martin 2007

Osteogenesis Imperfecta:Epidemiology and Pathophysiology

Elizabeth Martin, MHS, and Jay R. Shapiro, MD

Corresponding authorJay R. Shapiro, MDThe Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA.E-mail: [email protected]

Current Osteoporosis Reports 2007, 5:9197Current Medicine Group LLC ISSN 1544-1873Copyright 2007 by Current Medicine Group LLC

Osteogenesis imperfecta (OI) is the most common of the inherited connective tissue disorders that primar-ily affect bone. However, it is a systemic disorder, as evidenced by the occurrence of ocular complications, dentinogenesis imperfecta, hearing loss, joint laxity, restrictive pulmonary disease, and short stature. The OI classication initially included four phenotypes (IIV) involving COL1A1 and COL1A2 mutations. Three new phenotypes have been added, of which one, type VII, is the result of mutations of the cartilage-associated protein (CRTAP) gene. Investigation of recessive forms of OI particularly reported among South African blacks have revealed mutations involving both the CRTAPgene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, each involved in collagen proline-3 hydroxylation. Issues related to the treatment of OI with bisphosphonates involve patient selection, evaluation of the results of treatment, and the duration of treatment. Also, questions exist regarding the difference in treat-ment response between children and adults with OI. Other treatment options, such as recombinant human parathyroid hormone (1-34), Rank ligand inhibitors, and stem cell technology, are being evaluated or are of future investigative interest.

IntroductionOsteogenesis imperfecta (OI) is a heritable systemic disor-der of bone and connective tissue characterized by bone fragility leading to skeletal deformities in more severe cases, blue sclerae, hearing loss, and short stature. To date, the OI phenotype has been reported to be associated with mutations affecting four genes, most often diverse mutations affecting the type I collagen genes, COL1A1and COL1A2, which are transmitted as autosomal dominant traits. Recently, mutations involving other

collagen-related genes have been associated with pheno-types clinically classified as severe or lethal OI types and transmitted as autosomal recessive traits. These are the cartilage-associated protein (CRTAP) gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, which are required for the posttranslational prolyl 3-hydroxyl-ation of type I collagen. It is estimated that the CRTAPand LEPRE1 mutations, which were defined in patients in whom overmodification of procollagen was observed in the absence of COL1A1 or COL1A2 mutations, may account for 2% to 3% of severe or lethal disease in patients with phenotypes resembling OI.

OI is currently divided into seven types (Table 1). Types I through IV, originally proposed by Sillence and Rimoin [1], involve mutations in the COL1A1 and COL1A2 genes, which synthesize type I collagen proBchains. Approximately 800 mutations have been reported to date; these are available in the Human Collagen Muta-tion Database (http://www.le.ac.uk/genetics/collagen/). Type V was redefined in patients originally classified as having type IV, which was recognized as a clinically het-erogeneous group of patients [2].

EpidemiologyOI occurs worldwide without gender preference. It is estimated that there are approximately 25,000 to 50,000 affected individuals in the United States. Although the higher estimate may be excessive, encounters with indi-viduals with mild OI not previously diagnosed point to a population with occasional fractures in whom the diagno-sis is overlooked. One case of OI occurs in approximately 10,000 live births in the United States, but the incidence worldwide is variable. In Great Britain, there are 3400 reported cases. In Denmark, the point prevalence at birth was 21.8 per 100,000 and the population prevalence was 10.6 per 100,000 inhabitants [3]. The database of the Latin-American Collaborative Study of Congenital Mal-formations (ECLAMC) for the years 1978 to 1983 shows that the prevalence rate for OI was 0.4 per 10,000 births [4]. Of interest is the greater incidence of type III OI in the black population, in which the estimated minimum population frequency per 100,000 for OI type III is 0.6, compared with 0.1 for OI type I. These figures are the reverse of those calculated for white Australians, in which

92 Epidemiology and Pathophysiology

the ratio between OI types I and III is of the order of 7 to 1 [5,6]. As discussed below, this population also harbors a greater incidence of recessive disease. Of course, the recent reports of new genes in phenotypes that have fea-tures such as rhizomelia and recessive inheritance broaden the population of potentially involved persons.

