Hypercalcaemia in osteogenesis imperfecta treated with pamidronate

Accepted 10 September 1996The 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.     

Child abuse or osteogenesis imperfecta: how can we tell?

Osteogenesis imperfecta may be difficult to differentiate from nonaccidental trauma. Social history may prejudice the physician in favor of or against considering the diagnosis of child abuse. Three cases of osteogenesis imperfecta that were initially diagnosed as nonaccidental trauma are presented. The availability of biochemical analysis of type I collagen was instrumental in confirming the diagnosis of osteogenesis imperfecta in all three cases.     

Bruck syndrome

The combination of arthrogryposis multiplex congenita and osteogenesis imperfecta is extremely rare. This combination is named Bruck syndrome. A 34 week male baby weighing 1.7 kg at birth was noted to have multiple flexion contractures and pterygia at elbows, wrists and knees, in addition to right foot talipes equinovarus deformity. Postnatally the child developed multiple swellings involving both the upper and lower limbs. A plain radiograph revealed the presence of fractures involving the long bones of the upper and lower limbs. A diagnosis of osteogenesis imperfecta with arthrogryposis multiplex congenita was made, and the patient was labeled as a case of Bruck Syndrome. The aim of this report is to make the readers aware regarding this rare entity and to specifically look for presence of features suggestive of osteogenesis imperfecta when encountered with a neonate born with arthrogryposis multiplex congenita.     

Use of bisphosphonates in children and adolescents

The bisphosphonates are chemically simple compounds that have been used mainly for the treatment of osteoporotic conditions and for hypercalcaemia. They have had relatively limited use in children. Their action is principally to interfere with the activity of osteoclasts by causing apoptosis. Their use in children has been for problems of soft tissue calcification (e.g. idiopathic arterial calcification, myositis ossificans progressiva and dermatomyositis), hypercalcaemia (e.g. caused by malignancy, immobilisation or hyperparathyroidism), generalised bone disease (e.g. osteogenesis imperfecta, idiopathic juvenile osteoporosis and steroid-induced osteoporosis) and localised bone disease (e.g. Gaucher's disease and McCune-Albright syndrome). In general they cause few short-term side effects although the long-term side effects have yet to be determined, but are probably relatively unimportant. The bisphosphonates are likely to prove a useful addition to the armamentarium of treatment modalities for bone disease in children.     

Anthropometry of patients with osteogenesis imperfecta.

Standing height, sitting height, armspan, subischial leg length, head circumference, and growth hormone-insulin-like growth factor I (IGF-I) axis were determined in 86 patients with osteogenesis imperfecta. The aim of this study was to determine standing height and body proportions and their variability among osteogenesis imperfecta types and collagen defects. Mean standing height was reduced in all groups of patients, to the greatest extent and variability in osteogenesis imperfecta type III/IV and in those with qualitative collagen defects. The mean standing height of patients with osteogenesis imperfecta was lower than that of their unaffected first degree family members. Truncal height of patients with osteogenesis imperfecta was reduced; head size was increased, and this was more pronounced in patients with osteogenesis imperfecta type III/IV and qualitative collagen defects than in patients with osteogenesis imperfecta type I and quantitative collagen defects. Mean concentrations of IGF-I and IGF binding protein 3 (IGFBP-3) were low, but most values were within age specific reference values. The reduction of standing height appears to correlate with osteogenesis imperfecta type and the type of collagen defect. A relatively short trunk is typical and head circumference and body length are disproportionate.     

Serum concentrations of procollagen I C-terminal propeptide,osteocalcin and insulin-like growth factor-I in patients with non-lethal osteogenesis irnperfecta

Serum concentrations of procollagen I C-terminal propeptide (PICP) were studied in 74 patients with various forms of non-lethal osteogenesis imperfecta and 27 unaffected family members. Using the standard deviation (SD) score, PICP concentrations were found to be ≤— 1 SD in 16%, between — 1 and —2 SD in 26% and ≤— 2 SD in 58% of the patients with osteogenesis imperfecta compared to healthy controls. PICP values were lowest in osteogenesis imperfecta type I (- 2.4 ± 0.4 SD, n= 37) followed by type III (-1.9 ± 0.5 SD, n = 13) and type IV (- 1.3 ± 0.7 SD, n= 20). Four patients with osteogenesis imperfecta with an atypical clinical course had normal or even elevated levels which may indicate heterogeneity in the underlying primary defects. In osteogenesis imperfecta type I, PICP concentrations proved to be a helpful serum marker for pedigree screening. Osteocalcin was high in 25 of 28 patients with osteogenesis imperfecta in the first decade but only in 1 of 18 older patients. Insulin-like growth factor-I was within the normal range in 53 cases of osteogenesis imperfecta, decreased in 2 and elevated in 3 patients. We conclude that PICP concentration is a useful parameter in the clinical management of osteogenesis imperfecta, including the assessment of future therapeutic interventions.     

