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[18I Osteogenesis Imperfecta HORACIO PLOTKIN*, DRAGAN PRIMORAC t, and DAVID ROWE ~ *Inherited Metabolic Diseases Section, Department of Pediatrics, University of Nebraska Medical Center and Children's Hospital, Omaha, Nebraska tLaboratory of Clinical and Forensic Genetics, Split University Hospital and School of Medicine, Split, Croatia CDepartment of Genetics and Developmental Biology, University of Conneticut Health Center, Farmington, Conneticut

INTRODUCTION

pyknodysostosis [9]. The back of the skull can be flat due to bone fragility and lack of head control in infants

During the past decade, the concept of osteogenesis imperfecta (OI) has changed from "a collagen disorder caused by mutations in the collagen genes, divided in four types, for which there is no medical treatment" to a fascinating group of heterogeneous conditions characterized by bone fragility, caused by numerous different mutations, with at least 10 different clinical forms and with effective symptomatic treatment and exciting prospects for gene therapy. The prevalence of OI is estimated to be 1 in 15,000-20,000 infants [1], but misdiagnosis is frequent because it is a heterogeneous condition. The prevalence appears to be the same throughout the world [2-5]. During the evolution of understanding of the disease, OI has served as the paradigm for heritable disease of connective tissue from which advances in molecular diagnosis, mode of inheritance, and new concepts of therapy have been applied. It should continue to play this pivotal role in the future. In the vast majority of cases, mutations within the C O L I A 1 or C O L I A 2 genes are responsible for the phenotype, although it is now recognized that mutations in other genetic loci can produce a similar clinical outcome (Table 18). A comprehensive list of the mutations within type I collagen genes resulting in OI [6] is maintained in the OI mutation database (http://www.le.ac.uk/genetics/collagen).

The hallmark of OI is brittle bones. All other characteristics of OI are variable, with heterogeneity even in different members of the same family [7]. Wormian bones are present in the skull in approximately 60% of cases [8] (Fig. 1), although they can be present in other conditions, such as progeria, cleidocranial dysplasia, Menkes syndrome, cutis laxa, Cheney syndrome, and

Pediatric Bone

FIGURE 1 Wormian bones are detached portions of the primary ossification centers in adjacent membranous bones. Theyare suggestive of osteogenesis imperfecta but not pathognomonic.

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Copyright 2003, Elsevier Science (USA). All rights reserved.

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CLASSIFICATION

FIGURE 2 Skull in a severe case of OI. Infants with severe OI have soft skulls that are easily flattened in the back because of the inability to support their heads.

with severe OI (Fig. 2). Affected children may suffer recurrent fractures resulting in pain and immobilization, particularly in preschool years. The long-term evolution of the disease is also a matter of concern, particularly in women after menopause. It is wellknown that the peak of bone mass accretion is attained during puberty [10,11]; therefore, it is in the early years of life when treatment efforts should be focused. These individuals have osteopenia due to the basic defect, often worsened by immobilization secondary to fractures or surgery, and decreased physical activity. They also have muscle weakness and ligament laxity. Fractures do not cease at puberty [12] and bone fragility persists throughout life. Chronic, unremitting bone pain may also be present. Thus, this is a complex life-long disease for which the pediatrician will play an essential role in developing a plan that optimizes the quality of life for patients.

The severity of OI ranges from mild forms with no deformity, normal stature, and few fractures to forms that are lethal in the perinatal period. OI was classified into two forms by Looser in 1906 [13]. He classified OI as congenita (Vrolik) or tarda (Lobstein) depending on the severity of presentation. Infants with OI congenita have multiple fractures in utero, whereas in individuals with OI tarda fractures occur at the time of birth or later. OI tarda has also been subdivided into gravis and levis [13]. This classification is no longer used because it understates the complexity of the disease. The first clinical classification of OI to reflect the spectrum of the disease severity was proposed by Sillence [4,14]. Although there is no consistency in the literature regarding the characteristics of the different types, and even though members of the same family (that should have the same OI type) may differ dramatically in severity and clinical presentation [15], the classification has received general acceptance. In the original report [4], Sillence, et al. classified 154 subjects into four groups. Common use has derived into the definition of "types." Group 1 included individuals with bone fragility, blue sclerae, and presenile deafness. The majority of the subjects in this group had their first fracture in the preschool period (in 5 patients, fractures were present at birth). This is an important issue when evaluating cases of suspected child abuse. Of note is that 50% of the subjects in this group were short for age by adult life. Head circumference was large for age. Inheritance was dominant in all cases. Group 2 included patients with lethal perinatal OI with radiographically crumpled ("accordion-like") femora and beaded ribs. In most cases, sclera was blue, but it was white in some. Group 3 patients had progressive deformity and pale blue sclerae at birth becoming normal at puberty.. Easy bruising was not considered common in these individuals. All cases in this group were sporadic. Group 4 patients had white sclerae, and inheritance was dominant. Clinical features were heterogeneous. As per Sillence et al., patients in this group may or may not have a history of fractures, skeletal defomities are variable, and all have osteoporosis and white sclera. They may have dentinogenesis imperfecta but no hearing loss. Paterson et al. [16] described 48 subjects who had white sclerae and dominant inheritance, providing a more extensive description of Sillence's type 4. They found that there is a wide range for age at first fracture and for total number of fractures. They note the differ-

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ent level of severity of members of the same family, including parents with mild manifestations who had children with severe phenotype. The authors classify the patients according to the color of the sclerae, although they mention that several subjects included in Sillence's type 4 had pale blue sclerae. Sillence made it clear that patients in group 4 may have blue sclerae at younger ages that fades as they grow [17]. On these bases, it may not be possible to differentiate group 1 and group 4 individuals at an early age. In clinical practice, scleral hue has very little significance in the diagnosis and classification of OI because blue sclera may occur in normal children and in several other diseases. The numeric classification of OI should be used with caution, and the clinical form and severity must be referred to in each individual case. Hanscom et al. [18] proposed classifying OI according to X-rays. They classified subjects into six groups (A-F), depending on bowing of long bones, the shape of vertebrae, cystic changes of metaphysis, and cortex of long bones and ribs. Unfortunately, some of the changes suggested for classification do not present until age 5 or 10 years, so young children cannot be classified. This approach seems to be realistic and could be developed in more detail. Others classified OI according to severity [12,19]. The mode of inheritance in OI is almost always dominant, and there is a high incidence of new mutations, regardless of the form of OI. Exceptions to this type of inheritance are Type VII OI [20] and osteoporosis pseudoglioma syndrome [21]. Also, in some families from South Africa and Ireland, a recessive pattern of inheritance has been demonstrated [22,23]. The possibility of a germ cell mosaicism [24] has been proposed to explain cases in families with healthy parents who have more than one child with OI [25,26]. These cases were previously thought to have been transmitted in a recessive fashion. It is considered that in at least 6% of cases of lethal OI, one of the parents is a carrier of a germ cell line mosaicism [27]. Thus, there is no clear genotype/phenotype correlate in individuals with OI, and classification should remain clinical. More types were added to the four described by Sillence, including osteoporosis with pseudoglioma [28,29], OI type VI (with mineralization defect) [30], OI with congenital joint contractures (Bruck's syndrome) [31,32], Rhizomielic OI [20], and OI with craniosynostosis and ocular proptosis (Cole-Carpenter syndrome) [33]. Following Rowe and Shapiro [34], we propose that patients should be described in reference to their severity, regardless of the type. Clinical forms described in the literature are summarized in Table 1.

TABLE 18

Recognized regions of mutations in patients with Osteogenesis Imperfecta

Mutation Location

3p22-24. 1

Gene

Phenotype

UNK

Rhizomielic OI (85) OP + pseudoglioma (88)

1lq12-13

LRP5 (87)

chromosome 17

UNK

OI + contractures (95)

17q21.3-q22

Pro-Collagen

Heterogeneous (6)

7q21.3-q22.1

Pro-Collagen

Heterogeneous (6)

TYPES OF Ol (MODIFIED FROM SlLLENCE, ET AL. [4,14] AND ROWE AND SHAPIRO [34]) N o n d e f o r m i n g Ol (Type 1) Mild Ol with Normal Stature

People with mild OI typically have normal stature and few fractures, mostly during the first years of life. They do not present with bowing of the long bones. This condition is transmitted with an autosomal dominant trait. Bone density can be very low, with little relationship to clinical severity. Typically, they are fully ambulatory. Fractures may be present during the first years of life, even at birth [35], but decrease dramatically after puberty. In some cases, the diagnosis is made after the disease is detected in an offspring, or it is an incidental finding after a fracture [36]. Therefore, it is very important to examine the parents of any child with OI in whom an aggravated form of osteoporosis may be the adult manifestation of the disease. Dentinogenesis imperfecta (DI) can be present, and it has been suggested that this is useful to distinguish two discrete forms of mild OI [37]. Early hypoacusia is typical of this form of OI. The cause is not clear. Some studies suggest that it is a neuronal syndrome [38], whereas others indicate it is a conductive abnormality [39]. Cardiovascular problems can be present in these patients, particularly aortic valvular disease [35]. The most common mutation (silenced allele) causing type I OI reduces the expression of otherwise normal type I collagen. Because of the two-to-one requirement for the formation of heterotrimeric collagen, the level of COL 1A1 expression directly influences the production of normal type I collagen molecules. Reduced output from a single COL1A1 allele will cause decreased production of heterotrimeric collagen. Thus, the degree that one of the COL1A1 alleles underperforms may be one of the determinanants of the severity of osteopenia in type I OI.

