Three years follow-up of pamidronate therapy in two brothers with osteoporosis-pseudoglioma syndrome (OPPG) carrying an LRP5 mutation

Osteoporosis-pseudoglioma (OPPG) is a rare syndrome characterized by severe osteoporosis and ocular defects caused by homozygotic inactivation mutations in the LRP5 gene. Bisphosphonate has been demonstrated to improve bone mineral density (BMD) in children with OPPG. We present here a 3 years follow-up of two brothers with OPPG carrying a novel mutation in the LRP5 gene, who were treated with intravenous pamidronate. PATIENT REPORT: We looked for a mutation in the LRP5 gene in two brothers (12 and 4 years old) with clinical features of OPPG (blindness, low BMD and fragility fractures) and in their consanguineous parents to confirm the diagnosis of OPPG. The patients were treated with bisphosphonate for 3 years. They received 1 mg/kg/day of pamidronate for 2 consecutive days, every 3 months during the first year, and every 4 months in subsequent years. Calcium, phosphorus, total alkaline phosphatase, parathyroid hormone, hepatic transaminases, creatinine and hemogram tests were performed before each infusion. Bone densitometry was performed at baseline and at the end of the follow-up. RESULTS AND CONCLUSION: The affected brothers carry a missense mutation in the third codon of exon 8 (AAT-->ATT) that led to the exchange of an asparagine for an isoleucine (N531I). Both parents were found to be heterozygous for this mutation. The intravenous pamidronate therapy was safe for up to 3 years of use. Moreover, increased BMD and decreased fracture rate were observed in our patients with OPPG.     

Cyclic pamidronate therapy in children with osteogenesis imperfecta: results of treatment and follow-up after discontinuation

BACKGROUND: Cyclic intravenous pamidronate treatment is widely used for symptomatic therapy of osteogenesis imperfecta (OI). However, data after discontinuation are very limited. AIM: The results of cyclical pamidronate treatment in 14 patients with moderate/severe OI and follow up of six of them after discontinuation are presented to assess the effects of pamidronate and its discontinuation. PATIENTS AND METHODS: Pamidronate was administered at a dosage of 0.5 mg/kg for 3 successive days every 2 months in 14 patients with OI aged 5.10 +/- 3.68 years. Treatment was stopped in six patients after a duration of 16.33 +/- 4.63 months, due to stable bone mineral density (BMD) values and/or no fracture in the last 6 months, or due to family demand. The main outcome measures were areal BMD (aBMD) of the lumbar spine, biochemical markers of bone metabolism, fracture rate, and clinical evaluation. RESULTS: Areal BMD and aBMD z-scores showed significant improvement during the treatment period. Both serum and bone-specific alkaline phosphatase values were significantly decreased. Fracture rate reduced significantly from 3.5 +/- 1.01 to 0.83 +/- 0.77 fractures/year. Bone pain, which was severe in five patients, disappeared just after the first cycle, and the activity and mobility of patients increased. aBMD and aBMD z-scores were decreased 1.5 years after discontinuation, although not statistically significant. Annual fracture rate increased significantly. Bone pain recurred in four patients. Pamidronate treatment was reinstituted in five of these patients at the end of 1.5 years. CONCLUSION: Cyclical pamidronate treatment is very effective in children with moderate/severe OI. This treatment should be started early enough before the occurrence of irreversible deformities and must be given for a longer time during the growth period.     

Low-dose intravenous pamidronate reduces fractures in childhood osteoporosis

Despite the proven efficacy of low-dose pamidronate in adults with osteoporosis, the efficacy of the low-dose regimen in children has not been studied. Pamidronate (1 mg/kg) was administered intravenously once every 3 months to 11 children with osteoporosis. Treatment was associated with reduced fracture rates and increased areal (BMD) and volumetric (BMAD) bone mineral density measured by dual energy X-ray absorptiometry (DXA). The mean annualized percent gain was 20.1 +/- 16.9 (4.7 to 59.1, n = 9) for spinal BMD and 15.1 +/- 18.1 (-11.0 to 40.2, n = 9) for spinal BMAD. Common adverse effects including fever, muscle aches, nausea and fatigue were self-limited and generally occurred only after the first infusion. Clinically significant hypocalcemia did not occur. Low-dose pamidronate appears promising in the treatment of childhood osteoporosis.     

