Research Publications

A qualitative exploration of patient perspectives on psychosocial burdens and positive factors in adults with osteogenesis imperfecta. Rork WC, Hertz AG, Wiese AD, Kostick KM, Nguyen D, Schneider SC, Shepherd WS, Cho H; Members of the BBDC; Murali CN, Lee B, Sutton VR, Storch EA. Am J Med Genet A. 2023 Sep;191(9):2267-2275. doi: 10.1002/ajmg.a.63323. Epub 2023 Jun 15. PMID: 37317786

Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders associated with a wide range of symptoms, including fragile bones that break easily. Although progress has been made in understanding the spectrum of physical symptoms, less is known about the impact of OI on psychosocial well-being, as well as factors that can help lessen negative outcomes.

In this study, researchers developed a qualitative approach to assess perspectives from individuals with OI on psychosocial burdens and positive factors related to OI. Among 15 adults with varying disease status, the team conducted semi-structured interviews and identified themes from responses.

Participants reported negative psychosocial outcomes related to bone fractures and recovery, uncertainty of future fractures, and self-image. Participants also described positive traits related to OI and their lived experience with a chronic disease. Authors note that these insights highlight a need for continued research on the relationship between OI disease status and psychosocial outcomes, as well as the development of psychological interventions designed for individuals with OI.

Approach to the Patient: Pharmacological therapies for fracture risk reduction in adults with osteogenesis imperfecta. Liu W, Lee B, Nagamani SCS, Nicol L, Rauch F, Rush ET, Sutton VR, Orwoll E. J Clin Endocrinol Metab. 2023 Jan 20:dgad035. doi: 10.1210/clinem/dgad035. Epub ahead of print. PMID: 36658750.

Osteogenesis imperfecta (OI) is a group of 21 rare, inherited disorders caused by 19 gene mutations resulting in fragile bones that break easily. The effectiveness of medications used for fracture reduction in adults with OI, as well as practice recommendations, are not well established.

In this review paper, researchers summarize current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. In addition to manual searches of reference lists, the team performed a PubMed online database search of all study types published in the English language using the terms “osteogenesis imperfecta,” “OI,” and “brittle bone disease.”

Findings show that despite limited clinical trial data, bisphosphonate and teriparatide therapies may help improve bone mineral density in adults with OI. Authors state that further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.

A multicenter study to evaluate pain characteristics in osteogenesis imperfecta. Rodriguez Celin M, Kruger KM, Caudill A, Murali CN, Nagamani SCS, Members Of The Brittle Bone Disorders Consortium Bbdc, Smith PA, Harris GF. Am J Med Genet A. 2022 Oct 22. doi: 10.1002/ajmg.a.63009. Epub ahead of print. PMID: 36271817.

Osteogenesis imperfecta (OI) is a group of rare, inherited disorders caused by gene mutations resulting in fragile bones that break easily. Symptoms include skeletal and joint deformities, hearing loss, a bluish tint to the sclerae (whites of the eyes), dental problems, respiratory problems, and chronic pain. In this study, researchers aimed to describe pain characteristics and treatments used in individuals with varying severity of OI, as well as investigate variables associated with pain. Using data from a natural history study of OI conducted by the Brittle Bone Disorders Consortium (BBDC), the team analyzed the prevalence, characteristics, treatments, and predictors of chronic pain. Among 861 individuals with OI, results showed that 41.8% had chronic pain, which was most frequently located in the back. Predictors of chronic pain for all OI types included age, use of a wheelchair, and number of fractures per year. Compared to participants without chronic pain, participants with chronic pain missed more days from school or work per year and performed worse in all mobility metrics. The most common treatments were nonsteroidal anti-inflammatory drugs and bisphosphonates. These results show that chronic pain is prevalent in OI across all types, affects mobility, and interferes with participation.

Targeting TGF-β for treatment of osteogenesis imperfecta. Song IW, Nagamani SC, Nguyen D, Grafe I, Sutton VR, Gannon FH, Munivez E, Jiang MM, Tran A, Wallace M, Esposito P, Musaad S, Strudthoff E, McGuire S, Thornton M, Shenava V, Rosenfeld S, Huang S, Shypailo R, Orwoll E, Lee B. J Clin Invest. 2022 Apr 1;132(7):e152571. doi: 10.1172/JCI152571.

