REVIEW

Recent Advances in Osteogenesis Imperfecta

Tim Cundy

Received: 23 January 2012 / Accepted: 2 March 2012 / Published online: 27 March 2012

� Springer Science+Business Media, LLC 2012

Abstract ‘‘Osteogenesis imperfecta’’ is a term used to

describe a group of genetic disorders of variable phenotype

usually defined by recurrent fractures, low bone mass, and

skeletal fragility. Most cases are associated with mutations

in one of the type I collagen genes, but in recent years

several other forms have been identified with recessive

inheritance. In most instances the latter result from muta-

tions in genes encoding proteins involved in type I colla-

gen’s complex posttranslational modification or in genes

regulating bone matrix homeostasis. This article reviews

the recent discoveries and an approach to classification and

diagnosis. Bisphosphonates are widely used in patients

with osteogenesis imperfecta, but some important ques-

tions about their optimal usage, their utility in children and

adults with milder phenotypes, and their potential adverse

effects are not yet resolved.

Keywords Bisphosphonate � Matrix protein �Osteogenesis imperfecta � Pediatric bone disease �Type I collagen

Osteogenesis Imperfecta

The term ‘‘osteogenesis imperfecta’’ (OI) encompasses a

group of genetic disorders usually defined by recurrent

fractures, low bone mass, and skeletal fragility. Most cases

are associated with mutations in the genes encoding either

type I collagen (the most abundant and main structural

protein of bone) or (in about 10% of cases) genes encoding

proteins involved in type I collagen’s complex posttrans-

lational modification and intracellular trafficking. How-

ever, they are not synonymous with OI as a number of

genetic disorders affecting type I collagen or its post-

translational modification that have skeletal phenotypes are

not usually included under the OI rubric. These include

Caffey disease and the kyphoscoliosis, arthrochalasia, and

dermatosparaxis types of the Ehlers-Danlos syndrome

(types VI, VIIA/B, and VIIC, respectively). In addition,

some genetic disorders of skeletal fragility included in

classifications of OI are the consequence of mutations in

key osteoblast genes (LRP5 and SP7) that code for proteins

concerned with matrix homeostasis and are not directly

related to collagen metabolism and matrix structure.

Type I Collagen

Type I collagen is initially synthesized in the rough

endoplasmic reticulum as a precursor molecule (type I

procollagen) that combines two proa1(I) and one

proa2(I) peptide chains (coded by COL1A1 and COL1A2,

respectively) in a triple helix. Proa1(I) and proa2(I) have

similar structures, with a core triple-helical domain of

1,014 amino acids composed of uninterrupted Gly-Xaa-

Yaa tripeptide repeats, flanked by propeptides at both the

N- and C-terminal ends. During and after translation the

three chains undergo extensive modification. Prolyl-4-

hydroxylase converts virtually all Y-position proline resi-

dues to 4-hydroxyproline, an alteration that is essential for

thermal stability of the assembled trimer. In the absence of

this modification, the trimer melts (i.e., the individual

The author has stated that there is no conflict of interest.

T. Cundy (&)

Department of Medicine, Faculty of Medical & Health Sciences,

University of Auckland, Private Bag 92019, Auckland,

New Zealand

e-mail: t.cundy@auckland.ac.nz

123

Calcif Tissue Int (2012) 90:439–449

DOI 10.1007/s00223-012-9588-3

chains unfold from the stable triple helix, at about 27�C,

whereas with full hydroxylation the melting temperature is

about 42�C). Some Y-position lysine residues within the

triple-helical domain are hydroxylated by the enzyme lysyl

hydroxylase-1 and glucose and galactose groups added by

glycosyltransferases. Hydroxylation of these triple-helical

residues is part of the pathway to form stable complex

intermolecular cross-links that provide the tensile strength

in tissues. Most of these modifications are completed dur-

ing translation and occur on individual chains. If there is a

delay in triple-helix folding, the process can continue but

the physical properties of the chains and molecules are

altered and contribute to an OI phenotype.