Mechanisms of Bone Disease in OICellular mechanismsStudies of cultured OI osteoblasts indicate two general processes leading to defective bone matrix formation: 1) the secretion of half the normal amount of type I col-lagen owing to the null allele effect and 2) the secretion of type I procollagen molecules incorporating mutated proB1or proB2 chains, a dominant/negative mechanism. Studies of human osteoblasts in OI demonstrate decreased levels of not only collagen but also other bone matrix glycoproteins in these bone cells [7,8]. Osteonectin and three proteogly-cans (chondroitin sulfate proteoglycan, biglycan [PGI], and decorin [PGII]) are present in lower concentrations in tissue

culture, whereas thrombospondin, fibronectin, and matrix hyaluronan are present in higher concentrations than in age-matched controls. The proteins reduced in OI cells appear to be most significantly affected at the developmen-tal age at which osteonectin and proteoglycans are usually at their highest levels in normal development [7]. Although the predominant mutations in OI occur in type I procolla-gen, COL1A1 and COL1A2 genes, the alteration in the production of other extracellular matrix proteins and cel-lular proliferation suggest a connection between collagen synthesis and cellular proliferation [8]. Thus defects in type I collagen may affect proteins of the extracellular matrix and impair cellular growth, resulting in the characteristi-cally shorter stature of patients with OI.

Genetic mechanismsThe basic mechanism remains abnormalities in the synthe-sis of the normal type I collagen molecule (Table 1). Type I collagen is a heterotrimer composed of two pro-B1(I) chains and one pro-B2(I) chain in a triple helical arrange-ment. The basic proB chain formula is the repeating triplet

Table 1. Classication of types of osteogenesis imperfecta (OI)

Type Mutation Effect on collagen Phenotype

Autosomal dominant OI

Type I Primary collagen mutations leading to premature termination codons and allele-specic reductions of

nuclear RNA (null alleles)

Quantitative: 50% of normal procollagen chains are secreted

Mild, dominantly inherited OI

Type II Primary collagen mutation: Dominant structural mutations

in COL1A1 and COL1A2

Qualitative: Abnormal protein is formed, leading to formation of

disorganized collagen polymer and matrix disruption. Pro-A1(I) mutations are more often lethal than pro-A2(I)

Lethal OI: perinatal death due to pulmonary

insufciency

Type III Primary collagen mutation: Dominant structural mutations

in COL1A1 and COL1A2

Qualitative: Abnormal protein is formed, leading to formation of disorganized collagen polymer

and matrix disruption

Severe, progressive and deforming OI, short

stature, scoliosis

Type IV Primary collagen mutation: Dominant structural mutations

in COL1A2

Qualitative: Abnormal protein is formed, leading to formation

of disorganized collagen polymer and matrix disruption

Moderate OI, a phenotype representing inclusion of different genotypes

Type V Mutations not identied; associated with formation of hyperplastic callus following fracture and

ossication of the interosseous membrane at the forearm

OI of varying severity, including radial head

dislocation, hyperplastic callus, and interosseous

calcication

Type VI Mutations not identied; associated with distinct histology suggesting a primary mineralization defect

Moderate OI: hyperosteoidosis on bone biopsy

Recessive lethal OI

Type VII; types II, III (recessive)

Secondary mutation: Mutations in LEPRE1 and CRTAP genes,

disrupting prolyl-3 hydroxylation of Pro986 in the B1(I) chain

Qualitative: Excess lysyl hydroxylation and prolyl 4-hydroxylation with

little to no prolyl 3-hydroxylation of Pro986, causing collagen

overmodication

Type VII: moderate to severe, with intrauterine fractures and rhizomelia;

types II, III: same as dominant

Osteogenesis Imperfecta Martin and Shapiro 93

(gly-x-y)331, where x and y are proline and hydroxyproline. The most frequently reported mutation involves substitu-tion of the first-position glycine with cysteine or serine. The other permissible substitutions are alanine, arginine, aspartate, glutamine, and valine. Substitution in the second or third position with a large branched chain (valine) or charged amino acids (eg, aspartate or glutamate) is associ-ated with more severe disease. C-terminal substitutions are more severe than N- terminal mutations because the chains assemble from the C-terminal to N-terminal direction.

