Brittle Bone Disease: Knowns, Unknowns and the Road Ahead

Slow but steady progress vs. rare inherited connective tissue disorder


By Chad Deal, MD, and Marvin Natowicz, MD, PhD


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Few U.S. centers offer expertise in managing osteogenesis imperfecta (OI), a rare inherited connective tissue disorder also called brittle bone disease. As the primary mode of inheritance is autosomal dominant, management often is a family affair that spans generations and involves long-term specialized care. This article surveys progress made in understanding this distinctive condition in recent years and shares some insights gleaned from our experience managing families afflicted by OI.

OI at a glance

OI refers to a heterogeneous group of connective tissue syndromes stemming from genetic defects that result in an abnormal type I collagen bone matrix. This abnormality typically leads to a heightened risk of fractures over the lifespan (Figures 1 and 2), often with little or no trauma.


Figures 1 and 2. Osteopenia and fractures are the major manifestations of OI, as shown in these fracture images.

Evaluation of bone mineral density (BMD), through dual-energy X-ray absorptiometry or by quantitative CT, also reveals significantly reduced bone density (generalized or localized) in most individuals with OI. Common but nonuniversal features include:

  • Blue sclera
  • Short stature
  • Hearing loss
  • Dentinogenesis imperfecta
  • Progressive skeletal deformity (Figure 3)

Severity ranges from cases of perinatal lethality to asymptomatic persons with normal stature and lifespan having a mild predisposition to fractures.


Figure 3. The most severe forms of OI, as in this example, cause severe skeletal deformities due to excessive bone malleability.

Four syndromic types

The current classification of OI derives from a notable 1979 study by Sillence and colleagues that initially defined four syndromic types based on clinical characteristics and inheritance pattern:

  • Type I: Dominantly inherited OI with blue sclera
  • Type II: Perinatally lethal OI with radiographically apparent crumpled femurs and beaded ribs
  • Type III: Progressively deforming OI with normal sclera
  • Type IV: Dominantly inherited OI with normal sclera

Autosomal dominance was recognized as the mode of inheritance in most cases of OI, but it was apparent that some individuals had an autosomal recessive form. Radiographic heterogeneity within major types of OI was also recognized and then used for subcategorization. Since 1979 there have been additional reconsiderations of OI nosology, with the original classification serving as a framework that has been updated by advances in the molecular genetic understanding of OI.

Evolving understanding of genetics, molecular pathophysiology

Another major development came in 1983 with elucidation of the first genetic cause of OI, a deletion within a collagen gene, COL1A1. Type I collagen, the predominant collagen of bone, skin and tendons, is a heterotrimer initially synthesized as a procollagen precursor that contains two proα1(I) and one proα2(I) polypeptide chains encoded by the COL1A1 and COL1A2 genes, respectively. Newly synthesized procollagen molecules have short amino (N) and carboxy (C) propeptide domains flanking a central helical domain that consists of a long stretch of an uninterrupted domain of Gly-X-Y sequences where X and Y are usually proline and hydroxyproline, respectively.

Initial processing occurs in the endoplasmic reticulum with aligning and folding of the polypeptide chains to form a triple helical structure. Further intracellular modifications ensue, followed by exocytosis, cleavage of the C- and N-propeptides, and cross-linking of collagen type I molecules to form mature collagen fibrils. Each modification results from a different enzymatic activity; a deficiency of any of these enzymes is associated with different genetic (collagen) connective tissue disorders.

Many additional mutations of COL1A1 and COL1A2 genes were later identified, and some genotype-phenotype associations became apparent. About 80 to 90 percent of OI cases are attributable to an autosomal dominant mutation in one of these two collagen genes.

In 2006, the first mutation in a noncollagen gene (CRTAP) was identified in an individual with OI. Since then, mutations in many additional noncollagen genes have been found to be able to cause the less common autosomal recessive forms of OI. All of these genes code for proteins involved in the binding, modification, mineralization, folding, cross-linking or chaperoning of newly synthesized collagen or in osteoblast development.

The paradigm of the molecular pathogenesis of OI has evolved based on these newer findings. While most cases are due to heterozygous mutations of COL1A1 or COL1A2 that result in a reduced amount and/or a qualitative defect of type I collagen, a minority of cases are due to defective function of a protein that interacts with type I collagen or is critical to osteoblast development. It’s now clear that there exists a network of proteins and processes that when perturbed can result in cellular and tissue pathology causing a phenotype within the OI spectrum.

These new insights will undoubtedly advance a deeper understanding of the structure and function of extracellular matrix in both normal and disease states — and should aid the discovery of still more causes of as-yet-undiagnosed cases of OI and similar disorders.


Therapy: Bisphosphonates and beyond

Bisphosphonates are commonly prescribed to individuals with OI in an attempt to increase BMD and reduce fractures. A recent Cochrane analysis of 14 trials with a collective 819 participants demonstrated that either oral or IV bisphosphonates increase BMD in children and adults with OI. Although it was unclear whether oral or IV bisphosphonate treatment consistently decreased fractures, multiple studies reported this independently, and no studies reported an increased fracture rate with treatment. Functional status and quality of life were conclusively demonstrated to improve (reduced pain; improved growth and functional mobility). The authors concluded that the optimal method, optimal duration and long-term safety of bisphosphonate therapy require further investigation. They also noted that attention should be given to long-term fracture reduction and improvement in quality-of-life indicators.

A recent study of teriparatide in 79 adults with OI demonstrated a teriparatide-induced anabolic response, with increases in hip and spine areal BMD, vertebral volumetric BMD by CT scan, and estimated vertebral strength using finite element analysis. Response was most pronounced in patients with less severe OI (type I).

Ongoing trials of pharmacotherapy for OI include:

  • NCT01679080, comparing IV bisphosphonate therapy with teriparatide (primary outcome, BMD; secondary outcome, fracture)
  • NCT02352753, investigating denosumab in children ages 2 to 17 (primary outcome, BMD; secondary outcome, fracture)

As our insights into the molecular pathophysiology of OI continue to expand, the hope is that they will serve to advance the development of additional therapies for OI and related challenging conditions.

Dr. Deal is Director of the Center for Osteoporosis and Metabolic Bone Disease in Cleveland Clinic’s Department of Rheumatic and Immunologic Diseases.

Dr. Natowicz is a staff physician and researcher in Cleveland Clinic’s Genomic Medicine Institute and Department of Clinical Pathology.

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