lumbar spine areal bone mineral density Z-score was -4.0 and iliac bone histomorphometry showed elevated bone turnover (bone formation rate per bone surface: 91 µm³/µm²/year; age-matched control values 37 [10], mean [SD]) and mildly low trabecular bone volume per tissue volume (17.2%; age-matched control values 25.7 [5.3]). Bone mineralization density distribution (BMDD) in trabecular bone was increased (Ca(Peak) 22.70 wt% Ca; age-matched control values 21.66 [0.52]). Patient 2, a 17-year-old girl, suffered from diffuse bone pain but had not sustained fractures. At 14 years of age, her lumbar spine areal bone mineral density Z-score was -3.4. Iliac bone histomorphometry at that age confirmed low bone mass (bone volume to tissue volume 10.1%, same control values as above) and high bone turnover (bone formation rate per bone surface 70 µm³/µm²/year). BMDD in trabecular bone was significantly shifted toward increased mineralization (Ca(Peak) 22.36 wt% Ca). Thus, it appears that LDS can be associated with low bone mass and high bone turnover but increased matrix mineralization of trabecular bone.

Efficacy and safety of 2-year etidronate treatment in a child with generalized arterial calcification of infancy.

UNLABELLED: Generalized arterial calcification of infancy (GACI, MIM#208000) is a rare autosomal recessive disorder characterized by extensive calcifications in the media of large- and medium-sized muscular arteries. Most affected children die in early infancy because of cardiac failure. GACI is linked to mutations in the ENPP1 gene, which encodes for an enzyme that generates inorganic pyrophosphate (PP(i)), a potent inhibitor of hydroxyapatite crystal formation. Treatment with bisphosphonates, which are synthetic PP(i) analogues, has been proposed as a means of reducing arterial calcifications in GACI patients, but no formalized treatment approach exists. We report on the long-term survival of a severe case of GACI linked to a novel homozygous missense mutation c.583T/C in the ENPP1 gene, diagnosed prenatally, and treated with bisphosphonates. Intravenous disodium pamidronate (three infusions at days 8, 15, and 18 of 0.25, 0.50, and 0.50 mg/kg, respectively) was changed to oral disodium etidronate (starting dose of 20 mg/kg daily, 50 mg die) at 3 weeks of age. Although the etidronate dose was maintained at 50 mg daily in our patient (corresponding to a progressive decrease from 20 to 5 mg/kg daily), the progressive resolution of arterial calcifications seen by 3 months of age was maintained until 2 years of age. Throughout the 2-year follow-up, our patient developed mild hypophosphatemia, due to renal phosphate wasting, without clinical, biochemical, or radiological sign of rickets. CONCLUSION: High-dose bisphosphonate therapy may not be necessary for an extended period of time in children with GACI.

Influence of orthopedic implant structure on adjacent bone density and on stability.

We evaluated the ability of a porous metallic interbody fusion implant made with porous nitinol (PNT) to achieve intervertebral fusion and the capacity of stabilization at the implantation site 3, 6, and 12 months after implantation. Sixteen sheep each received 1 PNT implant and 1 titanium (TiAIV) cage at intervertebral lumbar levels L2-L3 and L4-L5; 3 other sheep were used as untreated controls. The TiAIV cage was used as a control implant. After animal sacrifice, computed tomography was used to study peri-implant bone mineral density (BMD), and histologic slices were used to evaluate implant osseointegration. BMD around PNT implants was close to physiological (control value) BMD, whereas BMD around TiAIV cages was usually higher (sclerosis) than physiological BMD. Histologic analysis showed better osseointegration with PNT implants than with TiAIV cages. Sclerosis might result from bone acting to stabilize implants in their implantation sites. Compared with PNT implants, TiAIV cages seemed to be unstable in their implantation sites. For PNT implants, osseointegration was successful, and surrounding BMD was close to physiologic BMD.

Clinical and cellular manifestations of OSTM1-related infantile osteopetrosis.

UNLABELLED: Infantile ARO is a genetic disorder characterized by osteoclast dysfunction that leads to osteopetrosis. We describe a novel mutation affecting the OSTM1 locus responsible for ARO. In addition to common clinical features of osteopetrosis, the patient developed a unique neuronal pathology that provided evidence for an essential role of OSTM1 in normal neuronal cell development. INTRODUCTION: Infantile autosomal recessive osteopetrosis (ARO) is a genetic disorder characterized by osteoclast dysfunction that leads to osteopetrosis. We describe a novel mutation affecting the OSTM1 locus responsible for ARO. In addition to common clinical features of osteopetrosis, the patient developed a unique neuronal pathology that provided evidence for an essential role of OSTM1 in normal neuronal cell development. MATERIALS AND METHODS: We report a new case of ARO caused by an homozygous mutation in OSTM1. In addition to osteopetrosis and bone marrow failure, this patient also had neurological impairment not related to bone entrapment. Retinal dystrophy with absent evoked visual potentials and sensorineural deafness were documented, as well as cerebral atrophy and bilateral atrial subependymal heterotopias. RESULTS: The patient developed generalized seizures and had a profound developmental delay. Nerve biopsy failed to show inclusion material suggestive of neuroaxonal dystrophy. Bone marrow transplantation was declined considering the severe neurological compromise. The patient died at 1 yr of age. Osteoclasts derived from peripheral blood were mature and multinucleated. Expression analysis showed that the amount of OSTM1 cDNA transcript was significantly lowered but not absent. CONCLUSIONS: These results support the role of OSTM1 in osteoclast function and activation. However, they also suggest that OSTM1 has a primary role in neural development not related to lysosomal dysfunction.