Null mutationsMutations identified in patients with OI type I lead to pre-mature termination codons and allele-specific reductions of nuclear mRNA (termed nonsense-mediated mRNA decay or NMD), resulting in a COL1A1 null allele. In this circumstance, the mutated proB chain is degraded intra-cellularly, permitting the secretion of normal procollagen chains, but in 50% of the normal amount.

Structural mutationsIn more severe OI types, mutations involving the structure of either pro-B1(I) or pro-B2(I) lead to the formation of an abnormal protein that may be secreted into the extracel-lular matrix, leading to the formation of a disorganized

collagen polymer and matrix disruption. The most com-mon are first-position glycine substitutions by cysteine, serine, and arginine. Also common are splice-site muta-tions leading to frame shifts, followed in frequency by deletions, insertions, and gene duplications. Mutations involving the pro-B1(I) chain are more often lethal than are those associated with the pro-B2(I) chain. Substitu-tions with a charged residue, aspartic and glutamic acids and arginine, or a branched-chain amino acid valine are associated with severe or lethal disease [9].

CRTAP and LEPRE1 mutations in recessive OIThese mutations, identified in the CRTAP/LEPRE1 com-plex that posttranslationally modifies Pro986 in type I procollagen, disrupt the proline 3 hydroxylation of type I collagen (Fig. 1). The two encoded proteins, CRTAP and prolyl 3-hydroxylase 1 (P3H1) from LEPRE1, form a complex with cyclophilin B inside cells. This complex interacts with collagen and specifically hydroxylates proline in the type I collagen chains. Because CRTAP is a complex, there are probably several loci that can be involved. CRTAP/LEPRE1 mutations result in a number of recessive phenotypes from OI type II and OI type III, as well as autosomal recessive OI type VII. Although not fully characterized, the phenotypes of recessive syn-

Missense and nonsense mutations,including IVS1+1GlC, Gln276lStop,and Met1lIle in the CRTAP start codon,prevent CRTAP translation or cause earlytermination of CRTAP mRNA. WithoutCRTAP, Proline 986 is not hydroxylated.These mutations are estimated to cause2%3% of lethal osteogenesis imperfecta.

LEPRE1Mutations in LEPRE1, including IVS5+1GlT, lead to premature translational termination, minimal mRNA, and low protein levels. This causes minimal 3-hydroxylation of Pro986, but excessive lysyl hydroxylation and glycosylation. Mutations may result in delayed helix folding and longer exposure to lysyl hydroxylases and prolyl 4-hydroxylases, causing overmodication of collagen.

Lysyl hydroxylase: (Xaa-Lys-Gly)m

hydroxylysine

Prolyl 4-hydroxylase: (Xaa-Pro-Gly)m

4-hydroxyproline

Type I procollagen

Undergoes intracellular posttranslational modications:In the ER: P3H1 is essential for the

synthesis, folding, and assembly of collagen

Pro986 in the A1(I) chain(Pro-4Hyp-Gly)

Complex:P3H1

+CRTAP

+cyclophilin B

3-hydroxyproline (986)

CRTAP and LEPRE1 mutations result in a phenotype of osteogenesis imperfecta with excess posttranslational modication and without a primary collagen mutation. Defects in LEPRE1 causesevere to lethal bone dysplasia, with white sclerae, severe growth deciency, extreme skeletal undermineralization, and bulbous metaphyses. Defects in CRTAP cause severe to lethal bone dysplasia.

Figure 1. New genotypes of osteogenesis imperfecta (OI): recessive severe or lethal OI. CRTAPcartilage-associated protein; ERendoplasmic reticulum; LEPRE1leucine proline-enriched proteoglycan 1; P3H1prolyl 3-hydroxylase 1. (Data from Barnes et al. [13] and Cabral et al. [14].)


dromes, characterized by their severity, rhizomelia, and absent Wormian bone formation in type VII, may be con-sidered as related to (but not necessarily consistent with) other OI phenotypes.

Bone biopsies in children with OIRauch et al. [10] have best characterized iliac crest bone histology and its response to treatment. In each OI type, baseline histology was characterized by small biopsy core width, decreased cancellous bone volume due to a 41% to 57% decrease in trabecular number, and decreased cor-tical width. Trabecular thickness was decreased by 15% to 27% [10]. Of interest was the finding that trabecular number did not decrease with age in controls or patients with OI. Although relatively distinctive patterns were seen in individual OI types, these offer little insight into the basic pathobiology of the disease, and no correlation of genotype with histology has been attempted because the numbers are insufficient.