Pamidronate treatment of osteogenesis imperfecta--lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and treatment response

Severe forms of osteogenesis imperfecta (OI) are characterised by osteoporosis with multiple fractures, deformity, progressive loss of mobility and chronic bone pain. Bisphosphonates, as osteoclast inhibitors, reduce bone turnover and improve osteoporosis. OBJECTIVE: To investigate the effect of pamidronate treatment of severe OI in children, and find any correlation between clinical severity, age at start of treatment, type of predicted collagen mutation and treatment response. DESIGN: Open, observational trial. PATIENTS: A two-year study of pamidronate treatment was undertaken in a cohort of 18 children, (1.4-14.5 years) with OI types III and IV. INTERVENTIONS: Disodium pamidronate, 1 mg/kg/day for 3 days every 4 months, by i.v. infusion with measurement of bone turnover, bone density, vertebral morphology and skin biopsies to assess collagen mutation. RESULTS: Eleven children have completed 2 years of treatment and three more have completed 20 months. Sustained cessation of bone pain, improved mobility and decreased fracture rate were seen in all patients. Bone turnover decreased slightly but was not statistically significant. Bone mineral density (BMD) of lumbar spine increased by a mean of 124.7 +/- 75.7% over 2 years (Z score mean -5.08 +/- 1.27, to -3.30 +/- 1.71, p <0.001); the greatest change in BMD was seen in the most severely affected patients: 138 +/- 50.6% (severe), 62.47 +/- 22.9% (mild). There was a mean increase in vertebral height at L4 of 68.5% and in vertebral area of 85.4%. The majority of patients had slow electrophoretic migration of type I collagen alpha chains or reduced secretion of type I collagen, indicative of structural, helix-breaking mutations. There was no correlation between phenotypic severity, age at start of treatment and treatment response (r2 = 0.14) CONCLUSIONS: Pamidronate treatment of severe forms of OI is an effective therapeutic modality to increase bone density, decrease fracture rate, increase mobility and improve quality of life, irrespective of the severity of the mutation or clinical phenotype. It has a good short-term safety profile.     

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.     

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.     

Treatment of symptomatic pediatric osteoporosis with cyclic single-day intravenous pamidronate infusions

OBJECTIVES: To examine the response to single-day intravenous pamidronate in a heterogeneous population with symptomatic osteoporosis. STUDY DESIGN: Patients (n = 18) 6 to 21 years of age, meeting treatment criteria were offered treatment with a single-day infusion of pamidronate every 3 months. Baseline and follow-up data were recorded and compared between persons with risk factors of progressive chronic illness or ongoing glucocorticoid usage (group 1) and persons with neither risk factor (group 2). We also examined the association between changes in urinary N-telopeptide percentile and spinal bone mineral density (BMD). RESULTS: Spinal BMD Z score increased in all patients after 6 months of treatment. Although patients had an average of 1.9 fractures in the year preceding treatment, only 2 patients had fractures once treatment began. No significant differences in baseline data were noted between the two groups. However, group 1 had significantly less gain in BMD (P =.04) than group 2. No evidence of growth impairment was seen, and no association between changes in urinary N-telopeptide percentile and changes in BMD were noted. CONCLUSIONS: Single-day intravenous infusion of pamidronate is efficacious and well tolerated in a heterogeneous group of pediatric patients with symptomatic osteoporosis.     

Two doses of pamidronate in infants with osteogenesis imperfecta.

