Osteogenesis imperfecta (OI) has been treated with bisphosphonates for many years, with some clear clinical benefits. In adults, there are reports of a new pattern of atraumatic subtrochanteric fractures with bisphosphonate treatment. This study assesses if bisphosphonate treatment leads to an altered pattern of femoral fractures.
Retrospective review of imaging for a cohort of 176 bisphosphonate-treated OI patients to identify the locations of femoral fractures over a two-year period, as compared to a historical control group managed pre-bisphosphonates.
Sixteen femoral fractures were identified in this time period in the bisphosphonate-treated group. All but two were within the subtrochanteric region. In comparison, the historical group—composed of 26 femoral fractures—had a more widespread fracture pattern, with the most frequent location being the mid-diaphysis. Many of the subtrochanteric fractures in the treatment group occurred with minimal trauma.
It appears that concerns over the treatment of the adult osteoporotic population with bisphosphonates are amplified and mirrored in OI. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs increase the risk of this type of injury, which warrants further modification of surgical management of the femur.
Osteogenesis imperfecta; Bisphosphonates
This is a case report of a 15-month-old patient with osteogenesis imperfecta (OI) who sustained atlanto-axial dislocation. Our objective is to report a unique case of traumatic atlanto-axial subluxation in a child with osteogenesis imperfecta associated with bilateral femoral fractures. The management is discussed. Atlanto-axial dislocation occurring with associated osteogenesis imperfecta is very rare. There have been no previous reported cases. A 15-month-old girl with osteogenesis imperfecta sustained a traumatic atlanto-axial dislocation. The child was followed-up through presentation, diagnosis, management and post-discharge. The initial diagnosis was confirmed with a CT scan. The patient was treated conservatively with a halo-traction for 4 weeks followed by a halo jacket for a further 4 weeks. Both appliances were fitted under general anaesthetic. An anatomical reduction was achieved. There was no neurological deficit at any stage. The child has had a successful outcome. She is asymptomatic with a full range of movement at the atlanto-axial joints at 9 months. In conclusion, this paper records our management of this rare problem.
Atlanto-axial dislocation; Osteogenesis imperfecta; Bilateral femoral fractures; Halo-traction; Conservative treatment
We report the 11-year follow-up of a man with osteogenesis imperfecta type I who was treated with bisphosphonates and alfacalcidol. A 36-year-old Japanese man with osteogenesis imperfecta type I who had frequently experienced painful fragility fractures consulted our clinic because of chronic back pain. The patient had multiple morphometric vertebral fractures and a low bone mineral density (BMD) at the lumbar spine. The patient was treated with cyclical etidronate 200 mg, for 2 weeks every 3 months, plus alfacalcidol 1 μg daily, for 2 years; and alendronate 5 mg daily or 35 mg weekly, plus alfacalcidol 1 μg daily for 9 years. After 11 years of treatment, BMD at the lumbar spine increased by 6.4%, following a 20.3% reduction in serum alkaline phosphatase. Serum calcium, phosphorus, and intact parathyroid hormone levels remained within the normal ranges. Three clinical fractures occurred at two ribs and the metacarpus, and two morphometric vertebral fractures occurred at the thoracic spine during the 11-year treatment period, but the patient experienced no adverse effects. Thus, the present case report shows the long-term outcome and safety of bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I.
etidronate; alendronate; fragility fracture; bone mineral density; osteogenesis imperfecta
Osteogenesis imperfecta (OI) is a rare inherited disorder with a broad spectrum of clinical and genetic variability. The genetic diversity involves, in the majority of the cases, mutations in one of the genes that encodes the type 1 collagen protein (COL1 A1 and COL1 A2), but it is not a requirement for the diagnosis. The most benign form is OI type I. The authors present a case report of a 25-year-old woman who had severe low back pain associated with incapacity to walk and breast-feed post-partum. Symptoms developed 2 weeks after delivery. The radiological examination revealed severe osteoporosis with no abnormalities in the laboratory findings. The clinical signs and a positive personal and family history of multiple fractures in childhood suggested OI type I, although other diagnosis, such as pregnancy-associated osteoporosis, was also considered. The atypical presentation of this rare disorder in adulthood calls attention to the need for early diagnosis for prompt treatment. Treatment of OI is never curative, but it improves the quality of the patient’s life.