Phenotypes of OITypes I through IVThese phenotypes (Table 1) account for approximately 95% of all patients with OI. Of these, Type I is estimated at 45%; type II may account for 10%; type III, for 25%; and type IV, 20%. These are inherited as autosomal dom-inant traits.

Recessive OI phenotypesIn addition to the type VII recessive phenotype noted below, clarification has been brought to two additional groups of patients: 1) patients in the indigenous South African black population with type III OI, in whom recessive inheritance has been established; and 2) a group of patients with severe or lethal disease in whom type I collagen mutations were not previously identified but in whom electrophoresis gels have shown enhanced posttranslational modification, sug-gesting a defect in synthesis.

Gonadal mosaicism and recessive OI phenotypesOI types I through V are transmitted as autosomal domi-nant disorders. Somatic and gonadal mosaicisms have been reported in a few families, in which affected children were born to apparently normal parents with normal bone mineral density (BMD). However, recessive inheritance was recognized, particularly in South African families. The recent demonstration of CRTAP mutation in type VII OI where recessive inheritance has been recognized led to a search for the mutation in the African families.

Phenotype and genotype relationshipsWith reference to the type I collagen molecule, mutations of the types described above are distributed throughout the helical domain of the B1(I) and B2(I) chains. As a general rule, mutations in the N-terminal domain are less severe

than those involving the mid-terminal or C-terminal heli-cal domains because the molecule assembles in a C- to N-terminal process. Mutations have also been reported to involve the N-terminal and C-terminal propeptide regions. N-terminal propeptide mutations have also been associated with an OI phenotype that displays features of the Ehlers-Danlos syndrome [11]. The Consortium for OI Mutations has reported on genotype/phenotype relationships for the lethal OI syndromes with the follow-ing conclusions: mutations in the N-terminal one fifth of the B chain are nonlethal, one third of lethal mutations occur in the B1(I) chain, and these decrease in severity in a nonlinear pattern from the C-terminal to the N-ter-minal regions [12]. For the B2(I) chain, glycine residue substitutions associated with lethal disease occurred in eight widely spaced clusters along the chain.

The new OI phenotypesAs noted above, the designation OI refers to an inherited bone disorder with brittle bones and a susceptibility to fracture. Certainly, other fragile bone syndromes exist that are as yet undefined. OI types V, VI, and VII have been reported under the OI umbrella as new syndromes in addition to the four collagen-based types of OI originally described. Of these new types, type VII is now associated with mutations involving the CRTAP gene [13,14]. Types V and VI are not collagenopathies and the responsible gene has not been identified.

Type VType V was identified within the Sillence type IV group by Glorieux et al. [2] because of its association with hyperplastic callus following fractures. Type V probably represents about 5% of patients with OI. The clinical severity of type V cases varies. Cases seen at the authors clinic have shown little or no skeletal deformity, whereas the Canadian cases had moderate to severe increased fra-gility of long bones and vertebral bodies. Although the responsible gene has not been identified, the disorder has been linked to chromosome 3. The major characteristics of this phenotype include hyperplastic callus formation in several cases, bilateral anterior dislocation of the radial heads, and progressive calcification of the forearm interos-seous membrane (Fig. 2). Thus, pronation and supination of the forearm are limited. None of the patients with type V had blue sclerae or dentinogenesis imperfecta. Radio-graphs show a radiodense metaphyseal band adjacent to the growth plate in growing patients. Iliac crest bone biopsies have shown decreased cortical and cancellous bone and irregularly oriented trabeculae with a distinc-tive meshwork-like appearance under polarized light. By contrast, in OI type IV the pattern generally is better preserved, although lamellae are thinner than in con-trols. Of interest is the observation of normal resorption parameters for type V, whereas parameters reflecting bone formation processes at remodeling sites were decreased.


This contrasts with the remainder of the type IV groups, in which remodeling parameters were greater than in type V. Successful treatment has been reported with pamidro-nate, and surgical resection of the dislocated radial head has improved function.