The three chains—proa1(I)2 and proa2(I)—that form a

trimer interact through regions in the carboxyl-terminal

propeptide of each chain. This creates the unusual situation

in which the full-length chain must be maintained in an

unfolded state while the carboxyl-terminal propeptides

fold, associate, and then begin the process of triple-helix

formation. Propogation of the collagen triple helix requires

a number of enzymes and molecular chaperones to ensure

correct folding and trimerization. These include peptidyl

disulfide isomerase, which also forms part of the prolyl

4-hydroxylase complex and likely involves prolyl peptidyl

cis–trans isomerase B (also known as cyclophilin B). This

protein can act on its own, to assist in the folding around

prolyl residues, such as those in the carboxyl-terminal

propeptide adjacent to cysteine residues, and as part of a

complex that includes two additional proteins, cartilage-

related protein and prolyl 3-hydroxylase, to modify certain

triple-helical prolines. The function of this last process is

not yet entirely clear, but when the complex is missing, the

propagation of the triple helix is altered and modification of

the chains increased.

Disulfide bonds between the carboxyl-terminal region of

the chains require protein-disulfide isomerase and act to

secure the three chains in a trimer. Lysine residues outside

the major triple-helical domain of type I collagen and

needed for the formation of mature intermolecular cross-

links are hydroxylated by lysyl hydroxylase-2. These

complex modifications, which are necessary for correct

folding, assuring thermal stability of the triple helix, and

cross-link formation between collagen molecules once they

are secreted into the matrix, need to take place in an orderly

and timely sequence; and various chaperone proteins,

including HSP47 and FKBP65, help to regulate this pro-

cess. Procollagen trimers are then transported via the Golgi

network and packaged into membrane-bound organelles,

where lateral aggregation, the intial phase of fibril forma-

tion, occurs. As secretion occurs, the procollagen mole-

cules are further processed into mature type I collagen

molecules by proteolytic cleavage of the N- and C-terminal

propeptides (by the enzymes ADAMTS-2 and BMP1,

respectively). Finally, the trimers are assembled into col-

lagen fibrils and fibers [1–3] and anchored in those posi-

tions by intermolecular lysine-derived cross-links in a

process that is begun by modification of specific residues

by lysyl oxidase.

Classification

The Sillence classification, published more than 30 years

ago, was the first systematic classification of OI phenotype

[4]. Although the original numbering system is somewhat

counterintuitive in that the ascending numbers do not

correlate with severity, the distinctions between the non-

deforming (type I), moderate (type IV), severe or pro-

gressively deforming (type III), and perinatal lethal forms

(type II) remains clinically useful [4].

In recent years, the genetic complexity of the molecular

basis of OI has become increasingly evident, and at the

same time the extensive phenotypic variation arising from

single loci has been documented clearly. The International

Skeletal Dysplasia Society has suggested that it is unten-

able to try to maintain tight correlations between ‘‘Sillence

types’’ and their molecular bases. They recommend

retaining the essence of the Sillence classification to

describe the phenotypic severity in OI, to free the clinical

classification from direct molecular reference, and to limit

the proliferation of new numbered ‘‘OI types’’ with each

new genetic discovery [5]. When faced with a patient with

possible OI, the clinician should firstly carefully define the

phenotype and the inheritance; taken together these will

usually point to the path by which one can identify the

likely genetic defect.

Defining the Phenotype

The important points to be taken from the history and

physical examination include a detailed family history of

bone disease; the presence of fractures detected in utero or

in the neonatal period; the nature, chronology, and outcome

of subsequent fractures; growth velocity and current height

and skeletal proportions; the presence and progression of

long bone deformity, acetabular protrusion, and kypho-

scoliosis. The distinction between mild, moderate, and

severe phenotypes is broadly based on the number of

fractures, the degree of deformity and growth impairment,

and the age at which abnormalities are first recognized.

Other phenotypic features of importance are head circum-

ference, joint mobility (measured, e.g., on the Beighton

scale) or joint contractures, scleral color, hearing, cardiac

murmurs, and tooth abnormalities, particularly dentino-

genesis imperfecta (Fig. 1a–c).

