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.     

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.     

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.     

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.     

Bone mineral density in pediatric and adolescent renal transplant patients: how to evaluate

Reduced bone mass is a common complication of renal transplantation in adults but only few data are present for pediatric transplant patients. Bone mineral status of pediatric renal transplant patients ages ranging from 7.5 to 17.6 years (mean age 14.9 +/- 2.3) who were at least 6 months postrenal transplantation was examined. Bone mineral density (BMD) of lumbar vertebrea and femoral neck was determined by dual energy X-ray absorptiometry (DEXA) and z-scores according to age, puberty, height and bone age were compared to sex and ethnic specific reference data. z-scores were calculated for both areal and volumetric bone density. BMD L1-4 z-scores were more than 2 SD below the mean according to chronological age in 12 patients (63%), pubertal status in six patients (31.5%), bone age in five patients (26.3%) and height in five patients (26.3%). The BMD femoral neck z-scores were more than 2 SD below the mean according to age in 10 patients (55.5%), puberty in five patients (27.7%), bone age in three (16.6%) patients and height in five (26.3%) patients. Correction of the vertebrae and femoral neck for bone size yielded osteoporotic values for seven patients (36.8%) for lumbar BMD and for four patients (22%) for femoral neck BMD. The use of aBMD in growth-retarded children has some restrictions in determining z-scores. Deficits in spinal bone density still persisted after correcting for height, puberty, bone age and volume. In renal transplant patients who have short stature it is reasonable to give values corrected for height, puberty, bone age and bone size and interpret each of these values for each patient.     

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.     

Intravenous pamidronate treatment of polyostotic fibrous dysplasia associated with the McCune Albright syndrome

OBJECTIVES: An open trial of pamidronate treatment was undertaken in 5 children and 4 young adults with polyostotic fibrous dysplasia associated with McCune Albright syndrome to assess clinical response, bone turnover, and cardiovascular status over a 2-year period.Study design: Pamidronate was administered by intravenous infusion 1 mg/kg/d for 3 days every 6 months for 2 years. Bone turnover was measured at 0, 6, 12, 18, and 24 months with bone mineral density, and cardiac output was assessed by echocardiography at 0, 12, and 24 months. RESULTS: All subjects reported marked reduction in bone pain and sustained increased mobility. The fracture rate decreased in most. Orthopedic insertion of intramedullary rods was successful with maintenance of rod position. Mean osteocalcin levels fell from 35.5 +/- 5.6 microg/L to 28.4 +/- 4.1 microg/L (P <.03). Other bone turnover marker changes were not significant. The mean bone mineral density at lumbar spine increased from 0.5 +/- 0.08 to 0.67 +/- 0.03 g/cm(2) (P <.002) in children and 1.16 +/- 0.6 to 1.33 +/- 0.08 g/cm(2) in adults (P <.005). Other changes in bone mineral density were not significant. Cardiac output did not change significantly. CONCLUSIONS: Pamidronate treatment is an effective therapeutic modality for children with polyostotic fibrous dysplasia, with a good short-term safety profile. Failure to demonstrate major biochemical or bone densitometry improvements is due to the nature of the fibrous dysplasia and intercurrent microfracture.     

Efficacy of low dose schedule pamidronate infusion in children with osteogenesis imperfecta

BACKGROUND: Osteogenesis imperfecta (OI) is a rare condition in which bones are abnormally brittle with frequent fractures. A variety of therapeutic agents has been used with low efficacy. In this study, we present three patients treated for 4 years with i.v. pamidronate. PATIENTS AND METHODS: Three prepubertal patients, aged 9 (M), 9 (F) and 11 (F) years old, with OI, were treated with 30-60 mg i.v. pamidronate every 6 months over four years. Determinations were made of plasma 1,25-dihydroxycholecalciferol, 25-hydroxycholecalciferol, insulin-like growth factor-I (IGF-I) and its transport protein (IGFBP3), osteocalcin, total alkaline phosphatase and its osseous fraction, and parathormone (PTH) at baseline and after every pamidronate infusion, Densitometry and X-ray of the vertebral column were performed at the same intervals. RESULTS: Significant reductions of number of bone fractures and pain were observed in all patients, despite lack of any modification in biochemical parameters. Lumbar X-ray and densitometry showed a striking improvement by the end of the treatment period. CONCLUSION: Pamidronate seems to be useful in the treatment of patients with osteogenesis imperfecta.     

