A comparison of oral and intravenous bisphosphonate therapy for children with osteogenesis imperfecta

Bone mineral density and fracture rates in children with osteogenesis imperfecta improve with intravenous bisphosphonates. The efficacy of oral bisphosphonates has not been established. This report is an analysis of an open-label, prospective, randomized clinical trial of oral compared to intravenous bisphosphonate medications in children with osteogenesis imperfecta. Children were stratified according to bone age, pubertal stage, and type of osteogenesis imperfecta and then randomized to receive intravenous pamidronate, 3 mg/kg over 3 days every 4 months, or oral alendronate 1 mg/kg, from a minimum of 10 mg to a maximum of 20 mg daily. The primary efficacy outcome was change in bone mineral density. Secondary outcomes included change in biomarkers of bone turnover, fracture incidence, and growth rate. Ten children were randomized (6 oral and 4 intravenous). Two other children were assigned to intravenous treatment due to chronic abdominal pain. In each group, three patients had type III/IV osteogenesis imperfecta, while three had type I. All 12 children completed 8 months of therapy; nine completed 12 months. Bone mineral density increased in both oral and intravenous groups equally and beyond that expected with normal growth. All children had a decrease in biochemical markers of bone turnover. Linear growth showed a moderate increase above that for age. There was a non-significant decrease in fracture incidence in both groups.     

Bone densitometry in pediatric patients treated with pamidronate

Background: Increasing numbers of children are being treated with the bisphosphonate pamidronate for low bone mineral density, particularly children with increased risk of fractures caused by bone disorders or low/non-weight bearing. Objective: To determine the effect of intravenous pamidronate on the bone mineral density of children with osteogenesis imperfecta and spastic quadriplegic cerebral palsy. Materials and methods: Charts of 38 children with osteogenesis imperfecta (n=20) and spastic quadriplegic cerebral palsy (n=18) treated with pamidronate were retrospectively reviewed. Patients were selected for treatment because of prior fracture and/or abnormally low bone mineral density. All received intravenous pamidronate at two-month to eight-month intervals and were periodically examined using dual energy X-ray absorptiometry. Results: All patients had abnormally low bone mineral density prior to treatment. Lumbar spine bone mineral density and z-scores showed serial improvement in 31 of 32 patients. Spine bone mineral density increased 78±38.1% in OI and 47.4±39.0% in children with cerebral palsy. The area of greatest lateral distal femur bone mineral density improvement was in the metaphysis adjacent to the growth plate, with a 96±87.8% improvement in the osteogenesis imperfecta group and 65.7±55.2% improvement in the cerebral palsy group. Increases in bone mineral density exceeded that expected for age-specific growth. This was demonstrated by improvement in both spine and femur z-scores for both groups. No children with spastic quadriplegic cerebral palsy experienced fractures after the first week of treatment, whereas patients with osteogenesis imperfecta continued to have fractures but at a decreased rate. Conclusions: Intravenous pamidronate given at 3- to 4-month intervals proved to be effective in increasing bone mineral density in patients with osteogenesis imperfecta and spastic quadriplegic cerebral palsy. The greatest gains in bone mineral density were observed in the children with osteogenesis imperfecta, but they did continue to fracture, albeit at a decreased rate. Children with cerebral palsy gained bone mineral density and did not continue to fracture.     

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.     

Osteogenesis imperfecta: a new, early therapeutic approach with biphosphonates. A case report]

Management of type III osteogenesis imperfecta (O.I.) (brittle bone disease) is primarily supportive; early introduction of cyclic intravenous pamidronate administration in children younger than 2 years of age is an innovative and promising therapeutic approach. CASE REPORT: We present the case of a 6-month-old infant, whose preliminary data have already been partly published, with severe type III O.I. referred because of aching and crumbling from multiple fractures. Cyclic intravenous disodic pamidronate administration improved the clinical status (fracture incidence, pain, growth curve) and biological status (bone density, osseous alkaline phosphatases, urinary desoxypiridoline excretion), allowing a remarkable recovery. CONCLUSION: Biphosphonates are a new and innovative therapeutic agent in O.I. Clinical safety, easy administration, and overall efficacy are likely to extend their use in severe type III O.I. from the very first months of life, the time of best efficacy.     