Alterations of a serum marker of collagen X in growing children with osteogenesis imperfecta. Nicol LE, Coghlan RF, Cuthbertson D, Nagamani SCS, Lee B, Olney RC, Horton W; Members of the Brittle Bone Disease Consortium, Orwoll E. Bone. 2021 Aug;149:115990. doi: 10.1016/j.bone.2021.115990. Epub 2021 Apr 28.

Osteogenesis imperfecta is a genetic disorder characterized by bone fragility, abnormal bone growth, and short stature. In this study, researchers sought to better understand the mechanisms by which abnormalities in collagen contribute to growth plate dysfunction. Growth plates are the areas of new bone growth in children and teens, which are made up of cartilage. Researchers examined the presence of Type X collagen (CXM), which has been found to be a reliable marker for new bone formation in cartilage, in blood samples of 187 subjects ages 8 months to 40 years with OI compared with control subjects. All subjects had higher levels of CXM early in life and during puberty, but there was greater variability for the OI cohort and a weaker relationship with growth velocity. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. Results suggest that the relationship between growth plate and the end point of skeletal growth is disrupted in OI.

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. Marom R, Burrage LC, Venditti R, Clément A, Blanco-Sánchez B, Jain M, Scott DA, Rosenfeld JA, Sutton VR, Shinawi M, Mirzaa G, DeVile C, Roberts R, Calder AD, Allgrove J, Grafe I, Lanza DG, Li X, Joeng KS, Lee YC, Song IW, Sliepka JM, Batkovskyte D, Washington M, Dawson BC, Jin Z, Jiang MM, Chen S, Chen Y, Tran AA, Emrick LT, Murdock DR, Hanchard NA, Zapata GE, Mehta NR, Weis MA, Scott AA, Tremp BA, Phillips JB, Wegner J, Taylor-Miller T, Gibbs RA, Muzny DM, Jhangiani SN, Hicks J, Stottmann RW, Dickinson ME, Seavitt JR, Heaney JD, Eyre DR; Undiagnosed Diseases Network, Westerfield M, De Matteis MA, Lee B. Am J Hum Genet. 2021 Sep 2;108(9):1710-1724. doi: 10.1016/j.ajhg.2021.08.002. Epub 2021 Aug 26.

Vesicle coat proteins help cells sort and transport or “traffic” proteins and lipids. Pathogenic variants (mutations) in genes that encode subunits of coat complexes called coatomers are believed to contribute to a number of genetic disorders called coatopathies that can affect the skeletal and central nervous systems. In this study, researchers examined loss-of-function variants in the gene COPB2, which encodes for a protein in the coatomer complex, in six individuals from five unrelated families who have osteoporosis or osteopenia (brittle bones that may fracture easily) and variable degree of developmental delay. Researchers also used zebrafish and mouse models to further study the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone development. The authors conclude that COPB2 haploinsufficiency (meaning only 50% of the normal active form of a particular protein is expressed) is a cause of this form of coatopathy. They also tested ascorbic acid supplementation as a potential treatment and found that it had a beneficial effect on animal models.

Health-related quality of life in adults with osteogenesis imperfecta. Murali CN, Slater B, Musaad S, Cuthbertson D, Nguyen D, Turner A, Azamian M, Tosi L, Rauch F, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SCS. Clin Genet. 2021 Jun;99(6):772-779. doi: 10.1111/cge.13939. Epub 2021 Feb 22.

Missing and unerupted teeth in osteogenesis imperfecta. Taqi D, Moussa H, Schwinghamer T, Vieira AR, Dagdeviren D, Retrouvey JM, Rauch F, Tamimi F; Members of the BBDC. Bone. 2021 Sep;150:116011. doi: 10.1016/j.bone.2021.116011. Epub 2021 May 18.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and craniofacial and dental abnormalities. It is believed that OI patients have missing or unerupted teeth at a rate twice the general population. To better understand the factors influencing missing and unerupted teeth, researchers studied 144 OI patients. They examined clinical phenotype (OI type), the genetic variant type, the tooth type and the onset of biophosphonate treatment, which slows bone loss. They found that the presence of missing and unerupted teeth varied according to the nature of the collagen variants and OI type. These findings highlight the role of collagen in tooth development and eruption.