Type VIAs with type V disease, the type VI phenotype was culled from the larger group of Sillence type IV patients by Glorieux et al. [15]. Because its distinctive histologic appearance suggests a primary mineralization defect, one could question its designation as an OI type. The responsi-ble gene has not been identified and genetic transmission has not been determined. Consanguinity was present in three of the original eight patients. Diagnosed between 4 and 18 months of age, type VI was described as a moder-ate to severe form of brittle bone disease. These patients were reported to experience fractures more frequently than those in the general type IV group, and they developed long-bone deformities. Four of the original eight patients were wheelchair-bound. Wormian bones were not seen. All patients had vertebral compression fractures. Sclerae were faintly blue or white, but dentinogenesis imperfecta did not occur. Again, iliac crest bone biopsies were characteristic, showing hyperosteoidosis, prolonged mineralization lag time, and decreased mineral apposition rate. Unlike other type IV patients, serum alkaline phosphatase values were elevated, in keeping with a mineralization defect (409 145 U/L vs 295 95 U/L in type IV).

Type VII This syndrome was initially described in four children liv-ing in a First Nations community in northern Quebec [16]. Unlike types I through IV, there was autosomal recessive

transmission. The phenotype includes moderate to severe clinical severity, intrauterine fractures, blue sclerae, rhizo-melic extremities, coxa vara, and decreased bone density. The disorder maps to chromosome 3p22-24.1, which is outside the loci for type I collagen genes [17].

Treatment IssuesIssues related to the treatment of OI with bisphosphonates involve questions of patient selection, doses and schedules, the duration of treatment, and the evaluation of treatment results. Questions also exist regarding differences in treat-ment response between children and adults with OI.

The use of a nitrogen-containing bisphosphonate is now generally accepted treatment for OI, although this is off-label use. The reader is referred to the recent article by Rauch and Glorieux [18] for a discussion of treatment in children with OI. Other treatment options such as recom-binant human parathyroid hormone (1-34) (teriparatide [Forteo, Eli Lilly and Company, Indianapolis, IN]), inhibitors of the receptor activator of nuclear factor-LBligand (RANKL), and stem cell technology are being evaluated or are of future investigative interest.

The aims of treatment in both children and adults are to increase bone strength and decrease the number of fractures. Two additional outcomes are possible: relief of musculoskeletal pain and improvement in vertebral mor-phology in children. A controlled study has reported an improvement in vertebral morphology and a decrease in the fracture rate in the upper extremities but not in the lower extremities; there was no improvement in the com-plaint of generalized pain [19].

Multicenter clinical trials in children have included intravenous pamidronate and oral alendronate. Several

Figure 2. Radiograph showing forearm interosseous membrane calcication characteristic of Type V osteogenesis imperfecta in a 45-year-old woman.


factors make assessment of bisphosphonate treatment dif-ficult, however: 1) most studies have been uncontrolled; 2) different bisphosphonates, doses, and schedules have been employed; 3) the consistent use of recommended calcium and vitamin D supplements has varied; 4) the use of frac-tures as an outcome measure in adults is limited by an almost universal decline in fracture rate after puberty.

Treatment of childrenThe administration of pamidronate to children with OI has proven a signal advance in the treatment of the disorder [20,21]. Several studies (only few of which are placebo-controlled) have consistently reported an increase in bone density for a period of about 2 to 4 years, a decrease in fracture rate of about 50%, improved vertebral morphology where vertebral compression had existed, and a decrease in musculoskeletal pain with an improvement in mobility [22].

Treatment also leads to improved bone histology in children and adults with OI. In a study conducted by Rauch et al. [23] with biopsies at baseline, 2.7 years, and 5.5 years, the mean cortical width increased by 87% and cancellous bone volume increased by 38% between base-line and the first time point during treatment. Although cortical width did not change significantly afterwards, there was a trend toward higher cancellous bone volume. It is important to note that in these studies, at the pamidro-nate doses used (9 mg/kg/y), the average bone formation rate decreased by 70% after treatment was initiated and showed a trend toward a further decline in the second part of the study interval. As a corollary, BMD increased by 72% in the first half of the observation period but by only 24% in the second half [23].

