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Biomedical subjects

F Rauch

Publications and source records attributed to F Rauch.

At least 19 recordsLinked to original sources
PubMed2005

Single-dose pharmacokinetics and tolerability of alendronate 35- and 70-milligram tablets in children and adolescents with osteogenesis imperfecta type I.

CONTEXT: Alendronate (ALN) is a bisphosphonate compound that can be administered orally and has potential use in pediatric osteoporotic conditions. OBJECTIVE: The objective was to evaluate the pharmacokinetics and single-dose tolerability of ALN in children with osteogenesis imperfecta. DESIGN: ALN was administered iv and orally in a two-period, randomized crossover study, with doses separated by a 2-wk washout and follow-up carried out within 2 wk after the last ALN dose. SETTING: The study was conducted at the pediatric metabolic bone research unit at the Shriners Hospital for Children, Montréal, Canada. PATIENTS: Twenty-four children (aged 4-16 yr; eight girls) with osteogenesis imperfecta type I participated. INTERVENTIONS: All patients received iv ALN at a dose of 125 mug. In addition, patients weighing less than 40 kg received an oral dose of ALN 35 mg, whereas those weighing 40 kg or more received ALN 70 mg orally. MAIN OUTCOME MEASURES: Total urinary excretion and oral bioavailability of ALN, blood and urine safety parameters, and adverse events were the main outcome measures. RESULTS: The total urinary excretion of ALN after the iv dose was similar for both weight groups. The mean oral bioavailability (95% confidence interval) was 0.43% (0.28, 0.64%) for patients weighing less than 40 kg and 0.56% (0.36, 0.87%) for patients weighing 40 kg or more. Eighteen patients reported a total of 44 clinical adverse experiences, none of which were serious. The most common adverse experiences were mild to moderate headache (n = 7), nausea (n = 7), fever (n = 5), and abdominal pain (n = 6). Eighty percent of the adverse experiences (35 of 44) occurred within 48 h of medication administration, 91% (40 of 44) lasted less than 24 h, and 84% (37 of 44) were reported after oral dosing. Laboratory safety monitoring revealed a marginal decrease in absolute lymphocyte count and serum alkaline phosphatase after the study compared with baseline for both weight categories. CONCLUSIONS: The mean oral bioavailability of 35- and 70-mg ALN tablets was less than 0.6%, comparable to adult studies. Adverse experiences from single-dose ALN were minor, and the drug was generally well-tolerated.

Adolescent↗
PubMed2005

Peripheral quantitative computed tomography of the distal radius in young subjects - new reference data and interpretation of results.

Application of bone densitometry to clinical use requires the availability of accessible reference data and is helped by an interpretative framework that is based on bone physiology. The aim of this contribution is to provide both reference data and help in the interpretation of results for peripheral quantitative computed tomography (Stratec XCT2000 performed at the distal radius of young subjects. Data from a previous reference data study on 478 subjects between 6 and 40 years were re-analyzed and smooth curves were fitted. The corresponding equations allow for calculation of age- and sex-specific z-scores of bone mineral content, volumetric bone mineral density (vBMD) of the trabecular compartment, vBMD of the entire radial cross-section, total cross-sectional area and cortical thickness. These data should facilitate the clinical use of peripheral quantitative computed tomography in young subjects.

Adolescent↗
PubMed2004

Osteopathia striata with cranial sclerosis: clinical, radiological, and bone histological findings in an adolescent girl.

Osteopathia striata with cranial sclerosis (OS-CS) is a rare skeletal dysplasia characterized by linear striations of the long bones, osteosclerosis of the cranium, and extra-skeletal anomalies. We provide a comprehensive description of the skeletal phenotype in a French-Canadian girl with a moderate to severe form of sporadic OS-CS. Multiple medical problems, including anal stenosis and the Pierre-Robin sequence, were evident in the first few years of life. At 14 years, she was fully mobile, with normal intellect and stature. She suffered chronic lower extremity pain in the absence of fractures, as well as severe headaches, unilateral facial paralysis, and bilateral mixed hearing loss. Biochemical indices of bone and mineral metabolism were within normal limits. Bone densitometry showed increased areal bone mineral density in the skull, trunk, and pelvis, but not in the upper and lower extremities. An iliac bone biopsy specimen revealed an increased amount of trabecular bone. Trabeculae were abnormally thick, but there was no evidence of disturbed bone remodeling. In a cranial bone specimen, multiple layers of periosteal bone were found that covered a compact cortical compartment containing tightly packed haversian canals. Bone lamellation was normal in both the iliac and skull samples. Osteoclast differentiation studies showed that peripheral blood osteoclast precursors from this patient formed functional osteoclasts in vitro. Thus, studies of bone metabolism did not explain why bone mass is increased in most skeletal areas of this patient. Cranial histology points to exuberant periosteal bone formation as a potential cause of the cranial sclerosis.

