CORR Insights®: Cardiopulmonary Status in Adults with Osteogenesis Imperfecta: Intrinsic Lung Disease May Contribute More Than Scoliosis

Where Are We Now?

The phenotypic expression of osteogenesis imperfecta varies, but all forms have an increased risk of fractures. Its current classification was originally described by Sillence et al. [10] in 1979, with later modifications. Lifespan is unaffected in patients with the mild type (Type I), while a shortened lifespan is seen in patients with the moderate and severe types (Types IV and III). Type II is lethal at the time of birth. All types are similar in that the structures of Type I collagen and folding or other proteins that are important for the function of Type I collagen are affected, although the exact genetic cause cannot always be identified [5, 8].

Because of the relative rarity of osteogenesis imperfecta, with a prevalence of approximately 20 in 100,000 births and a population prevalence of about 10 in 100,000, most clinical studies are based on relatively small sample sizes [1, 4, 8]. They usually include several types of osteogenesis imperfecta.

With the recognition of osteogenesis imperfecta as not only a brittle-bone disease but also a connective tissue disease, other aspects of the disease now are being studied [5]. Cardiopulmonary failure is a leading cause of death in patients with the more-severe types of osteogenesis imperfecta [9]. Previous studies have described correlations between kyphoscoliosis and pulmonary function [5, 9, 11]. A previous experimental study has suggested that pulmonary parenchyma disorders and diaphragmatic dysfunction are possible reasons for diminished lung function [2]. Previous clinical studies have tried to discern whether there is a relationship between spinal deformity and the pulmonary aspect of osteogenesis imperfecta, but there are few studies on this topic [3, 5, 11]. The study by Khan et al. [7] in this issue of Clinical Orthopaedics and Related Research® gives additional information on the relationship between scoliosis and lung function, including data on pulmonary function, radiography results, electrocardiography, and echocardiography. With their detailed approach, the authors have done great work to advance knowledge in this field. We learn that scoliosis and restrictive lung function are common in patients with osteogenesis imperfecta. However, there was no correlation between the scoliosis curve and signs of restrictive lung function, except in individuals with very large curves. Also, signs of intrinsic pulmonary dysfunction were independent of curve size.

Where Do We Need To Go?

There is an apparent association between scoliosis and lung function in patients with larger curves. However, lung function depends not only on the thoracic cage, but also on factors directly affecting the pulmonary parenchyma. It is important to monitor cardiac and pulmonary function in these patients. Future studies will need to collect detailed data on lung function, thoracic parameters, and cardiac function. We need to treat spinal deformity before it becomes severe in patients with osteogenesis imperfecta, but this study [7] and others [3, 5, 11] inform us that a work-up including cardiac and pulmonary function should be performed before surgery for a spinal deformity. It would also be important to study the development of cardiac and pulmonary function after surgery to treat scoliosis.

This study also raises the question of whether today’s treatment of osteogenesis imperfecta, such as established treatment with bisphosphonates, which has the potential to decrease the risk of fracture and scoliosis development, also has positive effects on lung and cardiac function [6].

How Do We Get There?

Multiple studies, both observational and treatment, on osteogenesis imperfecta are ongoing (see, for example, studies registered at clinicaltrials.gov, including NCT03735537, NCT04115774, and NCT02432625). The outcomes of most of these trials are fracture and quality of life, while pulmonary and cardiac outcomes are not always part of ongoing study protocols. The study by Khan et al. [7] and others [3, 5, 11] indicate that lung and cardiac function should be evaluated as an outcome in future studies. If treatment studies address the risk of fracture and thoracic deformity only and not intrinsic pulmonary and cardiac problems that are independent of the thoracic deformity, important conclusions may be overlooked.

To get additional information and better delineate the cause of pulmonary and cardiac dysfunction, longitudinal studies are needed. These could recruit younger individuals with the aim of regularly following them during growth for lung and cardiac function, and these studies could evaluate thoracic and spine parameters, as well as pulmonary function. The number of patients with osteogenesis imperfecta is small and the present study [7] and other ongoing studies should encourage in collaborative efforts to achieve large sample sizes. The use of prospective national clinical registries is one way to proceed (for example clinicaltrials.gov, NCT04115774). Researchers should try to agree on which variables to collect on the individual level for future observational studies collecting data from several centers, both national and international. Such efforts would soon increase the amount of available data, increase the certainty of study conclusions, and improve the study of different osteogenesis imperfecta types and subtypes. I think most people with osteogenesis imperfecta and their families would be more than happy to contribute to such efforts in the future.