Background Severe osteogenesis imperfecta is a disorder characterizedby osteopenia, frequent fractures, progressive deformity, lossof mobility, and chronic bone pain. There is no effective therapyfor the disorder. We assessed the effects of treatment witha bisphosphonate on bone resorption.
Methods In an uncontrolled observational study involving 30children who were 3 to 16 years old and had severe osteogenesisimperfecta, we administered pamidronate intravenously (mean[±SD] dose, 6.8±1.1 mg per kilogram of body weightper year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinicalstatus, biochemical characteristics reflecting bone turnover,the bone mineral density of the lumbar spine, and radiologicchanges were assessed regularly during treatment.
Results Administration of pamidronate resulted in sustainedreductions in serum alkaline phosphatase concentrations andin the urinary excretion of calcium and type I collagen N-telopeptide.There was a mean annualized increase of 41.9±29.0 percentin bone mineral density, and the deviation of bone mineral densityfrom normal, as indicated by the z score, improved from –5.3±1.2to –3.4±1.5. The cortical width of the metacarpalsincreased by 27.0±20.2 percent per year. The increasesin the size of the vertebral bodies suggested that new bonehad formed. The mean incidence of radiologically confirmed fracturesdecreased by 1.7 per year (P<0.001). Treatment with pamidronatedid not alter the rate of fracture healing, the growth rate,or the appearance of the growth plates. Mobility and ambulationimproved in 16 children and remained unchanged in the other14. All the children reported substantial relief of chronicpain and fatigue.
Conclusions In children with severe osteogenesis imperfecta,cyclic administration of intravenous pamidronate improved clinicaloutcomes, reduced bone resorption, and increased bone density.
Osteogenesis imperfecta, often referred to as "brittle-bonedisease," is a heritable disorder characterized in most affectedpersons by either a reduction in the production of normal typeI collagen or the synthesis of abnormal collagen as a resultof mutations in the type I collagen genes.1 The clinical severityof its expression varies widely. In its milder form (type I),fractures before puberty occur occasionally, deformity is minimal,and stature is normal. In its most severe form (type II), fracturesin utero lead to pulmonary insufficiency, causing perinataldeath. In type III osteogenesis imperfecta, a high frequencyof fractures causes severe deformities and short stature, whereasin type IV, deformities and dwarfism are present but are lesssevere.2 In most children with type III and many with type IVosteogenesis imperfecta, the disorder is progressive, with increasingdeformity of the limbs and spine, dependence on others for helpin walking, and chronic pain. A variety of agents (includinganabolic steroids, sodium fluoride, magnesium oxide, and calcitonin)have been used in attempts to increase bone mass and to reducethe risk of fracture, but none have resulted in sustained improvement.3,4,5,6
The bisphosphonate compounds are potent inhibitors of bone resorption,and they have been reported to have beneficial effects in childrenwith osteogenesis imperfecta.7,8,9,10 We have reported the resultsof histomorphometric studies of bone suggesting that this disorderis associated with an increase in osteoclastic activity anda reduction in the formation of new bone.11 Our study was designedto assess the effects of bisphosphonate treatment in childrenwith severe osteogenesis imperfecta.
Methods
Subjects
Between October 1992 and December 1997, we administered pamidronateto 30 children, 3 to 16 years old, who had severe osteogenesisimperfecta (Table 1). All had severe osteopenia, and 27 weresmall for their age (below the third percentile for height).All but five had moderate-to-severe restrictions in ambulation.The study was approved by the ethics review board of our institution,and parents or legal guardians gave written informed consent.
Table 1. Characteristics of 30 Children with Osteogenesis Imperfecta before Pamidronate Treatment and Their Treatment Schedules.
In nine children the osteogenesis imperfecta was classifiedas type III, and in nine others as type IV. In 12 children thedisorder could not be classified; these children had featuressimilar to those of type IV osteogenesis imperfecta but withvarious combinations of severe long-bone deformity resultingfrom fractures after birth, vertebral collapse, and changesin the long-bone metaphyses. Four of these 12 patients had theclinical features of the newly described type V osteogenesisimperfecta.12
Treatment
Pamidronate disodium (Aredia, Ciba–Geigy, Dorval, Que.,Canada) was diluted in 250 to 500 ml of isotonic saline andadministered by slow intravenous infusion over a four-hour periodon each of three successive days. The dose, based on the dosegiven to adults for the treatment of Paget's disease of bone,13,14was 1.5 or 3.0 mg per kilogram of body weight per infusion cycle.Half the children received the lower dose during the first yearof treatment, after which their regimen was shifted to the higherdose. The other half received only the higher dose. In one child,because of a slow initial response to therapy, the dose wasincreased after one year to 3.75 mg per kilogram per cycle.Overall, the children received a mean (±SD) of 6.8±1.1mg per kilogram per year and 4 to 12 cycles of treatment. Themean duration of treatment was 765 days (range, 490 to 1813[approximately 1.3 to 5.0 years]) (Table 1). Initially, theinterval between cycles was six months. However, monthly measurementsof the serum alkaline phosphatase concentration and the urinaryexcretion of calcium revealed an increase in both after fourmonths, and therefore the interval between cycles was shortenedto four months. The patients' calcium intake was regularly evaluatedand was maintained at 800 to 1000 mg per day through diet andsupplementation. Their vitamin D intake was at least 400 IUper day.