Pamidronate: Treatment for severe hypercalcemia in neonatal subcutaneous fat necrosis.

BACKGROUND: Subcutaneous fat necrosis (SCFN) of the newborn is an uncommon disorder that occurs in the first weeks of life after foetal distress. It can be complicated by potentially life-threatening hypercalcemia. Treatments of hypercalcemia have included hydration, furosemide and corticosteroids. Only one report has described the use of intravenous bisphosphonates for this condition. We propose that pamidronate could be the first line therapy for severe hypercalcemia in SCFN. PATIENTS AND RESULTS: Four newborns presented between 2001 and 2004 with SCFN complicated by severe hypercalcemia. At diagnosis, ionized calcium levels were higher than 1.4 mmol/l and were associated with high urinary calcium/creatinine ratios and high 1,25-dihydroxyvitamin D levels. Despite treatment with IV fluids, low calcium diet and furosemide, calcium levels remained high. The patients were given 3-4 doses (0.25-0.50 mg/kg/dose) of pamidronate. Urinary calcium/creatinine ratios and calcium levels decreased within 48-96 h. 1,25-dihydroxyvitamin D levels normalized with resolution of the skin lesions. No persistent nephrocalcinosis was observed. CONCLUSION: Pamidronate is effective, well-tolerated in the short-term and obviates the need for prolonged treatment with furosemide and corticosteroids. To prevent nephrocalcinosis, pamidronate might be considered as first line treatment for severe hypercalcemia in SCFN.

Safety profile of frequent short courses of oral glucocorticoids in acute pediatric asthma: impact on bone metabolism, bone density, and adrenal function.

OBJECTIVE: Our study was designed to establish in children with asthma the safety profile of repeated short courses of oral glucocorticoids on bone mineralization and metabolism and adrenal function. METHODS: This cross-sectional study compared the bone density, bone metabolism, and adrenal function of children who were and were not exposed to bursts of oral glucocorticoids. Children were considered exposed when, in the preceding year, they received >or=2 courses of oral glucocorticoids and were prescribed the same therapy for the index exacerbation. Children were considered unexposed when they had no exposure to oral glucocorticoids and were not prescribed any for the index exacerbation. Indices of bone metabolism were measured during the subsequent month. Cortisol responses to adrenocorticotrophic hormone stimulation and bone density were assessed 30 days after the index exacerbation. RESULTS: Eighty-three children (48 exposed, 35 unexposed) aged 2 to 17 years were enrolled. The median exposure level was 4 courses (range: 3-11) in the preceding year. Among exposed children, a transient decrease in serum osteocalcin was observed at the end of the 5-day course with a return to baseline by 30 days; no change was observed in urine pyridinoline cross-links. Mean bone density z score was similar in the exposed (-0.61 +/- 1.0 [standard deviation]) and unexposed (-0.67 +/- 0.9) groups. No cases of abnormal response to adrenocorticotrophic hormone suggestive of adrenal insufficiency were documented in the exposed (95% confidence interval: 0%-7%) or unexposed (0%-10%) groups. CONCLUSIONS: Repeated short courses of oral glucocorticoids in the treatment of asthma seem to be reasonably safe; this practice was not associated with any lasting perturbation in bone metabolism, bone mineralization, or adrenal function.

Dispensing error leading to alendronate ingestion.

OBJECTIVE: To report a case of medication dispensing error by administration of similarly packaged drugs. CASE SUMMARY: A 6-year-old East Indian boy with asthma was mistakenly given alendronate, a bisphosphonate, for 3 months instead of montelukast, a leukotriene-receptor antagonist. Symptoms of esophageal irritation developed and disappeared on discontinuation of alendronate. DISCUSSION: Alendronate and montelukast have very similar packaging and are available in dosages that also can be similar for some patients. Alendronate caused symptoms of irritative gastritis in this child before the error was identified. This case report emphasizes one of the possible sources of medication dispensing errors: a mistaken identification due to similar packaging (confirmation bias). Manufacturers can help to prevent medication errors in many ways; in this case, more distinct packaging would have decreased the risk of error. A standard bar-coding scheme among manufacturers could lead to an important improvement in the safety of medication dispensation. Practitioners are also encouraged to report such errors to the United States Pharmacopoeia Medication Errors Reporting Program. CONCLUSIONS: With increased awareness of medication errors, healthcare practitioners, manufacturers, and patients should take precautionary steps to prevent dispensing errors and their consequences.