Osteogenesis Imperfecta, bone cell function

CEO of Brittle Bone Society Patricia Osborne, revisits aspects of the condition and shares what is known around current medical research and treatments, speaking to experts attached to the Charity

Brittle bone disease, or Osteogenesis Imperfecta (OI), is a genetic bone disorder characterised by easily breakable fragile bones. It is a rare condition and is currently estimated that one in every 15,000 people are born with OI, equating to around 5,000 individuals in the UK. The BBS Charity offers front line support, provides approved fact sheets and imparts general information to those diagnosed with the condition. The condition of OI may be hereditary or sometimes may occur as a spontaneous mutation.

The Charity was approved by the AMRC in 2016 and has since embarked on an exciting path to support relevant research that will hopefully provide better outcomes for the OI community.

OI experts

Patricia caught up with BBS Trustee, former Chairman of the Charity’s Medical Board and a member of its Scientific Advisory Board, Professor Nick Bishop, a Professor of Paediatric Bone Disease who has published a lot in the OI area, and Genetics Expert Dr Meena Balasubramanian, who serves on the Charity’s Medical Advisory Board and is a Senior Clinical Lecturer in Musculoskeletal Genetics. Both experts are based at the University of Sheffield and work within the Highly Specialised Severe, Complex and Atypical OI Service. Patricia asked for their take on current medical research and treatments for OI, and what is on the near horizon.

Current research and treatment

The nature of the bone tissue in OI is that it is more brittle than normal bone. None of the established or currently researched drugs will alter that. Current approaches to treating children and adults with OI focus on existing drugs that increase bone mass. In children, these approaches are focused on drugs that stop patients from losing bone tissue. We do expect that drugs that can increase the amount of bone produced by bone-forming cells will become more widely used, and there are at least two studies in this area currently underway in adults, and one planned in children. The overall aim is to reduce fracture risk.

Management of OI is mainly focused on multi- disciplinary care with bisphosphonates remaining the mainstay of medical treatment. However, even if bisphosphonates are used, many children still have fractures and other issues and the benefit in adults is doubtful.

Genetics of Osteogenesis Imperfecta

The majority of OI is caused due to pathogenic variants in genes encoding type 1 collagen i.e. COL1A1/ COL1A2 with an autosomal dominant pattern of inheritance. Most other OI is also caused by variants in genes involved in the processing and secretion of type 1 collagen/bone mineralisation/osteoblast differentiation defects.

The use of Gene therapy

One of the challenges of delivering gene therapy in OI is that the majority of severe OI is caused due to dominant-negative faults in genes encoding for type 1 collagen (COL1A1/A2) resulting in a qualitative defect in type 1 collagen rather than a quantitative defect.

There has been a lot of interest in developing gene therapy for inherited conditions since the recent success of a one-off NICE approved £1.79 million treatment, Zolgensma (also called onasemnogene abeparvovec and made by Novartis Gene Therapies) for babies aged up to 12 months with type 1 spinal muscular atrophy which is a serious, debilitating condition. Approaches are being studied across several diseases, and it is anticipated that in due course OI may be a “target.” However, there are significant technical issues to overcome; the genes affected in the majority of those with OI are quite large and unfortunately not amenable to the gene therapy approach.

Nevertheless, using sophisticated cell engineering techniques developed by Prof Yamanaka, (2012 Nobel Prize winner), it is now possible to transform patient cells into firstly stem and then bone cells (osteocytes), characterise their properties using cutting-edge genomics technologies and measure the activity of specific receptors, known to be dysregulated. We can then develop gene therapy tools to replace the defective type 1 collagen in patient cells to see whether we can restore normal type 1 collagen levels and bone cell function.

Osteogenesis Imperfecta Cell therapy

Cell therapy is another interesting therapeutic option for OI as 100% correction of cells is not necessary for normal skeletal growth and function. Mosaic carriers of OI have normal skeletal growth with a 40-75% burden of osteoblasts with COL1A1 variant. Theoretically, these transplanted stem cells would produce normal cells with self-renewing potential providing long term treatment.

Rapid progress has occurred in OI cell therapy with published reports on preclinical and clinical studies. Foetal mesenchymal stromal cells (MSCs) are known to have greater proliferative capacity and can differentiate more readily to bone and muscle cells compared to adult-derived cells.

Gene and cell therapy are ideal treatments, but specific areas remain to be addressed before they can be used as real treatment options. Specificity, efficacy and method of delivery are the main issues that need further research.

Gene silencing

Gene silencing is the inactivation of the mutated copy of a gene by disruption of mRNA translation and would result in haploinsufficiency, converting severe OI caused by a structural defect to mild OI caused by a quantitative defect. A short strand of nucleic acid (RNA/DNA or chemical analogue) complementary to the mRNA for the mutant protein binds to the target mRNA preventing its translation. Intracellular enzymes digest the paired complementary molecule and mRNA. Antisense molecules used so far include oligonucleotides, hammerhead ribozymes, siRNAs (short interfering RNAs) and shRNAs (short hairpin RNAs). There are over 1000 pathogenic variants reported to date and creating SiRNA for specific variants may therefore not be practically possible. Recent studies have used mutation independent method targeting the alleles (single nucleotide polymorphisms (SNPs) or insertions/deletion polymorphisms (indels)), rather than specific variants.

The future for Osteogenesis Imperfecta

Correcting the underlying defective collagen production pathway by gene or cell therapy could provide a definitive cure for OI. Gene therapy for OI is still in its infancy, with published reports mainly in ex-vivo and in-vitro studies. Gene silencing using antisense technology has been widely investigated in OI, which is a dominant-negative disorder.


Boost Brittle Bones Before Birth is a clinical trial investigating the use of foetal MSCs pre and/or postnatally for the treatment of OI. More information can be found here.

BBS Charity research

The Charity has recently announced their next grants funding timeline for 2022, beginning 1st April. There are hopes to emphasise a series of themed ‘calls’ to the wider research community such as proposals based on acute therapies focused on pain and fatigue. Furthermore, in 2018, the Charity consulted with members in relation to what the priority areas should be in relation to research. The full report can be read on the Charity’s website.

Contributor Profile

Chief Executive
Brittle Bone Society
Phone: +44 (0)1382 204 446
Website: Visit Website


Please enter your comment!
Please enter your name here