A Closer Look at Osteogenesis Imperfecta

Image captured by the Osteogenesis Imperfecta Foundation

What is Osteogenesis Imperfecta?

Osteogenesis imperfecta (OI), otherwise referred to as brittle bone disease, is a rare genetic disorder that causes bones to weaken and break easily.

Causes of Osteogenesis Imperfecta

For most, OI is caused by mutations in the COL1A1 and COL1A2 genes, which produce type I collagen, an important structural protein found in skin, bones, and tendons. Mutations in these genes result in the body producing either insufficient quantities of collagen or misformed collagen. These altered genes can be inherited or sporadically arise before birth. Most OI occurrences are the result of autosomal dominant mutations, where either parent must carry a single copy of the variant gene to transmit the condition to their child.

Classification & Symptoms

OI is estimated to affect 1 in every 10,000 people, with those diagnosed exhibiting a diverse range of symptoms based on OI type. In 1979, Dr. David Sillence constructed a classification system that categorized OI into four distinct types (types I to IV) according to disease severity. To date, this scheme has grown to include 23 distinct OI types, however, types I through IV remain the most common.

Type I	Type II	Type III	Type IV
-Most common and least severe form of OI -Bone fractures are likely induced by mild injury and tend to arise prior to puberty	-Most severe type of OI -While in the womb, the baby suffers from many broken bones and bone deformities -Likely to cause death at or soon after birth due to underdeveloped lungs and insufficient rib cage formation	-Most serious type among infants that survive beyond birth - Type III OI-affected individuals have severe bone defects that predispose them to fractures -Those with type III OI have a short stature, weak muscles, and physical disabilities	-Less serious relative to type III OI, but more severe in comparison to type I OI

Image created by the Osteogenesis Imperfecta Federation Europe (OIFE)

Since type I collagen performs numerous functions within our body tissues, those with OI may also display non-skeletal symptoms. These can include blue sclerae (white of the eyes appearing blue), hearing loss, difficulty breathing, dental problems, heart issues, and muscle weakness.

Diagnosis

Given the broad spectrum of symptoms associated with OI, patients displaying milder forms of this condition may be misdiagnosed with other bone-related disorders (e.g., osteoporosis) or fail to receive an accurate diagnosis until adulthood. However, a correct OI diagnosis can still be obtained through a collection of imaging and genetic assessments. 

After formulating a record of previous bone injuries and gathering a detailed family history, healthcare providers will order X-rays and bone density scans to locate bone fractures and deformities. Physicians also conduct genetic blood tests on patients to pinpoint mutated genes contributing to OI, followed by a series of supplementary tests to determine whether these genes were inherited.

In some cases, a pregnancy physician may speculate that a fetus has OI prior to birth based on images captured during an ultrasound appointment. To confirm their suspicion, the provider may perform an amniocentesis, wherein a sample of amniotic fluid surrounding the fetus is collected and tested, or wait until the baby is born to establish a formal diagnosis. 

Treatment

Although no cure exists for OI, treatment for this condition aims to support patients in managing their symptoms, strengthening their bones, and improving their overall quality of life. Major treatments can include the following:

Physical Rehabilitation

Physical and occupational therapists can support OI-affected individuals in strengthening their bones and motor function with targeted exercise programmes. Additionally, these specialists can prescribe assistive equipment (e.g., walkers, wheelchairs, braces, and crutches) to facilitate independence in the completion of everyday tasks. For infants diagnosed with OI, caregivers can receive strategies on how to safely handle their child to prevent injuries.  

Surgical Interventions

Orthopedic physicians can treat fractured bones with appropriate casting measures and may perform surgical procedures to rectify curved bones in OI patients. For instance, doctors may perform rodding surgery, in which a metallic rod is inserted to stabilize and prevent fractures from occurring in long bones. These rods can be altered to increase in length as the OI patient grows. 

Medications

Medicinal therapies used for treating OI tend to fall into two major classes: antiresorptive and anabolic medications. Of the medications described below, bisphosphonates (BPs) are used most frequently, whereas the others are either administered sparingly or are undergoing further study.