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The most frequent cause of diminished activity from a collagen gene is a mutation that introduces a premature stop codon in the collagen m R N A [40-42]. This type of mutation leads to rapid destruction of the RNA by a recently described cellular process called nonsense-mediated RNA decay [43-45]. This process appears to be an important mechanism for preventing a truncated protein from being expressed, thus saving the cell from producing proteins with unintended function. Mutations of these surveillance genes are incompatible with development [46]. A truncated 0~1(I) chain produced from a COL1A1 transcript in vitro helps to determine the presence and location of such a stop codon [47]. Otherwise, finding the mutation using a molecular approach is laborious and the mutation can be missed. A second cause of an underproducing COL1A1 allele is a mutation that leads to retention of an intron within the mature transcript. Although this is an uncommon cause of a type I OI, it has provided insight into the normal pathway for splicing a complex transcript such as collagen [48]. Other causes for diminished transcriptional activity from a collagen gene are extremely rare. Mutations within the 3t untranslated region affecting polyadenylation has been reported, and mutations in the 5t untranslated region are predicted to have a modified phenotype but have not been observed. Finally, a nonfunctional collagen gene can result from the synthesis of a procollagen chain that is unable to incorporate itself within the triple-helical molecule. Frameshift mutations within the terminal exon of either collagen gene have been identified that lead to the synthesis of a full-sized procollagen chains, which are rapidly degraded intracellularly when failing to incorporate into the collagen molecule [49].

D e f o r m i n g Ol

Lethal OI (Type II) In this form of OI, newborns do not survive the perinatal period. Death is caused by extreme fragility of the ribs and pulmonar hypoplasia [50] or by central nervous system malformations [51] or hemorrhage. Bone mineral density is severely decreased, and infants present with multiple intrauterine fractures (including skull, long bones, and vertebrae), beaded ribs, and severe deformity of the long bones [52]. Prenatal ultrasound may show shortened and broad limbs, with very low echogenecity and absent acoustic shadow [53], abnormal compressibility of the vault by the transducer, unusually good visualization of the orbits, increased visualization of arterial pulsations, increased through-transmission of the ultrasound beam due to extremely poor mineralization, and abnormally small thorax [54]. However, prenatal differ-

ential diagnosis between severe and lethal OI is not possible. Differential diagnosis includes chondrodysplasia punctata [55] and other forms of OI. In extremely severe cases, patients can be born dismembered [56]. They may have low birth weight, micro- or macrocephalus, and cataracts [57]. In the majority of cases, they are caused by autosomal dominant new mutations [27,58,59]. Unaffected parents may have more than one child with lethal OI due to germ cell line mosaicism [60]. There may be different clinical forms of lethal OI [61]. Virtually all of the mutations that cause the deforming forms of OI act in a dominant negative manner (i.e., the presence of the abnormal type I collage gene product causes the disease). The deleterious effect of the mutant collagen gene is a consequence of the three-dimensional structure of the collagen fibril that is dependent on the tight association of the Gly-X-Y amino acid triplet. A glycine substitution in the helical domain of the collagen ~1(I) chain is the most common mutation. Glycine is the smallest amino acid and must fit in a sterically restricted space in which the three chains of the triple helix join. Depending on the helical location of a mutation, disease severity can range from lethal to severely deforming and mildly deforming. The potential amino acid substitutions are cysteine, alanine, arginine, aspartic acid, cysteine, glutamic acid, serine, valine, and tryptophan. Substitution destabilizes the conformation of the collagen helix, although current biochemical analysis does not always predict clinical severity. Since the helix assembles from the C-terminal propeptide, a mutation in the Cterminal helical and propeptide region results in greater instability and more severe disease, whereas mutations in the midhelical domain tend to be less severe. However, mutations in the midhelical domain can have a severe phenotype, suggesting that subdomains within the helix are critical for functions other than contributing to an intact helical structure. Mutations located at the N-terminal domain of either chain can be extremely mild and are classified as type I OI. Maps relating mutation type and location to clinical phenotype are graphically presented in an interactive pdf format at http://www.le.ac. uk/genetics/collagen/. Other molecular mechanisms that result in a disrupted collagen helix include mutations in the consensus donor or acceptor site that can lead to exon skipping, and the production of a shortened helix [62]. Much less common are mutations that delete a portion of the gene and a number of inframe exons [63] or mutations that insert a segment of intron that remains inframe with the entire transcript [64]. Severe disease results from a dominant negative mutation in the type I collagen gene with the exception of a null mutation of the COL1A2 gene. Formation of the heterotrimeric collagen molecule requires that the

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~2(I) chain account for 50% of the available chains when the procollagen molecule is assembled. When this requirement is not met, because of either underproduction of the 0r chain or overproduction of the 0~1(I) chain, homotrimeric molecules are formed. The severity of disease depends on the balance between homotrimeric and heterotrimeric molecules within the bone matrix. This may explain the spectrum of disease severity ranging from type III OI type, when both COL1A2 alleles are affected, to measurable osteopenia and fragility in the heterozygous state [65,68] and an association with osteoporosis due to the spl polymorphic alteration in the COL1A1 gene. This variation in disease severity acts in a recessive manner or as a quantitative trait in which gene dosage contributes to the severity of bone disease.

Severe Ol with Triangular Face (Type III) Due to overdevelopment of the head and underdevelopment of the face bones, these patients have a characteristic triangular face. They also have short stature, severe deformities of the long bones, vertebral fractures, and scoliosis and chest deformities. Characteristically, they have marked elongation of the pedicles of the vertebrae in all cases and posterior rib angulation [67]. They are frequently wheelchair bound, although some are able to walk with canes or a walker. Prenatal diagnosis is sometimes possible using ultrasonography [68]. Long bones are severely deformed, and altered structure of the growth plates lead to a particular "popcorn" appearance of the metaphyses and epihpyses (Fig. 3).

Moderate Ol with Short Stature (Type IV) These individuals have short stature for age, bowing of long bones may be present, and frequently they also have vertebral fractures. Scoliosis and joint laxity may be present. Patients with moderate OI are generally ambulatory, although sometimes they need aids for ambulation. Interestingly, birth length appears to be normal in this form of OI (personal observation). As with mild OI, moderate OI has been subdivided into two forms: with and without DI [37].

O t h e r Clinical Forms of O!

Type V Ol Some patients with OI develop hyperplastic calluses in long bones that can appear spontaneously or follow fracture or intramedullary rodding [36] (Fig. 4a). These patients present with hard, painful, and warm swellings over bones that initially may suggest inflammation or even osteosarcoma. After a rapid growth period, the

FIGURE 3 "Popcorn" appearance of the epiphysis. Severe OI causes distortion of the growth plate, with zones of partially calcified cartilage and broadening of the epiphysis.

size and shape of the callus may remain stable for many years [70], unless a new fracture occurs at the same site. Microscopically, there is increased production of poorly organized extracellular matrix, which is incompletely mineralized [71]. The first description of hyperplastic callus formation in OI was made in 1908 [13]. A number of case reports have been published [13,70,72-77]. In a series of 60 patients, 10 (17%) developed hyperplastic callus before age 20 years [78]. In a follow-up of 334 patients with OI, we detected hyperplastic callus in 9 patients (2.6%) [data not published]. Familial occurrence of hyperplastic callus with an autosomal dominant pattern of inheritance has been described [19,36,77]. These calluses were in some cases associated with calcification of the interosseous membrane between radius and ulna and irregular collagen fibril diameter [13,70,79]. Magnetic resonance imaging of the hypercallus is not contributory in the differential diagnosis with osteosarcoma, but computed tomography shows a calcified rim of the lesion associated with the absence of cortical destruction that may be useful for ruling out malignancy [80]. It is important to note that although rare, osteosarcoma may develop in patients with OI [81,82]. The

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Inheritance appears to be autosomal dominant, with variable penetrance.

