View source for Osteogenesis imperfecta

{{Short description|Group of genetic disorders resulting in fragile bones}}
{{Redirect|Brittle bone disease|the etiologically distinct disease arising primarily from malnutrition rather than exclusively from genetic mutation|rickets|text=}}
{{Good article}}
{{Use dmy dates|date=August 2021}}
{{Infobox medical condition
| name          = Osteogenesis imperfecta&nbsp;(OI)
| image         = Characteristically blue sclerae of patient with osteogenesis imperfecta.jpg
| caption       = [[Blue sclerae]] are a classic [[non-pathognomonic]] sign of osteogenesis imperfecta.
| pronunciation = {{IPAc-en|ˌ|ɒ|s|t|i|oʊ|ˈ|dʒ|ɛ|n|ə|s|ɪ|s|_|ˌ|ɪ|m|p|ɜːr|ˈ|f|ɛ|k|t|ə}}<ref name="pronunciation">{{unbulleted list citebundle|{{Cite dictionary |url=http://www.lexico.com/definition/osteogenesis |archive-url=https://web.archive.org/web/20210823000000/http://www.lexico.com/definition/osteogenesis |archive-date=2021-08-23 |title=osteogenesis |dictionary=[[Lexico]] UK English Dictionary |publisher=[[Oxford University Press]]}} {{Cite dictionary |url=http://www.lexico.com/definition/osteogenesis+imperfecta |archive-url=https://web.archive.org/web/20210823000000/http://www.lexico.com/definition/osteogenesis+imperfecta |archive-date=2021-08-23 |title=osteogenesis imperfecta |dictionary=[[Lexico]] UK English Dictionary UK English Dictionary |publisher=[[Oxford University Press]]}}|{{Cite Merriam-Webster|osteogenesis|access-date=2021-08-23}} {{Cite Merriam-Webster|osteogenesis imperfecta|access-date=2021-08-23}}}}</ref><br/> {{respell|OSS|tee|oh|JEN|ə|siss|_|IM|pur|FEK|tə}}
| field         = [[Pediatrics]], [[medical genetics]], [[orthopedics]]
| synonyms      = Brittle bone disease,<ref name="Shapiro2014"/> Lobstein syndrome,<ref name="Shapiro2014"/>{{rp|5}} fragilitas ossium,<ref name="Roger1983"/> Vrolik disease,<ref name="Shapiro2014"/>{{rp|5}} osteopsathyrosis idiopathica<ref name="Davel1956"/>{{rp|347}}
| symptoms      = Bones that [[bone fracture|break]] easily, blue tinge to the [[sclera]] (whites of the eye), short height, [[joint hypermobility]], [[hearing loss]]<ref name="Rowe2008" />
| onset         = Birth
| onset_always  = y
| duration      = Long term
| causes        = [[Genetics|Genetic]] ([[autosomal dominant]] or ''[[Germline mutation|de novo]]'' [[mutation]])<ref name="Zhytnik2019" />
| diagnosis     = Based on symptoms, [[DNA testing]]
| prevention    = [[Pre-implantation genetic diagnosis]]
| management    = Healthy lifestyle (exercise, no smoking), metal rods through the [[long bones]]
| medication    = [[Bisphosphonates]]<ref name=Phi2016/>
| prognosis     = Depends on the type
| frequency     = 1 in 15,000–20,000 people<ref name=Forlino2016/>
}}

{{Multiple image
| perrow            = 2
| align             = right
| direction         = horizontal
| total_width       = 313
| image1            = Osteogenesis_imperfecta_X-ray_(clinically_type_IV)_of_left_forearm.png
| image2            = Osteogenesis_imperfecta_X-ray_(clinically_type_IV)_of_spine,_chest,_and_pelvis.png
| image3            = Osteogenesis_imperfecta_X-ray_(clinically_type_IV)_of_right_arm.png
| image4            = Osteogenesis_imperfecta_X-ray_(clinically_type_IV)_of_right_femur.png
| footer            = Four [[X-ray]]s of a 24-year-old American man ([[Fredrick Brennan]]), who had had more than one hundred [[bone fractures]] in his lifetime, and received a childhood [[clinical diagnosis]] of [[#Type IV|type IV–B]] OI. [[Genetic diagnosis]] in 2018 identified a previously uncatalogued [[pathogenic variant]] in the [[gene]] which encodes [[COL1A2|proα2(I) chains of type I procollagen]], ''COL1A2'', at [[exon]] 19, [[point mutation|substitution]] [[coding DNA|c.]]974[[guanine|G]]>[[adenine|A]]. Due to [[childhood neglect]] and poverty, Brennan never received [[Orthopedic surgery|surgery]] to implant [[intramedullary rod]]s. [[Malunion]]s are evident as the [[humerus]] and [[femur]] were broken in adolescence, but orthopedic care did not follow. Severe [[scoliosis]], as well as [[kyphosis]], are also evident. The unavoidably low contrast in the film is due to a combination of Brennan's [[obesity]] and low [[bone mineral density]] (BMD). His BMD [[Z-score]] was [[Osteoporosis#Dual-energy X-ray|-4.1]] according to results of a [[dual-energy X-ray absorptiometry]] (DXA) scan also done in 2018.
| alt1              = Left forearm
| alt2              = Spine, chest, and pelvis
| alt3              = Right forearm
| alt4              = Right femur
}}