440 T. Cundy: Recent Advances in OI

123

The standard biochemical tests of bone turnover are

generally unhelpful in diagnosis. There are a few exceptions:

plasma concentrations of procollagen-1 N-propeptide and

procollagen-1 C-propeptide are low in patients with hap-

loinsufficiency [6], and the ratios of pyridinoline to deoxy-

pyrodinoline in urine are altered in the Bruck syndrome

variants of OI (due to mutations in FKBP10 or PLOD2)

where the formation of lysine cross-links is impaired. Plain

radiography is very useful in defining the phenotype, but

bone density testing is of little diagnostic value and can be

difficult to perform and interpret when there is deformity or

short stature. It is, however, commonly used in monitoring

responses to bisphosphonate treatment.

Dominantly Inherited OI

Most patients with OI (* 90%) have mutations in one of

the type I collagen genes, COL1A1 or COL1A2. These are

large genes (51 and 52 exons, respectively), and disease-

causing mutations occur all along both. COL1A1 and

COL1A2 mutations are dominantly inherited, and the

phenotype can vary from the very mild to in utero lethal. It

is generally not necessary to undertake in vitro studies of

type I collagen or to sequence these genes if the diagnosis

is clear from the family history and phenotype. However,

further investigation is indicated if there are atypical fea-

tures or if there is uncertainty about the diagnosis or a need

for genetic counseling about recurrence risk, prenatal

diagnosis, or preimplantation genetic diagnosis.

There are two general classes of mutations in the type I

collagen genes that result in OI: those that cause a quanti-

tative defect with synthesis of structurally normal type I

procollagen at about half the normal amount (haploinsuffi-

ciency) and those that result in synthesis of a structurally

abnormal collagen. The former are usually the result of

premature termination codons in one COL1A1 molecule that

initiate nonsense-mediated decay of the mRNA from the

affected allele. These generally result in a mild, nonde-

forming phenotype with blue sclerae (type I in the original

Sillence classification) [1]. The class of mutations that

change the protein sequence in the triple-helical domain has

Fig. 1 Clinical features of OI in

adults. a Blue sclerae in a

woman and her daughter with

OI of mild phenotype. The

scleral color can vary

substantially between patients

and is commonly darker in

infancy. b Dentinogenesis

imperfecta in an adult patient

with a mild phenotype. The

lower teeth are commonly more

severely affected than the upper.

As is typically the case with

dentinogenesis imperfecta, skin

fibroblast studies indicated the

production of both normal and

abnormal collagen.

c Hypermobility in an adult

patient with a moderate-to-

severe OI phenotype. d OI

presenting as ‘‘postpartum

osteoporosis.’’ This patient had

a mild phenotype associated

with a missense mutation in

COL1A2. Four months after her

first pregnancy she sustained a

single vertebral fracture. Three

weeks after her second

pregnancy, age 38, she

developed severe back pain with

height loss. The radiograph

shows multiple vertebral

compression fractures

T. Cundy: Recent Advances in OI 441

123

a wide phenotypic range (from mild to lethal). The most

prevalent mutations result in substitution for one of the

invariant glycine residues that have a critical role in helix

formation (glycine is the only amino acid residue small

enough to be accommodated in the sterically restricted inner

aspect of the helix). Other mutations cause alterations in

splice sites that can lead to exon skipping, intronic inclusion,

or activation of cryptic sites in introns or exons. Mutations

affecting the C-propeptides of either of the chains are also

common.

The test most frequently employed to distinguish these

two classes uses cultured skin fibroblasts to examine the

secretion of type I procollagen and the electrophoretic

mobility of its constituent chains. With haploinsufficiency

for COL1A1 only normal collagen is made but in reduced

amount. Mutations that alter the sequence of the proa chains

often slow folding of the triple helix and allow increased

posttranslational modification so that the electrophoretic

mobility of the constituent chains is altered (Fig. 2). This test

may be normal in cells from individuals with mutations in

the C-propeptide region that simply prohibit chain interac-

tion and in some of the recently identified recessive types of

OI (e.g., with FKBP10, PLOD2, SERPINH1, SERPINF1,

SP7, and LRP5 mutations).

In the future it is probable that the analysis of cultured

cells will be relegated to a second-tier investigation for the

diagnosis of OI. There are problems with the test: first, it is

invasive; second, it requires facilities in which to grow

cells and experienced personnel to understand and interpret

the results; and third, the time to results is often

8–10 weeks. The ease of genomic sequence analysis has

led to the development of gene-based tests for identifica-

tion of mutations in all the genes now associated with OI.

