Bisphosphonates in Children with Osteogenesis Imperfecta may Improve Bone Mineralization but not Bone Strength. Report of Two Patients

Roldán, Emilio J. A.; Pasqualini, Titania; Plantalech, L.

doi:10.1515/jpem.1999.12.4.555

Cited by 29 publications

(18 citation statements)

References 7 publications

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“…25 Moreover, recent reports indicate that the increased bone mineralization seen with bisphosphonate treatment may not improve bone strength. 26 Bisphosphonates, which inhibit bone remodeling, may also adversely affect other biomechanical properties of bone, 27 thereby Growth velocity is defined as the difference between the first and last measurement of each interval, reported as a percentage of the median growth velocity for age-and sex-matched healthy children. 21 Controls were children with OI who did not receive specific therapy during the observation period.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

Horwitz

Prockop

Gordon

et al. 2001

Blood

519

353

View full text Add to dashboard Cite

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“…(9,(17)(18)(19)(20)(21)(22)(23)(24)26,27) Most have reported uncontrolled observational studies or have involved historical controls. Vertebral BMD increased in treated children, as expected from the known action of pamidronate.…”

Section: Discussionmentioning

confidence: 99%

“…Cautions have been raised about long-term bisphosphonate treatment. (37) Roldan et al (18) used QCT to show decreased moment of inertia in treated long bones. Alendronate treatment of the Brtl mouse model for OI worsened the brittleness of treated murine femurs.…”

Section: Discussionmentioning

confidence: 99%

Controlled Trial of Pamidronate in Children With Types III and IV Osteogenesis Imperfecta Confirms Vertebral Gains but Not Short-Term Functional Improvement

Letocha

Cintas

Troendle

et al. 2005

Journal of Bone and Mineral Research

185

154

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Bisphosphonates have been widely administered to children with OI based on observational trials. A randomized controlled trial of q3m intravenous pamidronate in children with types III and IV OI yielded positive vertebral changes in DXA and geometry after 1 year of treatment, but no further significant improvement during extended treatment. The treated group did not experience significantly decreased pain or long bone fractures or have increased motor function or muscle strength.Introduction: Bisphosphonates, antiresorptive drugs for osteoporosis, are widely administered to children with osteogenesis imperfecta (OI). Uncontrolled pamidronate trials in OI reported increased BMD, vertebral coronal area, and mobility, and decreased pain. We conducted a randomized controlled trial of pamidronate in children with types III and IV OI. Materials and Methods: This randomized trial included 18 children (4-13 years of age) with types III and IV OI. The first study year was controlled; 9 children received pamidronate (10 mg/m

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“…Therefore, these variables may help study the apparently paradoxic fractures in subjects who experience mineral density gains, as seen in children with osteogenesis imperfecta under longterm treatment with antiresorptive drugs. Bone mineral gain alone, without the necessary structural development of the bone cross section, may indeed be detrimental in these patients [35].…”

Section: Validation Reproducibility and Specifi City Of Pqct Measurmentioning

confidence: 99%

Assessment of material, structural, and functional properties of the human skeleton by pQCT systems

Roldán

Bogado

2009

Curr Osteoporos Rep

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Peripheral quantitative computed tomography (pQCT) systems measure bone parameters noninvasively using low radiation doses. This limits image resolution but is practical for the diagnosis and quantitative monitoring of the properties of the peripheral human skeleton. pQCT determines volumetric bone mineral density separately in trabecular and cortical bone. It may combine densitometry determinations with geometric estimates and use strain-stress indexes, and it may be used to analyze muscle variables in some areas, allowing the study of regional fragility. Experimental and clinical ex vivo studies show that pQCT variables correlate with biomechanical predictors of fragility and/or fractures. Since pQCT was approved by the US Food and Drug Administration in 1997, new skeletal regions (human femur and mandible) have been considered in the development of the system. Basically, pQCT explores intraindividual and interindividual variations in greater detail and compares the impact of skeletal diseases, risk factors, and anabolic and catabolic treatments within a given bone cross section.

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Bisphosphonates in Children with Osteogenesis Imperfecta may Improve Bone Mineralization but not Bone Strength. Report of Two Patients

Cited by 29 publications

References 7 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

Controlled Trial of Pamidronate in Children With Types III and IV Osteogenesis Imperfecta Confirms Vertebral Gains but Not Short-Term Functional Improvement

Assessment of material, structural, and functional properties of the human skeleton by pQCT systems

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