Ol with Mineralization Defect (Type VI) This is a rare form of OI [30], with a prevalence of approximately 6%, and it is undistinguishable from moderate to severe OI on a clinical basis. It is diagnosed by iliac crest bone biopsy, from which a mineralization defect affecting the bone matrix and sparing growth cartilage is evident. These patients have no DI or wormian bones. There are no radiological signs of growth plate involvement compatible with rickets, despite the mineralization defect. The pattern of inheritance is not clear, but the case of two siblings from healthy consanguineous parents has been described, suggesting gonadal mosaicism or a somatic recessive trait. There are no mutations of COL1A1 and COL1A2 genes, and collagen is normal.

Type VII Ol

FIGURE 4 OI with hypercallus formation. Individualswith OI with hypercallus formation develop redundant bony formations around fractures (a), which are sometimesconfused with osteosarcoma. These patients also present with ossificationof the interosseousmembrane of the forearm and the leg (b).

hypercallus may also be present in flat bones [83]. Gloriuex's group analyzed in depth a group of seven children with OI who presented with specific changes in the bone biopsy of the iliac crest [69]. Matrix lamellae were arranged in a mesh-like fashion, as opposed to a parallel arrangement that is seen in controls and in patients with other types of OI. Five patients also had hyperplastic callus formation in long bones, and all showed radiological signs of calcification of the interosseous membrane of the forearm. This determines a clinical sign: patients are unable to pronate and supinate the forearm. The membrane between the tibia and fibula may also present with abnormal calcification (Fig. 4b). The patients also had hyperdense metaphyseal bands in the metaphyses of long bones. The significance of these bands is unknown. None presented with blue sclerae or DI. Electron microscopy analysis of bone of patients with this form of OI showed failure of patches of bone to mineralize [84]. It was not possible to demonstrate any mutations in the collagen genes in this group of patients.

A rareform of OI was recently described in a First Nations community in Quebec [20]. The affected individuals have rhizomelia: shortness of humeri and femora. The phenotype is moderate to severe, with fractures at birth, early lower limb deformities, coxa vara, and osteopenia. Histomorphometrically, the bone in this form of OI is not different from that of type I OI. This type of OI is inherited in an autosomal recessive fashion, and the disease locus has been mapped to the short arm of chromosome 3 by linkage analysis [85]. This genomic location excludes COL1A1 and COL1A2 (respectively located in chromosomes 7q and 17q) as candidate genes. Direct sequencing has also excluded PTH/ PTHrP and TGF-[3 R II genes.

Osteoporosis-Pseudoglioma Syndrome This form of OI was first described in 1972 in three families [86]. Subsequently, the syndrome was described in a South African family of Indian stock [21]. Six members of this family had a severe form of OI and also blindness due to hyperplasia of the vitreous, corneal opacity, and secondary glaucoma. The pedigree was consistent with autosomal recessive inheritance. Bone involvement is mild to moderate. Cases have been observed in the United States and Canada that follow a similar inheritance mode (unpublished data). It has been speculated that ocular pathology results from failed regression of the primary vitreal vasculature during fetal growth [87]. The genetic defect was mapped to chromosome region 1 lq12-13 [88], and later it was shown that the defect is in the L R P 5 gene, which encodes for the low-density lipoprotein receptor-related protein 5 [87].

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It is a member of the Wnt signaling pathway, which has been extensively studied in flies and mice as a fundamental molecular pathway controlling early organogenesis including the skeleton. Ventricular septal defect was also seen in three affected siblings of a consanguineous family [89]. Two other forms of OI with ocular involvement have been described: one variant with optic atrophy, retinopathy, and severe psychomotor retardation [90] and another with microcephaly and cataracts [57].

Ol with Craniosynostosis and ocular proptosis(ColeCarpenter Syndrome) Two boys and a girl have been described with this particular form of OI [33,91]. All were normal at birth, but after several months they developed multiple metaphyseal fractures associated with low bone density in the entire skeleton and craniosynostosis, hydrocephalus, ocular proptosis, and facial dysmorphism. One of the patients also had hypercalciuria. Neurological development is normal in this form of OI. All patients were wheelchair bound at adult age, with very short stature, severe bone involvement (Fig. 5), and normal intellectual and neurological development (unpublished data).

Ol with Congenital Joint Contractures (Bruck Syndrome) This form of OI was first described by Bruck et al. in 1897 in an adult patient [92]. Patients with Bruck's syndrome are born with brittle bones, leading to multiple fractures and joint contractures and pterygia (arthrogryposis multiplex congenita) [31,32]. Wormian bones are present in the skull. It appears to be inherited in a recessive fashion [93,94]. In three patients studied, it was not possible to demonstrate any mutations in the COL1A1 and COL1A2 genes [32]. The basic defect in this syndrome was mapped to locus 17p12 (18 cM interval), and a defect in bone specific telopeptidyl hydroxylase has been identified[95]. This leads to underhydroxilated lysine residues within the telopeptides of collagen type I and, therefore, to aberrant cross-linking in bone but not in cartilage or ligaments. The lysine residues within the triple helix are normally modified, suggesting that collagen cross-linking is regulated primarily by tissue-specific enzymes that hydroxylate only telopeptide lysine residues but not those in the helical portion of the molecule [95].

DIFFERENTIAL DIAGNOSIS Frequently, family history, biochemical profile, and clinical features are sufficient for diagnosing OI. When

FIGURE 5 Severebony involvementin a patient with Cole-Carpenter syndrome. There is no identifiable bone in the midshaft of the humerus of this 17-year-old male with OI with craniosynostosis and ocular proptosis.

feasible, a bone biopsy with histomorphometric analysis is best for making the differential diagnosis of OI. Genetic testing may also be useful, although it is not always possible to find mutations in the COL1A1 and COL1A2 genes; therefore, the diagnosis of OI should not rely on genetic test results. Currently, two laboratories in the United States offer molecular diagnostic services based on DNA sequencing from peripheral blood or cultured fibroblasts (http://www.som.tulane.edu/ gene_therapy/ matrix/matrix_dna_diagnostics.shtml) or on collagen products from cultured cells (http://www.pathology. washington.edu/clinical/byers.html). Readers can inquire about laboratories in Europe offering diagnostic services through [email protected] or [email protected]. Premature infants are at risk of osteopenia. Eighty percent of bone mineralization in fetuses occurs during

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the third trimester [96]. Inadequate postnatal management of parenteral or enteral nutrition may also lead to osteopenia. Nonaccidental injury (NAI) is one of the most challenging differential diagnosis of OI [97]. Although the social history may be contributory and certain signs are suggestive of NAI [97], such as hand fractures in the nonambulant child, acromial fractures, fractures of the outer end of the clavicle, and spinal, posterior rib, and metaphysial fractures [98,99], diagnosis is often difficult [100]. Metaphyseal fractures may occur in children with OI but probably only in the presence of obvious bone disease with radiologically abnormal bones [101]. This is complicated by the fact that children with OI may also suffer NAI [102,103]. It is important to note that there are no pathognomonic radiological signs of NAI [104]. Idiopathic juvenile osteoporosis (IJO) is another difficult differential diagnosis. Although IJO is an acquired form of osteoporosis, it is often difficult to be certain that the bone problem was not present from birth, and it was not found because it was not severe enough to cause fractures of the long bones. It is possible to make a differential diagnosis of IJO and OI using histomorphometry: In IJO, there is a twofold decrease in cancellous bone formation, suggesting that there is a lower bone turnover compared with that of OI, with no evidence of increased bone resorption [105]. Hypohposphatasia can resemble OI clinically, but low levels of serum alkaline phosphatase activity and radiological characteristics make the diagnosis [106]. Other differential diagnoses include Cushing's disease, glucocorticoid induced osteoporosis, homocystinuria, lysinuric protein intolerance, glycogen storage disease, congenital indifference to pain, calcium deficiency, malabsorption, immobilization, anticonvulsant therapy, and acute lymphoblastic leukemia [107].