Pamidronate treatment of 10 children with type VI OI led to a decrease in annualized fracture incidence from 3.1 fractures per year before treatment to 1.4 per year during treatment (P < 0.05), but no improvement was seen in the underlying mineralization defect [24].

Trials comparing oral alendronate to intravenous pami-dronate have given variable results. Improvement with oral alendronate was reported in certain trials, but in a large multi-center trial, only bone density, not fracture rate, improved following oral alendronate [19]. Also, some children, par-ticularly with type III and IV disease, do not respond to intravenous pamidronate administration. The reasons for this difference are not clear; the correlation between geno-type and treatment response has not been studied.

Other trials now in progress in children involve risedro-nate and zoledronic acid. The multicenter zoledronic acid protocol was recently terminated after 2 years because of a reported increase in fracture rate, the reasons for which are not available at this time.

Treatment of adults The effectiveness of bisphosphonates in altering BMD appears to differ in adults with OI. Our treatment results,

and those reported to us from other patients, indicate that lumbar BMD increases during 1 to 2 years of oral or intravenous bisphosphonate treatment but then pla-teaus. As noted, fracture incidence is difficult to evaluate because of a lower fracture rate in adults. At The Ken-nedy Krieger Institute in Baltimore, MD, we observed that among adult patients with OI types I, III, IV, and V, intravenous pamidronate seemed slightly more effective than oral bisphosphonates such as alendronate or risedro-nate, based on the percentage increase in lumbar BMD. However, these differences in adults were insignificant in comparison with the increase in lumbar spine BMD seen in children receiving pamidronate infusions.

In a limited study of adults with type I OI, pamidro-nate treatment led to significant increases in BMD in the lumbar spine at 12 months and in the femur neck at 24 months [25]. Significant increases in BMD were also seen in the femoral trochanter at 12 and 24 months. Iliac crest bone biopsy after treatment revealed a significant 6.3% increase in mean bone trabecular volume, and the bone formation rate increased from 6.6 to 15.3 mm2/y. In a placebo-controlled 3-year study of oral alendronate, Chevrel et al. [26] reported an increase in lumbar spine BMD of 10% 9.8% compared with 0.7% 5.7% in the controls. The sample size (n = 64) did not permit assess-ment of the fracture rate.

The bone density in adults appears to plateau over 2 to 3 years of treatment, for reasons that are not clear. Bone turnover rates are lower in adults than in children, so the effect of antiresorptive treatment might be less, and geno-type/treatment correlations have not been conducted. Most importantly, only a limited number of bone biopsies have been reported after bisphosphonate treatment in adults.

Teriparatide has been approved for use in adults with osteoporosis and is currently under study in a multicenter trial in adults with OI. The rationale for its use rests on its action to increase osteoblastic bone formation. However, it should be noted that OI is a disease of the collagen-producing osteoblast, so the response to teriparatide remains to be evaluated [27]. Although it appears that physicians are prescribing it for OI patients, no data are currently available to support that recommendation out-side of the current multicenter trial.

Adequate intake of calcium and vitamin D is recom-mended at this time, although the effect on bone mass in OI has not been tested. A similar issue relates to estrogen replacement therapy in postmenopausal women with OI.

ConclusionsInterest in OI has expanded logarithmically during the past decade, in part because of increased awareness of the disorder and the availability of effective treatment, par-ticularly in children. However, many questions remain: 1) the impact of different matrix protein gene mutations on osteoblast function, 2) genotype/phenotype relationships


as regards bone morphology and the response to treat-ment, and 3) the effectiveness of treatment with oral or intravenous bisphosphonates (or teriparatide) on fracture rate, pain, and quality of life in children and adults. Most available data indicate that bisphosphonate treatment is effective in children, at least for a period of 2 to 4 years, based on histologic response and improvements in BMD. The data are limited in adults, but they suggest that the effect on bone density may be of shorter duration than in children. Nonetheless, pending the results of the current trial of teriparatide, bisphosphonate treatment, which is relatively low-risk, may be appropriate for children with a significant fracture history or very low BMD, as well as for adults with very low BMD and high fracture risk.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as: Of importance Of major importance

1. Sillence DO, Rimoin DL: Classification of osteogenesis imperfecta. Lancet 1978, 8072:10411042.

2. Glorieux FH, Rauch F, Plotkin H, et al.: Type V osteogen-esis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000, 15:16501658.