Measurements
Clinical evaluation, including assessment of anthropometricvariables and pubertal development, occupational-therapy evaluation,and bone densitometric measurements, were performed at eachadmission for pamidronate infusion. Accurate records for usein evaluating the growth rate before treatment were availablefor 21 of the 30 children (10 prepubertal and 11 pubertal).
The subjects fasted overnight. Blood and urine (from the secondmorning voiding) were obtained before each infusion of pamidronate,and blood alone immediately thereafter. Serum and urine concentrationsof calcium, phosphate, and creatinine and the serum concentrationof alkaline phosphatase were measured by colorimetric methods(Monarch, Instrumentation Laboratory, Lexington, Mass.). Theurinary excretion of the cross-linked N-telopeptide of typeI collagen, a marker of bone resorption, was measured by enzyme-linkedimmunosorbent assay (Osteomark, Ostex, Seattle).
X-ray films of the skull, upper and lower limbs, and spine (anteroposteriorand lateral views) were obtained at 6-to-12-month intervals.Films were examined on an ongoing basis by pediatric radiologistsunaware of the treatment status of the children. Changes inthe bone mineral density of the lumbar spine, both in termsof absolute values and in terms of age-corrected values (z scores),were measured by dual-energy x-ray absorptiometry (QDR 2000W,Hologic, Waltham, Mass.). The coronal area of the first fourlumbar vertebrae, automatically measured by the software usedfor absorptiometric analysis, was taken as an index of vertebral-bodysize. The coefficient of variation for the bone mineral densityof the lumbar spine was 1 percent on repeated measures in healthychildren. On posteroanterior radiographs of the hand taken ata uniform 40-in. (102-cm) tube-to-film distance, the corticalwidth of the metacarpals (defined as the distance between theexternal cortical surfaces minus the width of the medullarycavity) was measured with vernier calipers at the midpoint ofthe second left metacarpal. These measurements were made immediatelybefore treatment and after one or two years of treatment. Onthe same radiographs, the bone age was determined accordingto the method of Greulich and Pyle.15 All available radiographsfrom the two years before treatment and those obtained duringtreatment were assessed for evidence of fractures.
Occupational therapists experienced in the care of childrenwith osteogenesis imperfecta evaluated the subjects' mobilityand ambulation using a five-point scale, as follows: 0 (bed-or wheelchair-bound), 1 (able to walk with aids, but not functionallymobile), 2 (able to walk in the household, with or without aids),3 (able to walk short distances, with or without aids), and4 (able to walk independently).16
Statistical Analysis
The children were treated for various lengths of time, and thereforethe magnitude of the effect of treatment on most outcome measureswas extrapolated to an annualized percent change from base linefor each child. In general, the longer-term data were negativelyskewed in distribution, and therefore the data were log-transformedto obtain a near-normal distribution. Analyses were performedwith two-sided paired t-tests or the Mann–Whitney rank-sumtest, as appropriate. All the analyses were performed with DataDesksoftware (version 5.0.1; Data Description, Ithaca, N.Y.).
Results
Biochemical Changes
Before treatment, all 30 children had normal serum concentrationsof calcium and phosphate. After each infusion cycle, there wasa transient (two-to-four-week) decrease in serum calcium (meandecrease, 12±7 percent) and serum phosphate (23±18percent). Over a three-to-four-month period, there were moresustained decreases in the serum concentration of alkaline phosphatase(14±18 percent), the urinary excretion of calcium (66±49percent), and the urinary excretion of the N-telopeptide oftype I collagen (43±31 percent). Throughout the treatmentperiod, there were steady decreases in serum levels of alkalinephosphatase (13±8 percent per year, P<0.001) and urinaryexcretion of N-telopeptide of type I collagen (26±17percent per year, P<0.001).
