Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple ...fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually.
Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting.
During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 ± 2.61 (mean ± SD) to - 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks.
On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.
Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been ...excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting
SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating
SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with
SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion.
SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.
Background Whole-body vibration (WBV) is a method utilizing vibrating platforms to expose individuals to mechanical vibration. In its various applications, it has been linked to improved muscular, ...skeletal, metabolic, or cognitive functioning, quality of life, and physiological parameters such as blood pressure. Most evidence concerning WBV is inconclusive and meta-analytical reviews may not readily produce insights since the research has a risk of misunderstandings of vibration parameters and incomplete reporting occurs. This study aims at laying an empirical foundation for reporting guidelines for human WBV studies to improve the quality of reporting and the currently limited comparability between studies. Method The Delphi methodology is employed to exploit the integrated knowledge of WBV experts to distil the specific aspects of WBV methodology that should be included in such guidelines. Over three rounds of completing online questionnaires, the expert panel (round 1/2/3: 51/40/37 experts respectively from 17 countries with an average of 19.4 years of WBV research experience) rated candidate items. Results A 40-item list was established based on the ratings of the individual items from the expert panel with a large final consensus (94.6%). Conclusion The final consensus indicates comprehensiveness and valuableness of the list. The results are in line with previous guidelines but expand these extensively. The present results may therefore serve as a foundation for updated guidelines for reporting human WBV studies in order to improve the quality of reporting of WBV studies, improve comparability of studies and facilitate the development of WBV study designs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered ...third-generation bisphosphonate, in children with the disease. Methods In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4–15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov , number NCT00106028. Findings Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7–11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. Interpretation Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. Funding Alliance for Better Bone Health (Warner Chilcott and Sanofi).
Whole-body vibration (WBV) is an exercise modality or treatment/prophylaxis method in which subjects (humans, animals, or cells) are exposed to mechanical vibrations through a vibrating platform or ...device. The vibrations are defined by their direction, frequency, magnitude, duration, and the number of daily bouts. Subjects can be exposed while performing exercises, hold postures, sitting, or lying down. Worldwide, WBV has attracted significant attention, and the number of studies is rising. To interpret, compare, and aggregate studies, the correct, complete, and consistent reporting of WBV-specific data (WBV parameters) is critical. Specific reporting guidelines aid in accomplishing this goal. There was a need to expand existing guidelines because of continuous developments in the field of WBV research, including but not limited to new outcome measures regarding brain function and cognition, modified designs of WBV platforms and attachments (e.g., mounting a chair on a platform), and comparisons of animal and cell culture studies with human studies. Based on Delphi studies among experts and using EQUATOR recommendations, we have developed extended reporting guidelines with checklists for human and animal/cell culture research, including information on devices, vibrations, administration, general protocol, and subjects. In addition, we provide explanations and examples of how to report. These new reporting guidelines are specific to WBV variables and do not target research designs in general. Researchers are encouraged to use the new WBV guidelines in addition to general design-specific guidelines.
Objective To use peripheral quantitative computed tomography to determine the cross-sectional area (CSA) of subcutaneous fat and muscle (fat CSA, muscle CSA) in transverse forearm scans in patients ...with osteogenesis imperfecta (OI). Study design Fat and muscle CSA were quantified in 266 individuals (142 female) aged 5-20 years who had a diagnosis of OI type I, III, or IV and who had mutations in COL1A1 or COL1A2 . Results were compared with those of 255 healthy controls. Results In a subgroup of 39 patients with OI type I, % fat CSA correlated closely with total body percentage fat mass as determined by dual-energy x-ray absorptiometry (R2 = 0.69; P < .001). In the entire study cohort, muscle CSA adjusted for age, sex, and forearm length was lower in OI type I and III than in controls ( P < .05 each), but fat CSA was similar between OI types and controls. No relationship between the type of disease-causing mutation in the COL1A1 or COL1A2 genes and fat CSA or muscle CSA was found. Conclusions Children and adolescents with OI have low muscle size but a normal amount of subcutaneous fat at the forearm.
Abstract The present text deals with the relationship of muscle force and mass to bone mass and geometry in the developing skeleton of children and adolescents. Recent results of the last ten years ...are discussed with reflection on Harold Frost’s ‘mechanostat hypothesis’. Bone mass and geometry follow the development of body size and muscle force in children and adolescents. Thereby, bone is adapted to the tissue strain due to biomechanical forces. This process is modified by hormonal signals (i.e., estrogens and androgens). Therefore, the quantified relationship of muscle force to bone stability is a reasonable approach to distinguish between primary and secondary bone diseases. Primary bone diseases are characterized by a disturbed adaptation of bone to biomechanical forces. In contrast, secondary bone diseases show a correct adaptation of bone to loaded forces in combination with a decline of muscle force. Therefore, the ‘Functional Muscle-Bone Unit’ was introduced into the diagnostics of pediatric bone diseases. The ratio of two parameters – referred to bone strength on the one and to biomechanical forces on the other side – is a reasonable diagnostic approach to distinguish between primary and secondary bone diseases.
Malignancy in a child or something else? Hoyer-Kuhn, Heike, Dr; Schoenau, Eckhard, MD; Jackels, Miriam, MD ...
The lancet oncology,
06/2017, Letnik:
18, Številka:
6
Journal Article
Recenzirano
A 2-year-old girl presented at the outpatient centre for rare skeletal diseases in children at the Children's Hospital, University of Cologne (Cologne, Germany) in 2015 with a massive swelling of the ...left femur, which her family reported had grown rapidly during the preceding 3 weeks. Because of the rapid growth of the mass, the partial destruction of the cortex, and the fact that the girl was in pain, a malignant process was suspected-specifically, a malignant...
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