Recent Advances in Osteogenesis Imperfecta
“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 mutations in genes encoding proteins involved in type I collagen’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 questions about their optimal usage, their utility in children and adults with milder phenotypes, and their potential adverse effects are not yet resolved.
KeywordsBisphosphonate Matrix protein Osteogenesis imperfecta Pediatric bone disease Type I collagen
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 posttranslational modification and intracellular trafficking. However, they are not synonymous with OI as a number of genetic disorders affecting type I collagen or its posttranslational 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 proα1(I) and one proα2(I) peptide chains (coded by COL1A1 and COL1A2, respectively) in a triple helix. Proα1(I) and proα2(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 residues 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 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 during 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—proα1(I)2 and proα2(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 process. Procollagen trimers are then transported via the Golgi network and packaged into membrane-bound organelles, where lateral aggregation, the intial phase of fibril formation, occurs. As secretion occurs, the procollagen molecules 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 collagen fibrils and fibers [1, 2, 3] and anchored in those positions by intermolecular lysine-derived cross-links in a process that is begun by modification of specific residues by lysyl oxidase.
The Sillence classification, published more than 30 years ago, was the first systematic classification of OI phenotype . Although the original numbering system is somewhat counterintuitive in that the ascending numbers do not correlate with severity, the distinctions between the nondeforming (type I), moderate (type IV), severe or progressively deforming (type III), and perinatal lethal forms (type II) remains clinically useful .
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 untenable 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 . 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 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 haploinsufficiency , and the ratios of pyridinoline to deoxypyrodinoline 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 features 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 quantitative defect with synthesis of structurally normal type I procollagen at about half the normal amount (haploinsufficiency) 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, nondeforming phenotype with blue sclerae (type I in the original Sillence classification) . The class of mutations that change the protein sequence in the triple-helical domain has 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.
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 identification 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 interpretations 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 phenotype. 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.
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 proα1(I) and 63% of proα2(I) substitutions)
33% of glycine substitutions are lethal in proα1(I), 20% lethal in proα2(1)
Substitutions of large amino acid residues (arginine, valine, glutamic acid, aspartic acid) for glycine in proα1(I) beyond position ~200 are usually lethal
Glycine substitutions at N-terminal end of either proα1(I) or proα2(I) are nonlethal and not associated with dentinogenesis imperfecta
18% are splice-site, exon-skipping, intronic inclusion, or activation of cryptic sites—rarely lethal
Mutations in proα1(I) severe to lethal, in proα2 (I) mild to moderate phenotype
There are some rare examples of apparently specific phenotypes associated with genotypes—for example, mutations at the C-peptide cleavage site in COL1A1 may result in a relatively high bone mass with skeletal fragility , and substitutions for glycine near the very end of the triple-helical domain of proα2(I) encoded in exon 49 of the COL1A2 gene have been associated with brachydactyly and intracerebral hemorrhage, in addition to a severe OI phenotype .
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), calcification 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
Autosomal recessive forms of OI
Genes regulating matrix structure
Rhizomelia, popcorn metaphyses; head circumference small
Prolyl 3-hydroxylase 1
Impaired calvarial calcification, popcorn metaphyses
Peptidyl-prolyl isomerase B
FK506-binding protein 10 (FKBP65)
Contractures, scoliosis, acetabular protrusion
Telopeptide lysyl hydroxylase
Heat shock protein 47
Bone morphogenetic protein 1
Pigment-derived epithelium factor
Hyperosteoidosis with abnormal lamellation
Genes regulating matrix homeostasis
LDL receptor-related protein 5
Blindness; heterozygotes have low bone mass
Delayed tooth eruption
In patients at the severe-to-lethal end of the OI spectrum the question of dominant inheritance is, for obvious reasons, rarely put to the test; and in Sillence’s original classification the perinatal lethal and progressive deforming 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 cartilage-related protein, part of the three-protein complex responsible for the 3-hydroxylation of proline at position 986 of the triple helix in the proα1(I) chain. Very soon after, patients with similar phenotypes with mutations in the genes for the other components of this complex, LEPRE1 (prolyl 3-hydroxylase, PH3) and PPIB (cyclophilin 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 procollagen 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 arthrogryposis. Two causative genes, FKBP10 (Bruck 1) and PLOD2 (Bruck 2), have been identified [19, 20, 21, 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, acetabular protrusion, and scoliosis has been recognized . 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 homozygosity for a missense mutation in the gene SERPINH1, which encodes another collagen chaperone, HSP47 .
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 .
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 . Knowledge of such locally occurring mutations can significantly aid diagnosis.
The osteoporosis pseudoglioma syndrome (originally designated 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 . 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 . Heterozygosity for LRP5 loss-of-function mutations differs from other recessive forms of OI in that carriers clearly have an osteopenic phenotype . 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 specifically expressed in osteoblasts in the developing skeleton .
OI in Adults
Children with severe phenotypes have significantly reduced life expectancy, predominantly because of problems associated with respiratory insufficiency and pulmonary hypertension, secondary to kyphoscoliosis and small lung volumes. Although survival of patients with severe phenotypes into adulthood is not uncommon only ~ 20% survive beyond the age of 40 . Thus, most patients who survive into adulthood have a mild or moderate phenotype. In these patients the fracture rate typically falls after puberty (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 postpartum period (Fig. 1d), and the fracture rate for both vertebral and long bones increases after the menopause in women  and in later life in men.
Deafness is a common problem for adults, particularly those with a mild phenotype due to haploinsufficiency. 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 . Cardiac valve dysfunction (aortic or mitral regurgitation) is a recognized 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 .
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 ; oral alendronate, given daily for 3 years ; or oral risedronate, given weekly for 2 years . 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 bisphosphonates were first suggested as treatment to improve bone fragility in children with severe OI 25 years ago , 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 . 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 bisphosphonate 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 . Because of slow periosteal bone formation, the long bones in OI are typically narrow (although this is often partially compensated 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. Bisphosphonates inhibit the former process (but not the latter), permitting an increase in cortical thickness and, thus, improvement in bone strength . 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 mineralization and decrease bone turnover ; but in OI the bones are already hypermineralized , so this mechanism 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.
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 controlled trials of oral bisphosphonates in children with predominantly (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 . The authors pointed out that in both their control and bisphosphonate-treated groups the fracture rate fell with increasing age, emphasizing the challenge that future 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 necessary. One small trial has looked at the effects of 1-year growth hormone treatment in conjunction with neridronate vs. neridronate alone . The growth hormone–treated subjects had greater increases in bone mass at various sites and improved growth velocity, but the study was underpowered to detect any difference in fracture rates. Experimental 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.
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 bisphosphonate 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 determining responses to treatment.
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