This strategy uses a single approach, which can be adapted

to new technologies. In addition, the data are digital and

qualitative rather than analogue and quantitative. The only

‘‘art’’ required is knowledge of the effects of different

classes of mutations and the ability to transmit the inter-

pretations in a facile manner. Further, the results of genetic

studies are readily translated into family studies, prenatal

diagnosis, and preimplantation diagnosis and allow a base

for genotype/phenotype analysis. Some mutations are

missed by this approach, but the analysis of proteins and

mRNA from cultured cells can often point to the effects of

mutations and then to the target genes and locations in the

genes. In addition, the effects of splice-site mutations

cannot be predicted from sequence alone, although, to

some extent, can be inferred from correlation with phe-

notype. All in all, DNA sequence analysis seems likely to

provide more ‘‘bang for the buck’’ or a richer set of data for

prediction than studies of collagens. A major limitation is

access to the full library of mutations identified by all the

diagnostic laboratories.

With COL1A1 and COL1A2 mutations the relationship

between genotype and phenotype is complex. A number of

recent publications have addressed this topic, and the data

are summarized in Table 1 [1, 7–10]. In brief, in patients

with haploinsufficiency the phenotype is milder in almost

all respects than those producing an abnormal collagen (the

exception is the high prevalence of hearing impairment in

the former, but this may in part reflect the longer life

expectancy of these patients). The presence of clinically

overt dentinogenesis imperfecta almost always indicates

abnormal collagen. Most lethal mutations arise from sub-

stitutions for glycine in the triple-helical domain, with an

almost 2:1 preference for mutations in COL1A1 [1].

There are some rare examples of apparently specific

phenotypes associated with genotypes—for example,

mutations at the C-peptide cleavage site in COL1A1 may

Fig. 2 Secretion and electrophoretic mobility of type I collagen from

cultured skin fibroblasts. Cells from individuals with mild (type I,

lanes 5 and 10), lethal (type II, lanes 4 and 9), and moderate (type IV,

lanes 2 and 7) OI and controls (lanes 1, 3, 6, 8) were plated at

confluent density, allowed to attach and spread, and then labeled with

[3H]proline overnight in the presence of ascorbic acid. Proteins were

harvested separately from the medium and cell layer, precipitated

with ethanol, and then separated on 5% SDS polyacrylamide gels

under reducing conditions to separate the constituent chains of type I

and type III procollagen. In the medium from the mild OI (type I)

cells, the ratio of proa1(I) to proa1(III) is markedly reduced and the

amount of proa2(I) chains reduced, but there is no intracellular

storage of the chains. This reflects haploinsufficiency for the COL1A1

mRNA and the requirement that there must be at least two

proa1(I) chains in each type I procollagen molecule. The result is

decreased production of type I procollagen. In cells from the

individual with lethal OI (type II) there is a marked shift in the

electrophoretic mobilities of some of the proa1(I) and proa2(I) chains

(lane 4). In addition, there is significant intracellular retention of the

abnormal molecules inside the cells (lane 9). These findings reflect

the substitution of a glycine near the carboxyl-terminal end of the

triple-helical domain by a larger amino acid and the slow folding and

increased posttranslational modification of the unwound chains. The

sample from the patient with moderate OI (type IV) has a much more

subtle defect in chain mobility, represented by the blurring of the

space between the proa1(I) and proa1(III) chains, and illustrates one

of the aspects of the ‘‘art’’ of interpreting protein studies

442 T. Cundy: Recent Advances in OI

123

result in a relatively high bone mass with skeletal fragility

[11], and substitutions for glycine near the very end of the

triple-helical domain of proa2(I) encoded in exon 49 of the

COL1A2 gene have been associated with brachydactyly

and intracerebral hemorrhage, in addition to a severe OI

phenotype [12].

To date, only one dominantly inherited OI variant not

related to COL1A1 and COL1A2 mutations has been

described. This variant (type V) has a mild-to-moderate

phenotype and is distinguished clinically by hyperplastic

callus formation (particularly in the lower limbs), calcifi-

cation of the forearm interosseous membrane (causing

limitation of pronation/supination), anterior dislocation of

the radial head and a radiodense metaphyseal band

immediately adjacent to the growth plate in growing

patients, white sclerae, and no dentinogenesis imperfecta.