INTRODUCTION: Current regimens of intravenous pamidronate for infants and children with osteogenesis imperfecta (OI) typically deliver 3-12 mg/kg/year of drug. We wished to ascertain the effect of pamidronate at 6 or 12 mg/kg/year on skeletal health in infants with OI. METHODS: We recruited 12 infants over a period of 4 years. Infants received either 6 or 12 mg/kg/year of pamidronate. Bone outcomes were assessed by skeletal surveys and DXA bone density measurements at baseline and at 12 months. RESULTS: Bone mass increased in both groups. Infants receiving 12 as opposed to 6 mg/kg/year pamidronate had increased spine bone density after adjusting for covariates at study entry (p = 0.04). Crush fractures improved or remained unchanged in all but one infant. Biochemical markers of bone turnover fell but remained within or above the normal range for age. Metaphyseal remodelling was not impaired. CONCLUSIONS: Pamidronate dose in infants may influence lumbar spine bone acquisition. Pamidronate improved vertebral size after prior crush fracturing and did not over-suppress bone turnover.     

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.     

Effects of 3 years of intravenous pamidronate treatment on bone markers and bone mineral density in a patient with osteoporosis-pseudoglioma syndrome (OPPG)

We present a 21 year-old woman with osteoporosis-pseudoglioma syndrome (OPPG) suffering from bone pain and frequent long bone fractures (approximately 1 or 2 fractures/year) who was treated with i.v. pamidronate for 3 years. OPPG is a rare autosomal recessive disorder characterized by severe widespread osteoporosis leading to pathological fractures and congenital or early onset blindness. Bone mineral density (BMD) (g/cm2) was determined at lumbar spine and femur neck by dual energy X-ray absorptiometry. BMD studies were also performed in her parents and 18 year-old brother who were phenotypically normal. Within 2 months of the first pamidronate treatment the patient reported considerable decrease in bone pain and improved mobility. During the treatment period no important side effects and no recurrent bone fracture were reported. There were substantial increases in BMD, T score and z-score at both lumbar spine and femoral neck during therapy. Baseline lumbar spine BMD increased from 0.416 to 0.489 g/cm2 and femoral neck BMD increased from 0.455 to 0.532 g/cm2 after 3 years. Although her parents and brother did not have any history of fracture, BMD measurements revealed that her parents were osteopenic and her brother was osteoporotic. We demonstrated that pamidronate therapy seems to be safe and beneficial in both spinal and peripheral skeleton osteoporosis in patients with OPPG. Moreover, the present study clearly indicates that bone density studies and LRPS gene screening for mutations should be performed in phenotypically normal family members of patients with OPPG.     

Efficacité des biphosphonates oraux sur la déminéralisation osseuse des patients atteints de mucoviscidose

Disturbances in bone mineralization are frequent in cystic fibrosis but few studies have focused on the use of biphosphonates in this indication, and none on the use of oral etidronate. We report our experience using this latter treatment. METHODS: The study was retrospective and included five children and three adults with cystic fibrosis (six males and two females) aged seven to 30 years with Z-scores for lumbar bone density lower than -2 SD after one year of calcium (1 g/day) and vitamin D (900 UI/day and 300,000 UI/6 months) supplementation. All were treated during one year with etidronate: four courses of 15 days (one course per trimester) with doses ranging from 4 to 8 mg/kg per day. Calcium and vitamin D supplementation was continued between the etidronate treatment course. Total body and lumbar bone mineral density (BMD) were measured three times: at the beginning and the end of the year of calcium and vitamin D supplementation and at the end of the year of supplementation plus the four courses of etidronate treatment. RESULTS: The increase in BMD in absolute value (g/cm2) and in Z-score was significantly higher (P <0.05) after the year of combined supplementation and etidronate treatment (total body g/cm2: 3+/-1%, Z-score: 2+/-1% and lumbar spine g/cm2: 6+/-5%, Z-score: 3+/-4%) than after supplementation alone (total body g/cm2: -1+/-3%, Z-score: -4+/-3% and lumbar spine g/cm2: -1+/-3%, Z-score: -4+/-4%). Supplementation alone improved the total BMD in only one patient and the lumbar BMD in three, whereas after etidronate treatment the total and lumbar BMD were improved in the eight patients. None of the patients presented with side effects that could be attributed to the treatment. CONCLUSION: Oral etidronate treatment is well-tolerated and capable of improving bone mineralization in patients with cystic fibrosis. Further work will be necessary to determine the optimal dosage and the optimal frequency for the treatment series.     