Adolescent↗
PubMed2004

Effect of gene dose and parental origin on bone histomorphometry in X-linked Hyp mice.

X-linked hypophosphatemia (XLH) is characterized by rickets and osteomalacia and arises from mutations in the Phex and PHEX genes in mice (Hyp) and humans, respectively. The present study was undertaken to examine the effect of gene dose on the skeletal phenotype using a histomorphometric approach. Metrical traits (vertebral length, growth plate thickness, cancellous osteoid volume per bone volume, and cancellous, endocortical, and periosteal osteoid thickness) were compared in caudal vertebrae of mutant female (Hyp/+, Hyp/Hyp) and male (Hyp/Y) mice and their normal female (+/+) and male (+/Y) littermates. Mutant animals had trait values that differed significantly from those of normal animals. However, with the exception of vertebral length and cancellous osteoid thickness, values were not significantly different between the three mutant genotypes. We also examined the effect of gamete-of-origin on histomorphometric parameters in obligate Hyp/+ females derived from male or female transmitting parents. The metrical trait values in both groups of Hyp/+ mice were similar, with the exception of vertebral length and cancellous osteoid volume per bone volume. In summary, we demonstrate that the amount of osteoid per bone volume is similar in the three mutant genotypes and conclude that the extent and magnitude of the mineralization defect is fully dominant and likely not affected by gene dose. The differences in vertebral length in the mutants suggest that rickets and osteomalacia are not the only causes of decreased vertebral growth in Hyp mice and that Phex protein may influence bone growth and mineralization by distinct pathways.

Animals↗
PubMed2004

Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna.

Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH)(2) vitamin D was very low (14 pM; N: 40-140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33-105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

Base Sequence↗
PubMed2003

Osteogenesis imperfecta--clinical and molecular diversity.

Osteogenesis imperfecta is a heritable disorder of bone formation resulting in low bone mass and a propensity to fracture. It exhibits a broad range of clinical severity, ranging from multiple fracturing in utero and perinatal death to normal adult stature and a low fracture incidence. The disorder is currently classified into seven types based on differences in clinical presentation and bone architecture. Mutation in one of the type I collagen genes is commonly associated with osteogenesis imperfecta, but is not a prerequisite for the diagnosis. Indeed, the newer forms of osteogenesis imperfecta (types V, VI and VII) are not associated with type I collagen gene defects. Amongst the type I collagen gene mutations that can occur, missense base substitutions involving glycine codons in the exons encoding the central triple-helix forming domain predominate. Such mutations can occur in all the classical forms of osteogenesis imperfecta (types I-IV), but genotype/phenotype correlations are complex and often unpredictable. Treatment of osteogenesis imperfecta by bisphosphonate therapy can improve bone mass in all types of the disorder, and while not being a cure for the disorder does improve the quality of life of the patient.

Genetic Variation↗
PubMed2003

The regulation of bone development as a biological system.

A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often, events at the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost's mechanostat theory. In this model, the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone.

Animals↗
PubMed2003

[Management of other ectopic pregnancies (cornual, interstitial, angular, ovarian)].

OBJECTIVES: To provide recommendations for management of interstitial and ovarian pregnancies. MATERIALS AND METHODS: A Medline search was conducted and discussed by a study group of experts. RESULTS: Ovarian and interstitial pregnancies are rare forms of ectopic pregnancy. Diagnostic criteria and methods are described on the basis of a review of the literature. Surgery is the usual management of interstitial pregnancy. Conservative treatment has replaced hysterectomy. Laparoscopy is an attractive way to manage interstitial pregnancies but laparotomy may still be used. Cornual resection is required. Medical treatment with methotrexate is another alternative. Local MTX seems to be more efficient than systemic administration. Management of interstitial pregnancy under laparoscopic control is an attractive way if feasible. Strong recommendations cannot be established due to the small number of reported cases reports. The pre therapeutic score cannot be used as doses are still not clear for interstitial pregnancies. For ovarian pregnancy, management is often surgical. Laparoscopy is more and more used for small gestational sacs. Methotrexate has also been used for ovarian pregnancies. Laparoscopic treatment associated with systemic MTX seems to be the more efficient way. CONCLUSION: Because of limited data it is very hard to establish recommendations from low power studies (NP 5).