<!-- Definition and symptoms -->
'''Osteogenesis imperfecta''' ({{IPAc-en|IPA|ˌ|ɒ|s|t|i|oʊ|ˈ|dʒ|ɛ|n|ə|s|ɪ|s|_|ˌ|ɪ|m|p|ɜːr|ˈ|f|ɛ|k|t|ə}};<ref name="pronunciation" /> '''OI'''), colloquially known as '''brittle bone disease''', is a group of [[genetic disorders]] that all result in [[bone]]s that [[bone fracture|break]] easily.<ref name="Shapiro2014" />{{rp|85}}<ref name="GHR2016">{{Cite web|date=2020-08-18|title=Osteogenesis imperfecta|url=https://medlineplus.gov/genetics/condition/osteogenesis-imperfecta|url-status=live|archive-url=https://web.archive.org/web/20210829154516/https://medlineplus.gov/genetics/condition/osteogenesis-imperfecta/|archive-date=29 August 2021|access-date=2021-08-15|website=Genetics Home Reference|publisher=[[U.S. National Library of Medicine]], [[National Institutes of Health]]}}</ref> The range of symptoms—on the [[skeleton]] as well as on the body's other [[Organ (biology)|organs]]—may be mild to severe.<ref name="Rowe2008" />{{rp|1512}} Symptoms found in various types of OI include [[sclera|whites of the eye]] (sclerae) that are blue instead, [[short stature]], [[joint hypermobility|loose joints]], [[hearing loss]], breathing problems<ref name="NIH2015" /> and problems with the teeth ([[dentinogenesis imperfecta]]).<ref name="Rowe2008">{{Cite book|title=Principles of bone biology|vauthors=Rowe DW|publisher=[[Elsevier]]|year=2008|isbn=978-0-12-373884-4|edition=3rd|location=Amsterdam|pages=1511–1531|chapter=Osteogenesis imperfecta|oclc=267135745|quote=Dentinogenesis imperfecta (DI) is most frequent in OI types III and IV, and overall, affects about 15% of OI patients among the different phenotypes.}}</ref> Potentially life-threatening [[Complication (medicine)|complications]], all of which become more common in more severe OI, include: tearing ([[Dissection (medical)|dissection]]) of the major [[arteries]], such as [[Aortic dissection|the aorta]];<ref name="Shapiro2014" />{{rp|333}}<ref>{{cite journal | vauthors = McNeeley MF, Dontchos BN, Laflamme MA, Hubka M, Sadro CT | title = Aortic dissection in osteogenesis imperfecta: case report and review of the literature | journal = Emergency Radiology | volume = 19 | issue = 6 | pages = 553–556 | date = December 2012 | pmid = 22527359 | doi = 10.1007/s10140-012-1044-1 | s2cid = 11109481 }}</ref> [[pulmonary insufficiency|pulmonary valve insufficiency]] secondary to distortion of the [[ribcage]];<ref name="Shapiro2014" />{{rp|335–341}}<ref name="LoMauro2012">{{cite journal | vauthors = LoMauro A, Pochintesta S, Romei M, D'Angelo MG, Pedotti A, Turconi AC, Aliverti A | title = Rib cage deformities alter respiratory muscle action and chest wall function in patients with severe osteogenesis imperfecta | journal = PLOS ONE | volume = 7 | issue = 4 | article-number = e35965 | date = 2012-04-27 | pmid = 22558284 | pmc = 3338769 | doi = 10.1371/journal.pone.0035965 | doi-access = free | bibcode = 2012PLoSO...735965L }}</ref> and [[basilar invagination]].<ref name="Wallace2017" />{{rp|106–107}}