	Antiresorptive Medications	Anabolic Medications
Function	Aims to reduce the activity of osteoclasts, which are cells specialized in breaking down bone	Strives to enhance bone development as opposed to impeding osteoclast activity
Medication Examples	Bisphosphonates (BPs) are a successful antiresorptive therapy for OI patients, proven to enhance bone mass and reduce bone pain. However, a notable drawback of BPs is their tendency to collect on the surface of bone for extensive periods of time.  Denosumab, a laboratory-engineered antibody, bypasses the limitation associated with BPs as they are completely metabolized by the body a couple of months after usage. Importantly, Denosumab has provided encouraging results for patients with types I, III, and IV OI who otherwise fail to respond to BPs.	Teriparatide, a synthetic version of the human parathyroid hormone, has been shown to decrease the occurrence of fractures in adults with type I OI. However, findings from rodent studies have sparked concerns as prolonged use of this anabolic therapy has been associated with an increased chance of developing osteosarcoma, a type of bone cancer.  Sclerostin Inhibitors are engineered molecules that directly counteract the function of the protein sclerostin. In our body, sclerostin manages bone growth by inhibiting the production of osteoblasts (that is, specialized bone-forming cells). Sclerostin inhibitors, on the other hand, increase bone formation by stimulating the activity of osteoblasts and have been proven to reduce fracture rates in rodents with OI. Researchers are currently investigating the effectiveness of these inhibitors in comparison to BPs for treating children with OI.

Future Treatment Avenues

Emerging therapies are underway to curatively address the cellular and genetic basis of OI. The two most promising approaches include mesenchymal stem cell (MSC) therapy and gene therapy.

In MSC therapy for OI, MSCs (that is, cells capable of developing into any cell type found in the body) undergo a process of specialization to become osteoblasts. Animal studies have revealed that human-fetus derived MSCs can enhance the quantity of collagen and bone density in OI-affected mice.

CRISPR/Cas9 gene editing technology constitutes a form of gene therapy and inhibits the expression of the mutated genes, such as those causing OI. However, a current obstacle with this approach is the risk of imprecise gene amendments.  

Final Remarks

As knowledge surrounding OI continues to grow in both science and society, treatments intended to lessen symptom severity and enhance the overall quality of life for those affected are bound to improve. 

If you are interested in learning more about OI from the perspectives of those diagnosed, feel free to check out the following: 

• Jay & Pamela – A reality TV show following a couple as they navigate life with type III OI

• FunsizedStyle – A YouTube channel created by beauty influencer Michaela Davert, who documents her passion for fashion and life with type III OI

References

Chaugule, S., Constantinou, C. K., John, A. A., Micha, D., Eekhoff, M., Gravallese, E., Gao, G., & Shim, J-H. (2025). Comprehensive Review of Osteogenesis Imperfecta: Current Treatments and Future Innovations. Human Gene Therapy, 36(5–6), 597–617. https://doi.org/10.1089/hum.2024.191 

Cleveland Clinic. (2025, June 19). Osteogenesis Imperfecta (Brittle Bone Disease). https://my.clevelandclinic.org/health/diseases/osteogenesis-imperfecta-brittle-bone-disease 

Johns Hopkins Medicine. (n.d.). Osteogenesis Imperfecta. https://www.hopkinsmedicine.org/health/conditions-and-diseases/osteogenesis-imperfecta 

Marini, J. C., Forlino, A., Bächinger, H. P., Bishop, N. J., Byers, P. H., Paepe, A. D., Fassier, F., Fratzl-Zelman, N., Kozloff, K. M., Krakow, D., Montpetit, K., & Semler, O. (2017). Osteogenesis Imperfecta. Nature Reviews Disease Primers, 3(1), 1–19. https://doi.org/10.1038/nrdp.2017.52 

National Institute of Arthritis and Musculoskeletal and Skin Diseases. (2022, November). Osteogenesis Imperfecta. https://www.niams.nih.gov/health-topics/osteogenesis-imperfecta 

Rossi, V., Lee, B., & Marom, R. (2019). Osteogenesis Imperfecta: Advancements in Genetics and Treatment. Current Opinion in Pediatrics, 31(6), 708–715. https://doi.org/10.1097/MOP.0000000000000813 

Stasek, S., Zaucke, F., Hoyer-Kuhn, H., Etich, J., Reincke, S., Arndt, I., Rehberg, M., & Semler, O. (2025). Osteogenesis Imperfecta: Shifting Paradigms in Pathophysiology and Care in Children. Journal of Pediatric Endocrinology & Metabolism, 38(1), 1–15. https://doi.org/10.1515/jpem-2024-0512 

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