Osteogenesis imperfecta tooth level phenotype analysis: Cross-sectional study. Taqi D, Moussa H, Schwinghamer T, Ducret M, Dagdeviren D, Retrouvey JM, Rauch F, Tamimi F; Members of the BBDC. Bone. 2021 Jun;147:115917. doi: 10.1016/j.bone.2021.115917. Epub 2021 Mar 16.

Pregnancy in women with osteogenesis imperfecta: pregnancy characteristics, maternal, and neonatal outcomes. Rao R, Cuthbertson D, Nagamani SCS, Sutton VR, Lee BH, Krischer J, Krakow D. Am J Obstet Gynecol MFM. 2021 Jul;3(4):100362. doi: 10.1016/j.ajogmf.2021.100362. Epub 2021 Mar 26.

Women with rare diseases considering pregnancy often lack data regarding outcomes, specific risks, and management strategies. The Brittle Bone Disorders Consortium established an Osteogenesis Imperfecta Pregnancy Registry to collect data on pregnancy, maternal, and neonatal outcomes in women with osteogenesis imperfecta (OI), or brittle bone disease. A total of 132 participants with OI completed a cross-sectional, survey-based study. Of respondents, 34% had moderate to severe OI. Researchers compared self-reported information on pregnancy and maternal and neonatal outcomes of women with OI with data on the general population, referenced by literature-based standards. Results indicated that women with OI had higher rates than the general population of diabetes in pregnancy, cesarean delivery, need for blood transfusion, and fractures before or after delivery. Individuals with moderate or severe OI reported higher maternal hospitalization and delivery rates than those with mild OI. Babies born to women with OI had higher rates of neonatal intensive care unit admissions and higher neonatal mortality, regardless of neonatal OI status. Study authors say that patients and providers should be aware of these findings, particularly the need for blood products (hemorrhage) and the increased rate of fractures, low birthweight infants, and neonatal mortality. They suggest that survey results can support both preconception counseling and proactive measures to reduce harm and recognize modifiable risk factors related to pregnancy.

A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta. Rodriguez Celin M, Kruger KM, Caudill A, Nagamani SCS; Brittle Bone Disorders Consortium (BBDC); Linked Clinical Research Centers (LCRC), Harris GF, Smith PA. JB JS Open Access. 2020 Sep 11;5(3):e20.00031. doi: 10.2106/JBJS.OA.20.00031. eCollection 2020 Jul-Sep.

Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles. Rauch D, Robinson ME, Seiltgens C, Sutton VR, Lee B, Glorieux F, Rauch F. Bone. 2020 Nov;140:115547. doi: 10.1016/j.bone.2020.115547. Epub 2020 Jul 27.

Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study. Machol K, Hadley TD, Schmidt J, Cuthbertson D, Traboulsi H, Silva RC, Citron C, Khan S, Citron K, Carter E, Brookler K, Shapiro JR, Steiner RD, Byers PH, Glorieux FH, Durigova M, Smith P, Bober MB, Sutton VR, Lee BH; Members of the BBD Consortium, Nagamani SCS, Raggio C. Am J Med Genet A. 2020 Apr;182(4):697-704. doi: 10.1002/ajmg.a.61464. Epub 2019 Dec 26.

Malocclusion traits and oral health-related quality of life in children with osteogenesis imperfecta: A cross-sectional study. Najirad M, Madathil SA, Rauch F, Sutton VR, Lee B, Retrouvey JM; Members of the Brittle Bone Diseases Consortium, Esfandiari S. J Am Dent Assoc. 2020 Jul;151(7):480-490.e2. doi: 10.1016/j.adaj.2020.03.040.

Pediatric Outcomes Data Collection Instrument is a Useful Patient-Reported Outcome Measure for Physical Function in Children with Osteogenesis Imperfecta. Murali CN, Cuthbertson D, Slater B, Nguyen D, Turner A, Harris G, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SCS. Genet Med. 2020 Mar;22(3):581-589. doi: 10.1038/s41436-019-0688-6. Epub 2019 Nov 27.

