Reading Time:

9 minutes


Numerous factors are involved in the process of bone generation. An imbalance in this process can lead to serious diseases such as osteogenesis imperfecta (OI), a genetic disease characterized by extremely brittle bones.

“OI is characterized by evidence of connective tissue malfunction and its clinical presentation is extremely variable: affected individuals are susceptible to fractures from the mildest trauma; reduced bone mass; varying degrees of short stature; progressive skeletal deformities; blue sclerae; dentinogenesis imperfecta; joint laxity; and adult onset deafness. The clinical heterogeneity of OI ranges from death in the perinatal period, through marked short stature and severe bone deformity, to normal life expectancy with only mild osseous fragility and slightly decreased bone mass; the prognosis and the achievement of walking and autonomy are greatly influenced by the number of fractures and deformities and the age at which they begin.”1

There are 4 subtypes of OI, depending on the genetic mutation:

  • Osteogenesis imperfecta type I
  • Osteogenesis imperfecta type II
  • Osteogenesis imperfecta type III
  • Osteogenesis imperfecta type IV
  • Osteogenesis imperfecta type V

“Osteogenesis imperfecta (OI) is a group of orphan diseases characterized by varying degrees of skeletal fragility. Fractures and bone deformities occur with trivial trauma. The most widely used system to classify the different types of OI is developed by Sillence et al. It is based of clinical, genetic and radiographic findings:

  • Type I: the most common form, is autosomal dominant and is characterized by blue sclerae, a typical feature of OI. The number of fractures is fairly small and the deformities are modest, causing little loss of stature.
  • Type II: which is also autosomal dominant, is the lethal form of the disease. The sclerae are blue and death is due primarily to lung underdevelopment cause by rib fractures.
  • Type III: is autosomal dominant or recessive and is the most severe non-lethal form. The sclerae are white, the face triangular and the fractures commonly accompanied with progressive deformities and short stature.
  • Type IV: is autosomal dominant and usually characterized by white sclerae, short stature and skeletal deformities that are less severe than those in type III. Type IV is the most heterogeneous group because it comprises those patients who do not meet the criteria for the other three types.
  • Type V: characterized by hypertrophic calluses, sometimes mistaken for osteosarcomas, and by classification of the interosseous membranes. Type V does not seem to be related to the COL1A1 or COL1A2 genes.”2


Characteristic of subjects affected by OI according to types
Fig. 1. Characteristic of subjects affected by OI according to types. Reprinted from “Osteogenesis imperfecta: potential therapeutic approaches. PeerJ, 6, e5464.” By Rousseau, M., & Retrouvey, J. M. (2018).


Clinical Features

“The clinical features can be broadly classified into skeletal and extraskeletal. Skeletal features include excess/atypical fractures, short stature, scoliosis, and basilar skull deformities. Extraskeletal manifestations include hearing loss which is a mixture of conductive and hearing loss and seen in 50% of adults by 50 years and in 5% of children with OI. Abnormal dentin leading to the appearance of small deformed teeth and which are opalescent due to a higher ratio of transparent enamel to opaque dentin is called dentinogenesis imperfecta and along with malocclusion are the major dental abnormalities. The sclera may be blue or gray in color. Connective tissue abnormalities leading to joint hyperextensibility may result in dislocation of joints and the head of the radius. Hypercalciuria seen in 36% of patients may result in renal calculi. Cardiovascular involvement leads to aortic root dilatation and mitral valve prolapse. Neurological manifestations include macrocephaly, hydrocephalus, basilar invagination (will present as headache, lower cranial nerve palsies, dysphagia, quadriparesis, ataxia, and nystagmus) and cervical spine kyphosis (can cause compression of cervical spine cord, sensory or motor disturbances of upper or lower extremities progressing to quadriparesis).”3

Osteogenesis is the normal biological process of bone formation. It begins in the eighth week of embryonic development, during which the ability to repair possible future fractures occurs. It must be taken into account that the bones of the human skeleton derive from three embryonic structures: the mesoderm, the somites and the neural crest.


The mesoderm is one of the three cell layers from which the entire embryo develops. In the beginning, there are three layers of mesoderm cells: ectoderm, endoderm and mesoderm (between the ectoderm and endoderm). The mesoderm gives rise to the bones of the extremities.


Somites are transient embryonic structures fundamental for the development of the segmented structures that are characteristic of vertebrates. Moreover, bones that are part of the central axis of the body or axial skeleton derive from somites, such as the hyoid bone, the ribs, the spine, the sternum, the skull and auditory bones.

