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.     

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.     

Hypercalcaemia in osteogenesis imperfecta treated with pamidronate

The response to the bisphosphonate, 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: anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy

BACKGROUND: Administration of bisphosphonates represents a beneficial therapy in children and adolescents with severe osteogenesis imperfecta (OI) because it significantly reduces the annual rate of bone fractures. AIM: To evaluate the anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy in OI. METHODS: Ten patients, aged 5 mo to 25 y, with OI received cyclical intravenous pamidronate. The yearly dose of pamidronate was approximately 9 mg/kg/d at all ages. Duration of treatment varied from a minimum of 2 y to a maximum of 5 y. Growth, bone mass and mineral metabolic parameters were studied at baseline and repeated every year thereafter. Bone mass was assessed by calculation of bone mineral apparent density (L2-L4 BMAD). This represents the first study on the changes in size-adjusted measures of bone mass observed with such therapy. RESULTS: While on therapy, all children and adolescents grew normally but did not experience any manifest catch-up growth. A significant decrease in the incidence of bone fractures was observed. In seven patients with severe forms, L2-L4 BMAD increased by 80% after the first 2 y of therapy but tended to stabilize or even decrease over the following years despite maintenance of therapy. A significant inverse correlation could be established between urinary Ca excretion and L2-L4 BMAD (r = -0.30, p < 0.05). CONCLUSION: Our results confirm that cyclical pamidronate infusions reduce the incidence of bone fractures and allow normal growth. The improvement in bone mass initially observed after the first 2 y of therapy is not always sustained over the following years despite maintenance of therapy.     

Osteoporosis pseudoglioma syndrome: treatment of spinal osteoporosis with intravenous bisphosphonates

OBJECTIVES: To determine whether intravenous bisphosphonate treatment is helpful for children with osteoporosis pseudoglioma syndrome who have severe osteoporosis. METHODS: Three children (ages 9 to 11 years) with osteoporosis pseudoglioma syndrome who had multiple vertebral collapse were treated over a 2-year period with intermittent intravenous bisphosphonate infusions (pamidronate in 2, clodronate in 1). The responses to therapy were assessed with clinical and radiographic evaluation and bone densitometry of the spine. RESULTS: All 3 subjects reported early reductions in bone pain and improved mobility. Radiographs showed dense new bone in the vertebral end plates and remodeling of the vertebral bodies. Areal bone mineral density at the lumbar spine (age-appropriate SD score) improved from a mean of -4.5 before treatment to -2.8 after 2 years (P <.05). No new fractures occurred, and side effects were minimal. Growth and pubertal development proceeded normally. CONCLUSIONS: Intravenous bisphosphonate therapy appears safe and beneficial in patients with this condition and may prevent progressive vertebral deformity.     

Bisphosphonate treatment of pediatric bone disease

The science of measuring bone mineral density has developed rapidly and, with it, an improved understanding of the efficacy and safety of various therapeutic interventions in adults. In contrast, the meaning and precision of such measurements in children are equivocal, and the concept of treatment for low bone density in the young patient is still largely undecided. In this report we review the present state of knowledge regarding the use of bisphosphonates during childhood to ameliorate the skeletal abnormalities associated with osteogenesis imperfecta, idiopathic juvenile osteoporosis, fibrous dysplasia of bone and cerebral palsy. Because of the paucity of long-term studies among children regarding the safety and efficacy of these drugs, it is difficult to formulate strong evidence-based recommendations for their use, except perhaps in children with osteogenesis imperfecta.     

Treatment of children with Osteogenesis imperfecta in Estonia

AIM: To analyse the changes in fracture rate, bone density and histology in children with Osteogenesis imperfecta receiving treatment with alendronate (oral bisphosphonate) and calcitriol. METHODS: Children treated at Tartu University Hospital from 1995 to 2001 were examined for Osteogenesis imperfecta. Radiographs and bone density measurements were obtained for all patients at the beginning of the study. Four patients also had bone biopsies prior to and one year after beginning treatment. The children were then given alendronate in weight-dependent dosages and also calcitriol. The number of fractures during the treatment period was recorded and follow-up bone density measurements were made. RESULTS: Fifteen patients were treated during the 6-y period; mean follow-up approximately 3 y. It was found that the number of bone fractures had decreased significantly (p < 0.0001). Bone density improved in all 15 patients. Histologic studies revealed an increased number of osteoblasts and thickness of bone trabeculae as well as a more regular bone lamellar structure at the time of the second operation. CONCLUSION: The complex treatment of Osteogenesis imperfecta should include alendronate and calcitriol to decrease fractures and improve bone mineral density.     

