Intravenous pamidronate treatment in osteogenesis imperfecta

Bembi, Bruno; Parma, A; Bottega, M.; Ceschel, S.; Zanatta, Mirko; Martini, Carmen; Ciana, Giovanni

doi:10.1016/s0022-3476(97)70074-x

Cited by 112 publications

(70 citation statements)

References 18 publications

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“…There is no cure for OI, and only one class of drugs, the bisphosphonates, which can reduce or prevent bone resorption, appear to have therapeutic potential. [12][13][14] Ideally, therapy for OI should be directed toward improving bone strength by improving the structural integrity of collagen and thereby the quality of the bone. 15,16 Although the existence of circulating osteoblast progenitors is controversial, 17 preclinical studies have demonstrated that whole bone marrow contains cells that can engraft and become competent osteoblasts after transplantation.…”

Section: Introductionmentioning

confidence: 99%

Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta

Horwitz

Prockop

Gordon

et al. 2001

Blood

519

353

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Preclinical models have shown that transplantation of marrow mesenchymal cells has the potential to correct inherited disorders of bone, cartilage, and muscle. The report describes clinical responses of the first children to undergo allogeneic bone marrow transplantation (BMT) for severe osteogenesis imperfecta (OI), a genetic disorder characterized by defective type I collagen, osteopenia, bone fragility, severe bony deformities, and growth retardation. Five children with severe OI were enrolled in a study of BMT from human leukocyte antigen (HLA)-compatible sibling donors. Linear growth, bone mineralization, and fracture rate were taken as measures of treatment response. The 3 children with documented donor osteoblast engraftment had a median 7.5-cm increase in body length (range, 6.5-8.0 cm) 6 months after transplantation compared with 1.25 cm (range, 1.0-1.5 cm) for age-matched control patients. These patients gained 21.0 to 65.3 g total body bone mineral content by 3 months after treatment or 45% to 77% of their baseline values. With extended follow-up, the patients' growth rates either slowed or reached a plateau phase. Bone mineral content continued to increase at a rate similar to that for weight-matched healthy children, even as growth rates declined. These results suggest that BMT from HLA-compatible donors may benefit children with severe OI. IntroductionBone marrow mesenchymal cells can differentiate to a variety of tissues including bone, cartilage, muscle, and fat. 1-7 Thus, in principle, bone marrow transplantation (BMT) could provide effective therapy for disorders that involve cells derived from mesenchymal precursors. 8 One attractive candidate is osteogenesis imperfecta (OI) or "brittle bone disease," a genetic disorder caused by defects in type I collagen, the major structural protein of the extracellular matrix of bone. [9][10][11] Patients with severe OI have numerous painful fractures, progressive deformities of the limbs and spine, retarded bone growth, and short stature. There is no cure for OI, and only one class of drugs, the bisphosphonates, which can reduce or prevent bone resorption, appear to have therapeutic potential. [12][13][14] Ideally, therapy for OI should be directed toward improving bone strength by improving the structural integrity of collagen and thereby the quality of the bone. 15,16 Although the existence of circulating osteoblast progenitors is controversial, 17 preclinical studies have demonstrated that whole bone marrow contains cells that can engraft and become competent osteoblasts after transplantation. 18 Moreover, because collagen is a secreted product, even a low level of osteoblast engraftment might be beneficial to OI patients. 6,19 Guided by this rationale, we undertook a pilot study to demonstrate the feasibility of transplanting bone marrow-derived mesenchymal cells in children with OI.Although providing a basis for continued testing of this strategy, our initial analysis 20 included only 6 months of clinical follow-up and did not directly compare resul...

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Section: Introductionmentioning

confidence: 99%

Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta

Horwitz

Prockop

Gordon

et al. 2001

Blood

519

353

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“…Lansmeer-Beker et al (12) in 1997 reported a decrease in fracture number, an increase in calcification of long bones, and amelioration of vertebral shape in three boys with severe OI type III treated for 5-7 y with the bisphosphonate olpadronate. Bembi et al (13) first reported an increase in BMD in children with OI treated with pamidronate for a period ranging from 22 to 29 mo. Astrom and Soderhall (14) reported a major improvement in well-being, pain, and activities of daily life using pamidronate over a 2-5 y treatment period.…”

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confidence: 99%

Alendronate Treatment for Infants with Osteogenesis Imperfecta: Demonstration of Efficacy in a Mouse Model