Glykosaminoglykan- und Kollagenanalysen bei Osteogenesis imperfecta

Comparative studies on cartilage, bone, skin, and aorta in a case of osteogenesis imperfecta (male, three and a half year), and a healthy control (male, three and a half year) showed the following results:

1. The content of collagen in cartilage and skin in osteogenesis imperfecta is about 12–38 percent higher in the acetone dried tissue than in the control; however, in aorta and demineralized bone it is lower compared to the control (21 and 25 percent respectively). The amount of acidic glycosaminoglycans in costal and femur-kondyle cartilage in osteogenesis imperfecta exceeds that of the control by about 50 and 300 percent respectively.
2. The mineral content of bone (diaphysis of femur) was found to be 34.1 percent in osteogenesis imperfecta, and 54.7 percent in the control (dry weight of tissue). In two collagen preparations isolated from the citrate soluble and insoluble fraction of demineralized bone (femur diaphysis) the proline and hydroxyproline content was found to be the same in osteogenesis imperfecta and control. In contrast the content of hydroxylysine was increased in osteogenesis imperfecta. The lysine: hydroxylysine ratio was accordingly reduced: 0.9 in osteogenesis imperfecta compared to 1.7 in the control.
3. From the data presented it may be concluded that the biochemical defect in osteogenesis imperfecta is either an abnormally high glycosylation of the hydroxylysine residues of collagen, or a deficient desamination of hydroxylysine. The result in both cases will be a deficiency in the cross linking reactions of collagen.

     

Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta.

OBJECTIVE: 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. AIM: To evaluate the effect of treatment started in infancy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Experience with bisphosphonates in osteogenesis imperfecta

Until recently, medical management of osteogenesis imperfecta, a genetic disorder of reduced bone mass and frequent fractures, was elusive, and treatment was focused on maximizing mobility and function. The introduction of bisphosphonates for the treatment of osteogenesis imperfecta 14 years ago changed this paradigm. Cyclic intravenous pamidronate therapy leads to an increase in bone density and a decrease in fracture rate in patients with osteogenesis imperfecta. Pamidronate therapy has a positive impact on functional parameters including improved energy, decreased bone pain, and increased ambulation. Histomorphometric studies have shown that the reduced osteoclast activity results in gains in cortical thickness and trabecular bone volume. Potential negative effects may include prolonged time to heal after osteotomies and a decrease in the rate of bone remodeling. Overall, it seems clear that the benefits of pamidronate therapy outweigh its potential risks in moderate-to-severe osteogenesis imperfecta, and pamidronate therapy has become the standard of care for patients with this condition. Questions remain regarding when treatment should be stopped and the need for pamidronate therapy in patients with mild osteogenesis imperfecta.     

Non-accidental injury or brittle bones

When a child presents with one or more unexplained fractures, non-accidental injury (NAI) should be considered in the differential diagnosis. This article reviews some of the other differential diagnoses, particularly osteogenesis imperfecta and the alleged “temporary brittle bone disease”. Received: 18 June 1996 Accepted: 8 November 1996     

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence‐based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non‐fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence‐based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.     

Postural balance,handgrip strength and mobility in Brazilian children and adolescents with osteogenesis imperfecta

ObjectiveTo describe postural balance, handgrip strength and mobility in children and adolescents with different types of osteogenesis imperfecta.MethodsCross-sectional study. Fifty selected subjects diagnosed with types I (n = 11), III (n = 21), and IV (n = 18), followed up at Brazilian reference center for osteogenesis imperfecta in the Midwest region, aged 2–21 years (9.2 ± 5.0), were enrolled in this study. Children and adolescents were evaluated for postural balance in the upright position with eyes-open and eyes-closed conditions, handgrip strength and the mobility domain (Pediatric Dysfunction Assessment Inventory). Data normality and difference between groups was verified.ResultsHandgrip strength was significantly lower in people with type III of osteogenesis imperfecta when compared to the osteogenesis imperfecta types I and IV, and to the age-specific reference data. Center of pressure length and mean velocity in the condition with eyes closed were worse compared to the open-eyes condition for children and adolescents with type I of osteogenesis imperfecta. There were worse results in the mobility domain for the participants classified with the most severe type of osteogenesis imperfecta.ConclusionsIt was observed that the severity of the osteogenesis imperfecta disease affected handgrip strength and locomotor function assessed by the mobility domain. Comparing osteogenesis imperfecta types, the higher the severity of osteogenesis imperfecta, the lower the handgrip strength. These results can contribute to new strategies of treatment focused on improving functional capacity and quality of life in people with osteogenesis imperfecta.     