osteogenesis imperfecta; collagen; pregnancy; osteoporosis
Osteogenesis imperfecta is a genetic disorder characterized by increased susceptibility to fractures and vascular injuries due to connective tissue fragility. In this case report, we present a patient with osteogenesis imperfecta type I who sustained a transverse fracture of the right acetabulum while transferring from bed to chair. The fracture was repaired through an ilioinguinal approach. During the surgery, an iatrogenic injury to the femoral artery and vein occurred. This intraoperative complication was salvaged by immediate vascular repair. We discuss the possible causes of iatrogenic vascular injuries in patients with osteogenesis imperfecta. Orthopaedic surgeons should be aware of this potentially devastating complication in this particular patient cohort.
Although osteogenesis imperfecta is a well-known skeletal disorder, reports of spondylolisthesis in osteogenesis imperfecta are rare. Only very few cases of spondylolisthesis caused by elongation of lumbar pedicles have been described in the literature. Here we report three patients suffering from osteogenesis imperfecta showing a severe form of hyperlordosis caused by lumbar pedicle elongation and consecutive spondylolisthesis. Radiographs in the course of childhood and adolescence show a rapid progression of pedicle elongation and hyperlordosis with increased mechanical loads. The treatment strategy consists of physiotherapy, medical treatment with bisphosphonates, and orthopedic surgery and is preferably conservative. In the three patients reported here, one patient was treated with laminectomy and postero-lateral fusion, whereas in the other two patients surgery is currently not considered as necessary.
Osteogenesis imperfecta; Spondylolisthesis; Pedicle elongation; Hyperlordosis
Accepted 10 September 1996
The response to the bisphophosphonate, pamidronate, is reported
in a child with osteogenesis imperfecta who had recurrent symptomatic
hypercalcaemia after immobilisation following fractures. Oral
clodronate was effective in the prevention of immobilisation hypercalcaemia in the same child. The bisphosphonates may have other
roles in osteogenesis imperfecta by decreasing bone turnover.
Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the ‘Sillence classification’), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI.
Collagen type I; Fractures; Osteogenesis imperfecta
The aim of our study was to compare the surgical and conservative treatment of patients affected by fragility fractures and deformities of long bones in osteogenesis imperfecta (OI).
Our series consisted of 29 consecutive OI patients treated at our Institute. The series comprised 14 females and 15 males of different ages. The mean age at the time of the first treatment was 8 years (median 6 years; SD ± 15; range 1 to 75). The mean follow-up was 88 months. The Sillence classification was used to classify OI. Fifteen patients were classified as Type I; five as Type III and nine as Type IV.
A total number of 245 procedures were recorded. Of these, 147 were surgical (pinning; intramedullary nailing and plating) while 98 were conservative (cast, braces and bandages). Bisphosphonate use was a major variable in the study. Clinical charts and radiographic films were analyzed for complications (delayed union, nonunion, malunion, hardware loosening). We recorded 58 complications: 13 in Type I; 28 in Type III and 17 in Type IV OI. The rate of each complication was: 15/245 nonunions (6.1%), 14/245 delayed unions (5.7%), 14/245 malunions (5.7%) and 15/245 hardware loosenings (6.1%).
We found no statistically significant differences between surgical and conservative treatments. Type III OI, which is a very crippling form of the disease, was associated with radiographically poorer results than the other types. In our analysis, the two groups were unbalanced and only five patients were treated with bisphosphonates. Nevertheless, bisphosphonate use can be considered a good adjuvant to both the conservative and surgical treatment of OI in order to reduce the rate of complications.
osteogenesis imperfecta; surgical treatment; conservative treatment; complications; bisphosphonates
This article presents a case of osteogenesis imperfecta and reviews the clinical and radiographic features of this condition.
A 27-year–old woman presented with pain in her left hand after a fall while dancing. Plain films revealed multiple fractures in the digits of her left hand.
Intervention and Outcome
The patient was referred to an orthopedic specialist for treatment.