GENERAL CLINICAL FINDINGS Laboratory Markers of bone metabolism are difficult to interpret in children with OI. After a fracture, serum alkaline phosphatase may be elevated, especially in the case of patients with OI type V when there is hypercallus formation. The bone resorption marker type I collagen Ntelopeptide normalized to urinary creatinine (NTX/ uCr) is higher than the 50th age- and sex-specific percentile in 25 and 75% of patients with type I and III OI, respectively [108]. NTX/uCr is significantly higher in type III than in type I OI patients. However, serum creatinine is lower in patients with type III OI, and

serum creatinine is negatively correlated with NTX/ uCr. Differences in NTX/uCr between type I and type III OI are not significant after adjusting for serum creatinine. These findings suggest that the increased NTx/uCr in type III OI could be a consequence of decreased serum creatinine. Serum creatinine is a function of muscle mass in the absence of renal impairment. Therefore, higher NTX/uCr in type III OI may at least be partly due to the underdeveloped muscle system of these children [109]. In severely affected children, hypercalciuria may be present [110], but there is no compromise of renal function [111]. Kidney stones and nephrocalcinosis may also be present [8]. Neurological involvement Basilar invagination is an uncommon but potentially fatal complication of OI. The incidence of this complication in patients with OI is unknown. There is no gender predominancy for this complication [112]. Symptoms of basilar invagination in OI are headache (in approximately 76% of patients), lower cranial nerve palsy, dysphagia, hyperreflexia, quadriparesis, ataxia, nystagmus, and hearing loss. Patients can be asymptomatic and present with large, normal, or small head circumferences [113]. Sawin and Menezes [112] recommend ventral decompression followed by occipitocervical fusion with contoured loop instrumentation to prevent further squamooccipital infolding. The authors note that basilar invagination tends to progress despite fusion in 80% of cases, and that prolonged external orthotic immobilization may stabilize symptoms and halt further invagination [112]. One case of paraplegia occurring in an adolescent girl with OI after chiropractic manipulation has been reported [114]. Reflex sympathetic dystrophy has been described in adults with OI [115]. The cases described in the literature occurred in patients 26-59 years of age. The incidence of this condition in OI patients is not clear [116]. Other neurological manifestations of OI include benign communicating hydrocephalus; macrocephalus; cerebral atrophy [117], usually with no alteration of intellectual status; Dandy-Walker malformation; and idiopatic seizures. Abnormalities of the central nervous system were noted in autopsies of patients with the lethal form of OI, including perivenous microcalcifications, hippocampal malrotation, agyria, abnormal neuronal lamination, white matter gliosis, and migrational defects [118,119]. Hypoaccusia is present in approximately 50% of individuals with mild forms of OI, generally only after the third decade of life [120]. However, this problem is probably more prevalent than appreciated because of the lack of proper studies in children. King and Boblechko [13]

18. Osteogenesis lmperfecta suggested that the incidence of deafness is directly related to severity. The prevalence of hearing loss in OI appears to be between 20 and 60% [121,122]. With increasing age, the prevalence of hearing impairment in patients with OI may be approximately 100% [123]. Hearing loss may be due to otosclerosis [124,125], to middle and inner ear pathology [126,127], or a neuronal syndrome [38]. It has been suggested that there is a structural change in the mineral crystals of the ear bones from hydroxyapatite to brushite in patients with osteosclerosis [128]. It has also been recommended that children with OI undergo audiometry at 10 years of age and repeat the study every 3 years thereafter [129]. Stapedectomy has been performed in patients with OI with success [130-132]. Other otologic findings include lopped pinna, notching of the helix of the pinna, rosy flush of the medial wall of the middle ear, and vestibular abnormalities [127]. Cardiovascular involvement There are several published reports of congenital malformations of the heart in children with OI [8,133], but their incidence is probably not higher than that in the unaffected population. In a series of 58 children with OI, 4 (6.9%) had congenital cardiac malformations [134]. Aortic regurgitation was present in only 2% of patients in another series of affected individuals, whereas aortic root dilatation was present in 12.1% [133] Dilatation was mild [133,135]. The prevalence of mitral valve prolapse varies from 3.4% [134] to 6.9% [133] in published series, which is not different from the prevalence of mitral valve prolapse in the general population (4-8%) [136]. Others have found that the prevalence of mitral valve prolapse in OI is slightly higher (10%) than in the normal population [135]. These lesions are rarely clinically important [34]. Valve replacement has been performed successfully in patients with OI [137-139]. Epoetin-~ has been used to increase hematrocrit preoperatively in mitral valve replacement surgery because of the high risk of perioperative bleeding [140]. Ulnar artery aneurism has been reported in a patient with OI [141], which may be due to increased weakness of vessel walls that can also produce spontaneous carotidcavernous fistulas [142]. Renal involvement Hypercalciuria is a common finding in children with OI, being present in 36% of a series of 47 patients [110,111]. In 124 patients from 14 days to 18 years of age, studied at the Montreal Shriners Hospital, 24 (19%) had at least one episode of hypercalciuria, during a period of observation that ranged from 1 to 8 years,

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before receiving bisphosphonate treatment (unpublished data). This hypercalciuria did not affect renal function, concordant with what was previously described in one series of 12 hypercalciuric patients [111]. In a series of 58 patients, 4 patients developed kidney stones and 1 had papillary calcification without kidney stones. However, it was not clear if these patients were hypercalciuric [134]. One patient was described in the literature with chronic renal failure secondary to obstructive uropathy caused by bony pelvic outlet deformities [1431. Endocrine c h a n g e s Growth hormone (GH) deficiency is rare in patients with OI. Of 22 children with OI tested by Marini et al. [144], none fulfilled the standard criteria for GH deficiency. Children with OI may present with hypopituitarism [145]. Some patients with OI have a hypermetabolic state, typically reflected by excessive diaphoresis and associated with increased oxygen consumption and elevated thyroxine levels [146]. The cause of this hypermetabolic state is not known. For reasons that are unclear, women with OI have late menarche [147]. Respiratory p r o b l e m s Patients with OI may have respiratory complications secondary to kyphoscoliosis. Young patients with OI appear to have normal ventilation/perfusion rates, and restrictive complications are associated with spine deformities [148]. Pulmonary hypoplasia has been described in a newborn with lethal OI [53]. Studies of pulmonary function in patients with OI may show different results [148], and some patients may develop restrictive lung disease, leading to right ventricular failure. When hypoxemia was present, it was not severe, and hypercapnia was never observed [50]. Connective tissue alterations Individuals with OI have a tendency to bruise easily. This may be related to increased capillary fragility caused by the underlying collagen defect. Decreased platelet retention and reduced factor VIII R:Ag have also been described in individuals in OI [149]. Skin of people with OI is stiffer and less elastic than normal skin [150]. Muscle strength is reduced in moderate and severe forms of OI [151,152]. Joint hyperlaxity is common, especially in affected females [153], and it can lead to dislocation of hips and radial heads. Certain individuals with OI are prone to sprains. Flat feet are commonly seen in patients with OI. Hernias can be present [154].

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Constipation is common, which may be due to severe protusio acetabulae and pelvic deformation in children with severe OI [155]. Treatment of constipation is difficult and frequently frustrating.

Ocular changes Individuals with mild OI frequently demonstrate blue sclerae and premature arcus corneae. Arcus corneae juvenilis is an unusual eye finding commonly associated with hypercholesterolemia, but in a large series of patients it was not associated with other clinical or laboratory findings of hypercholesterolemia [17]. In subjects with mild OI there is a progressive arcus corneae that can first be seen in some patients in their late teens [156]. Contrary to what is commonly stated, scleral thickness is normal in OI type I, and the blue color is not a consequence of its transparency. The blue hue results from differential back-scattering of short wavelengths of light by the abnormal molecular organization of the matrix in the sclerae [17]. Scleral collagen fibrils are of normal diameter in OI type I, but there is an increase in electron-dense granular matrix material between collagen fibrils [157]. In other types of OI, the sclerae may be thin, scleral collagen fibrils are reduced in diameter, and the intercollagenous matrix is normal. On the other hand, corneal thickness is significantly reduced in OI type I [156], as in other types of OI. Teeth Some individuals with OI have DI (Fig. 6) [158]. Although the enamel of the teeth with DI is normal anatomically, it may not attach normally to the dentin [159]. The pulp chambers and root canals are completely or partially obliterated by abnormal dentin. The junctions between the crowns and roots are more constricted than normal [160]. The severity of DI is not related to the severity of skeletal involvement in the case of OI,

FIGURE 6 Dentinogenesis imperfecta (DI). Teeth of affected individuals appear transparent due to abnormal dentin. Enamel is normal. The severity of the DI has no relation to the severity of the skeletal involvement in the case of OI. (see color plate.)