Bone biopsies reveal irregular, mesh-like lamellation [13,

14]. The underlying genetic locus has not yet been

identified.

Recessively Inherited OI

This is a fast-moving field; in the past decade the genetic

bases of 10 new OI variants have been discovered, seven

(or possibly eight) of which result from mutations in genes

encoding proteins involved in the posttranslational modi-

fication of type I procollagen [15–28]. The rate of dis-

covery shows no sign of slowing, with the technique of

exome sequencing now permitting the identification of

genetic causes in families of small size. One of the main

interests in these variants is that they help to define the

minimal degree of change to type I collagen that can result

in an OI phenotype, and that could eventually lead to

effective therapies. Phenotypic data on the recessively

inherited forms of OI is summarized in Table 2, although it

should be noted that for some of these disorders very few

individuals have been described, so our appreciation of the

clinical spectrum is likely to change as further cases are

found.

Collagen-Related Genes

In patients at the severe-to-lethal end of the OI spectrum

the question of dominant inheritance is, for obvious rea-

sons, rarely put to the test; and in Sillence’s original

classification the perinatal lethal and progressive deform-

ing types (types II and III) were thought to be recessively

inherited. However, it was not until 2007 that mutations in

CRTAP were identified in patients without mutations in

COL1A1 or COL1A2 but with excess posttranslational

modification of type I collagen, indicative of delayed

folding of the triple helix [15, 16]. CRTAP encodes carti-

lage-related protein, part of the three-protein complex

responsible for the 3-hydroxylation of proline at position

986 of the triple helix in the proa1(I) chain. Very soon

after, patients with similar phenotypes with mutations in

the genes for the other components of this complex,

Table 1 Genotype–phenotype relationships in OI resulting from COL1A1 or COL1A2 mutations

Haploinsufficiency: compared to helical-domain mutations

Nonlethal, nondeforming, taller

Blue sclerae usual

Normal life expectancy

Fewer fractures—fracture rate falls after adolescence

No dentinogenesis imperfecta

Fewer skull-base abnormalities

Sensorineural deafness common

Greater size-adjusted lumbar spine areal BMD

Greater cortical bone width

Wormian bones less common (28% vs. 81%)

Helical-domain mutations—with production of an abnormal collagen

82% are glycine substitutions: ? serine, arginine, or cysteine are the most common (*78% of proa1(I) and 63% of proa2(I) substitutions)

33% of glycine substitutions are lethal in proa1(I), 20% lethal in proa2(1)

Substitutions of large amino acid residues (arginine, valine, glutamic acid, aspartic acid) for glycine in proa1(I)

beyond position *200 are usually lethal

Glycine substitutions at N-terminal end of either proa1(I) or proa2(I) are nonlethal and not associated with dentinogenesis imperfecta

18% are splice-site, exon-skipping, intronic inclusion, or activation of cryptic sites—rarely lethal

C-propeptide mutations

Mutations in proa1(I) severe to lethal, in proa2 (I) mild to moderate phenotype

Data compiled from references 1, 7–10, 30

T. Cundy: Recent Advances in OI 443

123

Ta

ble

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rmia

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imp

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feat

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calc

ifica

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po

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ase

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ever

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10

(FK

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ite

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ntr

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ever

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No

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ity

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SE

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men

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fact

or

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equ

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ite

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abn

orm

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mel

lati

on

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,26

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9

444 T. Cundy: Recent Advances in OI

123

LEPRE1 (prolyl 3-hydroxylase, PH3) and PPIB (cyclo-

philin B), were identified [17, 18]. It is not clear that the

importance of this enzyme complex is due solely to its

effect on prolyl 3-hydroxylation. The genetic test of

substituting the proline 986 residue has not been done

either by nature or in the laboratory. The 3-hydroxylation

of additional X-position proline residues may be important

to make normal molecules, and cyclophilin B, a prolyl cis–

trans isomerase, may have other targets in type I procol-

lagen chains; thus, the effects of mutations in any of these

genes are likely to be biochemically complex.