Osteogenesis imperfecta is a heritable disorder of bone, which predisposes patients to fractures after trivial trauma, as was demonstrated in this case.
Osteogenesis imperfecta; Collagen type I; Osteoporosis
Osteogenesis imperfecta is often regarded as a form of osteoporosis. In many cases, particularly those in whom the first fracture occurs outside the neonatal period, bones that have not been fractured may appear radiologically normal. In a group of 24 adults with osteogenesis imperfecta the thickness of the metacarpal cortex was normal but their bones were often slender. Osteoporosis is probably not an inevitable feature of such cases, and some of the radiological abnormalities reported may be the results of previous fractures and their treatment.
Long courses of bisphosphonates are widely administered to children with osteogenesis imperfecta (OI), although bisphosphonates do not block mutant collagen secretion and may affect bone matrix composition or structure. The Brtl mouse has a glycine substitution in col1a1, and is ideal for modeling the effects of bisphosphonate in classical OI. We treated Brtl and wild-type mice with alendronate (0.219 mg/kg/wk sq) for 6 or 12 weeks and compared treated and untreated femora of both genotypes. Mutant and wild-type bone had similar responses to Aln treatment. Femoral areal BMD and cortical vBMD increased significantly after 12 weeks, but femoral length and growth curves were unaltered. Alendronate improved Brtl diaphyseal cortical thickness and trabecular number after 6 weeks, and cross-sectional shape after 12 weeks. Mechanically, Aln significantly increased stiffness in wild-type femora, and load to fracture in both genotypes after 12 weeks. However, predicted material strength and elastic modulus were negatively impacted by 12 week Aln in both genotypes, and metaphyseal remnants of mineralized cartilage also increased. Brtl femoral brittleness was unimproved. Brtl osteoclast and osteoblast surface were unchanged by treatment. However, decreased MAR and BFR/BS and the flattened morphology of Brtl osteoblasts suggested that Aln impaired osteoblast function and matrix synthesis. We conclude that alendronate treatment improves Brtl femoral geometry and load to fracture, but decreases bone matrix synthesis and predicted material modulus and strength, with striking retention of mineralized cartilage. Beneficial and detrimental changes appear concomitantly. Limiting cumulative bisphosphonate exposure of OI bone will minimize detrimental effects.
Brtl Mouse; Bisphosphonates; Osteogenesis Imperfecta; Biomechanics; Histomorphometry; Bone Quality
Kyphoplasty is a recognized treatment option in the management of symptomatic osteoporotic compression fractures, osteolytic vertebral metastases or haemangioma. To our knowledge, kyphoplasty with polymethylmethacrylate in a patient with type I osteogenesis imperfecta (OI) and a vertebral compression fracture has not been reported so far. We report on a 58-year-old patient with type I OI and a vertebral compression fracture at L2 with undislocated posterior vertebral wall and an additional older L1 fracture. Because of severe back pain resistant to conservative therapy over 5 months the indication for percutaneous kyphoplasty was made. Preoperative adjacent endplates of L2 were nearly parallel. Radiologically a minimal loss of height of the L2 vertebra was seen without adjacent fractures at 9 months follow-up. A slight increase of the preoperative kyphotic angle of overlying vertebrae L1 (8.7°/10.3°) and T12 (10.4°/11.0°) was apparent. The visual analogue scale showed decrease of low back pain from 10 to 2 allowing mobilization with a walking frame. Kyphoplasty constitutes a minimal invasive therapeutic alternative in the treatment of vertebral fractures in type I OI and pain, resistant to conservative treatment. Similar to the results of osteoporotic fractures the immediate reduction of pain and stabilization of the fracture in undislocated fragments can be achieved. No adjacent fractures occurred 9 months postoperatively after kyphoplasty in type I OI. Preoperative parallelism of the endplates seems to protect from adjacent fractures.