and it may be present in patients with mild and severe forms of the condition. Severity may be different in affected members of the same family [161]. The primary dentition is always more affected than the permanent dentition. Radiographically, the teeth show bulbous crowns with a constriction at the coronal-radicular junction. The roots are shorter and more slender than normal. The pulpal spaces are narrow or obliterated [162]. Subjects with OI do not have an increased susceptibility to cavities and do not necessarily have more dental pain. There is no effective way to prevent the problems associated with teeth in persons with OI. One method for treating DI is to crown the teeth as they erupt. The back teeth are especially important to help guide the permanent teeth into place and for proper chewing throughout life. Malocclussion is a common finding in patients with OI, particularly class III (the cusp of the posterior mandibular teeth interdigitate a tooth or more ahead of their opposing maxillary counterparts [163]), and the prevalence is 60-80% [161,164]. This complication is more common than DI, with a prevalence of approximately 28% [164]. Patients may require surgical correction of the malocclussion [166]. Changes in the position of the basal bones also may require orthognatic surgery, which has been performed successfully in these patients [167,168]. Unerupted first and second molars are frequent in OI patients in permanent dentition, which is rare in the general population [164]. Other abnormalities include invaginations and hypodontia [169], which have no relation to the existence of DI. Dental treatment to help prevent dental fractures is available, such as ready-made crowns for primary dentition and tooth-colored crowns for permanent dentition [170]. Birth a n d a n e s t h e t i c c o m p l i c a t i o n s a n d life e x p e c t a n c y There is an increased incidence of breech presentation of OI fetus at term [171]. Recently, a retrospective study on the mode of delivery of children with OI concluded that cesarean delivery does not appear to decrease fracture rates at birth in infants with nonlethal forms of OI, nor does it prolong survival for those with lethal forms [171]. Patients with OI should be considered as high risk for anesthesia [172]. They are prone to fracture and may have neck and jaw deformities that will make intubation difficult, and sometimes severe thoracic deformities and kyphoscoliosis may cause restrictive problems [173]. Also, DI and valvular heart disease may increase the anesthetic risk of these patients. Children with OI may have hyperthermia during anesthesia, but this is

18. Osteogenesis lmperfecta usually not associated with muscle rigidity and rarely progresses to malignant hyperthermia (MH) [173,174], although a case of MH in OI has been described in the literature [175]. MH is a familiar disease, and patients with OI may also be affected, but prophylactic use of dantrolene in these patients is not warranted [174] because MH is considered to be a coincidental occurrence in patients with OI [176]. However, certain drugs should be avoided in patients with OI. Succinylcholine may cause fractures as a result of muscle fasciculation. Pancuronium bromide and atracurium are the muscle relaxants of choice [174]. Despite all these potential problems, life expectancy in subjects with nonlethal OI appears to be the same as that for the normal population [177], except in cases of severe OI with respiratory or neurological complications [178].

PATHOPHYSIOLOGY Collagen plays an essential role in forming an interactive network between the cells that make the extracellular matrix [179] and noncollagenous proteins that lead to proper mineralization of bone. Thus, it is not surprising that when the fundamental structure of the helix is disturbed by a mutation a complex series of secondary consequences will develop. The following discussion categorizes these consequences at increasing levels of tissue organization.

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mutant molecules [189], allowing for a substratum of relatively normal collagen fibers to accumulate. Other matrix proteins can modify the size and organization of otherwise normal type I collagen fibrils and can affect the mechanical properties of the collagen fibers [190,191 ]. For example, copolymerization of type V collagen within the type I collagen fibril influences the size and structure of the type I collagen fibril [192,193]. Another modifier of collagen fiber size is the incorporation of unprocessed type I procollagen producing another form of Ehlers-Danolos Syndrome (EDS) that can overlap with features of type I OI. The EDS-OI-like symptoms appear to result from impairing cleavage of the procollagen propeptide secondary to glycine substitution disruption in the N-terminal helical domain. A similar problem might be expected with a mutation affecting cleavage of the C-terminal propeptide [194]. Mutations in noncollagenous proteins such as decorin [195], fibromodulin [196,197], and microfibrillin [198] can affect the structure or organization of type I collagen fibers, indicating that physical interaction between the two components plays an important role in this process. It would not be surprising if the nonclassical forms of OI result from mutations in proteins that affect some of these binding interactions. Although the absolute amount and composition of hydroxyapatite within OI bone are probably not abnormal, the deformed crystal structure probably contributes to the overall weakened nature of the bone [199-204]. How the helix influences the interaction of noncollagenous proteins and mineral is not fully understood.

Formation of O s t e o i d a n d Mineralization

Function of t h e Ol o s t e o b l a s t

The impact of the glycine substitution on the structure of the collagen triple-helical structure has been demonstrated by X-ray diffraction [180], nuclear magnetic resonance, and circular dichroism [181-184]. The altered structure of the individual triple-helical molecule affects the subsequent formation of collagen fibrils that form from lateral association of individual collagen molecules. X-ray diffraction has shown small fibers with less welldefined lateral growth and more fiber disorganization in tissue obtained from OI subjects [185]. Transmission and scanning electron myography have shown that the periodicity of OI fibrils is normal but the fibrils are disorganized and have wide variation in fiber diameter [186]. Mutations that interrupt the helix decrease the thermal stability of procollagen molecules and render the molecules more susceptible to proteolytic attack by tissue proteases [187]. This may explain the observation that mutant collagen molecules are not uniformly distributed throughout matrix but are found on the surface of bone [188]. Tissue proteases probably select against the

The rough endoplasmic reticulum of OI fibroblasts and osteoblasts is grossly dilated [205] and the secretion of fully formed but mutant procollagen is impaired [206,207]. The role that the hsp47 chaperone protein plays in determining the trafficking of normal and mutant molecules within these cells is believed to be important in detecting the mutant collagen chains and eliciting a cellular mechanism to prevent their secretion [208]. In fact, gene knockout of the hsp47 protein is an embryonic lethal in which an abnormal type of collagen accumulates [209], suggesting that this chaperone protein plays an essential role in selecting for correctly assembled collagen molecules [210]. The retention of the mutant procollagen molecule also leads to posttranslational overmodification of the lysine residues in the helical domain that may further affect the quality of fibril formation. In vitro studies of osteoblasts derived from OI humans [209,210] or OIM mice [211] show diminished markers of osteoblastic differentiation, as well as a reduced rate of

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cell proliferation. If this property of the OI osteoblast persists in vivo, it may be a secondary contributor to the severity of bone disease. Not only is there an impairment in the quantity or quality of the matrix that is produced, but the number of differentiated osteoblasts capable of making a mineralized matrix may also be reduced. The mechanism for diminished osteoblast proliferation and differentiation could be a direct consequence of the retained procollagen molecules with the distended rough endoplasmic reticulum. It may reflect an indirect effect of the quality or quantity of the extracellular matrix made by the preosteoblastic cell that is necessary for osteoblast differentiation [306,307]. Possibly, the high rate of bone turnover characteristic of this disease may lead to exhaustion and/or premature senescence of stem cells capable of generating vigorous osteoblastic cells in vitro, which if present in intact bone will further contribute to the severity of the bone disease, particularly in elderly subjects with OI. M e t a b o l i c activity of Ol b o n e Intact bone is able to sense its mechanical environment and initiate a new round of bone removal or reformation when defective matrix, usually a microfracture, develops (Fig. 7). This fundamental principle of bone biology is continuously called on in OI because the matrix that is produced is defective and subject to microfracture. This situation is reflected in the histology of OI bone, which shows a state of ineffective high bone formation by increased numbers of osteoblasts and osteocytes [84] and an increased number of double-labeled surfaces of normal thickness [214]. In the case of type I OI, the amount of bone formed during a remodeling cycle is decreased compared to controls [214]. It is of note that the occurrence of nonunion fractures is increased in children with OI [215], which is probably related to the decreased bone formation mentioned previously. The level of bone matrix destruction in OI, although not obvious in histological studies, is revealed in the urinary excretion of bone collagen degradative products. Although the measurements are variable because of differences in growth rate and in the underlying mutation [216-218], the dramatic decrease in excretion of degradative products and subsequent increase in bone matrix accretion after bisphosphonate treatment attest to the contribution of osteoclastic activity to the pathogenesis of OI. Murine models of OI are particularly instructive in defining the pathophysiology of OI bone. The OIM mouse model is equivalent to severe nonlethal OI in humans. Analysis of osteoblastic activity in this model suggests that the osteoblast lineage is under constant stimulation to proliferate to build up sufficient numbers