MCCARTHY

2002

Pediatric Research

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Recent non-placebo-controlled studies of the bisphosphonate pamidronate have shown it to be effective in reducing fractures and improving bone density in infants and children with osteogenesis imperfecta (OI). To evaluate the effects of bisphosphonate treatment in a controlled study, the oim/oim mouse model of OI was studied. Nursing infant mouse pups (~2 wk old) with moderate to severe OI (oim/oim mouse) and age-and background-matched control mice (ϩ/ϩ) were treated either with the third-generation bisphosphonate alendronate (ALN), or with saline. Fracture risk, bone quality, and growth were evaluated over a 12-wk treatment period. ALN at a dose of 0.03 mg/kg/d or saline was administered via s.c. injection to infant oim/oim and wild-type (ϩ/ϩ) mice from 2 to 14 wk of age (n ϭ 20 per subgroup). The average number of fractures sustained by the ALN-treated oim/oim mice was reduced significantly compared with the untreated oim/oim mice (0.7 Ϯ 0.7 fractures/mouse versus 2.0 Ϯ 0.2 fractures/mouse). Bone density increased significantly in the femur and the spine with treatment (2.0 Ϯ 0.5 versus 1.2 Ϯ 0.5 in femur and 2.1 Ϯ 0.5 versus1.6 Ϯ 0.5 in spine). Histologic evaluation revealed the percentage of metaphyseal tibial bone increased significantly with treatment in both ϩ/ϩ and oim/oim mice. Mechanical testing revealed an increase in structural stiffness for both treated ϩ/ϩ and oim/oim mice compared with untreated animals. None of the material properties examined were significantly altered with treatment, nor was spinal curvature affected. Weight gain and long bone growth were comparable in the treated and untreated oim/oim mice. In wild-type mice, femur lengths were significantly shorter in the treated mice compared with untreated counterparts. This animal study demonstrates that treatment of OI in mice as early as 2 wk of age with ALN appears to be effective in reducing fractures and increasing bone properties. Based on the data from this study, ALN therapy in infants with OI should prove to be effective. Abbreviations OI, osteogenesis imperfecta oim/oim, mice homozygous for spontaneous mutation causing the skeletal defects of OI ؉/؉, wild-type mice AP, anteroposterior ML, mediolateral BMD, bone mineral density ALN, alendronate OI, also known as "brittle bone disease," occurs in about 1 in 20,000 births (1). The real incidence is probably higher because a significant number of children are not diagnosed at birth due to mild expression of the disease (2). OI is predominately a collagen defect, caused by heterogeneous genetic mutations that result in an array of clinical manifestations, ranging from blue sclerae and dentinogenesis imperfecta to extremely short stature and progressive limb/spine deformities secondary to multiple fractures. Surgical treatment of the extremities and spine are often indicated to stabilize the long bones and optimize functional ability and walking capacity. According to the Sillence classification (3) there are four forms of OI, although recent data has added additional variants (4). Typ...

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“…In contrast, experience with BPs in children with various pathologies, such as juvenile osteoporosis, has been limited until recently and most of the current reports refer to small numbers of patients. [83][84][85][86] Following limited early studies, 87,88 several researchers have demonstrated that oral (olpadronate 89,90 and alendronate 91,92 ) or intravenous (pamidronate [93][94][95][96][97][98][99][100][101] and neridronate 102,103 ) BP treatment has a beneficial effect on children with severe OI. 104 In a large non-controlled observational study involving 30 children (aged 3 to 16 years) with severe OI, Glorieux and colleagues demonstrated that the cyclic administration of intravenous pamidronate improved clinical outcomes, decreased the incidence of fractures, reduced bone resorption, increased bone density and the size of vertebral bodies.…”

Section: Treating Osteogenesis Imperfectamentioning

confidence: 99%

“…106 Despite unanswered questions concerning them, BP treatment does appear to have a strong positive effect on the morbidity of severe forms of OI and it seems reasonable to continue the treatment more extensively. 107 These studies [93][94][95][96][97][98][99][100][101][102][103] reported encouraging results and strongly indicate that BPs are useful in the symptomatic treatment of children with severe OI, moreover without serious adverse effects. As with earlier studies these current trials share a common limitation, namely they are all open trials, therefore these favorable results should be confirmed in double-blind controlled studies.…”

Section: Treating Osteogenesis Imperfectamentioning

confidence: 99%

Current and emerging treatments for the management of osteogenesis imperfecta

Monti

Mottes²,

Fraschini³

et al. 2010

TCRM

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Osteogenesis imperfecta (OI) is the most common bone genetic disorder and it is characterized by bone brittleness and various degrees of growth disorder. Clinical severity varies widely; nowadays eight types are distinguished and two new forms have been recently described although not yet classified. The approach to such a variable and heterogeneous disease should be global and therefore multidisciplinary. For simplicity, the objectives of treatment can be reduced to three typical situations: the lethal perinatal form (type II), in which the problem is survival at birth; the severe and moderate forms (types III-IX), in which the objective is 'autonomy'; and the mild form (type I), in which the aim is to reach 'normal life'. Three types of treatment are available: non-surgical management (physical therapy, rehabilitation, bracing and splinting), surgical management (intramedullary rod positioning, spinal and basilar impression surgery) and medical-pharmacological management (drugs to increase the strength of bone and decrease the number of fractures as bisphosphonates or growth hormone, depending on the type of OI). Suggestions and guidelines for a therapeutic approach are indicated and updated with the most recent findings in OI diagnosis and treatment.

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Intravenous pamidronate treatment in osteogenesis imperfecta

Cited by 112 publications

References 18 publications

Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta

Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta

Alendronate Treatment for Infants with Osteogenesis Imperfecta: Demonstration of Efficacy in a Mouse Model

Current and emerging treatments for the management of osteogenesis imperfecta

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