Osteogenesis imperfecta; Kyphoplasty; Compression fracture; Polymethylmethacrylate; Spine
this paper reports an association between an increased Nuchal Translucency (NT) and Osteogenesis Imperfecta (OI), a type of skeletal dysplasia. Measurement of fetal NT at 10–14 weeks of gestation is a sensitive and effective screening method for chromosomal abnormalities.
a 35-year- old Caucasian woman in her fourth pregnancy was referred to our clinic for an ultrasound scan at 12 weeks of gestation, that confirmed increased Nuchal Translucency. Chorionic villi sampling was performed, showing a normal karyotype. The patient was evaluated by a team of experienced ultra sonographers for pregnancy follow-up at our Department, that is a tertiary center.
in our case the ultrasound scan at 12 week of gestation revealed only an increased NT (3 mm). Cytogenetic analysis on chorionic villi demonstrated a normal male karyotype. US follow-up, performed every 3–4 weeks, confirmed normal anthropometric parameters except for shortening of both femurs, but at 23 weeks an incorrect attitude of the feet was revealed. A clinical and radiographic diagnosis of OI type III was made only at birth, and through follow-up continuing to date.
NT screening was successful for chromosomal abnormalities at 11–14 weeks of gestation. An increased NT thickness is also associated with numerous fetal anomalies and genetic syndromes in a chromosomally normal fetus. In our case there were no sonographic signs of imperfect osteogenesis in the first trimester, although there was an increased NT with a normal karyotype.
currently, in literature, there are not other cases of OI type III associated with an increased NT. Our report is the first to suggest an association between an increased nuchal translucency, short femur length and osteogenesis imperfecta type III.
osteogenesis imperfecta; skeletal dysplasia; nuchal translucency; ultrasound scan
Treatment for craniocervical junction lesions associated with osteogenesis imperfecta (OI) has been described, but there are divergent views on operative procedures and preoperative and postoperative therapies due to the small number of cases. It has been suggested that a major procedure such as combined anterior and posterior surgery with concomitant ventriculoperitoneal (VP) shunting is required for OI associated with basilar impression (BI). However, here we report a case with a good outcome after posterior decompression fusion only. The patient was a 29-year-old woman with OI (Sillence type-IA) who had neurological symptoms of vertigo, nausea, and shaking during walking. Diagnostic imaging revealed hydrocephalus, severe BI, and Chiari type-II malformation. Preoperative Halo traction led to improvement in symptoms, and posterior decompression fusion from the occipital bone to C6 was subsequently performed. Lateral mass screws and Nesplon cables as sublaminar wiring for reinforcement for fusion were used in the operation. The patient wore a Halo vest for 4 weeks postoperatively. She experienced no symptoms postoperatively. Bone fusion and improved hydrocephalus were clear on images at 3 years after surgery, and the postoperative course has been good. In craniocervical junction lesions associated with OI, instability with compression of the nerve and bone fragility in multiple sites can become problematic. Anterior odontoid resection and posterior fusion are required for OI with BI to give ideal decompression on images. However, the results of this case suggest that a good postoperative outcome can be achieved by performing not the combination of anterior odontoid resection and VP shunting, but only with posterior decompression fusion, especially for OI cases of Sillence type-I.
Osteogenesis imperfecta; Basilar impression; Hydrocephalus; Posterior decompression fusion; Anterior odontoid resection
To examine the functional outcomes of children with osteogenesis imperfecta (OI) following initial Fassier–Duval (FD) rodding to the femur at 1 year, and to determine which factors are associated with change in gross motor function, ambulation, and functional performance.
Approval from our Institutional Review Board was obtained. A retrospective chart review identified 60 children (28 males, 32 females) with OI who underwent initial FD femoral rodding (101 rods) and who were receiving bisphosphonates. The mean age of the children was 3 years, 11 months at the initial femoral FD rodding. Two had type I OI, 30 type III, 27 type IV, and one type VI. The maximum length of follow-up was 4 years. Telescoping FD rods were used for the femurs, with surgeries performed one leg at a time, with a 1-week interval. The active range of motion (AROM) of the hips and knees in flexion was measured 4–5 weeks post-initial rodding. Outcomes on the Gillette Functional Assessment Questionnaire (FAQ) Ambulation Scale, the Gross Motor Function Measure (GMFM), and the Pediatric Evaluation of Disability Inventory (PEDI) were compared pre-operatively and at 1 year post-surgery using t-tests and multivariate linear regression.