of precursor cells that are then required to progress to full osteoblast differentiation [219]. The activated osteoblastic lineage can be demonstrated by measuring the content of collal m R N A in OI bone or the activity of a type I collagen promoter transgene that is sensitive to osteoblastic activity. In both cases, a high level of transcriptional activity for type I collagen can be demonstrated relative to normal bone. At the same time, the number of osteoclasts is greatly elevated, as is the excretion of collagen-derived cross-links. The net effect is an uncoupling between the signals transmitted from the bone matrix to the bone lineage, in which the bone cells do respond at the gene level but cannot deliver at the protein level. The lineage is already maximally stimulated in response to the activated osteoclastic pathways, but the new matrix that is produced does not improve the mechanical properties of the bone. By analogy, this form of OI can be viewed as a hemolytic anemia of bone. This concept is particularly important for understanding the growth retardation and enhanced fragility of bone during childhood (Fig. 8). It is the balance between matrix formation and resorption that determines bone strength in OI. During periods of rapid linear growth, the deficit between formation and resorption is maximal because bone turnover is enhanced beyond the level that is responsive to mechanical forces. Although normal bone has the reserve within the bone lineage to increase its rate of matrix formation, the OI bone lineage is already maximally stimulated so that it is during the period of linear growth that the deficit in net bone formation is most severe [219]. This may explain why fractures are so severe in the rapidly growing child. Growth retardation may also result from diminished bone formation at the collar region of the growth plate, where signaling between newly forming cortical bone and the proliferating chondrocyte has been demonstrated. With the completion of puberty and cessation of linear growth (the loss of proliferating chondrocytes), bone remodeling slows and a balance between bone formation and resorption becomes more favorable. Thus, puberty does not improve bone strength by stimulating the lineage but instead it stabilizes the skeleton and reduces the need for bone remodeling. When menopause reinstates a state of high bone resorption, the balance between formation and resorption again becomes unfavorable and fractures can return. The additional effect of a chronically stimulated osteoprogenitor lineage and gradual loss of proliferative or differentiation potential with advancing age could result in additional factors contributing to bone loss. Thus, one rationale for instituting antiresorptive therapy is to reduce the rate of bone turnover and prolong the ability of the osteoprogenitor lineage to generate productive osteoblasts into later adulthood.

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FIGURE 7 The bone-forming/resorbing unit and its relationship to OI. A remodeling cycle is initiated by osteoclasts removing old bone matrix followed by new bone matrix filling in the resorption pit. The osteoblast and osteoclast lineages are closely intertwined in this process such that bone mass is increased during childhood and maintained in adulthood. (A) The osteoblast lineage arises from a mesenchymal precursor cell and undergoes a series of proliferative and differentiation steps. (B) In normal bone, the activities of the two lineages are balanced. (C) In OI bone, the osteoclastic lineage is highly activated to remove defective matrix and the osteoblastic lineage responds in an attempt to replace the resorbed bone. However, the synthetic activity of the formation response is compromised and the new matrix that is produced is no better than that which was removed. Thus, OI bone is characterized by an increased number of bone-resorbing and -forming packets. The bone is more cellular because the rapid turnover precludes the time needed for late bone maturation and the formation of resting osteocytes.

T h e h e t e r o z y g o u s M o v 13 m o u s e is a m u r i n e m o d e l for mild nondeforming OI. Affected mice demonstrate h a l f o f n o r m a l levels o f collal m R N A as a c o n s e q u e n c e

o f i n a c t i v a t i o n b y a r e t r o v i r a l i n s e r t i o n a l event. T h e b o n e s s h o w d i m i n i s h e d c o r t i c a l t h i c k n e s s , w h i c h is c o n s i s t e n t w i t h h u m a n O I , a n d l o w levels o f p r o c o l l a g e n

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Normal

FIGURE 8 Bone formation and degradation in normal and OI bone. During the period of rapid growth, normal children have an accelerated rate of bone formation to make new matrix to support somatic growth and to replace the bone lost due to remodeling. Once the full skeletal mass is acquired, the rate of bone remodeling decreases, and the rate of growth decreases to match the remodeling rate. Thus, bone mass increases rapidly during somatic growth and peak volume is achieved in early adulthood. In OI, bone degradation is high due to the effort to remove defective matrix, and most of the bone-forming activity is expended to keep pace with the intrinsic rate of bone loss. The additional bone loss secondary to somatic growth is not compensated by a further increase in bone formation so that somatic mass does not increase during childhood. Thus, without the addition of bisphosphonates, bone mass increases and somatic growth occurs very slowly. Once puberty is attained and linear growth stops, the extra loss of bone matrix attributable to somatic growth is eliminated so that the bone formation effort can result in increased quantity and quality of the bone matrix. Thus, bone mass does increase after puberty and the fracture rate declines because the bone can be remodeled to become more structurally sound. With the loss of sex hormones and a return of a higher rate of bone degradation, the deficit in bone formation relative to bone loss will return.

propeptide in blood reflect the low output of the type I collagen-producing cells [220]. Histomorphometry does show increased osteoblast cellularity and bone-forming units, and dynamic histomorphometry suggests a decrease in osteoid seams [221]. Excessive osteoclastic activity does not appear to be present. In both mouse and man with type I OI, significant skeletal remodeling is apparent upon sexual maturation so that the mechanical properties of the bone are near normal [222,223]. Although further analysis of a murine model that is

healthy into adulthood is necessary, it appears that the deficit between bone formation and resorption in type I OI is much less than that in deforming forms of OI, particularly after the adult skeleton is established. Thus, it is during adulthood that a relatively normal bone matrix is accumulated and fractures are uncommon. Only during growth and menopause is this relationship unfavorable, again emphasizing the value of bisphosphonates for improving bone strength during these periods.

18. Osteogenesis Imperfecta THERAPY Until recently, treatment of OI focused on fracture management and surgical correction of deformity whenever possible. All medical therapies other than those directed at symptomatic pain relief had been ineffective [224], including vitamin C [225,226], sodium fluoride [12,227,228], magnesium [229,230], and anabolic steroids [231,232]. Early studies of the use of calcitonin for the treatment of OI appeared to show significant biochemical changes in patients with OI and a reduction in the number of fractures from pretreatment to treatment periods [233-235]. Other studies, however, showed that biochemical changes are not accompanied by significant clinical responses, and that patients may develop complications such as calcitonin dose-related hypomagnesemia [236,237]. The use of calcitonin treatment for OI has been abandoned. Antiresorptive a g e n t s Pamidronate is a second-generation bisphosphonate with a chemical structure based on pyrophosphate, the only naturally occurring inhibitor of bone resorption [238]. The exact mechanism of action of the bisphosphonates remains unclear, although effects on both osteoblasts [239,240] and osteoclasts [241] have been documented. There have been several case reports of treatment of children withOI with bisphosphonates [242,243,244,245, 313]. Glorieux and his group administered pamidronate by intermittent intravenous infusion for up to 9 years in more than 150 children with severe OI aged 2 months to 18 years. In the first publication [246], they studied 30 children over 3 years of age. Cyclical IV pamidronate resulted in sustained reduction in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9 + 29.0% in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3 + 1.2 to -3.4 + 1.5. The cortical width of the metacarpals increased significantly, and the increase in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased. Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. All children reported substantial relief of chronic pain and fatigue. In children younger than 3 years of age, the results were more remarkable. A group of nine patients severely affected with OI (types III and IV; mean age: 10.2 months at entry. Range: 2.6 to 20.7 months) received pamidro-

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nate treatment for 12 months [247]. The drug was administered intravenously in cycles of 3 consecutive days. Patients received doses ranging from 8.5 to 20.5 mg/kg/ year. This group was compared to a historical control group consisting of six age-matched, severely affected OI patients who had not received any treatment for OI but had followed the same multidisciplinary support program. Under cyclical pamidronate treatment, bone mineral density (BMD) increased 65-227% in 1 year. The z score increased significantly, whereas in the control group a significatn decrease in the BMD z score was observed. Vertebral coronal area increased in all treated patients but remained unchanged in the untreated group. In treated patients, the fracture rate was also significantly lower than in the control group. No adverse side effects were noted apart from the well-known acute phase reaction during the first infusion cycle. Signs of bone pain (e.g., crying while being handled) disappeared within days.Vertebral size increased in all treated children, as should be expected in growing individuals. In contrast, a decrease in vertebral size was noted in half of the untreated children, indicating that vertebral collapse had occurred in these patients. The youngest patient to start pamidronate treatment in the Montreal clinic was 14 days of age. The radiological and microscopic changes under treatment were striking (Figs. 9 and 10). Fracture incidence is a weak efficacy parameter in open therapeutic studies of OI patients because it can be influenced by external factors (e.g., mode of handling and mobility) and may also spontaneously decrease with age [8]. However, despite higher risk of injury due to increased mobility, a marked decrease in fracture rate was noted, suggesting a direct effect of therapy. Bisphosphonates, on the other hand, do not appear to interfere with fracture healing [248]. The disappearance of bone pain and decreased fracture incidence may have contributed to greater mobility [249]. Physical activity is an essential factor for the development of the skeletal system [250]. Thus, increased mobility may synergize with the direct inhibitory effect of pamidronate on bone resorption to increase bone mass. The effect of bisphosphonate therapy on growth was a matter of concern before the treatment was used in children. In animal studies, long-term treatment with bisphosphonates did not affect linear growth unless very high doses were administered [251]. In young patients, pamidronate did not have a detrimental effect on growth. Instead, the height Z score increased in all the patients who started treatment before 3 years of age [247]. In a larger group of patients, height Z-scores increased significantly in patients with type II OI and did not change in patients with type I and type IV OI after one year of pamidronate therapy. After four years of