Abortifacient Agents, Nonsteroidal↗
PubMed2002

Human fetal bone development: histomorphometric evaluation of the proximal femoral metaphysis.

Quantitative data on metaphyseal bone histology during early human development are scarce. In the present study the proximal femoral metaphysis of 35 fetuses and newborns (gestational age 16-35 weeks) was analyzed by histomorphometry. Averaged over the entire metaphyseal area, the relative amount of bone and cartilage was higher in the third compared to the second trimester. Osteoid thickness increased with gestational age, whereas indices of bone resorption decreased. The relative amount of cartilage decreased with increasing distance from the growth plate, whereas the relative amount of bone increased. This was due to trabecular thickening, which occurred at an estimated rate of 3 microm/day in areas close to the growth plate. Despite this rapid rate of net bone gain, osteoid indices were relatively low, indicating that mineralization occurred very rapidly after bone deposition. These observations suggest that modeling, not remodeling, is the predominant mechanism responsible for the development of femoral metaphyseal cancellous bone in utero.

Analysis of Variance↗
PubMed2002

Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease.

Osteogenesis imperfecta (OI) is a heritable disease of bone with low bone mass and bone fragility. The disease is generally classified into four types based on clinical features and disease severity, although recently fifth and sixth forms have also been reported. Most forms of OI are autosomal dominant. Rarely, autosomal recessive disease has been described. We report the clinical, radiological, and histological features of four children (age 3.9-8.6 years at last follow-up; all girls) and four adults (age 28-33 years; two women) with a novel form of autosomal recessive OI living in an isolated First Nations community in northern Quebec. In keeping with the established numeric classification for OI forms, we have called this form of the disease OI type VII. The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. Rhizomelia is a prominent clinical feature. Histomorphometric analyses of iliac crest bone samples revealed findings similar to OI type I, with decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone. The disease has subsequently been localized to chromosome 3p22-24.1, which is outside the loci for type I collagen genes. The underlying genetic basis for the disease remains to be determined.

Bone Density↗
PubMed2002

Gender-specific pubertal changes in volumetric cortical bone mineral density at the proximal radius.

It is well established that puberty affects the geometry of cortical bone differently in females and males. In the present study we investigated whether there are also gender differences in the volumetric bone mineral density of the cortical compartment (BMDcort). BMDcort was determined at the proximal radial diaphysis in 362 healthy children and adolescents (age 6-23 years; 185 females, 177 males) and in 107 adults (age 29-40 years; 88 women, 19 men) using peripheral quantitative computed tomography (pQCT). The densitometric result for BMDcort was similar in prepubertal girls and boys, but was significantly higher in females after pubertal stage 3. pQCT results for BMDcort are influenced by cortical thickness due to the partial volume effect. Therefore, these gender differences were reanalyzed in groups of subjects of the same developmental stage who were matched for cortical thickness. Thus calculated, no gender difference in BMDcort was detected in prepubertal children. However, adolescent females after pubertal stage 3 and adult women had a 3%-4% higher BMDcort than males at the same developmental stage. BMDcort is an integrated measure of both cortical porosity and mean material density of cortical bone. The metabolic activity of cortical bone (intracortical remodeling) increases cortical porosity and decreases the mean material density of cortical bone. Our results therefore suggest that intracortical remodeling is lower in postpubertal females than in males.

Adolescent↗
PubMed2002

Osteogenesis imperfecta type VII maps to the short arm of chromosome 3.

