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PubMed1986

Heterogeneity of osteogenesis imperfecta. Biochemical and morphological findings in a case of type III according to Sillence.

A male infant with pale-blue sclerae, who died at the age of 6 weeks through the aspiration of food, presented multiple fractures and deformation of the long tubular bones. The clinical and radiological findings and the course indicated osteogenesis imperfecta, type III, according to Sillence's classification. The family history was unremarkable. Light and electron microscopic studies of iliac crest bone obtained postmortem, showed an abrupt interruption of endochondral ossification, with an active periosteal ossification. In the region of the fractures, a mixed desmochondral callus was seen. The endoplasmic reticulum of the osteoblasts was markedly dilated, the mitochondria were swollen. The osteoid was reduced in quantity. A postmortem analysis of the collagen types I, II and III obtained from skin, cartilage and bone yielded chromatographically normal collagen constituents. An analysis of the amino acids of the collagen alpha-chains showed an increased hydroxylysine content. The radiological findings and the clinical course both indicated type III osteogenesis imperfecta: identical biochemical findings have been described only for type II. The morphological and biochemical findings described here may be a manifestation of a variable expressivity of type III osteogenesis imperfecta. On the other hand, heterogeneity of type II osteogenesis imperfecta cannot be ruled out.

Amino Acids↗

PubMed1984

Histological investigation of skin biopsies in otosclerosis and osteogenesis imperfecta.

Histological investigation of skin biopsies in four patients with osteogenesis imperfecta, nine patients with otosclerosis and 13 sex- and age-matched normal controls was carried out blindly. The dermal thickness was markedly reduced in osteogenesis imperfecta and slightly reduced in otosclerosis. Minor degenerative changes in the elastic fibres were seen in otosclerosis, while the elastic fibres were found to be more degenerated and more numerous in osteogenesis imperfecta. Our study does not support the hypothesis of otosclerosis being a localized form of osteogenesis imperfecta. The minor changes in the elastic fibres in otosclerosis indicate that further studies of the elastic fibres and of collagen will be necessary to determine whether otosclerosis is a localized disease or part of a general connective tissue disorder.

Adult↗

PubMed1997

Histopathologic and electron-microscopic features of corneal and scleral collagen fibers in osteogenesis imperfecta type III.

BACKGROUND: This report describes the histopathologic and electron-microscopic features of an eye from a patient with osteogenesis imperfecta type III. In particular, the diameters of corneal stromal and scleral collagen fibers were determined. METHODS: The eyes of an 18-year-old white male with osteogenesis imperfecta type III were examined by light and electron microscopy and the pathological features were compared with an age-matched control eye. RESULTS: The cornea was clear. The sclera had a blue color and was moderately thinned, especially at the equator. Light microscopy revealed absence of Bowman's layer. Transmission electron microscopy confirmed complete absence of Bowman's layer without evidence of scarring or inflammation. The collagen fibers of the corneal stromal lamellae were about 25% narrower than in the control, but the cornea was otherwise unremarkable ultrastructurally. The collagen fibers of the sclera were approximately 50% narrower than in the control and were much more uniform in size. Prominent portions of elastic fibers, which are usually only present in a small number in the inner portion of the sclera, were present throughout the sclera. CONCLUSION: We propose that it is the uniformity of the scleral collagen fibers which gives the sclera translucence, producing the blue color often observed clinically in osteogenesis imperfecta. Absence of Bowman's layer of the cornea did not interfere with the stability of the cornea in this case. This appears to be the first published pathological examination of the eye in osteogenesis imperfecta type III.

Adolescent↗

PubMed1979

Early osteogenesis in compact bone isografts: a quantitative study of contributions of the different graft cells.

