Osteogenesis imperfecta (OI), better known informally as brittle bone disease, is a skeletal fragility disorder[1] predominantly caused by mutations that affect collagen pathway, without a specifically developed pharmacological therapy.
Fig D.1: Diagram showcasing the differences between normal bones and OI-affected bones.
As seen in Fig D.1, in normal bones, the pores present within the diaphysis of the bone is significantly more numerous and voluminous than those in the normal pores.
Various symptoms arise from OI, including, but not limited to, brittle bones[2], a blue tinge to the whites of the eye, short stature, loose joints, hearing loss[3], breathing problems and problems with the teeth (dentinogenesis imperfecta). Potentially life threatening complications include cervical artery dissection and aortic dissection[3].
More than 20 types of OI have been discovered, with the main types listed here:
As shown in Table D.I, the symptoms that arise from OI range from mild to severe, and every type of OI listed is linked to malfunctioning genes.
In general, types I, III and IV arise from abnormal genes, which causes certain molecules to disrupt the signalling pathways in osteoblasts, cells that form new bone tissue. If one were to suppress the binding between such molecules and their respective receptors on the osteoblast cell membrane, then the effects of the disease can be reversed. But, which molecules are responsible for this disruption? How is this disruption achieved, and what solutions are readily available to us?
Originating in the SOST gene, this small glycoprotein, expressed most often in osteocytes (bone-destroying cells), is a non-classical bone morphogenetic protein antagonist. Specifically, it has been identified to exhibit binding to the LRP5/6 receptors in osteoblasts.
Why is this important? As shown in diagram D.2 below, this property of sclerostin disrupts the Wnt signalling pathway, a critical chemical pathway present in many species responsible for carcinogenesis, embryonic development, breast cancer, and tissue regeneration in adult bone marrow, skin and intestines, to name a few. Mutations of this pathway have been identified as causes to various other diseases, such as breast and prostate cancer, glioblastoma, type II diabetes, and many others.
Fig D.2: Diagram showcasing the differences between the normal Wnt pathway and the interrupted pathway.
Sclerostin disrupts this delicate protein signalling network, which induces the insufficiency of β-catenin in osteoblasts. It has been experimentally shown that inhibiting sclerostin is effective in reversing the effects of OI.
There are two approaches to resolve this problem: one, to inject β-catenin directly into the cell or two, to design a molecule that can bind to sclerostin directly. As β-catenin is involved in many other genetic processes, directly injecting β-catenin into osteoblasts may have many unfavourable clinical consequences. So, the only option is to design a molecule that can disable sclerostin.
Romosozumab is a humanised therapeutic sclerostin antibody administered to treat general osteoporosis. It has been found to decrease the risk of spinal fractures. It was not an immediate success, and has been rejected several times by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) before approval in October 2019 and April 2019 respectively.
There must be something wrong with the antibody that caused these two institutions to reject the approval of the drug, but what?
Fig D.3: Data from the phase III clinical trials of Romosozumab.
Referring to the phase III clinical trial data, in both trials, more than 75% of participants experienced some form of adverse events post-injection, and there were patients who experienced cardiac ischemic events. Some deaths have also been reported. Even when compared to alendronate, a bisphosphonate drug that prevents the loss of bone density and is another form of treatment against osteoporosis and other diseases, the amount of cardiac ischemic events in the antibody group were much higher.
Fig D.4: Therapeutically and genetically lowered sclerostin leads to a higher risk of cardiac ischemic events.
Sclerostin has been linked to protection against cardiac ischemic events contributed by chronic progressive inflammatory diseases like aortic aneurysms (AA) and atherosclerosis. The sclerostin antibody acting on sclerostin will allow the levels of inflammatory cytokines and chemokines to increase, which aggravates AA and atherosclerosis.
LEFT: Fig D.5: Illustration of how cardiac ischemic events evolve from atherosclerosis. RIGHT: Fig D.6: Illustration of how cardiac ischemic events evolve from aortic aneurysms.
As seen from figures D.5 and D.6, cardiac ischemic events can easily evolve from atheroma and aortic aneurysms simply by blocking the artery. This can occur in any blood vessel of the body at any time, without notice. This is a huge risk for patients of the antibody treatment to undertake, and is thus one of the main reasons the EMA and the FDA have rejected the application of romosozumab as a treatment for osteoporosis before.
In conclusion, sclerostin plays a dual role in the perspective of OI. Not only does it disrupt the Wnt pathway crucial for bone development, but it also offers protection and reduction of risks of developing cardiovascular risks. It seems impossible to reduce the occurrence of OI without also removing its protection of the cardiovascular system.
So, what now?
As news of the problems with the antibody treatment spread, concerns among OI patients during sclerostin antibody treatments rose significantly, and is continuing to grow, especially in those with cardiovascular abnormalities or those with a history with cardiovascular diseases.
Upon realising that the current antibody treatment used for OI causes severe side effects, and the grave consequences of the disease itself, our team has decided to create a next-generation sclerostin inhibitor for OI to promote bone formation without increasing the risk of inducing cardiovascular diseases.
[1] Joan C. Marini, et al. Osteogenesis imperfecta. Nature reviews. 3, 17052-17072 (2017). [2] Rowe DW (2008). "Osteogenesis imperfecta". Principles of bone biology (3rd ed.). Amsterdam: Elsevier. pp. 1511–1531. [3] Peterson CR, Monk EA, McAllion SJ (1 April 2001). "How common is hearing impairment in osteogenesis imperfecta?". The Journal of Laryngology & Otology. 115 (4): 280–282. [4] Turkalj M, Miranović V, Lulić-Jurjević R, Gjergja Juraški R, Primorac D (25 September 2017). "Cardiorespiratory complications in patients with osteogenesis imperfecta". Paediatria Croatica. 61 (3): 106–111.