We have identified a novel form of autosomal recessive osteogenesis imperfecta (OI) in a small First Nations community from northern Quebec. Mutation screening of the COL1A1/COL1A2 genes revealed no detectable mutations, and type I collagen protein analyses were also normal. By linkage analysis, we mapped this unique autosomal recessive variant of osteogenesis imperfecta to chromosome 3p22-24.1. Based on the assumption of a founder effect, genome-wide screening was performed on a DNA sample pooled from seven affected individuals. Familial as well as historical recombinations identified within an extended haplotype of 19 markers localized the disease between markers D3S2324 and D3S1561, separated by <5 cM. Based on chromosomal localization to 3p22-24.1, the transforming growth factor-beta receptor 2 gene and the parathyroid hormone/parathyroid hormone-related peptide receptor were tested, but were excluded as being associated with the phenotype. This study excludes type I collagen mutations in the pathogenesis of the disease and assigns this form of OI to a locus other than the ones containing the type I collagen genes.

Chromosome Mapping↗
PubMed2002

The bone formation defect in idiopathic juvenile osteoporosis is surface-specific.

We have previously shown that idiopathic juvenile osteoporosis (IJO) is characterized by a decreased cancellous bone volume and a very low bone formation rate on cancellous surfaces. Whether IJO similarly affects cortical bone is unknown. We therefore compared tetracycline double-labeled transfixing iliac-crest bone biopsies from eight children with typical clinical features of IJO (six girls; age 10-12 years) and from nine children (four girls; age 9-12 years) without metabolic bone disease. No differences in intracortical remodeling activity were detected. Both structural parameters reflecting intracortical remodeling (cortical porosity, active canal diameter, and quiescent canal diameter) and bone surface-based metabolic parameters (osteoid, osteoblast, mineralizing, osteoclast and eroded surfaces, and bone formation rate) were similar in IJO patients and controls (p > 0.2 each, t-test). Although the internal cortex of the biopsy was thinner in IJO patients than in controls (660 +/- 170 microm vs. 980 +/- 320 microm; p = 0.02), there was no difference in the width of the external cortex (p = 0.36). In growing children, both cortices exhibit an external modeling drift. Therefore, the difference in internal cortical width point to a decreased modeling activity on the endocortical surface of the internal cortex. In fact, bone formation rate on this surface was 48% lower in IJO patients than in controls (82 +/- 45 microm(3)/microm(2) per year vs. 159 +/- 162 microm(3)/microm(2) per year). However, this difference did not achieve statistical significance (p = 0.21) due to the high variability of bone formation rate on modeling surfaces. The disturbance of bone remodeling in IJO is limited to cancellous bone, but there may be a modeling defect affecting the internal cortex. Thus, the process causing IJO appears to mainly affect bone surfaces that are in contact with the bone marrow cavity.

Bone Remodeling↗
PubMed2002

Skeletal development in premature infants: a review of bone physiology beyond nutritional aspects.

Bone development is usually seen as a process of bone mineral accretion or increase in bone mass, and treatment of bone disorders usually consists of attempts to maximise bone mass accumulation by nutritional means only. However, from a functional perspective, bones should not be as heavy as possible, but rather as stable as necessary. It is therefore important to create conditions that stimulate bones to become more stable.

Bone Development↗
PubMed2002

Influence of puberty on muscle development at the forearm.

Despite its fundamental importance for physical development, the growth of the muscle system has received relatively little consideration. In this study, we analyzed the relationship between cross-sectional area (CSA) of forearm muscles and maximal isometric grip force with age and pubertal stage. The study population comprised 366 children, adolescents, and young adults from 6 to 23 yr of age (185 female) and 107 adults (88 female) aged 29 to 40 yr. By use of peripheral quantitative computed tomography, muscle CSA was determined at the site of the forearm, whose distance to the ulnar styloid process corresponded to 65% of forearm length. Both muscle CSA and grip force were higher in prepubertal boys than in girls. The gender differences decreased until pubertal stage 3 and reincreased thereafter. In girls at pubertal stage 5, muscle CSA no longer increased with age (P > 0.4), whereas there was still some age-related increase in grip force (P = 0.02). In boys at pubertal stage 5, both muscle CSA and grip force continued to increase significantly with age (P < 0.005 each). Specific grip force (grip force per muscle CSA) adjusted for forearm length increased by almost one-half between 6 and 20 yr of age, with no difference between the genders. In conclusion, forearm muscle growth takes a gender-specific course during puberty, indicating that it is influenced by hormonal changes. However, the increase in specific grip force is similar in both genders and thus appears to be independent of sex hormones.

Adolescent↗