Isografts of cortical bone were tranplanted subcutaneously in the rat and the rate of osteogenesis 12 to 14 days later was assessed by measurement of 85Sr uptake and by histology. Some grafts were implanted complete whereas others had had one or more of their cellular components (viz. periosteum, endosteum, osteocytes, marrow) removed by mechanical or enzymatic pretreatment. From an analysis of the differences in osteogenesis between grafts devoid of different combinations of cellular components, the contribution of each component to osteogenesis was determined. The results indicate that the endosteal lining cells and marrow stroma together produce more than half of the new bone, the periosteal cells contribute about 30%, the osteocytes possibly make a small (10%) contribution, and the free, hemopoietic cells of the marrow make no significant contribution. Evidence about the relative contributions to osteogenesis of graft and host cells is reviewed and the possible osteogenetic role of bone marrow is discussed.

Animals↗

PubMed1994

Post-traumatic dynamic change of carboxyterminal propeptide of type I procollagen, alkaline phosphatase and its isoenzymes as predictors for enhanced osteogenesis in patients with severe head injury.

Patients suffering from severe head injury and fractures of long bones or large joints often show enhanced osteogenesis, with hypertrophic callus formation and/or heterotopic ossifications. The advantage of this phenomenon is early consolidation of the fractures. An extreme disadvantage is extensive periarticular calcification, resulting in complete ankylosis of the affected joint. In spite of numerous efforts aimed at clarifying the way in which severe head injury can influence osteogenesis at a distant site, this phenomenon is still not understood. The process, once started, seems irreversible, but if diagnosed in time, could be prevented with non-steroid anti-inflammatory drugs that inhibit development of heterotopic ossifications. The major prerequisite for testing this possibility is to define parameters of an early diagnosis of enhanced osteogenesis. Thus, the aim of this study was to test whether serum values of some parameters related to bone regeneration could allow an early prediction of enhanced ossification following bone fracture in patients with severe head injury. Samples of sera were obtained from three groups of injured patients: fractures of long bones or large joints only (n = 6), severe head injury only (n = 8), severe head injury and fractures of long bones and large joints (n = 7) and from a group of apparently healthy volunteers (n = 10). The values for alkaline phosphatase (ALP), the bone isoenzyme, and the carboxy terminal propeptide of type I procollagen (PICP) were significantly higher (5-20 times as high) in patients with severe head injury and bone or joint fractures than in any other group. Significantly increased concentrations of PICP were already found in the 1st week after injury, and those of ALP and of the bone isoenzyme increased during the 2nd week after injury. Results show that these parameters are helpful for an early diagnosis of enhanced osteogenesis and heterotopic ossifications in patients with severe head injury and bone fractures. Further studies are necessary to verify these findings, while analysis of reasons for the specific patterns of dynamic change of these parameters could lead to better understanding of the mechanisms underlying the uncontrolled bone formation.

Adolescent↗

PubMed1997

Mandibular distraction osteogenesis. Preliminary results of an animal study with a dentally fixed distraction device.

Lengthening of the human mandible by distraction osteogenesis has become an accepted treatment for correction of severe mandibular disto-basal discrepancies in recent years. This usually entails the deployment of extra-orally located distraction devices. This type of device often causes conspicuous scarring. To avoid this scarring, an intra-oral device is to be developed. In the present animal study, 2 "Troll" mini-pigs and 2 "Yucatan" micro-pigs were fitted with a new solely dentally fixed orthodontic device for mandibular distraction osteogenesis. Following bilateral osteotomy in the dentigerous area of the mandibular body and a latent period of 2 to 7 days, the apparatus was activated 1 mm per day. Within a period of 9 days, a mandibular lengthening of 9 mm was reached. This situation was retained using the distraction device for 6 weeks. After removal of the apparatus, there followed another 6-week period of consolidation. During the experiment, the callus and bone formation and potential dental and periodontal reactions were radiologically examined and underwent histological examination at the end of the experiment. Twelve weeks after the mandibular lengthening, the osteogenesis in the distraction areas was complete. No destructive processes were recognizable, either at the roots or at the periodontium of the teeth near the osteotomy gap. Lengthening of the mandibular body using distraction osteogenesis with the help of a solely dentally fixed distraction device is thus feasible and can, in the future, become the appropriate treatment in the correction of severe mandibular deficiency.