Alendronate treatment in children with osteogenesis imperfecta

BACKGROUND: Recent studies reported beneficial effect of cyclical intravenous administration of pamidronate in children and adolescents with osteogenesis imperfecta (OI). However, this treatment requires frequent hospital admissions and is relatively expensive. Alendronate is an oral bisphosphonate effectively used in adults with osteoporosis. Experience with alendronate treatment in children with OI is limited. AIMS: To report our experience with alendronate in children with OI. METHODS: 12 children with OI (7 with type I, 4 with type III and 1 with type IV; 7 boys, 5 girls) aged 1.8 to 15.4 years (7.9+/-; 4.4 yrs) were included in this retrospective study. The patients were treated with alendronate in a dose of 5-10 mg/day along with calcium (500 mg/day) and vitamin D (400-1000 IU/day) supplements for 19.8+/-11.3 months (range: 7-46 months). Serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), osteocalcin (OC), pyrilinks-D and urinary Ca/Cr ratio were studied 3 monthly and bone mineral density (BMD) by DXA on 6-12 monthly basis. RESULTS: Fracture rate of the patients significantly decreased after treatment (1.2+/-1.5 vs. 0.16+/-0.32 per year, P<0.05). Treatment improved bone density in each individual case. Z-scores of lumbar DXA (L2-L4) significantly increased during treatment (-4.60+/-1.30 vs - 2.47+/-1.52, P< 0.05). Urinary pyrilinks-D decreased with treatment (90.8+/-136.3 vs. 35.1+/-29.9, P< 0.05). Serum Ca, P, ALP, OC and urinary Ca/Cr did not change significantly during treatment. CONCLUSION: We conclude that alendronate is effective, safe and practical alternative to intravenous bisphosphonates in treatment of children with OI.     

Oral bisphosphonate treatment for osteogenesis imperfecta--an Indian perspective

BACKGROUND: Various treatments for the management of osteogenesis imperfecta (OI) have been tried, of which bisphosphonates seem to have the maximum benefit in reducing fracture rate and improving bone density. This study investigated the value of oral alendronate for treating OI in Indian children. METHODS: Between 2002 and 2005, 11 patients with OI were referred for bisphosphonate therapy. The various types of OI were classified using the Sillence criteria. All patients underwent baseline biochemistry, radiographic studies and bone mineral density (BMD) measurements before commencing therapy. Patients were commenced on oral alendronate (0.5 mg/kg/day) and followed up for a period ranging from 1 month to 2 years. A retrospective analysis of pre- and post-treatment changes in fracture rate and bone density was undertaken using the paired sample t-test. RESULTS: One patient lost to follow-up was excluded from the study and three completed only 2 months of therapy. Pre-treatment fracture rate per year before treatment ranged from 0.5 to 6 with a mean (SD) of 2.95 (1.57) and median of 2.5. The post-treatment fracture rate was 1.1 (0.59)/year (p=0.02). Seven children underwent BMD analysis while on treatment and all had a rise in BMD, of which the change in lumbar spine BMD was statistically significant (p=0.001), and lumbar (p=0.005) and femoral neck t-score (p=0.04) showed a significant change. No significant change was seen in serum biochemistry except for disappearance ofhypercalciuria (p=0.04). No child had an adverse reaction to alendronate. CONCLUSION: After a median of 9.5 months of treatment, oral alendronate is associated with a lower fracture rate, improvement in BMD and a decrease in hypercalciuria.     

Effect of porcine calcitonin therapy on vitamin D metabolism and clinical response in a patient with osteogenesis imperfecta

A 1 11/12-year-old girl with osteogenesis imperfecta was treated with porcine calcitonin. Eight bone fractures occurred in the previous 20 months before therapy, but none occurred during eight months of therapy. There was also a significant improvement in linear growth and radiographic bone density. This is the first study of the effect of calcitonin on vitamin D metabolism in a human. The high plasma levels of 1,25 dihydroxy-vitamin D (1,25-(OH)2-D) and 24,25 dihydroxy-vitamin D (24,25-(OH)2-D) before calcitonin therapy decreased after therapy. Plasma 25 hydroxy-vitamin D (25-OH-D) concentration, which normal in level before calcitonin therapy, was normal or slightly decreased during administration. It is concluded that calcitonin probably influences vitamin D metabolism in a patient with osteogenesis imperfecta.     

Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis.