Neural Crest

Are transitory cell formations, typical of the early stages of development. Its main characteristic is the pluripotency of its cells. In other words, the cells of the neural crest allow the appearance any type of osseous structure of the body. For example, craniofacial bones and cartilages

Osteogenesis is also called ossification and consists of the transformation of preexisting tissue into bone tissue. To carry out this transformation there are two mechanisms:

  • Endochondral ossification:

It is a more complex process characterized by the formation of bone from cartilaginous tissue during embryonic development.

  • Intramembranous ossification:

Through this process, the flat bones of the skull are formed, where ossification occurs inside a membrane of connective tissue. Some cells from this membrane will become osteoblasts, the cells in charge of secreting the bone matrix. While others become part of the small blood vessels that supply the bones.

“Bone is formed through the processes of endochondral and intramembranous ossification. In each process mesenchymal progenitors condense and initiate developmental programs that include chondrogenesis and osteoblastogenesis. During endochondral ossification, mesenchymal cells differentiate into chondrocytes, which form the cartilage growth plate. The cartilage growth plate is then gradually replaced by bone. Most bones in the human skeleton are made through endochondral ossification. These include the long, short, and irregular bones. Flat bones, including those of the skull, facial bones, and pelvis are made by intramembranous ossification. In this process mesenchymal stem cells (MSCs) differentiate directly into osteoblasts to organized bone. In both processes, osteoblastic bone formation is identical. The synthesis of bone matrix initiates with the construction of type 1 collagen via osteoblasts. Most extracellular matrix protein of bone is type 1 collagen, which supplies strength and elasticity of bone, and scaffolding for the deposition of other matrix components such as hydroxyapatite.”4

If the process of osteogenesis is faulty, the result is osteogenesis imperfecta. Osteogenesis imperfecta (OI) is also known as brittle bone disease, a genetic disease characterized by excessive fragility of the bones.


“The clinical diagnosis of osteogenesis imperfecta is based mainly on the signs and symptoms outlined above. Traditionally, much emphasis has been laid on the presence or absence of blue sclera and dentinogenesis imperfecta as diagnostic signs of osteogenesis imperfecta. This practice still holds true, but some limitations should be recognized. Dark or bluish sclerae are very typical in healthy infants, and therefore this finding is not of much diagnostic use in this age-group. Dentinogenesis imperfecta is more frequently clinically evident in primary than in permanent teeth of patients with osteogenesis imperfecta. Radiological or histological examinations frequently show abnormalities, even in individuals whose teeth look normal oninspection. Clinically evident hearing loss is rare in the first two decades of life, even though subtle audiometric abnormalities can be recorded in a large proportion of children and adolescents with osteogenesis imperfecta. About half of patients older than age 50 years report hearing loss, and an even higher proportion of adults have clearly pathological audiometric findings. Diagnosis of osteogenesis imperfecta is straightforward in individuals with a positive family history or in whom several typical features are present, but can be difficult in the absence of affected family members and when bone is not associated with obvious extraskeletal abnormalities. The uncertainty in such cases is compounded by the fact that there are no agreed minimum criteria that establish a clinical diagnosis of the disorder. In this situation, analysis of the collagen type 1 genes can provide helpful information, which can be done by investigating the amount and structure of type 1 procollagen molecules that are derived from the patient’s cultured skin fibroblasts. Alternatively, genomic DNA can be extracted from white blood cells and the coding region of the COL1A1 and COL1A2 genes can then be screened for mutations. Both of these approaches are thought to detect almost 90% of all collagen type 1 mutations.”5

People who suffer from it suffer constant fractures in addition to other symptoms such as blue sclera. The physiopathology comes as a result of mutations in the genes Cola1A1 and Cola1A2, ending up with an altered structure for collagen type 1, an essential component of the bone matrix. The lack of normal collagen type 1 is responsible for the excessive fragility of the affected bones.