3. Andersen PE Jr, Hauge M: Osteogenesis imperfecta: a genetic, radiological, and epidemiological study. Clin Genet 1989, 36:250255.

4. Orioli IM, Castilla EE, Barbosa-Neto JG: The birth preva-lence rates for the skeletal dysplasias. J Med Genet 1986, 23:328332.

5. Beighton P, Versfeld GA: On the paradoxically high relative prevalence of osteogenesis imperfecta type III in the black population of South Africa. Clin Genet 1985, 27:398401.

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7. Fedarko NS, Moerike M, Brenner R, et al.: Extracellular matrix formation by osteoblasts from patients with osteo-genesis imperfecta. J Bone Miner Res 1992, 7:921930.

8. Fedarko ND, DAvis P, Frazier CR, et al.: Cell prolifera-tion of human fibroblasts and osteoblasts in osteogenesis imperfecta: influence of age. J Bone Miner Res 1995, 10:17051712.

9. Nishimura G, Haga N, Kitoh H, et al.: The phenotypic spec-trum of COL2A1 mutations. Hum Mutat 2005, 26:3643.

10. Rauch F, Travers R, Parfitt AM, Glorieux FH: Static and dynamic bone histomorphometry in children with osteogen-esis imperfecta. Bone 2000, 26:581589.

11. Makareeva E, Cabral WA, Marini JC, Leikin S: Molecular mechanism of B1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome: unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix. J Biol Chem 2006, 281:64636470.

12. Marini JC, Forlino A, Cabral WA, et al.: Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans [review]. Hum Mutat 2007, 28:209221.

This article reviews existing mutations reported in type I collagen alpha chains and discusses potential phenotype/genotype relationships.

13. Barnes AM, Chang W, Morello R, et al.: Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 2006, 355:27572764.

14. Cabral WA, Chang W, Barnes AM, et al.: Prolyl 3-hydroxy-lase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 2007, 39:359365.

In the majority of OI patients, autosomal dominant inheritance patterns are observed. This report presents new mutations involved in normal type I collagen synthesis in patients with recessive OI, a group not previously defined.15. Glorieux FH, Ward LM, Rauch F, et al.: Osteogenesis

imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002, 17:3038.

16. Ward LM, Rauch F, Travers R, et al.: Osteogenesis imper-fecta type VII: an autosomal recessive form of brittle bone disease. Bone 2002, 31:1218.

17. Labuda M, Morissette J, Ward LM, et al.: Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone 2002, 31:1925.

18. Rauch F, Glorieux FH: Treatment of children with osteo-genesis imperfecta [review]. Curr Osteoporos Rep 2006, 4:159164.

This is a current review of treatment programs in children with OI. The emphasis is on bisphosphonate treatment, which represents the major therapeutic effort to date.19. Letocha AD, Cintas HL, Troendle JF, et al.: Controlled

trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res 2005, 20:977986.

20. Glorieux FH, Bishop NJ, Plotkin H, et al.: Cyclic adminis-tration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998, 339:947952.

21. Plotkin H, Rauch F, Bishop NJ, et al.: Pamidronate treat-ment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 2000, 85:18461850.

22. Devogelaer J, Coppin C: Osteogenesis imperfecta: current treatment options. Treat Endocrinol 2006, 5:229242.

23. Rauch F, Travers R, Glorieux FH: Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of long-term therapy. J Clin Endocrinol Metab 2006, 91:511516.

24. Land C, Rauch F, Travers R, Glorieux FH: Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone 2007, 40:638644.

25. Shapiro JR, McCarthy EF, Rossiter K, et al.: The effect of intravenous pamidronate on bone mineral density, bone histomorphometry, and parameters of bone turnover in adults with type IA osteogenesis imperfecta. Calcif Tissue Int 2003, 72:103112.

26. Chevrel G, Schott AM, Fontanges E, et al.: Effects of oral alendronate on BMD in adult patients with osteogenesis imperfecta: a 3-year randomized placebo-controlled trial. J Bone Miner Res 2006, 21:300306.

27. Glorieux FH: Osteogenesis imperfecta. A disease of the osteoblast. Lancet 2001, 358(suppl):S45.

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