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.     

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.     

Pamidronate treatment of bone fibrous dysplasia in nine children with McCune-Albright syndrome

McCune-Albright syndrome is a rare genetic disorder consisting of skin and bone dysplasia and peripheral endocrinopathies. Little data have been collected regarding bisphosphonate treatment of bone fibrous dysplasia in paediatric patients with this syndrome. The aim of our study was to investigate the therapeutic efficacy of pamidronate in these patients. Nine patients with moderate to severe forms of bone fibrous dysplasia were treated with pamidronate intravenously (0.5-1 mg/kg/daily for 2-3 d) at 0.5-1-y intervals. Patients were treated over a time period of 0.5-3.5 y. During treatment no spontaneous fracture occurred. Bone pain and gait abnormality due to pain disappeared after 2-3 therapeutic cycles. Cranial asymmetry and limb length discrepancy remained unchanged. Elevated serum alkaline phosphatase and urine hydroxyproline values were reduced by the treatment, demonstrating drug activity at the lesional level. The effectiveness of pamidronate was also seen at the non-lesional level through an increase in bone density. Radiographic and scintigraphic evidence of lesion healing was not attained. Pamidronate treatment can ameliorate the course of bone fibrous dysplasia in children and adolescents with McCune-Albright syndrome.     

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.     

Bisphosphonates to treat osteopenia in children with quadriplegic cerebral palsy: a randomized,placebo-controlled clinical trial

OBJECTIVE: To evaluate in a double-blind, placebo-controlled clinical trial the safety and efficacy of intravenous pamidronate to treat osteopenia in nonambulatory children with cerebral palsy. STUDY DESIGN: Six pairs of subjects generally matched within each pair for age, sex, and race completed the protocol. One member of each pair randomly received plain saline placebo, the other pamidronate. Drug/placebo was administered intravenously daily for 3 consecutive days, and this 3-day dosing session was repeated at 3-month intervals for one year. Evaluations were continued for 6 months after the year of treatment. Bone mineral density (BMD) was measured in the distal femur, a site specifically developed for use in this contracted population, and the lumbar spine. RESULTS: In the metaphyseal region of the distal femur, BMD increased 89% +/- 21% (mean +/- SEM) over the 18-month study period in the pamidronate group compared with 9% +/- 6% in the control group. Age-normalized z scores increased from -4.0 +/- 0.6 to -1.8 +/- 1.0 in the pamidronate group and did not significantly change in the control group (-4.2 +/- 0.3 to -4.0 +/- 0.3). The first dosing with pamidronate caused a transient drop in serum calcium that was asymptomatic and not treated. No other potentially adverse effects were noted. CONCLUSIONS: In this small controlled clinical trial, pamidronate was found to be a safe and very effective agent to increase BMD in nonambulatory children with cerebral palsy.     

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.     

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.     

Bone mineral content and collagen defects in osteogenesis imperfecta

Whole-body and spine dual-energy X-ray absorptiometry was done in 63 patients with osteogenesis imperfecta aged 5 to 63 y, and the results were compared with OI types and collagen defects. Bone mineral content (BMC)-for-age, bone area (BA)-for-age, bone mineral density (BMD)-­for-age, and BMC-for-BA were reduced, especially in patients with OI III/IV and/or in those with a qualitative collagen defect. BA-for-height was normal. Some patients with OI I and/or a quantitative collagen defect had BMD at or above -2 z-scores. We conclude (i) that both BMC and BMD differ significantly between OI types and collagen defects, (ii) that reduced BMC-for-age in OI patients is due mainly to reduced height (“short bones”) and reduced BMC-for-BA (“light bones”), whereas BA-for-height (“bone width”) is normal, (iii) that most OI patients have lower than average BMC, but in some mildly affected patients brittleness may exist with only small reductions in BMC.     

Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3

OBJECTIVE: To examine the effect of carbamezapine and valproate on bone mineral density (BMD), IGF-I and IGFBP-3 levels in children. METHODS: The effects of at least 2 years valproic acid and carbamazepine therapy on BMD were evaluated in a cross-sectional and retrospective study. All children were ambulatory, prepubertal, and had normal activity and nutritionally adequate diets. Ambulatory epileptic patients were divided into two groups. Thirty-three patients (group 1; 17 boys, 16 girls; mean age: 8.8 +/- 2.0 years) were treated with valproic acid and 33 patients were treated with carbamazepine (group 2; 20 boys, 13 girls; mean age: 9.7 +/- 1.6 years). The control group consisted of 22 healthy children (13 boys, 9 girls; mean age: 8.9 +/- 2.3 years), who were age- and sex-matched with the patient groups. Children with metabolic bone disease, growth and neurological impairment, signs of malnutrition, or any chronic disease were excluded from the study. RESULTS: BMD values at lumbar spine in both the carbamazepine (-1.69 +/- 0.85 mean L1-4 BMD z-scores, mean 35.5 +/- 12.8 months treatment, and 19,478.6 +/- 6,301.3 mg/kg cumulative dose) and valproic acid (-1.28 +/- 0.80 mean L1-4 BMD z-scores, mean 33.7 +/- 15.0 months treatment, and 22,852.4 +/- 12,477.4 mg/kg cumulative dose) groups were significantly lower than that of the control group (-0.23 +/- 0.87 mean L1-4 BMD z-score). Serum ALP and PTH levels were significantly higher in the carbamazepine-treated group (65.4 +/- 21.1 pg/ml, 767 +/- 267 U/l, respectively) than those of the valproic acid-treated (39.1 +/- 12.8 pg/ml, 561 +/- 166 U/l, respectively) and control groups (36.3 +/- 4.9 pg/ml, 487 +/- 82 U/l, respectively). Serum 25-hydroxyvitamin D of the carbamazepine-treated group (9.8 +/- 3.2 microg/l) was significantly lower than the other groups (15.1 +/- 3.5, 16.6 +/- 4.7 microg/l, respectively). There were eight and 13 patients with plasma intact PTH above reference values in groups 1 and 2, respectively. Valproic acid and carbamazepine therapy results in a hyperparathyroid state and altered vitamin D metabolism, respectively. CONCLUSION: BMD values at lumbar spine were significantly reduced in both carbamezapine and valproic acid treated groups. Valproic acid and carbamazepine therapy do not change IGF-I and IGFBP-3 levels. Altering the hepatic conversion of vitamin D may be the mechanism of carbamazepine-associated reduction in BMD, but the mechanism of decreased BMD in valproate therapy remains unclear.     

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.     

Biochemical bone markers in the assessment and pamidronate treatment of children and adolescents with osteogenesis imperfecta

Aim: To assess the role of biochemical bone markers in classification of children with osteogenesis imperfecta (OI), their possible association with vertebral compression fractures in milder forms of OI and their role in monitoring of intravenous pamidronate (APD) treatment. Methods: Serum total alkaline phosphatase (ALP), bone ALP isoforms (in a subgroup), osteocalcin, type I procollagen carboxy‐terminal propeptide, carboxy‐terminal telopeptide of type I collagen, and urine deoxypyridinoline (DPD) were measured in a cross‐sectional study of 130 untreated individuals, 0.25–20.9 years (median 6.7), with OI types I, III and IV. Of those, sixty‐nine were also assessed longitudinally during monthly APD treatment. Bone mineral density (BMD) was measured by dual‐energy X‐ray absorptiometry. Results: Significant differences in bone markers, however not sufficient for individual clinical use, were found in the larger untreated group but not between subgroups with or without vertebral compressions. All bone markers decreased during treatment for 1.0–12.5 years, but with different relative amounts. Changes were not correlated to the improvement in BMD, mobility or pain. Conclusion: Bone markers are, despite significant differences, not useful for the classification of OI type in the individual child and are not associated with vertebral compressions. Serum ALP and urinary DPD are sensitive in monitoring bisphosphonate treatment.