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.     

Biphosphonates in children: present and future]

Biphosphonates are synthetic analogs of the natural pyrophosphate molecule, introduced primarily for the treatment of Paget disease of bone. Their main mechanism of action consisting in an inhibition of osteoclastic activity is critical for treatment of disorders including an increased bone resorption. In childhood osteoporosis (especially osteogenesis imperfecta), hypercalcemia and heterotopic calcifications are the three main situations in which they have been successfully used, with however few follow-up and no controlled studies. The evolution of these compounds generating more potent products, given orally, with limited effect on bone mineralization should allow an extension of their use in pediatric patients. Multicentric studies are now necessary to specify their efficacy and guidelines for use in children.     

Low-dose intravenous pamidronate treatment in osteogenesis imperfecta

Different therapy models have been tried in order to decrease bone resorption in osteogenesis imperfecta. Bisphosphonates are a group of drugs that mainly suppress osteoclast-mediated bone resorption, thus reducing bone turnover. We assessed the effects of low-dose bisphosphonate treatment in children with osteogenesis imperfecta. Sixteen osteogenesis imperfecta patients (12 female, 4 male) with severe deformities were treated with cyclic (3-4 mg/kg/year) intravenous infusions of bisphosphonate (Aredia-Novartis) therapy for a period ranging from 0.6 to 4.7 years (mean 2.50 +/- 1.09 years). Bone mineral density increased from 0.304 +/- 0.146 g/cm2 to 0.362 +/- 0.142 g/cm2 in the first year and to 0.421 +/- 0.146 g/cm2 in the second year. A clinical response was shown with a reduction in fracture rate and improvement in mobilization scores. Fracture rates decreased from a median of 4/year (0-30/year) before treatment to 0/year (0-5/year) during treatment. Ambulation improved in 10 children and remained unchanged in three. Two of the children were fully functional before therapy and one was below two years of age. No adverse effects were seen with pamidronate infusions of 7-10 mg/kg/year (monthly) or with 4 cycles/year 3-4 mg/kg/year. Low-dose cyclical pamidronate infusions markedly increased bone density and decreased bone fracture rate and should be considered as a part of a multi-disciplinary treatment.     

Osteoporosis in childhood: bone density of children in health and disease

Bone mineral density in later life largely depends on the peak bone mass achieved in adolescence or young adulthood. A reduced bone density is associated with increased fracture risk in adults as well as in children. Pediatricians should therefore play an important role in the early recognition and treatment of childhood osteoporosis. Juvenile idiopathic osteoporosis and osteogenesis imperfecta are examples of primary osteoporosis in childhood. However, osteoporosis is more frequently a complication of a chronic disease or its treatment. This paper provides an overview of bone and bone metabolism in healthy children and the use of diagnostic tools, such as biochemical markers of bone turnover and several bone densitometry techniques. Furthermore, a number of diseases associated with osteoporosis in childhood and possible treatment strategies are discussed.     

Use of bisphosphonate therapy for osteoporosis in childhood and adolescence

Congenital and acquired forms of osteoporosis in childhood and adolescence can result in morbidity from fracture and pain in childhood, and place an individual at significant risk for problems in adult life. A range of therapies exist for the prevention and treatment of osteoporosis, including optimization of daily calcium intake, adequate vitamin D status, weight-bearing exercise, treatment with sex steroids where delayed puberty is a problem and, more recently, use of bisphosphonate therapy. Intravenous pamidronate therapy (a bisphosphonate) has been shown to reduce fractures and improve bone density in children with osteogenesis imperfecta, and might prove to be of benefit in other osteoporotic conditions in childhood. However, a number of issues regarding the optimal use of bisphosphonate therapy in children and adolescents remain to be resolved, including total annual dose and frequency and duration of administration. Bisphosphonate therapy should, therefore, be used only in the context of a well-run clinical programme with specialist knowledge in the management of osteopenic disorders in childhood.     