Pre-operatively, the mean FAQ score was 2.0, and this increased to 5.8 at 1 year post-surgery. Statistically significant improvements (P ≤ 0.05) were found on the FAQ, crawling, standing, walking and running, and total domains of the GMFM, and PEDI mobility and self-care from baseline to 1 year. The results from the multivariate linear regression indicate that older age (P = 0.0045) and higher weight (P = 0.0164) are significantly associated with lower scores in the self-care domain of the PEDI, and that OI type III compared to type IV is significantly associated (P = 0.0457) with greater improvement on the crawling domain of the GMFM. Higher weight was also associated (P = 0.0289) with lower scores in the standing domain of the GMFM, as well as with the total GMFM score (P = 0.0398).
Our findings indicate that initial FD femoral rodding resulted in benefits in ambulation, gross motor function, self-care, and mobility for children with OI beyond physiological expectations due to developmental growth. FD rodding is a procedure which can improve the overall mobility in children with OI with significant femoral deformities.
Fassier–Duval rodding; Lower extremities; Functional outcomes; Bisphosphonates; Osteogenesis imperfecta
Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although anti-resorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials showed improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI-causing Gly->Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in Brtl/+ and WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI.
Osteogenesis imperfecta; Sclerostin antibody; collagen; bone mass; anabolic therapy
Currently, the standard treatment for osteogenesis imperfecta (OI) is bisphosphonate therapy. Recent studies, however, have shown delayed healing of osteotomies in a subset of OI patients treated with such agents. The current study sought to determine the effects of another therapy, RANKL inhibition, on bone healing and bone strength in the growing oim/oim mouse, a model of moderate-to-severe OI. Mice (73 oim/oim and 69 wildtype (WT)) were injected twice weekly with either soluble murine RANK (RANK-Fc) (1.5mg/kg) or saline beginning at 6 weeks of age. At 8 weeks of age, the animals underwent transverse mid-diaphyseal osteotomies of the right femur. Therapy was continued until sacrifice at 2, 3, 4 or 6 weeks post-fracture. At 6 weeks post-fracture, greater callus area (6.59±3.78mm2 vs 2.67±2.05mm2, p=0.003) and increased radiographic intensity (mineral density) (0.48 ± 0.14 vs. 0.30 ± 0.80, p=0.005) were found in the RANK-Fc vs saline oim/oim group, indicating a delay in callus remodeling. Despite this delay, mechanical tests at 6 weeks post-fracture revealed no significant differences in whole bone properties of stiffness and failure moment. Further, RANKL inhibition resulted in a greater failure moment and greater work to failure for the non-fractured contralateral WT bones compared to the non-fractured saline WT bones. Together, these results demonstrate that RANKL-inhibition does not adversely affect the mechanical properties of healing bone in the oim/oim mice, and is associated with increased strength in intact bone in the WT mice.
osteogenesis imperfecta; fracture healing; receptor activator of nuclear factor-κB; RANKL; mice; anti-resorptives
The first case of Osteogenesis Imperfecta Type V in the Polish literature is reported.
Skeletal survey of an 8 year old girl with a history of multiple fractures and bilateral dislocation of radial heads was received for consultation.
Generalised osteoporosis with multiple fractures, periosteal thickening and bilateral dislocation of the radial heads are characteristic signs of osteogenesis imperfecta Type V. The Nosology and Classification of Genetic Skeletal Disorders 2006 Revision classified Osteogenesis Imperfecta into 8 major types. Type V is recognizable on the basis of skeletal survey alone.
osteoporosis; fractures; radial head dislocation; periosteal thickening; ectopic ossification; osteogenesis imperfecta
Osteogenesis imperfecta (OI) is a heritable bone disorder with clinical features that include bone fragility, blue sclerae, and short stature. There are four main subtypes of OI, encompassing a wide range of clinical severity. The majority of patients have mutations in either the COL1A1 or COL1A2 gene that ultimately lead to an abnormal synthesis of or a decrease in the production of collagen. Bisphosphonates have been used effectively in adults and children to treat other bone disorders, since they have been proven to increase bone density through inhibition of bone resorption. Recent studies have demonstrated the advantages of pamidronate therapy in the treatment of children and adolescents with the more severe forms of OI. Pamidronate consistently increases bone mass, vertebral growth, and quality-of-life while decreasing the number of fractures in children with severe OI. Long-term effects are promising, and benefits of pamidronate therapy appear to outweigh the possible risks.