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pamidronate therapy, mean height Z-scores increased significantly in children with type IV OI, while patients with type I and type III OI showed non-significant trends of increase [252]. The success of bisphosphonate treatment in patients with Paget disease of bone appears to be related to the unremitting osteoclastic activity characteristic of OI. The effect of the drug can be monitored by measuring parameters of bone resorption, such as urinary calcium excretion and the excretion of collagen breakdown by-products such as the collagen hydroxylysine glycpsides [253] and the collagen cross-links pyridinoline and deoxypyridinoline. Plasma alkaline phosphatase activity (as a measure of bone osteoblast activity) also decreases [254,255]. Clinical symptoms of bone pain and diaphoresis also correlate with the inhibitory effect of the drug on osteoclastic activity, suggesting that it is the process of high bone turnover and associated high

blood flow, not unlike a pagetic lesion, that underlies these symptoms. The most common side effects are a flu-like syndrome in 80% of the patients the first time they received treatment and, in some infants, a transient decrease in blood cell count that recovered to normal values in 48-72 hours. Delayed fracture healing may be present with chronic pamidronate use (personal observation). Patients taking alendronate have the theoretical risk of gastric discomfort or even severe burning of the esophagus if the drug is not taken properly. Histomorphometric studies [256] showed that biopsy size does not change significantly with pamidronate treatment in children with OI, but cortical width increases by about 90%, and cancellous bone volume increases by about 45%. This is due to higher trabecular number, whereas trabecular thickness remained stable. Indicators of cancellous bone remodeling decrease by 26 to 75%. These results suggest that

FIGURE 9 Radiological changes under bisphosphonate treatment. Progressive healing of vertebral fractures (a), increased length and cortical width of long bones (b), and reshaping of the head due to growth of the facial bones (c) are observed with the use of intravenous pamidronate in children with OI. Note the hyperdense bands in the metaphysis; each one corresponds to a treatment cycle.

18. Osteogenesis Imperfecta

FIGURE 9

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in the growing skeleton pamidronate has a two-fold effect: Both bone resorption and formation are inhibited, but osteoclasts and osteoblasts are active on different surfaces (and are thus uncoupled) during modeling of cortical bone. This causes a selective targeting of resorption while continuing bone formation can increase cortical width. Importantly, there was no evidence for a mineralization defect in any of the 45 patients studied.

Biochemistry studies [108] showed that concentrations of ionized calcium drop and serum parathyroid hormone levels almost double after the first pamidronate infusion. At the same time, urinary excretion of the bone resorption marker type I collagen Ntelopeptide related to creatinine (uNTX/uCr) decreases by approximately 60-70%. Two to four months later, ionized calcium returns to pretreatment levels, and parathyroid

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FIGURE 10 Microscopic bone changes under bisphosphonate treatment in a 10-year-old boy with OI. Cortical width is significantly increased after 2 years of treatment with intravenous pamidronate, as seen in this pair of iliac crest biopsies stained with trichrome. The baseline biopsy is shown on the left. Bone biopsy courtesy of F. Rauch. (see color plate.)

hormone concentrations are still above baseline values in patients below two years of age. During four years of pamidronate therapy in 40 patients, ionized calcium levels remained stable, but parathyroid hormone levels increased by about 30%. However, no patient had a result that was more than 60% above the upper limit of the reference range, uNTX/uCr, expressed as a percentage of the age and sex-specific mean value in healthy children, decreased from a mean of 132 at baseline to a mean of 49 after four years of therapy. Therefore, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring, especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels that are lower than in healthy children. These treatments should always be given as part of a strictly controlled protocol. An adequated calcium and vitamin D intake is warranted, particularly in regions with low sun exposure. Daily vitamin D requirements are of 400 IU, and calcium requirements vary with age. Long-term effects of bisphosphonate treatment are not know. Therefore, this therapy should be administered under strict research protocols. Anabolic a g e n t s Growth hormone, insulin-like growth factor-l,and parathyroid hormone have the potential to increase bone mass. Except for a treatment protocol with GH in children with deforming OI, most experience with these

agents has been anecdotal. There are no large studies on the use of GH therapy in patients with OI. An increase of fracture rate during GH therapy has been reported [257,258]. In a controlled study comparing seven children with mild OI with seven children receiving no treatment, the fracture rate was not different between the groups [259]. Reported side effects of GH therapy are arthralgia, myalgia, carpal tunnel syndrome, pesudotumor cerebri, benign intracranial hypertension, slipped capital femoral epiphysis, and transient insulin resistance [260]. There are no data regarding final height in OI patients treated with GH. It has been suggested that GH should probably not be used as a first-line therapy in OI [261]. Like all children who are initially started on GH, OI children do experience an initial acceleration of growth rate [109]. Given the underlying physiological basis of OI, it would be surprising if an agent that furtherstimulates more bone turnover as part of its anabolic action has a longterm beneficial effect. The osteoblast lineage is already maximally stimulated and the addition of agents that enhance osteoclastic activity will only contribute to the deficit between formation and degradation. The transiently increasing growth rate that is seen in children with GH occurs because the growth plate is stimulated to proliferate. If the bone that contains the growth plate (collar region and primary spongiosa) is not more structurally sound than before the stimulus, damage to the growth plate might be anticipated. Potentially, the combination of GH and bisphosphonate might provide a compromise that is acceptable, and studies using this

18. Osteogenesis Imperfecta

combination may be of interest. However, this is another therapeutic setting requiring animal experimentation for concept validation. Orthopedic management The surgical outcome of patients with OI has improved significantly with the introduction of bisphosphonate treatment. Patients can now have rodding surgery as early as 18 months of age without complications. The preferred technique is to rod one leg and wait at least 7 days before rodding the other leg. Using this technique, the need for a blood transfusion is minimized (F. Fassier, personal communication). For the femora, the extensible rods (Dubow-Bailey [262,263] or Fassier-Duval [264]) are preferred, and the number of osteotomies should be as small as possible. Patients should weight-bear as soon as possible, usually approximately 3 weeks after surgery. After rodding surgery, most previously nonambulatory patients with OI are able to walk [265]. The complication rate for Dubow-Bailey rods ranges from 63.5% [266] to 72% [267] and is approximately 50% for nonelongating rods. The reoperation rate is similar for both types of rods. The most common complication is rod migration, and infections, pseudoarthrosis, lack of elongation or overelongation of rods. Loosening of the terminal T piece may also occur [266]. A new elongating rod, called Fassier-Duval [264], opens interesting possibilities for the surgical treatment of patients with OI. This rod allows for the introduction of the whole device through the greater trochanter without the need to open the knee joint. Post-operative management is then greatly facilitated. For tibiae, due to the difficulty of opening the ankle joint, proximal insertion of rush rods is preferred. Patients should wear below-knee orthosis to protect the bone from fracturing, particularly after they have outgrown the rod, and to prevent bowing of the unprotected distal part of the tibiae. Patients with severe OI almost always have spinal deformities, with a prevalence that may be as high as 92% [19,268]. More than half of the cases of scoliosis are located in the thoracic region, and pectus carinatum and pectus excavatum are common associated findings [269]. These deformities increase with age [268,270], and bracing does not stop the progression of the curve [271]. Thoracic scoliosis of more than 60 ~ has severe adverse effects on pulmonary function in patients with OI [272]. Fusion with bank bone graft [273] and with Keil bone graft without instrumentation [274] has been used for the treatment of severe scoliosis in patients with OI, as has halo gravity traction and posterior spondylodesis with instrumentation [275]. The ideal surgical treatment of severe scoliosis in patients with OI has yet