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.     

Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta

A prospective open study was performed to determine the efficacy and safety of pamidronate in improving bone mineralisation and reducing fracture incidence in osteogenesis imperfecta (OI). Intravenous pamidronate was administered at 1.5 mg/kg bi-monthly to six children with OI, over 12-23 months. The number of fractures decreased from median of 3 (range 1-12) to 0 fractures/year (range 0-4) (P<0.05). After 12 months of treatment, there was significant improvement in areal bone mineral density (BMD) z-scores of the lumbar spine from median of -2.40 (range -3.20 to -1.67) to -1.90 (range -2.38 to -0.91) (P<0.05) and in the volumetric BMD which increased from median of 0.095 to 0.146 g/cm3 (P<0.05). Urine N-telopeptide levels (bone resorption marker) decreased from a median of 461.5 bone collagen equivalent/creatinine (BCE/Cr) (range 129-721 BCE/Cr) to 223.5 BCE/Cr (range 107-312 BCE/Cr) (P<0.05) and serum alkaline phosphatase (ALP) (bone formation marker) from a median of 230.0 U/l (range 148-305 U/l) to 133.5 U/l (range 79-233 U/l) (P<0.05), reflecting reduced bone turnover. This may represent a net reduction in bone resorption and provides a biochemical explanation for the increase in bone mineralisation. Height standard deviation scores were not affected and there were no significant adverse effects. CONCLUSION: 1 year cyclical pamidronate is effective and safe in improving bone mineralisation and reducing fracture incidence in osteogenesis imperfecta.     

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.

     

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.     

Surgical treatment of osteogenesis imperfecta: current concepts

PURPOSE OF REVIEW: The treatment of osteogenesis imperfecta requires a multidisciplinary team to maximize function and comfort, and decrease fracture incidence. Medical treatment with bisphosphonates has allowed for safer, more effective surgical management of children with osteogenesis imperfecta. The purpose of this review is to outline treatment indications and choices of surgical techniques based on recent clinical studies, and in addition to identify persistent clinical problems addressed in recent literature. RECENT FINDINGS: Several new intramedullary rodding surgical techniques and modifications of older techniques have been developed to correct deformities of the long bones. These techniques decrease the trauma associated with surgical treatment. The newer techniques limit postoperative immobilization, enabling earlier rehabilitation, and allowing for treatment of multiple bones simultaneously. SUMMARY: Recent medical and surgical advances have allowed improved safety, function and comfort in treating children with osteogenesis imperfecta. The selection of surgical techniques is dependent on surgeon experience, severity of disease and patient function, and availability of specific instrumentation. Intramedullary fixation rather than plating is preferred, and allowing early protected weight bearing and rehabilitation of children with ambulatory potential is the ideal goal.     

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.     

Radiographic features of bisphosphonate therapy in pediatric patients

BACKGROUND: Pediatric patients are being treated with bisphosphonates for low bone mineral density. Skeletal radiographic findings have been described with bisphosphonates given orally and intravenously. OBJECTIVE: To determine and describe the radiographic findings of cyclic intravenous bisphosphonate therapy in the growing skeleton. MATERIALS AND METHODS: Retrospective review of radiographs of 32 patients with osteogenesis imperfecta or cerebral palsy treated with intravenous bisphosphonates on a quarterly schedule. RESULTS: Principal observations were metaphyseal bands and increased bone mineral density. The bands varied in spacing according to the age of the patient, rate of growth, and the location of the metaphysis. Fractures continued to be seen in patients with osteogenesis imperfecta. CONCLUSION: Cyclic bisphosphonate therapy results in distinctive radiographic findings in the growing skeleton.     