pamidronate; osteogenesis imperfecta; pediatrics
Osteogenesis imperfecta (OI) is characterized by extremely brittle bone. Currently, bisphosphonate drugs allow a decrease of fracture by inhibiting bone resorption and increasing bone mass but with possible long term side effects. Whole body mechanical vibrations (WBV) treatment may offer a promising route to stimulate bone formation in OI patients as it has exhibited health benefits on both muscle and bone mass in human and animal models. The present study has investigated the effects of WBV (45 Hz, 0.3 g, 15 minutes/days, 5 days/week) in young OI (oim) and wild type female mice from 3 to 8 weeks of age. Vibration therapy resulted in a significant increase in the cortical bone area and cortical thickness in the femur and tibia diaphysis of both vibrated oim and wild type mice compared to sham controls. Trabecular bone was not affected by vibration in the wild type mice; vibrated oim mice, however, exhibited significantly higher trabecular bone volume fraction in the proximal tibia. Femoral stiffness and yield load in three point bending were greater in the vibrated wild type mice than in sham controls, most likely attributed to the increase in femur cortical cross sectional area observed in the μCT morphology analyses. The vibrated oim mice showed a trend toward improved mechanical properties, but bending data had large standard deviations and there was no significant difference between vibrated and non-vibrated oim mice. No significant difference of the bone apposition was observed in the tibial metaphyseal trabecular bone for both the oim and wild type vibrated mice by histomorphometry analyses of calcein labels. At the mid diaphysis, the cortical bone apposition was not significantly influenced by the WBV treatment in both the endosteum and periosteum of the oim vibrated mice while a significant change is observed in the endosteum of the vibrated wild type mice. As only a weak impact in bone apposition between the vibrated and sham groups is observed in the histological sections, it is possible that WBV reduced bone resorption, resulting in a relative increase in cortical thickness.
Whole body vibration appears as a potential effective and innocuous means for increasing bone formation and strength, which is particularly attractive for treating the growing skeleton of children suffering from brittle bone disease or low bone density pathologies without the long term disadvantages of current pharmacological therapies.
► Whole body vibration (WBV) therapeutic impacts on bone were investigated in young osteogenesis imperfecta mice (oim). ► WBV beneficial impact on the cortical bone morphology of both femur and tibia in the wild type and oim mice ► Bone volume fraction was improved in the proximal tibia of oim vibrated mice. ► WBV has beneficial impact on bending properties in wild type vibrated mice but only a positive trend in oim mice. ► Bone apposition is not significantly improved in the mid-tibia cortical and proximal tibia trabecular bone in the oim vibrated mice.
Whole body vibration; Osteogenesis imperfecta disease; oim mouse model; Bone morphology; Bone formation; Bending properties
Children with the severe forms of osteogenesis imperfecta have in several studies been treated with intravenous pamidronate, but there are only few reports of the effect of early treatment.
To evaluate the effect of treatment started in infancy.
In a prospective observational study, with a historic control group, intravenous disodium pamidronate (APD) was given as monthly infusions to 11 children with osteogenesis imperfecta aged 3–13 (median 3.6) months, who had severe osteogenesis imperfecta with congenital bowing of the femora and vertebral compression fractures.
During treatment of children aged between 3 and 6 (median 4.5) years, dual‐energy x ray absorptiometry measurements of the lumbar spine showed a gradual increase in bone density. Bone metabolism parameters in serum (alkaline phosphatase, osteocalcin, procollagen 1 carboxy‐terminal peptide, collagen 1 teleopeptide) and in urine (deoxypyridinoline) indicated a decrease in bone turnover. An improvement of mobility was seen and at the latest recording, at the age of 3.3–6.5 (median 4.8) years, the children could all walk. Vertebral remodelling was seen, with increased vertebral height, and no child developed scoliosis, kyphosis or basilar impression. All children required femoral intramedullar rods for fractures, and five needed tibial rodding for extreme curvatures that prevented functional standing and walking. No adverse effects were seen on growth, fracture healing or blood chemistry.