Animals↗

PubMed2005

[Application of low intensity, pulsed ultrasound on distraction osteogenesis of the humerus. Case report].

Low intensity pulsed ultrasound accelerates fracture healing both clinically and experimentally. Based on recently published animal studies, an improvement in regenerative bone maturation after distraction osteogenesis due to low intensity, pulsed ultrasound is also expected. We report on an 18 year-old female patient suffering from an acquired shortening of the right upper arm of 10 cm after humeral osteitis as a baby. The patient was admitted to hospital for corticotomy and distraction osteogenesis at the afflicted humerus. Due to the published experimental results in animals which indicate an improvement in bone regeneration during callotasis with the additional application of low intensity, pulsed ultrasound, we decided to try this procedure. The calculated distraction consolidation index was 21 days/cm, which is below the mean of 30 days/cm reported in the literature for humeral lengthening by distraction osteogenesis. The calculated healing index according to Paley was 0.7 months/cm in our patient. Compared to reference data, in which a range of from 0.87 months/cm to 1.5 months/cm is reported, our patient showed an accelerated maturation of distraction callus. The duration of treatment of the patient was clearly shortened by the additional application of low intensity, pulsed ultrasound. If distraction osteogenesis is correctly indicated, the early use of low intensity, pulsed ultrasound should be considered, since an acceleration of callus formation with consecutive shortening of treatment time could be attained while wearing an external fixator, leading to a decrease in cumulative complications, such as pin tract infections. Further studies from our research group regarding this topic will follow.

Adult↗

PubMed2005

Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult.

The musculoskeletal manifestations of mild forms of osteogenesis imperfecta are not well defined in the adult. The aim of this study was to characterize the musculoskeletal manifestations and resulting impairments reported by adults with mild osteogenesis imperfecta. For this task a survey of musculoskeletal symptoms and impairments was hosted on the Osteogenesis Imperfecta Foundation web site for 6 weeks. Survey responses are reported herein. There were 111 unduplicated, adult respondents (78 female). Mean age was 40.8 years. More than one-quarter of 3,410 lifetime fractures occurred in adulthood. Nearly half of respondents reported an established diagnosis of "arthritis" (usually osteoarthritis), and the majority of these reported some degree of impairment attributable to arthritis. Articular pain, stiffness and instability were dominant in the large, weight-bearing joints of the lower extremities. Back pain and scoliosis were common. Of the respondents, 15% required assistance with light physical tasks and personal care. Two-thirds reported joint hyper-mobility, and one-third reported a previous tendon rupture. Complex regional pain syndrome was rare. Respondents reported frequent use of medications known to have potential adverse skeletal effects. In spite of these concerns the majority rated their overall physical health as good or excellent. Adults with mild osteogenesis imperfecta continue to sustain fractures into adulthood, and the majority reports some functional impairment due to musculoskeletal issues. Significant impairment is not rare.

Adult↗

PubMed2002

Static and dynamic osteogenesis: two different types of bone formation.

The onset and development of intramembranous ossification centers in the cranial vault and around the shaft of long bones in five newborn rabbits and six chick embryos were studied by light (LM) and transmission electron microscopy (TEM). Two subsequent different types of bone formation were observed. We respectively named them static and dynamic osteogenesis, because the former is characterized by pluristratified cords of unexpectedly stationary osteoblasts, which differentiate at a fairly constant distance (28+/-0.4 microm) from the blood capillaries, and the latter by the well-known typical monostratified laminae of movable osteoblasts. No significant structural and ultrastructural differences were found between stationary and movable osteoblasts, all being polarized secretory cells joined by gap junctions. However, unlike in typical movable osteoblastic laminae, stationary osteoblasts inside the cords are irregularly arranged, variously polarized and transform into osteocytes, clustered within confluent lacunae, in the same place where they differentiate. Static osteogenesis is devoted to the building of the first trabecular bony framework having, with respect to the subsequent bone apposition by typical movable osteoblasts, the same supporting function as calcified trabeculae in endochondral ossification. In conclusion, it appears that while static osteogenesis increases the bone external size, dynamic osteogenesis is mainly involved in bone compaction, i.e., in filling primary haversian spaces with primary osteons.