“During both fetal skeletal development and adult fracture repair, the creation of bone requires a precise coordination of genetic programs that mediate chondrogenesis, osteogenesis, angiogenesis, and bone remodeling. Substantial advances have been made in identifying some of the key molecules and mechanisms that regulate the processes of skeletal development and repair. Collectively, this work indicates that there are remarkable similarities between the cellular and molecular programs for bone formation that function in both embryos and adults. Whether during fetal skeletogenesis or adult healing, bone formation clearly involves a series of discrete phases that are highly coordinated to produce a complete, intact skeleton. Future studies focusing on the molecular and cellular regulation of skeletal morphogenesis and the development of new models of bone repair will undoubtedly provide the foundation for novel therapies to treat bone diseases and traumatic injuries.”6

“The poor quality of the bone in OI patients is the major impediment to improving their quality of life, as it limits physical activity and impedes corrective orthopedic. Thus a medical means of improving bone strength would be of considerable value. Several treatments have been tried to therapeutically augment bone with varying success. The greatest potential currently resides in bisphosphonate therapy. Once in blood, bisphosphonates avidly bind to the hydroxyapatite crystals of bone and act as anti-resorptive agents by disrupting osteoclast action. In so doing they can prevent the loss of both trabecular and cortical bone and result in an increased bone mass compared to that otherwise expected in the OI patient.”7

Dentinogenesis imperfecta and its management

“Osteogenesis imperfecta subjects present more dental problems than the average population. The main dental manifestation of OI is DI, but it is not visibly present in every subject affected by OI. The prevalence of DI varies by Type, from 21% to 73%, as reported in the literature. DI is present in 25% of the OI type I population, 60% of OI type IV, and up to 80% of OI type III. OI type V and VI do not seem to be affected by DI. The DI present in OI subjects is classified as Shields DI type I and is characterized by yellow to bluish-brown discoloration of teeth due to abnormal dentine and short roots. Initially, the primary pulp chambers are uncharacteristically large, but they will calcify fairly rapidly. The enamel, although normal, is prone to fracture due to the deficient dentinoenamel junction, which is smooth instead of scalloped. Studies suggest that teeth affected by DI are not at greater risk of developing carious lesions. This slow progression of caries is thought to be caused by the random nature of the dentinal tubules and the fact that there are fewer tubules. The primary dentition is usually more vulnerable to breakdown by DI than the permanent, although permanent teeth are still prone to deterioration over time. Although DI is not always clinically detectable in all OI subjects, some characteristics may still be observed due to the large degree of variation in the severity of the disease. Precautions regarding restorative dentistry should be taken in all OI subjects, as their teeth may still be affected despite a negative clinical diagnosis of DI. Obliteration of the pulp chambers, short roots, and bulbous crowns may compromise the restorability of the dentition.”8

Osteogenesis imperfecta is a disease considered rare since a small number of people suffer from this affliction. It has a very variable prognosis because there are different types of severity. In addition, the evolution of the disease itself also varies a lot between patients and depends on a large number of factors.



(1) Monti, E., Mottes, M., Fraschini, P., Brunelli, P., Forlino, A., Venturi, G., … & Antoniazzi, F. (2010). Current and emerging treatments for the management of osteogenesis imperfecta. Therapeutics and clinical risk management, 6, 367. Available online at

(2) Chevrel, G. (2004). Osteogenesis imperfecta. Update. Available online at

(3) Sam, J. E., & Dharmalingam, M. (2017). Osteogenesis imperfecta. Indian journal of endocrinology and metabolism, 21(6), 903. Available online at

(4) Shahi, M., Peymani, A., & Sahmani, M. (2017). Regulation of bone metabolism. Reports of biochemistry & molecular biology, 5(2), 73. Available online at

(5) Rauch, F., & Glorieux, F. H. (2004). Osteogenesis imperfecta. The Lancet, 363(9418), 1377-1385. Available online at

(6) Miclau, T., Schneider, R. A., Eames, B. F., & Helms, J. A. (2005). Common molecular mechanisms regulating fetal bone formation and adult fracture repair. In Bone Regeneration and Repair (pp. 45-55). Humana Press. Available online at

(7) Roughley, P. J., Rauch, F., & Glorieux, F. H. (2003). Osteogenesis imperfecta—clinical and molecular diversity. Eur Cell Mater, 5, 41-47. Available online at

(8) Rousseau, M., & Retrouvey, J. M. (2018). Osteogenesis imperfecta: potential therapeutic approaches. PeerJ, 6, e5464. Available online at


Robert Velasquez
10 September, 2018

Written by

Hello everyone, my name is Robert Velazquez. I am a content marketer currently focused on the medical supply industry. I studied Medicine for 5 years. I have interacted with many patients and learned a more:

Leave a Reply

If you would also like a response sent to your email please add it in the email box below.