Efficacy of cromoglycate in persistently wheezing infants.

Lumbar spine bone mineral density in a cross sectional study of healthy subjects increased by 0.012 and 0.016 g/cm2/year in boys and girls respectively between 5 and 11 years of age. These rates increased five-fold in girls and threefold in boys between the ages of 11 and 13 years as a result of the bone mineral content increasing more rapidly than the coronal area at this age. By the age of 11 years the girls had 66% of the coronal area, 61% of the bone mineral density, and 41% of the bone mineral content of subjects aged 18-23 years. The ratio (lumbar spine bone mineral content/body weight) was constant in boys aged 6-13 years, but there were significant variations in girls. Femoral neck bone mineral density in both sexes changed little between 6 and 11 years and at 11 years was 69% of the adult values. Subjects with osteogenesis imperfecta had a low bone mineral density and bone mineral content for their age and weight. The z score of bone mineral density at the femoral neck was significantly lower than at the lumbar spine. In patients with recurrent fractures a low bone mineral density may help in identifying those with osteogenesis imperfecta and assist in their subsequent management.     

Effect of intravenous pamidronate therapy on everyday activities in children with osteogenesis imperfecta

AIM: To evaluate the effect of intravenous pamidronate therapy on everyday activities, well-being, skeletal pain and bone density in children with osteogenesis imperfecta (OI). METHODS: In a prospective observational study, monthly intravenous pamidronate infusions were given to 43 children (aged 4 months-16 years) with different severity and form of OI. Outcome measures included the Pediatric Evaluation of Disability Inventory (PEDI), a score of well-being, registration of days with pain and bone density measured by using dual energy X-ray absorptiometry (DXA). Data were collected before and after the first year of treatment. RESULTS: Self-care and mobility measured by PEDI increased significantly in both the Functional Skill scale and in the Caregiver Assistance scale. The youngest children improved more than the older ones according to the PEDI. The days with skeletal pain were reduced and both well-being and bone density increased. CONCLUSIONS: Intravenous treatment with bisphosphonates influenced health status, according to the International Classification of Functioning, Disability and Health (ICF). This group of 43 children experienced beneficial effects on everyday activities, skeletal pain, well-being and bone density.     

Safety and efficacy of a 1-year treatment with zoledronic acid compared with pamidronate in children with osteogenesis imperfecta

Pamidronate (PAM) infusion is the standard treatment in children with osteogenesis imperfecta (OI). Zoledronic acid (ZOL) is a bisphosphonate with higher potency and faster intravenous infusion, but its efficacy and safety has not been established for OI patients. We report an open-label, prospective, and randomized clinical analysis to study the safety and efficacy of ZOL compared with PAM in 23 children with OI. They were selected to receive PAM (PAM group), 1 mg/kg/day, over 2 days or ZOL (ZOL group), 0.025-0.05 mg/kg/day, over 2 days every 3-4 months according to their ages, during a 1-year follow-up. They were observed for clinical and biochemical parameters, side effects, bone mineral density (BMD), and fracture rate. After treatment, the PAM and ZOL groups average lumbar spine (LS) BMD increased by 51.8% (p = 0.053) and 67.6% (p = 0.003), respectively. Parallel improvement was seen in LS Z-score in the PAM and ZOL groups, with scores of -5.3 to -3.8 (p = 0.032) and -4.8 to -2.3 (p = 0.007), respectively. LS Z-score for the ZOL group at the end of treatment was higher compared with the PAM group but only a borderline significance (p = 0.053). The total alkaline phosphatase (AP) in the ZOL group significantly decreased from baseline at third and fourth infusion (p = 0.032). Mild side effects were similar in both groups, but no severe clinical symptoms were reported. In conclusion, the present study shows that the use of ZOL in the dosage and period studied was safe and efficient to promote a clinical and densitometric improvement, similarly to PAM. Further studies are needed to establish optimal dosing and long-term safety.