Animals↗

PubMed2004

Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24/CCN2) during distraction osteogenesis.

To investigate the localization and expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24/CCN family member 2 (CTGF/Hcs24/CCN2) during distraction osteogenesis in the rat femur, we studied a total of 54 male rats (11 weeks old). We performed osteotomy in the midshaft of the right femur. After 7 days (lag phase), distraction was started, at the rate of 0.25 mm/12 h for 21 days (distraction phase) by using a small external fixator, and this was followed by a 7-day consolidation phase. Localization and expression of CTGF/Hcs24 during distraction osteogenesis in the femur were examined by immunostaining, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR). Immunostaining showed the localization of CTGF/Hcs24 in various cells located in the bone-forming area around the osteotomy site. During the distraction phase, in situ hybridization showed that CTGF/Hcs24 mRNA was expressed not only in hypertrophic chondrocytes and osteoblasts but also in fibroblast-like cells and mesenchymal cells at sites of end-ochondral ossification, and not only in osteoblasts but also in pre-osteoblasts and fibroblast-like cells at sites of intramembranous ossification. RT-PCR showed higher level expression of CTGF/Hcs24 mRNA in the distracted group than in the nondistracted group. These results revealed an elevated pattern of CTGF/Hcs24 mRNA expression during distraction osteogenesis, and suggest that CTGF/Hcs24 may play some roles in the endochondral and intramembranous ossification processes that occur during distraction osteogenesis.

Animals↗

PubMed2006

Expression of osteotropic growth factors and growth hormone receptor in a canine distraction osteogenesis model.

Osteotropic growth factors play an important role in bone metabolism. Nevertheless, knowledge about their expression in relation to distraction osteogenesis remains limited. The aim of the present study was to determine the expression of growth hormone (GH), growth hormone receptor (GHR), insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), and bone morphogenetic protein 2 (BMP-2) in distraction-induced bone regeneration. Expression of these factors was assessed during the consolidation phase, comparing distraction osteogenesis with osteotomy-induced bone formation. Real-time PCR was performed as a semiquantitative measurement of mRNA, and the relative expression levels of these factors were determined. In addition, plasma GH profiles and plasma concentrations of IGF-I, IGF-II, and insulin-like growth factor-binding protein 4 and -6 (IGFBP-4 and -6) were measured to assess their potential systemic role during bone formation. Expression of GHR, IGF-I, and BMP-2 had significantly increased in comparison with the expression of these factors in mature bone. Expression of GHR was significantly higher in distraction-induced bone regenerate than in osteotomy-induced bone. No significant differences were found for the expression of IGF-I and BMP-2 between distraction and osteotomy. Plasma concentrations of GH, IGF-I, IGF-II, IGFBP-4, and IGFBP-6 did not demonstrate any significant differences between treatment groups and controls. Upregulation of GHR expression in distraction osteogenesis may enhance sensitivity to endogenous systemic GH and thus promote consolidation of the regenerated bone. Changes in the systemic osteotropic growth factors GH, IGF-I, IGF-II, IGFBP-4, and IGFBP-6 do not seem to be of importance during distraction osteogenesis.

Animals↗

PubMed1988

Prenatal ultrasonographic diagnosis of osteogenesis imperfecta.

Between 1982 and 1986, osteogenesis imperfecta was diagnosed by ultrasound in seven fetuses. The known heterogeneity of osteogenesis imperfecta was confirmed by the prenatal ultrasonographic findings. Dependent on the type of osteogenesis imperfecta, the appearance of the limbs varied from severely shortened and broad, with very low echogeneity and absent acoustic shadow (type IIA), to only moderately shortened and thin, with almost normal echogeneity and acoustic shadow but clearly visible fractures causing angulation of the bone (types IIC and III). Ultrasonography offers the possibility to detect or exclude the lethal and severe forms of osteogenesis imperfecta early (type IIA) or halfway (types IIB, IIC, and III) through the second trimester. Prenatal diagnosis of the disease allows the option of elective abortion or may prevent unnecessary obstetric intervention.