The clinical and radiological assessment of cyclic intravenous pamidronate administration in children with osteogenesis imperfecta

Over the past 20 years, orally administered biphosphonates have been used extensively in the management of a number of common skeletal disorders of different etiology. Recently, in clinical practice, in a number of cases in whom oral therapy is insufficient or contraindicated, intravenous administration of pamidronate presents an alternative therapeutic option. In order to investigate the clinical and radiological effects of cyclic intravenous pamidronate administration in children with osteogenesis imperfecta, a prospective open study of pamidronate treatment was undertaken in a cohort of eight bed-bounded (3.6-13.8 years) patients with severe osteoporosis and vertebral deformities. Pamidronate was administered at a dose of 0.5 mg/kg/ day for three days. Tri-monthly cyclic intravenous infusions were performed over-one year. Bone density, verebral corpus heights, estimated volumetric bone density and biochemical measurements were analyzed. Side effects of the therapy were determined via questionnaire. Significant reductions in the number of bone fractures and pain were observed in all patients. Ambulation scores were significantly altered and seven of eight patients became independent. Serum alkaline phosphatase levels decreased significantly. Lumbar X-ray and densitometry showed a striking improvement by the end of the treatment period. Even spaced dense lines corresponding to infusion periods were observed on roentgenograms of the radio-ulnar region. Pubertal progression and growth velocity were not affected inversely during therapy. Although we did not observe any severe side effect, one patient's blood urea nitrogen level was altered slightly. In conclusion, one year cyclical pamidronate treatment seems to be effective and safe in improving bone mineralization and in reducing fracture incidence in severe osteoporosis.     

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.     

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.     

Responses of bone turnover markers and bone mineral density to growth hormone therapy in children with isolated growth hormone deficiency and multiple pituitary hormone deficiencies

Growth hormone deficiency (GHD) is an important cause of decreased bone mass in childhood and adolescence. The role of other pituitary hormone deficiencies on bone mass is still a query in children. Thirty-nine children (28 with isolated GHD [IGHD] and 11 with multiple pituitary hormone deficiency [MPHD]) were investigated to show the effects of IGHD vs MPHD on bone status. Bone turnover markers (calcium, phosphate, alkaline phosphatase [ALP] Bone ALP [BALP], osteocalcin [OSC], carboxyterminal propeptide of type-1 collagen [CPP-I], parathyroid hormone [PTH]) were measured before and every four months during growth hormone (GH) therapy; bone mineral density (BMD) of the lumbar spine was measured before and every six months during therapy. All bone turnover markers except calcium and PTH increased significantly during 1 year of GH therapy. There were no differences in the levels of bone turnover markers between children with IGHD and MPHD at baseline, and after 4, 8 and 12 months of therapy. Lumbar spine BMD SDS of all patients increased significantly during 1 year of therapy (p = 0.035 after 6 months and p <0.001 after 12 months compared with baseline). BMD SDS of both IGHD and MPHD groups were similar at baseline and after 6 and 12 months of therapy (p = 0.235, p = 0.295 and p = 0.384). Height SDS (HtSDS) at baseline was the most important predictor of baseline BMD SDS in children with GHD (t = 4.166, p <0.001). DeltaHtSDS was also positively related to deltaBMD SDS after 1 year of GH therapy. In conclusion, there was no difference in bone status of the patients with IGHD and MPHD at baseline. GH therapy yielded similar increases in bone mass in both groups. Increase in height contributed to increase in BMD during 1 year of GH therapy.     