Chest compressions in an infant with osteogenesis imperfecta type II: No new rib fractures

The case report of a newborn female with osteogenesis imperfecta type II who underwent cardiopulmonary resuscitation (CPR) with manual chest compressions for several minutes is presented. Chest radiographs taken before and after the chest compressions were administered were reviewed by several radiologists from 3 different hospitals and demonstrated no new radiographically visible rib fractures. Collagen analysis, the patient's clinical appearance, and clinical course, as well as a consultant's opinion aided in confirmation of the diagnosis of osteogenesis imperfecta type II. A review of 4 previous studies concerning rib fractures and CPR is included. This unique case supports previous articles that have concluded that rib fractures rarely, if ever, result from CPR in pediatrics, even in children with a lethal underlying bone disease, such as osteogenesis imperfecta type II. cardiopulmonary resuscitation, chest compressions, osteogenesis imperfecta, rib fractures, bone disease.     

Osteogenesis imperfecta and hearing loss in childhood

We report a case of bilateral hearing loss in a child, caused by osteogenesis imperfecta and we evaluate CT scan findings. A 12-year-old child consulted for bilateral hearing loss. A computed tomography scan of the petrous temporal bone showed bilateral extensive unmineralized bone involving the cochleae, vestibules, and semicircular canals extending to the internal auditory canals. Osteogenesis imperfecta of the temporal bone is a genetic connective tissue disorder with increased bone fragility, low bone mass, and other extraskeletal manifestations. Hearing loss is rare in the first 2 decades of life, but it is one of the frequent features of this disorder in adult patients. Thin-section CT scans of the temporal bone show a remarkable proliferation of unmineralized bone involving the otic capsule. This demineralization is similar to that observed in the cochlear form of otospongiosis.     

Calcitonin therapy of children with osteogenesis imperfecta

Two children, ages 13 2/12 and 6 6/12 years, with osteogenesis imperfecta were treated with salmon calcitonin. During the course of therapy the older child developed calcitonin dose-related hypomagnesemia on two occasions. The younger child, coincident with otitis media and vomiting, developed hypomagnesemia, hypophosphatemia, hyponatremia, and hypokalemia. Since rib biopsies obtained before and after one year of treatment with salmon calcitonin failed to demonstrate any histologic changes, therapy was discontinued because of the induced metabolic consequences of calcitonin therapy.     

Calcitonin: physiological actions and clinical applications

Calcitonin (CT) was first reported as a hypocalcemic principle, initially thought to originate from the parathyroid gland, a view subsequently corrected to an origin from parafollicular C-cells. Human CT is a 32 amino acid peptide with an N-terminal disulphide bridge and a C-terminal prolineamide residue, shown to potently inhibit bone resorption. More recent studies have demonstrated that this may take place through a direct osteoclastic action. A number of osteoclast CT receptors have subsequently been characterized and particular receptor regions necessary for ligand binding and intracellular signaling identified. Its potent anti-resorptive effect has led to its use in treating Paget's bone disease, osteoporosis, hypercalcaemia and osteogenesis imperfecta. This review summarises some key aspects of its synthesis, structure and its actions at the cellular and molecular levels, and leads on to its therapeutic uses that have emerged since its discovery as well as possibilities for future clinical applications.     

Effect of long-term calcitonin therapy by injection and nasal spray on the incidence of fractures in osteogenesis imperfecta.

The effect of calcitonin therapy by injection or nasal spray on the incidence of bone fractures was studied in patients with osteogenesis imperfecta. In contrast to injection of calcitonin, intranasal administration of calcitonin twice a week for 2 weeks, followed by 2 weeks of no therapy, was simple and seemed beneficial for decreasing bone fractures in patients with osteogenesis imperfecta.     

STRONTIUM KINETIC STUDIES IN CHILDREN WITH BONE DISORDERS

A technique for studying skeletal disorders by using stable strontium as a tracer for calcium is described. Patients with nutritional and hypophosphataemic vitamin resistant rickets, with osteoporosis and osteogenesis imperfecta, and with osteopetrosis have been studied. Results are correlated with other tests, particularly calcium infusion, calcium balance, bone biopsy and response to calcitonin. The test has proved helpful in delineating two distinct types of osteoporosis, and has provided further evidence for a primary bone defect in one child with vitamin resistant rickets.     

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 endoplasic 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 -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.Abbreviation OI osteogenesis imperfecta Supported by the Stiftung Volkswagenwerk, research project: Skeletal Dysplasia and by a grant of the Deutsche Forschungsgemeinschaft (Po 189/3-1)     

Osteogenesis imperfecta — Lobstein

Summary Two cases of osteogenesis imperfecta, one of the congenital and the other of the late variety, have been reported. Interesting features were the presence of blue sclera, arachnodactyly and muscular hypotonia in the congenital variety. In this case attention is drawn to the occurrence of more than one feature, namely, arachnodactyly and osteogenesis imperfecta, common to the parent disorder, “mesodermal dysplasia”. A special feature observed in the tarda type was the presence of transluscent teeth—odontogenesis imperfecta. From the Department of Pediatrics, Medical College, Jabalpore.