APD is an efficient symptomatic treatment for infants with severe osteogenesis imperfecta, but additional orthopaedic surgery is often needed. Early treatment may prevent scoliosis and basilar impression. Long‐term follow‐up is important.
Recently, a new class of agents targeting the receptor activator of nuclear factor-κB ligand (RANKL) pathway has been developed for the treatment of osteoporosis and other bone diseases. In the current study, inhibition of the RANKL pathway was evaluated to assess effects on “bone quality” and fracture incidence in an animal model of osteogenesis imperfect (OI), the oim/oim mouse. Juvenile oim/oim (~6 weeks old) and wildtype (+/+) mice were treated with either a RANKL inhibitor (RANK-Fc) or saline. After treatment, bone density increased significantly in the femurs of both genotypes. Femoral length decreased with RANK-Fc in +/+ mice. Geometric measurements at mid-diaphysis in the oim/oim groups showed increases in the ML periosteal and endosteal diameters and AP cortical thickness in the treated groups. Within +/+ groups, ML cortical thickness and ML femoral periosteal diameter were significantly increased with RANK-Fc. Biomechanical testing revealed increased stiffness in oim/oim and +/+ mice. Total strain was increased with treatment in the +/+ mice. Histologically, RANKL inhibition resulted in retained growth plate cartilage in both genotypes. The average number of fractures sustained by RANK-Fc-treated oim/oim mice was not significantly decreased compared to saline treated oim/oim mice. This preclinical study demonstrated that RANKL inhibition at the current dose improved density and some geometric and biomechanical properties of oim/oim bone, but it did not decrease fracture incidence. Further studies that address commencement of therapy at earlier time points are needed to determine whether this mode of therapy will be clinically useful in OI.
Bone; Osteogenesis Imperfecta; Oim/oim; Mouse; RANK/RANKL
Osteogenesis imperfecta is a heterogeneous group of inherited disorders characterized by bone fragility and recurrent fractures. It is currently classified into four types on clinical grounds and appears to arise from different disorders of bone collagen synthesis. The biochemical identification of disturbances in collagen metabolism and the genetic delineation of new mutations of collagen genes have made prenatal diagnosis by molecular methods feasible in some cases. Most people with osteogenesis imperfecta suffer frequent fractures (and sometimes consequent serious disability), for which there are few effective preventive measures. This disorder may have a profound psychosocial influence on patients and their families. In this report the extent of this influence is reviewed and aspects important to the medical community are highlighted; these include the emotional burdens imposed by unfounded suspicions of child abuse, the social and financial costs of repeated hospitalization and immobility, and the frustrations generated by the lack of helpful, practical information for families and health care workers. An important social outcome has been the rise of self-help organizations, exemplified by the Canadian Osteogenesis Imperfecta Society. For Canadian families the society has been an important vehicle for exchange of information and an active, positive response to a lifelong, often severely disabling disorder.
The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all perinatal lethal skeletal dysplasias (SD) in Northern Ireland over a 12 year period. Multiple sources of ascertainment, including genetic notes, radiological reports and post mortem findings, were used. 39 cases were identified. Thanatophoric dysplasia was the commonest diagnosis made (22), followed by osteogenesis imperfecta type II (four children) and achondroplasia (two children). Eleven other diagnoses each occurred once in the 12 year period. The minimum prevalence range, per live births, of each of the common skeletal dysplasias in Northern Ireland has been calculated; thanatophoric dysplasia 0.80/10,000, osteogenesis imperfecta type II 0.15/10,000 and achondroplasia 0.07/10,000. The prevalence range for thanatophoric dysplasia is much higher than reported in previous studies. We discuss reasons for the prevalence figures obtained.
Thanatophoric dysplasia; osteogenesis imperfecta type II; achondroplasia; prevalence; lethal skeletal dysplasias