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to be determined, and it remains a difficult procedure [276]. Occupational therapy and physiotherapy Physical activity is a key factor in the response of these patients to treatment and for the achievement of a better quality of life [277]. When a patient has a fracture and is immobilized for a certain period of time, the bone density declines dramatically [278]. The bisphosphonates will protect the patient from bone loss, but there may be little or no gain in the bone density for a while. It is important that physiotherapy be administered by professionals who have experience with patients with OI. Some evaluation tools have been validated for OI [279]. Exercises should be prescribed following a program designed specifically for each individual, encouraging parental participation and bonding. Water therapy is highly recommended for patients with OI. In three different groups of OI patients able to ambulate, it was found that preventable functional impairment is caused by shoulder joint and hand contractures and upper extremity weakness in children able to stand in braces; by hip flexion and plantar flexion contractures of the feet, shoulder joint contractures, and upper extremity weakness in patients able to ambulate short distances without braces; and by poor lower extremity joint alignment, impaired balance, and low endurance in children able to ambulate in the community without assistance [280]. The aim of these programs is to employ children in graded exercise regimes and foster their increased involvement in school and social situations. Results suggest that aggressive physical therapy and rehabilitation have a major role in the overall care of infants and children with OI [281]. Sitting devices should be designed to allow comfortable sitting positions as early as possible. Children develop tolerance for sitting position gradually by progressively decreasing the degree of tilt of the sitting devices. The goal is head control (J. Ruck-Gibis and K. Montpetit, personal communication). Psychosocial aspects are extremely important in the management of patients with OI. Issues regarding selfesteem, sexuality, and peer integration must be addressed to properly care for these patients, particularly during adolescence [282]. OI children have no intellectual deficits; therefore, they should be attending regular schools. The following rules should be followed to permit better school integration of children with OI: 9 School must be accessible for handicapped children. 9 The school should have an access ramp, accessible toilets, mobile tables and chairs, and a wheelchair in case of emergency. 9 The school should have an emergency evacuation plan adapted to handicapped children in case of fire.

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9 Some OI children lack balance and need better supervision in school yards or on icy surfaces. 9 OI children should leave 5 min before the end of classes in order to avoid crowds. 9 In physical education, OI children should not participate in any contact sport. However, participation in physical education should be strongly encouraged but with respect to the child's limits. 9 The equipment used should be soft (e.g., balls). 9 The child should rest when he or she is tired. 9 The child should wear ortheses at all times. 9 Other elements facilitating school integration include adjustable desks, wheelchairs with trays, floor mats for rest periods, adapted toilets, and reachers. Given the complexity of the clinical management of OI, a multidisciplinary clinical team approach to treatment is of greatest value for both the patient and the field. Not only are there significant orthopedic and medical issues but also problems of daily living are pervasive. Proper handling during infancy, mainstreaming within schools, driving an automobile, attending college, scoliosis and pulmonary insufficiency, neurological symptoms, pregnancy and genetic risk, and acceleration of bone disease after menopause are complex problems that are difficult for an individual clinician to manage and require an experienced and broad-based treatment team.

Future t h e r a p e u t i c o p t i o n s Because bisphosphonates do not correct the primary cause of OI and the long-term use and effectiveness of antiresorptive agents are uncertain, steps to correct the underlying genetic mutations are being evaluated in both humans and mice. The rationale for gene therapy in OI is derived from the analysis of individuals who are somatic mosaic for an OI mutation but do not have evidence of bone disease. This clinical phenomenon suggests that the deleterious effect of OI cells can be countered by the presence of normal cells. Thus, if it were possible to introduce normal cells into an individual with OI, the severity of bone disease would be reduced. This treatment strategy requires the ability to introduce cells from the osteoblast lineage into OI subjects, with the attendant problems of immune rejection unless a tissuematched donor can be identified. Human transplant studies with bone marrow cells have been performed in a limited number of children with severe OI [283,284]. The success of these initial studies is difficult to assess [285], and a proof of principle experiment in animals is required before human experimentation is undertaken. Perhaps developments using partially differentiated em-

bryonic stem cell will provide another approach for cell engraftment. Assuming that the immune problems related to bone cell transplantation will be a major impediment for longterm engraftment of bone, strategies are being developed to correct in vitro the primary defect in type I collagen production of an individual with OI followed by reintroduction of the corrected cells into the affected host. This requires a two-step process in which the output from the mutant collagen allele is inhibited and a replacement collagen gene for the inactivated mutant gene is inserted. Once corrected, the engineered cells must have the ability to engraft bone, proliferate, and participate in new bone formation. Each facet of these problems is in itself a major research undertaking. Allele-specific suppression of a mutant collagen gene is potentially possible at the genetic or the RNA level. Targeting the endogenous gene with a chimeric R N A DNA oligonucleotide [286] can correct the specified sequence. Although the frequency of this modification is variable, the change is permanent and the output of collagen production is restored to a normal level. The other option is to reduce the output by targeting the RNA from the mutant allele. Although antisense constructs to a RNA transcript is unlikely to have allele-specific discrimination, other strategies, such as hammerhead [287] and hairpin [288] ribozymes, U lsnRNA [289], RNA transplicing [290,291], and RNase P [292], have such a potential. Yet to be evaluated is vector expression RNAi, a strategy that is widely used in lower organisms and has recently been shown to be effective in mammalian cells [293-295]. A detailed description of the background and mechanism of each anti-RNA effector is beyond the scope of this chapter. It is unlikely that any one approach will have sufficient strength and specificity to inhibit the mutationcontaining transcript sufficiently to have a major impact on disease severity [296]. However, combining two or more anti-RNA approaches that act in different compartments within the cell and by different molecular mechanisms may attain this goal. Another challenge is the introduction of a procoUagen cDNA expression construct to replace the lost activity of the suppressed transcript. Collagen gene expression has problems that differ from those of gene replacement for an enzyme or clotting factor. In bone, type I collagen production can account for 20% of total protein synthesis so that an extremely strong promoter is required to drive the replacement cDNA. Another consideration is the vector that delivers the correcting construct. Although a collagen cDNA has been strongly expressed from an adenoviral construct [297], this approach does not achieve permanent expression. Retrovectors have the

18. Osteogenesis imperfecta

size capacity and permanent integration needed to contain and express a collagen promoter-collagen c D N A construct. However, expression of the transgene can be suppressed after the transduced cells are reintroduced into the host [298]. Modification of the retrovector that removes sequences responsible for suppression appears to overcome this problem, allowing for osteoblastspecific expression of the transgene throughout the life of the mouse [299]. It remains to be demonstrated that this vector approach can achieve the level of collagen c D N A expression equivalent to that of an endogenous collagen allele. The most severe problem for somatic gene therapy for OI is reintroduction into a host of cells that are capable of homing to bone and participating in new bone formation. Although the ability of marrow stromal cells to differentiate into mature osteoblasts in vitro or in subcutaneous implants is well-known [300,301], demonstration that this is possible when administered systemically is still unconvincing. Most studies in man and mouse can demonstrate a low degrees (1-5%) of engraftment of bone or bone marrow stroma as assessed by a transgenic or unique endogenous genetic marker [302-304]. In many cases, the marker gene does not discriminate whether this cell arises from a mesenchymal or macrophage lineage. Even when relatively pure populations of stromal cells are used for transplantation, minor contamination from the myeloid lineage could belie stromal cell engraftment. Only one study has demonstrated expression of a transgene that is a marker of a differentiated osteoblast [305], although the level of engraftment and its contribution to bone formation are difficult to assess. To complicate the analysis, stromal cells appear to have the ability to fuse with resident cells [285]. Fortunately for patients with OI, bisphosphonates have provided a therapeutic choice for improving bone health at a time when the promise of cell or gene therapy is yet to be demonstrated. These drugs have raised the bar for assessing the success of any new therapy because it will be necessary to demonstrate that an experimental approach has either short- or long-term advantages over existing pharmacological regimens. Animal studies are necessary to demonstrate that gene or cell therapy does offer options, and objective measures of success need to be developed that allow comparison of two treatment modalities.

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CHAPTER 18, FIGURE 6 Dentinogenesis imperfecta (DI). Teeth of affected individuals appear transparent due to abnormal dentin. Enamel is normal. The severity of the DI has no relation to the severity of the skeletal involvement in the case of OI.

CHAPTER 18, FIGURE 10 Microscopic bone changes under bisphosphonate treatment. Cortical width is significantly increased after 2 years of treatment with intravenous pamidronate, as seen in this pair of iliac crest biopsies stained with toluidine blue. The baseline biopsy is shown on the left.