Adult↗

PubMed1987

Nontraumatic subdural hematoma in a patient with osteogenesis imperfecta and renal failure.

Intracranial hematomas in patients with osteogenesis imperfecta rarely are reported despite an increased incidence of skull fractures. We present a case of a patient with osteogenesis imperfecta but without any history of trauma or chronic anticoagulation in whom a subdural hematoma occurred during hemodialysis. Despite operative intervention, the patient died. We could find no other cases in the medical literature of a patient with osteogenesis imperfecta who had an intracranial hematoma in the absence of a skull fracture. Patients with osteogenesis imperfecta may be at high risk for intracranial bleeding from coagulation abnormalities or otherwise trivial injuries.

Adult↗

PubMed1987

Sodium fluoride as an initiator of osteogenesis from embryonic mesenchyme in vitro.

Sodium fluoride, which preferentially and rapidly becomes incorporated into bone, is a potent stimulator of bone formation. As such, it has been used to increase total bone mass in patients suffering from osteoporosis. How NaF stimulates bone formation is little understood. Farley et al. (Science 222:330-332, 1983) demonstrated that NaF has a direct effect on proliferation and bone-forming activity of isolated bone cells and of bones exposed to NaF in vitro, that is, NaF stimulates ongoing osteogenesis. In this study, we ask whether NaF can allow preosteogenic embryonic mesenchymal cells to undergo their initial differentiation into osteoblasts and to deposit bone matrix. The mesenchymal cells were from mandibular mesenchyme from embryonic chicks. Mesenchyme from the mandibular arches has to undergo a tissue interaction with mandibular arch epithelium until 4 1/2 days of incubation before osteogenesis can be initiated. Therefore, mandibular arch mesenchyme from younger embryos (3 1/2-4 days), enzymatically freed from its epithelium, was used to provide a source of uninduced preosteogenic cells. Mesenchyme was cultured in the presence or absence of NaF (10(-5) M) in both serum-free and serum-supplemented medium. Osteogenesis was only initiated when NaF was present and only in the presence of serum. Mesenchyme from older embryos that failed to undergo osteogenesis in serum-free medium did form bone in the presence of NaF. It is concluded that preosteogenic embryonic mesenchyme can be stimulated by NaF to differentiate into osteoblasts and to deposit bone matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Early effects of electrical stimulation on osteogenesis.

The mechanism by which electrical stimulation causes osteogenesis is unknown. Bone marrow of the rabbit was stimulated by direct electrical current or electromagnetic fields to clarify the mechanism of osteogenesis by electrical stimulation. A total of 105 rabbits were separated into five groups: a direct current stimulation by Kirshner wire insertion group; a pulsed electromagnetic fields stimulation (PEMF) group; a PEMF with Kirshner wire insertion group; a Kirshner wire insertion group; and an intramedullary drilling control group. Measurement of intramedullary new bone formation and determination of alkaline phosphatase activity within the bone marrow were performed. Argylophilic nuclear organizer region (AgNOR) staining was done to evaluate the change in proliferative activity of the osteoblasts during electrical stimulation. In the direct current stimulation group and the PEMF accompanied by the insertion of the Kirshner wire group, alkaline phosphatase activity in the bone marrow and AgNOR staining increased at 7 days after surgery. At 14 days after surgery, alkaline phosphatase activity and proliferative activity of osteoblast were significantly higher in these two groups than in the other groups (PEMF group, Kirshner wire insertion alone group, intramedullary drilling group). Intramedullary new bone formation was most active in the direct current stimulation group. Electromagnetic stimulation of the inserted Kirshner wire also promoted bone formation significantly. The Kirshner wire insertion alone group and the intramedullary drilling group showed bone formation, but it was significantly less. Electromagnetic stimulation without the insertion of the Kirshner wire showed little bone formation. These findings revealed that the degree of osteogenesis induced by electrical stimulation is influenced by the tissue environment, and that osteogenesis is promoted markedly when electrical stimulation is provided in the environment of inflammation and reactive cells.