Bruck syndrome describes the occurrence of neonatal

fractures with contractures of the legs (and, in some cases,

the arms), which is occasionally misclassified as arthro-

gryposis. Two causative genes, FKBP10 (Bruck 1) and

PLOD2 (Bruck 2), have been identified [19–22]. FKBP10

mutations seem to be the more common, and as more cases

have come to light, a milder phenotype presenting in late

childhood or adolescence with long bone fractures, ace-

tabular protrusion, and scoliosis has been recognized [21].

FKBP65, the protein product of FKBP10, is a prolyl cis–

trans isomerase which seems to have multiple substrates,

among them being lysyl hydroxylase 2 (encoded by

PLOD2) and perhaps LH1 and HSP47 (see the following).

The effects of mutations in each gene probably share

phenotypic features because of this interaction. One child

with a severe phenotype has been described with homo-

zygosity for a missense mutation in the gene SERPINH1,

which encodes another collagen chaperone, HSP47 [23].

Among the most recent discoveries are the association of

mutations in the gene SERPINF1 with a variant known as type

VI OI [24, 25]. SERPINF1 encodes pigment epithelium-

derived factor (PEDF), a secreted glycoprotein of uncertain

function in bone; and it is not clear at present whether it acts on

collagen metabolism or in some other way. PEDF can be

measured in normal serum and is undetectable in the serum of

patients with this variant of OI. Bone from these individuals has

the distinctive feature of a marked increase in osteoid, with an

unusual ‘‘fish-scale’’ pattern when viewed under polarized

light. In addition, the response to bisphosphonate therapy in

affected children may be disappointing in terms of reducing

fracture rates and improving mobility [25].

Recessive disorders occur most commonly in areas of

the world where consanguineous marriage takes place or

where there are mutations in relatively small founder

populations. Many instances of the latter are seen in

recessively inherited OI. Examples include the splice-site

mutation in LEPRE1 (IVS5 ? 1G-T) seen both in West

Africa and in people of African descent dispersed to the

Americas (through the Atlantic slave trade) [15, 16] and

the insertion mutation in FKBP10 (c.948dupT) seen in

Samoa [21]. Knowledge of such locally occurring muta-

tions can significantly aid diagnosis.

Non-Collagen-Related Genes

The osteoporosis pseudoglioma syndrome (originally des-

ignated the ocular form of OI) is an example of how genetic

discoveries can advance understanding of bone metabolism

and open up therapeutic possibilities. This disorder is due to

mutations in the gene LRP5, which encodes lipoprotein

receptor protein 5 (LRP5), a key regulator of osteoblast

function. LRP5 affects bone accrual during growth and is

important for the establishment of peak bone mass but is not

directly related to type I collagen metabolism. The skeletal

phenotype of the osteoporosis pseudoglioma syndrome is

relatively mild, but the distinguishing feature is the ocular

involvement, which is due to failure of the normal involution

of the hyaloid vasculature [27]. The remnant forms a fibrous

mass (‘‘pseudoglioma’’) in the globe, causing retinal

detachment and blindness; nearly all subjects have near

complete loss of vision by the age of 25 years [28]. Heter-

ozygosity for LRP5 loss-of-function mutations differs from

other recessive forms of OI in that carriers clearly have an

osteopenic phenotype [28]. Some patients with familial,

idiopathic, or juvenile osteoporosis are heterozygous for

LRP5 mutations. Of note is that dominant gain-of-function

mutations in LRP5 give rise to a dense bone phenotype

because of activation of the same pathway in bone that is

diminished by the recessive loss-of-function mutations.

More recently, a child with a moderate OI phenotype

has been identified with homozygous mutations in SP7.

This gene encodes osterix, a transcription factor specifi-

cally expressed in osteoblasts in the developing skeleton

[29].

OI in Adults

Children with severe phenotypes have significantly reduced

life expectancy, predominantly because of problems asso-

ciated with respiratory insufficiency and pulmonary

hypertension, secondary to kyphoscoliosis and small lung

volumes. Although survival of patients with severe phe-

notypes into adulthood is not uncommon only * 20%

survive beyond the age of 40 [30]. Thus, most patients who

survive into adulthood have a mild or moderate phenotype.