Changes in Bone Density
All the children had low bone mineral density in the lumbarspine, with z scores ranging from –3.3 to –7.8.During treatment, the mean bone mineral density increased markedly,by 41.9±29.0 percent per year, and the mean z score improvedfrom –5.3±1.2 to –3.4±1.5 (P<0.001);the z scores of three patients reached the normal range. Therewere no significant differences between boys and girls or betweenprepubertal children and children undergoing puberty (Table 2).The changes in bone mineral density over time for the ninechildren treated for two or more years are shown in Figure 1.Concurrently with the change in bone mineral density, the meancoronal area of the first through fourth lumbar vertebrae increasedmarkedly, from 21.8±7.8 to 29.2±8.8 cm2 (Table 2).
Figure 1. Changes in the Bone Mineral Density of the First through Fourth Lumbar Vertebrae in Nine Children with Osteogenesis Imperfecta Who Were Treated with Cyclic Administration of Intravenous Pamidronate for Two or More Years.
The shaded area represents the normal range (mean ±2 SD) for age-matched healthy children (data from Hologic). The arrows indicate the initiation of treatment. Each symbol represents one measurement.
Radiologic Changes
On successive radiologic examinations of the thoracic and lumbarregions of the spine, no new vertebral crush fractures wereseen. Instead, an increase in vertebral height was noted overtime (Figure 2), corroborating the increase in vertebral coronalarea (Table 2). Characteristic dense lines appeared under thegrowth plates, particularly in the bones around the knees andin the distal forearms, as well as in the vertebrae and alongthe iliac crests (Figure 3). The regular spaces between theselines corresponded to the intervals between treatment cycles,demonstrating the continued growth of bone during therapy. Systematicsurveys of the epiphyses showed no evidence of widening or rachitis.In all the children, the bone ages corresponded to the chronologicage.
Figure 2. Lateral Radiographs of the Lumbar Spine of a Six-Year-Old Boy with Osteogenesis Imperfecta before (Left-Hand Panel) and after (Right-Hand Panel) 18 Months of Treatment with Pamidronate.
Increases in the heights of individual vertebrae are evident. The bone mineral density before treatment was 0.205 g per square centimeter, and after 18 months it was 0.371 g per square centimeter.
Figure 3. Anteroposterior Radiograph Showing Sclerotic Bands in the Metaphysis of the Distal Femur in an Eight-Year-Old Boy with Osteogenesis Imperfecta.
This child received seven cycles of treatment. The seven evenly spaced bands demonstrate that growth continued steadily during therapy.
An increase in the thickness of the cortex was often seen inthe diaphyses of the long bones. In 26 of the 29 patients forwhom previous x-ray films were available, the metacarpal corticalwidth increased by an average of 27.0±20.2 percent peryear (Table 2). This compares well with the gain of 8 to 9 percentper year in healthy children from 3 to 16 years of age.17
Effects on Growth
Before treatment, 10 prepubertal children grew an average of4.4±2.7 cm per year. During treatment, their growth ratewas maintained, at 5.7±2.2 cm per year (P=0.16). In 11children undergoing puberty, the pretreatment growth rate was2.2±1.7 cm per year and increased slightly, to 4.9±3.4cm per year, during treatment (P=0.11). In healthy childrenthe prepubertal growth rate averages 6 cm per year and increasesto 9 to 10 cm per year during puberty.18
Clinical Outcome and Side Effects
The earliest response to treatment was a marked reduction inchronic bone pain one to six weeks after the initiation of therapy,with only an occasional recurrence of pain in the days precedinga treatment cycle. Ambulation was assessed according to thechildren's degree of independence and mobility.16 Before therapy,5 children were fully functional (grade 4), whereas 16 wereconfined to a bed or a wheelchair (grade 0 or 1). Ambulationscores improved in 16 children: 6 gained one grade, 5 gainedtwo, and 1 gained three, and 4 children progressed from beingwheelchair-bound (grade 0 or 1) to walking independently (grade4). In the other 14 children, no change in grade was noticed.
The incidence of fractures decreased from 2.3±2.2 peryear before treatment to 0.6±0.5 per year during treatment.Nine children had no fractures during treatment, as comparedwith three children in the two years before treatment. Fracturehealing was not obviously delayed and there was no instanceof fracture nonunion during treatment.
In 26 children, body temperature increased on the second dayof the first infusion cycle, a change accompanied by back andlimb pain in some. This "acute-phase reaction"19 was controlledwith standard doses of acetaminophen and did not recur duringsubsequent treatment cycles. Despite the small decreases inthe serum calcium concentration that occurred soon after eachinfusion cycle, none of the children had symptomatic hypocalcemia.Renal function did not change with treatment.