Pamidronate treatment of less severe forms of osteogenesis imperfecta in children

BACKGROUND: Bisphosphonate therapy improves bone quality in children with severe osteogenesis imperfecta (OI). Children with milder phenotypes also have prepubertal fractures, bone pain and reduced bone mass, predisposing them to adult osteoporosis. OBJECTIVE: To evaluate treatment effects of pamidronate in children with mild phenotypes of OI. METHODS: Open label, 2-year observational study of 18 patients, using pamidronate, with clinical, biochemical and radiological monitoring. RESULTS: Over 2 years, bone pain decreased from 16 to 1 patient and disturbed sleep from 12 children to 0. Independent mobility improved from 10 to 17 children. Fracture incidence decreased from 1.6 to 0.5 fractures/child/year. Surgical interventions decreased from a mean 1.3 procedures/patient to 0 in the second year of treatment. Growth velocity remained stable at a mean 4.8 cm/year. Mean lumbar vertebral bone mineral density improved by 40.8%, from 0.375 to 0.528 g/cm2 (p <0.0001), z-score from -3.77 to -2.44 (p <0.0001). Mean vertebral height improved by 17.3%, from 15.6 to 18.38 mm (p = 0.07); plasma alkaline phosphatase decreased from 222 to 169 U/l (p = 0.0009) and urinary deoxypyridinoline crosslinks decreased from 26.7 to 21.8 nmol/mmol creatinine (p = 0.21). Two children with vitamin D insufficiency were concurrently treated. A significant association (r = -0.6, p = 0.008) was shown between age at start of treatment and percentage change in BMD after 2 years. CONCLUSIONS: Pamidronate treatment improves bone quality in children with mild types of OI. It ameliorates clinical symptoms, improves mobility, reduces fracture frequency and thus improves quality of life and in future is likely to reduce the severity and consequences of adult osteoporosis by improved peak bone mass in these children.     

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.     

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.     

Intravenous pamidronate in juvenile osteoporosis.

AIMS: To investigate the use of the aminobisphosphonate, disodium pamidronate, in children with vertebral osteoporosis. METHODS: Five children (aged 10-15 years) with vertebral osteoporosis who developed compression fractures in the thoracic and/or lumbar spine as a consequence of five different conditions, received treatment with intravenous disodium pamidronate in doses ranging from 0.5 to 12 mg/kg/y. RESULTS: Each child had rapid pain relief following the first treatment, followed by large increments in lumbar spine bone density over one year; the change in bone density standard deviation score ranged from 0.5 to 2.5 with percentage increments of 26% to 54%. CONCLUSION: Intravenous pamidronate appears to be a useful therapeutic option in childhood osteoporosis, but its use in children must still be regarded as experimental and therefore closely monitored.     

Determinants of bone mineral density in prematurely born children aged 6–7 years

The aim of this study was to assess the long-term effects of prematurity and growth during the first year on bone mineralization in prematurely born children. The study group consisted of 38 prematurely born Finnish children (17M, 21F) examined at the age of 6-7 y. After birth, all children were fed with banked human milk until discharge from hospital. Thereafter, 27 children were partially breastfed until the age of 5–7 months. Infants with gestational age (GA) <33 weeks ( n = 25) received calcium 45-50 mg/100 kcal, phosphorus 40-45 mg/100 kcal, vitamin A 1000 IU/d, vitamin C 2 mg/d and vitamin D 400 IU/d until 2.5 kg. Infants born > 33 weeks received only vitamin D 400 IU/d. Bone mineral density (BMD) and bone mineral content (BMC) were measured by dual energy X-ray absorptiometry (DXA) of the lumbar spine (L2-L4) at 6-7 y of age. At examination, all children had normal height and weight. BMD values were within the confidence interval of the Finnish reference values. In regression analysis bone area, present weight, GA and weight at 1 y were the most significant factors explaining 77.1% of the variance of BMC. After adjusting for other independent variables the prematurely born children who were thinner at 1 y of age subsequently had higher BMC values when examined at the age of 6-7 y. This study shows that growth patterns during the first year of life have long-term effects on bone mineralization.