In these patients the fracture rate typically falls after pub-

erty (as it does for most forms of childhood osteoporosis;

the strength of long bones is proportional to the fourth

power of their external radius, so bones get stronger as they

grow wider). Vertebral fractures can occur in the post-

partum period (Fig. 1d), and the fracture rate for both

vertebral and long bones increases after the menopause in

women [31] and in later life in men.

Deafness is a common problem for adults, particularly

those with a mild phenotype due to haploinsufficiency.

T. Cundy: Recent Advances in OI 445

123

About one-third of such patients are affected by the age of

30 and one-half by the age of 50, although the proportion

affected does not change much after that age. Hearing

impairment shows distinct familial trends, being common

in some families and infrequent in others [32]. Cardiac

valve dysfunction (aortic or mitral regurgitation) is a rec-

ognized but uncommon feature seen in people with OI, but

the mechanistic relationship between the two remains

unclear. Valve replacement may be necessary, but the

surgery is often complicated and should be undertaken in

centers with experience [33].

Bisphosphonate therapy in adults with OI has been

explored in three relatively small randomized controlled

trials: using intravenous neridronate, given 3-monthly for

2 years [34]; oral alendronate, given daily for 3 years [35];

or oral risedronate, given weekly for 2 years [36]. All of

these studies showed that bisphosphonate treatment had

statistically significant effects, increasing bone density at

the spine and hip, and decreasing bone turnover markers;

but there were was no difference in the fracture rate, which

was generally low. Given the relative rarity of OI, it will be

difficult to demonstrate efficacy at fracture reduction for

any intervention.

Bisphosphonate Therapy in Children and Adolescents

Physiotherapy, rehabilitation, and orthopedic surgery are

the mainstay of treatment for children and adolescents with

OI; and the best results are obtained when undertaken by

skilled multidisciplinary teams. Intravenous bisphospho-

nates were first suggested as treatment to improve bone

fragility in children with severe OI 25 years ago [37], and

although not subjected to randomized, placebo-controlled

trials, bisphosphonate treatment has rapidly become

established as a standard of care. Compared to historical

controls, intravenous bisphosphonate therapy is associated

with improvements in bone pain, well-being, longitudinal

growth and muscle strength, and vertebral and long bone

mass as well as with a reduced fracture rate [38]. In an

important series of studies the Montreal group has shown

clearly how bisphosphonate therapy has effects on both

trabecular and cortical bone mass. In OI, trabeculae are

reduced in number and abnormally thin. With bisphosph-

onate treatment, the number (but not the thickness) of

trabeculae is increased. During endochondral growth most

primary trabeculae are lost in the conversion of primary

into secondary spongiosa, but bisphosphonate treatment

inhibits the resorption of primary trabeculae, permitting

more to survive as secondary trabeculae [38]. Because of

slow periosteal bone formation, the long bones in OI are

typically narrow (although this is often partially compen-

sated by a relative narrowing of the marrow cavity that

conserves cortical bone width). During normal growth,

cortical width is determined by bone modeling in which

bone resorption at the endosteal surface takes place in

parallel with periosteal new bone formation. Bisphospho-

nates inhibit the former process (but not the latter), per-

mitting an increase in cortical thickness and, thus,

improvement in bone strength [38]. Bisphosphonates do

not increase bone width, and of course, if an abnormal

collagen is produced, then bone quality will also remain

unaffected. In adults, bisphosphonates increase bone min-

eralization and decrease bone turnover [39]; but in OI the

bones are already hypermineralized [40], so this mecha-

nism is unlikely to contribute to any improvement in bone

strength.

The mode of action of bisphosphonates is the same in all

forms of OI and, indeed, probably across all varieties of

childhood osteoporosis. Intravenous pamidronate is the

most widely used bisphosphonate; but the effects are

generic, and regimens employing longer-acting agents such

as zoledronate are being used increasingly.

Bisphosphonate therapy is not without side effects. In

addition to the well-known first dose reaction, uveitis has

been reported; and in children prolonged bisphosphonate

use can impair metaphyseal modeling [41]. Intermittent

intravenous therapy produces the characteristic metaphy-

seal lines, where remnants of calcified cartilage from the

growth plate have accumulated (Fig. 3a–c). Low bone

turnover induced by bisphosphonates can impair bone

healing, particularly after corrective osteotomy [42]. Sev-

eral important questions concerning bisphosphonate treat-

ment of moderate to severe OI in children remain

unresolved. These include how treatment should be mon-

itored, whether the regimen should be modified for long-

term use, and if and when treatment should be

discontinued.