A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta. Bains JS, Carter EM, Citron KP, Boskey AL, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sliepka JM, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SC, Raggio CL. JBMR Plus. 2019 Jan 7;3(5):e10118. doi: 10.1002/jbm4.10118. eCollection 2019 May.

Assessing Disease Experience across the Life Span for Individuals with Osteogenesis Imperfecta: Challenges and Opportunities for Patient-Reported Outcomes (PROs) Measurement. Tosi LL, Floor MK, Dollar CM, Gillies AP; Members of the Brittle Bone Disease Consortium, Hart TS, Cuthbertson DD, Sutton VR, Krischer JP. Orphanet Journal of Rare Diseases. 2019. 14:23. https://doi.org/10.1186/s13023-019- 1004-x. PMID: 30696467.

Caries Prevalence and Experience in Individuals with Osteogenesis Imperfecta. Ma MS, Najirad M, Taqi D, Retrouvey JM, Tamimi F, Dagdeviren D, Glorieux FH, Lee B, Sutton VR, Rauch F, Esfandiari S. Spec Care Dentist. 2019 Mar;39(2):214-219. Epub 2019 Feb 13. https://doi.org/10.1101/418806. PMID: 30758072.

Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5. Dagdeviren D, Tamimi F, Lee B, Sutton R, Rauch F, Retrouvey JM. Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5. Dagdeviren D, Tamimi F, Lee B, Sutton V, Rauch F, Retrouvey JM. Am J Med Genet A. 2018 Oct 5. doi: 10.1002/ajmg.a.40383. PMID: 30289614.

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Jain M, Tam A, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Mullins M, Bellur S, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Lee B, Sutton VR; , Members of the Brittle Bone Disorders Consortium*, Nagamani SCS. Genet Med. 2018 Jul 4. doi: 10.1038/s41436-018-0045-1. PMID: 29970925.

Identification of Functionally Distinct Mx1+αSMA+ Periosteal Skeletal Stem Cells. Ortinau LC, Wang H, Lei K, Deveza L, Jeong Y, Hara Y, Grafe I, Rosenfeld SB, Lee D, Lee B, Scadden DT, Park D. Cell Stem Cell. 2019 Dec 5;25(6):784-796.e5. doi: 10.1016/j.stem.2019.11.003.

Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community. Swezey T, Reeve BB, Hart TS, Floor MK, Dollar CM, Gillies AP, Tosi LL. Osteoporos Int. 2019 Feb;30(2):507-511. doi: 10.1007/s00198-018-4690-7. Epub 2018 Sep 6. PMID:30191258.

Mobility in Osteogenesis Imperfecta: A Multicenter North American Study. Kruger KM, Caudill A, Rodriguez Celin M, Nagamani SCS, Shapiro JR, Steiner RD, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Durigova M, Glorieux FH, Rauch F, Sutton VR, Lee B, Rush ET, Smith PA, Harris GF. Genet Med. 2019 Mar 28. doi: 10.1038/s41436-019-0491-4. PMID: 30918359.

Oro-dental and cranio-facial characteristics of osteogenesis imperfecta type V. Retrouvey JM, Taqi D, Tamimi F, Dagdeviren D, Glorieux FH, Lee B, Hazboun R, Krakow D, Sutton VR; Members of the BBD Consortium. Eur J Med Genet. 2019 Dec;62(12):103606. doi: 10.1016/j.ejmg.2018.12.011. Epub 2018 Dec 26.

Osteogenesis imperfecta: advancements in genetics and treatment. Rossi V, Lee B, Marom R. Curr Opin Pediatr. 2019 Dec;31(6):708-715. doi: 10.1097/MOP.0000000000000813.

A Multicenter Study to Evaluate Pulmonary Function in Osteogenesis Imperfecta. Tam A, Chen S, Schauer E, Grafe I, Bandi V, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Mullins M, Byers PH, Sandhaus RA, Durigova M, Glorieux FH, Rauch F, Reid Sutton V, Lee B; Members of the Brittle Bone Disorders Consortium, Rush ET, Nagamani SCS. Clin Genet. 2018 Dec;94(6):502-511. doi: 10.1111/cge.13440. Epub 2018 Sep 24. PMID: 30152014.