Alkaline Phosphatase↗

PubMed2005

Effect of recombinant human tissue inhibitor of matrix metalloproteinase-1 in mandibular distraction osteogenesis in rabbits: a computed tomographic study.

Matrix metalloproteinases (MMPs), together with their tissue inhibitors (TIMPs), are responsible for the controlled degradation of collagen in bone. We studied the long-term stability of the regenerated bone formed by distraction osteogenesis, and the effect of recombinant human TIMP-1 on the remodelling of bone formed by mandibular distraction osteogenesis in rabbits. Nine rabbits were subjected to distraction osteogenesis of the mandible and divided into three groups: a control group with no collagen implanted; a sham-control group with a collagen sheet implanted; and an experimental group with a collagen sheet impregnated with rhTIMP-1 implanted. Computed tomograms were taken at weeks 4, 12, and 24 after distraction, and micro-computed tomograms and histological examinations were made at week 24. There was no significant resorption of regenerated bone at the site of distraction in any group after 6 months of consolidation, suggesting that the regenerated bone formed by distraction osteogenesis is stable. We found no obvious influence of rhTIMP-1 in the collagen sheet on the bony regenerate after 6 months of consolidation.

Animals↗

PubMed2005

Systemic regulation of angiogenesis and matrix degradation in bone regeneration--distraction osteogenesis compared to rigid fracture healing.

Aim of this study was the investigation of systemic biochemical regulation mechanisms of bone regeneration by angiogenic and matrix-degrading enzymes during distraction osteogenesis compared to rigid osteotomy bone healing. Serum samples of 10 otherwise healthy patients with callus distraction for lower limb-lengthening and 10 osteotomy patients undergoing elective axis correction have been collected prospectively in a standardized time schedule before and up to 6 months after the procedure. At the end of the individual investigation period, concentrations of metalloproteinases (MMP-9, -13), tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) and the angiogenic factors angiogenin and VEGF have been detected by use of commercially available enzyme immunoassays. Results have been compared to our preliminary study on proMMP-1-3. In distraction osteogenesis, significantly elevated serum concentrations compared to baseline could be detected postoperatively for proMMP-1, MMP-9, TIMP-1, angiogenin and VEGF but not for proMMP-2, proMMP-3 or TIMP-2. In patients with rigid osteotomy healing, MMP-9, TIMP-1, TIMP-2, angiogenin and VEGF were significantly increased respectively. Comparison of both patient collectives revealed significantly higher increases of serum proMMP-1, VEGF and TIMP-1 in distraction patients during the lengthening period and significantly higher serum concentrations of TIMP-2 in late fracture healing period in osteotomy patients. Serum levels of MMP-13 were below the lowest standards, and therefore quantitative analysis was not possible. Bone regeneration in distraction osteogenesis and rigid osteotomy healing is accompanied by systemic increase of matrix-degrading and angiogenic factors in a certain time course and quantity. This might reflect biochemical regulation of local bone healing in the circulation. ProMMP-1, VEGF and TIMP-1 seem to be key regulatory factors during distraction osteogenesis.

Adult↗

PubMed2005

Distraction osteogenesis in the irradiated mandible. A case report.

BACKGROUND: Distraction osteogenesis has been suggested as a relatively simple method of mandibular reconstruction following ablative head and neck surgery. Some authors report good results in irradiated patients while other authors report limitations with this group of patients. PATIENT: In a 72-year-old male an attempt was made to reconstruct the irradiated mandible using distraction osteogenesis. RESULTS: Distraction osteogenesis only resulted in an enlarged soft tissue envelope, while there was no evidence of bone formation in the distraction gap. CONCLUSION: Based on this experience and a search of the literature, it is hypothesized that distraction osteogenesis is only a reliable reconstructive method in irradiated patients if the cumulative dose to the mandibular bone at the distraction site does not exceed a certain maximum still to be defined.

Aged↗