Debate continues on the use of bisphosphonates in

children with mild OI and whether oral administration is

just as effective as intravenous. Children with mild OI have

less to gain from treatment and potentially more to lose

from adverse events. Reports on two randomized con-

trolled trials of oral bisphosphonates in children with pre-

dominantly (but not exclusively) mild forms of OI have

been recently published [43, 44]. These showed that, at the

doses given, both oral risedronate and alendronate

increased spinal bone density and reduced bone turnover

markers, but there was no improvement in fracture rate

over a 2-year period. A randomized controlled trial of oral

risedronate in children with moderate or severe OI had

similar results, but there was a suggestion that the active

treatment slowed the progression of bone deformity [45].

The authors pointed out that in both their control and bis-

phosphonate-treated groups the fracture rate fell with

increasing age, emphasizing the challenge that future

446 T. Cundy: Recent Advances in OI

123

studies will need to be powered adequately to demonstrate

a fracture outcome.

The use of anabolic agents to increase bone mass and

size in children with severe forms of OI is an attractive

theoretical option, but there are formidable practical

problems. Parathyroid hormone is contraindicated in

childhood because of concerns about the possibility of

inducing osteosarcoma, so to date most attention has been

focused on growth hormone. Anabolic agents generally

increase bone turnover, which makes the development of

deformity more likely, so the coadministration of an

inhibitor of bone resorption would most likely be neces-

sary. One small trial has looked at the effects of 1-year

growth hormone treatment in conjunction with neridronate

vs. neridronate alone [46]. The growth hormone–treated

subjects had greater increases in bone mass at various sites

Fig. 3 Effects of prolonged

bisphosphonate treatment on

bone. a Femoral radiograph

from a 2.5-year-old boy with

severe OI who was treated with

intravenous bisphosphonates

from the age of 2 months. The

femoral diaphysis is narrow

(typical in OI), but the

metaphysis is wide because of

bisphosphonate-associated

impairment of bone modeling.

Horizontal white lines coincide

with his pamidronate infusions.

b Upper tibia and femur from

the same child age 10. He had

been treated with pamidronate

infusions from age 2 months to

6 years and with zoledronate

infusions from the age of 8

onward. The bone laid down in

the 2 years off bisphosphonate

treatment is notably less dense.

The junction between treated

and nontreated bone may be

vulnerable to fracture [47]. c A

transiliac bone biopsy from the

same child aged 10

(hematoxylin and eosin stain)

showing extensive retention of

mineralized cartilage (bluestain) with relatively little bone

tissue (pink stain). Calcified

cartilage contributes to greater

‘‘bone density’’ but may not be

resistant to fracture. Note also

the giant osteoclasts detached

from the surface of bone

(arrows) that are a common

finding in bisphosphonate-

treated bone [48]

T. Cundy: Recent Advances in OI 447

123

and improved growth velocity, but the study was under-

powered to detect any difference in fracture rates. Exper-

imental approaches such as bone marrow transplantation,

stem cell transplantation, and correction of the mutated

gene may eventually come to fruition but are not currently

ready for clinical trial.

Conclusions

There have been substantial advances in the understanding

of OI in recent years. The main progress has been in

understanding the genetic bases of this heterogenous group

of disorders that has provided better information for

genetic counseling and opportunities for prenatal diagnosis.

The mode of action and risks and benefits of bisphospho-

nate therapy are being clarified. Particular challenges for

future OI research will be to design therapeutic trials that

can convincingly demonstrate effects on deformity and

fracture and to determine the role of mutations in deter-

mining responses to treatment.

Acknowledgement My sincere thanks go to Dr. Peter Byers, Uni-

versity of Washington, for his great help in preparing this article and

for providing Fig. 2. The radiographs and the histology in Fig. 3 are

reproduced with kind permission of Dr. Paul Hofman and Dr. Michael

Dray, respectively.

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