Cone‐Beam Computed Tomography of Osteogenesis Imperfecta Types III and IV: Three‐Dimensional Evaluation of Craniofacial Features and Upper Airways. Reznikov N, Dagdeviren D, Tamimi F, Glorieux F, Rauch F, Retrouvey JM. JBMR Plus, Epub November 16, 2018; doi: 10.1002/jbm4.10124.

Heterozygous WNT1 variant causing a variable bone phenotype. Alhamdi S, Lee YC, Chowdhury S, Byers PH, Gottschalk M, Taft RJ, Joeng KS, Lee BH, Bird LM. Am J Med Genet A. 2018 Nov;176(11):2419-2424. doi: 10.1002/ajmg.a.40347. Epub 2018 Sep 24.

Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta. Bains JS, Carter EM, Citron KP, Boskey AL, Shapiro JR, Steiner RD, Smith PA, Bober MA, Hart T, Cuthbertson D, Krischer J, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sliepka JM, Sutton VR, Lee B, “Members of the BBD Consortium”, Nagamani SC, Raggio CL. JBMR Plus, Epub October 23, 2018; doi: 10.1002/jbm4.10118.

Oral Health-Related Quality of Life in Children and Adolescents with Osteogenesis Imperfecta: cross- sectional study. Najirad M, Ma MS, Rauch F, Sutton VR, Lee B, Retrouvey JM; Members of the BBD, Esfandiari S. Orphanet J Rare Dis. 2018 Oct 25;13(1):187. doi: https://doi.org/10.1101/424812. PMID: 30359278.

Osteogenesis imperfecta: potential therapeutic approaches. Rousseau M, Retrouvey JM; Members of the Brittle Bone Disease Consortium. PeerJ. 2018 Aug 17;6:e5464. doi: 10.7717/peerj.5464. eCollection 2018. PMID: 30128210.

Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-β Treatment. Bi X, Grafe I, Ding H, Flores R, Munivez E, Jiang MM, Dawson B, Lee B, Ambrose CG. J Bone Miner Res. 2017 Feb;32(2):347-359. doi: 10.1002/jbmr.2997. Epub 2016 Oct 20.

Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. Lietman CD, Lim J, Grafe I, Chen Y, Ding H, Bi X, Ambrose CG, Fratzl-Zelman N, Roschger P, Klaushofer K, Wagermaier W, Schmidt I, Fratzl P, Rai J, Weis M, Eyre D, Keene DR, Krakow D, Lee BH. J Bone Miner Res. 2017 Jun;32(6):1354-1367. doi: 10.1002/jbmr.3108. Epub 2017 Mar 20.

Genetic causes and mechanisms of Osteogenesis Imperfecta. Lim J, Grafe I, Alexander S, Lee B. Bone. 2017 Sep;102:40-49. doi: 10.1016/j.bone.2017.02.004. Epub 2017 Feb 15.

Orthodontic chart documentation. Abdelkarim A, Jerrold L. Am J Orthod Dentofacial Orthop. 2017 Jul;152(1):126-130. doi: 10.1016/j.ajodo.2017.03.018.

Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Bellur S, Jain M, Cuthbertson D, Krakow D, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Krischer J, Mullins M, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SC. Genet Med. 2016 Jun;18(6):570-6. doi: 10.1038/gim.2015.131. Epub 2015 Oct 1. PMID: 26426884.

Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. Grafe I, Alexander S, Yang T, Lietman C, Homan EP, Munivez E, Chen Y, Jiang MM, Bertin T, Dawson B, Asuncion F, Ke HZ, Ominsky MS, Lee B. J Bone Miner Res. 2016 May;31(5):1030-40. doi: 10.1002/jbmr.2776. Epub 2016 Feb 12.

A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. Lietman CD, Marom R, Munivez E, Bertin TK, Jiang MM, Chen Y, Dawson B, Weis MA, Eyre D, Lee B. J Bone Miner Res. 2015 Mar;30(3):489-98. doi: 10.1002/jbmr.2363.