Discussion
Osteopenia and bone fragility, the hallmarks of severe osteogenesisimperfecta, probably result from structural abnormalities inbone tissue1 and a reduced rate of osteogenesis.11 Histomorphometricand biochemical studies have indicated that increased resorptionof bone also contributes to the disorder.11,20,21 Our initialgoal in undertaking this study was to reduce bone resorptionand to increase bone mass in children with this disease. Cyclicadministration of intravenous pamidronate resulted in a rapidincrease in the mineral density of the lumbar vertebrae, resultingfrom an improvement in the balance between bone formation andbone resorption. The decrease in urinary excretion of the N-telopeptideof type I collagen, a measure of bone resorption, was rapidand progressive. Serum concentrations of alkaline phosphatase,a measure of bone formation, also fell, but to a lesser degree.Taken together, these results indicate that the rate of boneturnover declined during therapy as a result of changes in thebalance between formation and resorption that favored an increasein bone mass. However, the decrease in resorption did not compromisebone growth or fracture healing.
The bone mineral density of the lumbar spine, as measured byx-ray absorptiometry, is an area-related measurement that isaffected by both true bone mineral density and the volume ofthe vertebral body. In growing children, the area-related bonemineral density increases by 3 to 6 percent per year beforepuberty and by 14 to 16 percent per year during puberty.22,23In our patients, annualized gains in bone mineral density duringpamidronate therapy (41.9±29 percent) substantially exceededthese values. The z scores for bone mineral density take intoaccount the changes in volume caused by growth.24 In all thechildren in our study, the z scores improved during therapy,suggesting that pamidronate has a positive effect on bone mineraldensity. These changes were not caused by any crush-fracture–relateddecreases in vertebral-body size, which would artifactuallyincrease bone mineral density, since the vertebral area increasedin all the children (Table 2) and radiographs showed evidenceof new bone formation (Figure 2).
These positive effects were accompanied by a significant increasein the width of the metacarpal cortices (Table 2). Thicker corticeswere also seen on x-ray films of the long bones. These changesmay have resulted in part from the improvement in mobility inmany children as the mechanical strain of walking stimulatednew bone formation.25 The biologic importance of these effectsis underscored by the decrease in the rate of fractures, eventhough the risk of fractures may have increased with the children'simproved mobility and greater activity. In addition, all thechildren reported relief of chronic pain. Pain relief from bisphosphonateshas been noted previously in adults with fibrous dysplasia ofbone26 and in a child with vertebral collapse at the onset ofacute lymphoblastic leukemia.27
In children with severe osteogenesis imperfecta, the growthrate is greatly reduced before the age of six or seven years,and growth almost stops thereafter.28 In the children in ourstudy, growth was reduced but not arrested before treatment,and during treatment, linear growth proceeded at a slightly(but not significantly) increased rate. At least part of thisgain was probably due to increases in the size of the vertebralbodies. The sclerotic lines that appeared in the metaphysesduring treatment have no known functional importance and havebeen noted previously.7,9 Impairment of mineralization and wideningof the growth plates have been reported in a 13-year-old boywho received pamidronate at a dose similar to those we usedin the present study.26 We found no evidence of such changesin any of the 30 children in our study.
In this observational study, both the patients and their physiciansand other care givers had full knowledge of the treatment beingadministered. We cannot exclude the possibility that there wasa placebo effect, particularly with respect to the relief ofbone pain and the improvement in ambulation, or that the changesreflect the passage of time rather than the effects of the treatment.However, the consistency of the clinical, biochemical, and radiologicfindings suggests that the changes resulted from the administrationof pamidronate. This medical therapy does not stand alone: itshould be considered part of a coordinated, multidisciplinaryapproach to the treatment of children with osteogenesis imperfecta,including timely corrective surgery, physiotherapy, and occupationaltherapy. Continued follow-up will help delineate the responseto therapy over time and the limits of the gains that can beachieved.
Supported by the Shriners of North America. Dr. Bishop is therecipient of a European Society for Paediatric EndocrinologyResearch Fellowship, sponsored by Novo Nordisk.
We are indebted to Denyse Lavallée for secretarial help;to Mark Lepik for artwork; to Mireille Dussault and Anna Lisfor technical help; to Nancy Mallinak (of Ostex) for the Osteomarkkits; and to Kathleen Montpetit and Nathalie Gervais (occupationaltherapy), Joanne Gibis (physiotherapy), Rose-Marie Chiasson(social work), Jeffrey Hohenkerk (radiology), and the nursingstaff of Shriners Hospital for their untiring assistance inthe examination and treatment of our patients.
Source Information
From the Genetics Unit, Shriners Hospital for Children (F.H.G., N.J.B., H.P., G.C., G.L., R.T.), and the Departments of Surgery and Pediatrics (F.H.G., N.J.B.), McGill University, Montreal.
Address reprint requests to Dr. Glorieux at the Genetics Unit, Shriners Hospital for Children, 1529 Cedar Ave., Montreal, QC H3G 1A6, Canada.
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