AIMS: To evaluate the currently available evidence for the effectiveness of bisphosphonates in children with low bone mineral density (BMD) and fragility fractures associated with juvenile idiopathic arthritis (JIA), and the safety of bisphosphonates in JIA and other conditions. METHODS: Literature databases were searched using a structured search strategy. The effectiveness review included any studies of children with JIA treated with bisphosphonates. The safety review also included studies of osteogenesis imperfecta. Quantitative data analysis was not undertaken because of the heterogeneity of the studies; findings were summarised using tables and narrative synthesis. RESULTS: Ninety four studies were identified. Sixteen studies (78 JIA children) were included in the effectiveness review: one randomised controlled trial, three controlled cohort studies, 11 case series, and one case report. At baseline, children had low BMD below the expected values for age and sex matched children. In all studies, treatment with bisphosphonates increased BMD compared with baseline: the mean percentage increase in spine BMD ranged from 4.5% to 19.1%. Overall, studies were heterogeneous and of variable quality. A total of 59 papers were included in the safety review; treatment durations were up to three years. The most common side effect was a flu-like reaction with intravenous treatment. This occurred during the first infusion and was transient; the symptoms were managed with paracetamol and did not occur during subsequent cycles. CONCLUSIONS: Bisphosphonates are a promising treatment for low BMD and fragility fractures in children with JIA. However, the quality of the current evidence is variable and better studies are needed to more clearly assess their role.     

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.     

EFFECT OF PORCINE CALCITONIN THERAPY ON VITAMIN D METABOLISM AND CLINICAL RESPONSE IN A PATIENT WITH OSTEOGENESIS IMPERFECTA

ABSTRACT. A 1 11/12-year-old girl with osteogenesis imperfecta was treated with porcine calcitonin. Eight bone fractures occurred in the previous 20 months before therapy, but none occurred during eight months of therapy. There was also a significant improvement in linear growth and radiographic bone density. This is the first study of the effect of calcitonin on vitamin D metabolism in a human. The high plasma levels of 1,25 dihydroxy-vitamin D (1,25-(OH)₂-D) and 24,25 dihydroxy-vitamin D (24,25-(OH)₂-D) before calcitonin therapy decreased after therapy. Plasma 25 hydroxy-vitamin D (25-OH-D) concentration, which normal in level before calcitonin therapy, was normal or slightly decreased during administration. It is concluded that calcitonin probably influences vitamin D metabolism in a patient with osteogenesis imperfecta.     

Bisphosphonates: from grandparents to grandchildren

Bisphosphonates are synthetic analogues of pyrophosphate that inhibit bone resorption by their action on osteoclasts. Bisphosphonates have been extensively used in the elderly with primary and secondary osteoporosis, Paget's disease, and hypercalcemia of malignancy. In recent years, bisphosphonates have been used to treat children acutely for resistant hypercalcemia and chronically for various metabolic bone diseases. The theoretical concerns of possible adverse effects of these drugs on the growing skeleton have not been proven to be true. In the present review, we have critically analyzed the available literature on bisphosphonate therapy in both adult and pediatric clinical trials. Although not yet approved by the FDA for use in children, bisphosphonates, from published experience, demonstrate benefit to the child with no serious adverse effects. Based on the literature analysis the review furnishes detailed recommendations and practical guidelines regarding the use of oral and intravenous bisphosphonates in children. Bisphosphonates might be the first agents to provide the pediatrician with an opportunity to treat mineral and bone disorders of childhood, which until recently did not have satisfactory therapy.     

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.     

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.     

Growth of infants with osteogenesis imperfecta treated with bisphosphonate

Background:  Osteogenesis imperfecta (OI) is a heritable bone disease characterized by bone brittleness and various degrees of growth disorder. Cyclic pamidronate therapy is reportedly useful to prevent bone fracture in OI and in infants with OI, but, it remains unclear how infants with OI grow during bisphosphonate therapy.
Methods:  Height and weight measurements of OI infants treated with cyclic pamidronate therapy were taken before and every 6 months during therapy until 18 months. Vertebral morphometry and the concavity index were analyzed using X-ray films taken simultaneously.
Results:  Among OI patients, those in the group for which the height z- score decreased tended to have more femur fractures than those of the group for which the height z- score increased. Morphometry of the lumbar spine showed that compression fractures occurred less during cyclic pamidronate therapy, by which the lumbar bone mineral density increased.
Conclusions:  Bisphosphonate preserved vertebral morphometry during 18 months after starting therapy in infants. Prevention of femur fracture during the infantile period might help prevent short stature; therapeutic strategies during infancy must better emphasize prevention of long bone fracture before the beginning of gait.     

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.