<!-- Causes and diagnosis -->
The underlying mechanism is usually a problem with [[connective tissue]] due to a lack of, or poorly formed, [[type I collagen]].<ref name="Rowe2008" />{{rp|1513}} In more than 90% of cases, OI occurs due to [[mutation]]s in the ''[[COL1A1]]'' or ''[[COL1A2]]'' genes.<ref>{{Cite book|url=https://books.google.com/books?id=grNNko25htwC|title=The Bone and Mineral Manual: A Practical Guide|vauthors=Shapiro JR, Sponseller PD|date=2005-08-23|publisher=[[Elsevier Inc.]]|isbn=978-0-08-047074-0|veditors=Kleerekoper M, Siris ES, McClung M|page=45|language=en|chapter=10—Osteogenesis Imperfecta|access-date=17 September 2021|archive-date=20 September 2021|archive-url=https://web.archive.org/web/20210920212532/https://books.google.com/books?id=grNNko25htwC&newbks=0|url-status=live}}</ref> These mutations may be [[heredity|hereditary]] in an [[autosomal dominant]] manner but may also occur spontaneously (''[[De novo mutation|de novo]]'').<ref name="GHR2016" /><ref name="Folkestad2016" /> There are four [[Clinical diagnosis|clinically defined]] types: type I, the least severe; type IV, moderately severe; type III, severe and progressively deforming; and type II, [[perinatally]] lethal.<ref name="GHR2016" /><!-- The types here are ordered by severity for ease of understanding and should not be ordered numerically in the lead, as the numbers they have are historical artifacts. --> {{As of|2021|September}}, 19 different genes are known to cause the 21 documented genetically defined types of OI, many of which are extremely rare and have only been documented in a few individuals.<ref name="Marom2020" /><ref name="VanDijk2020" /> Diagnosis is often based on symptoms and may be confirmed by collagen [[biopsy]] or [[DNA sequencing]].<ref name="NIH2015">{{Cite web| vauthors=Lee B, Krakow D|date=July 2019|title=Osteogenesis Imperfecta Overview|url=https://www.bones.nih.gov/health-info/bone/osteogenesis-imperfecta/overview|archive-url=https://web.archive.org/web/20210509104555/https://www.bones.nih.gov/health-info/bone/osteogenesis-imperfecta/overview|archive-date=2021-05-09|access-date=2021-08-21|website=National Institute of Arthritis and Musculoskeletal and Skin Diseases|publisher=[[National Institutes of Health]]}}</ref>

<!-- Treatment, prevention, prognosis -->
Although there is no cure,<ref name="NIH2015" /> most cases of OI do not have a major effect on life expectancy,<ref name="Shapiro2014" />{{rp|461}}<ref name="Folkestad2016" /> death during childhood from it is rare,<ref name="NIH2015" /> and many adults with OI can achieve a significant degree of [[autonomy]] despite [[disability]].<ref name="Donohoe2020" /> Maintaining a [[healthy lifestyle]] by [[exercising]], eating a balanced diet sufficient in [[vitamin D]] and [[Calcium in biology|calcium]], and avoiding [[smoking]] can help prevent fractures.<ref>{{Cite web|date=November 2018|title=What People With Osteogenesis Imperfecta Need To Know About Osteoporosis|url=https://www.bones.nih.gov/health-info/bone/osteoporosis/conditions-behaviors/osteoporosis-oi|access-date=2021-09-18|website=Osteoporosis and Related Bone Diseases National Resource Center|publisher=[[National Institutes of Health]]|archive-date=18 March 2021|archive-url=https://web.archive.org/web/20210318041959/https://bones.nih.gov/health-info/bone/osteoporosis/conditions-behaviors/osteoporosis-oi}}</ref> [[Genetic counseling]] may be sought by those with OI to prevent their children from inheriting the disorder from them.<ref name="Shapiro2014" />{{Rp|101}} Treatment may include acute care of broken bones, [[pain medication]], [[physical therapy]], [[mobility aids]] such as [[leg braces]] and [[wheelchairs]],<ref name="NIH2015" /> [[Vitamin supplement|vitamin D supplementation]], and, especially in childhood, [[rodding surgery]].<ref name="Esposito2020" /> Rodding is an implantation of metal [[intramedullary rod]]s along the [[long bones]] (such as the [[femur]]) in an attempt to strengthen them.<ref name="NIH2015" /> [[Medical research]] also supports the use of medications of the [[bisphosphonate]] class, such as [[pamidronate]], to increase [[bone density]].<ref>{{cite journal | vauthors = Harrington J, Sochett E, Howard A | title = Update on the evaluation and treatment of osteogenesis imperfecta | journal = Pediatric Clinics of North America | volume = 61 | issue = 6 | pages = 1243–1257 | date = December 2014 | pmid = 25439022 | doi = 10.1016/j.pcl.2014.08.010 }}</ref> Bisphosphonates are especially effective in children;<ref name="Chevrel2006" /> however, it is unclear if they either increase [[quality of life]] or decrease the rate of fracture incidence.<ref name="Phi2016">{{cite journal | vauthors = Dwan K, Phillipi CA, Steiner RD, Basel D | title = Bisphosphonate therapy for osteogenesis imperfecta | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | article-number = CD005088 | date = October 2016 | issue = 10 | pmid = 27760454 | pmc = 6611487 | doi = 10.1002/14651858.CD005088.pub4 }}</ref>

<!-- Epidemiology and history -->
OI affects only about one in 15,000 to 20,000 people, making it a [[rare genetic disease]].<ref name="Forlino2016" /> [[Outcome measure|Outcomes]] depend on the genetic cause of the disorder (its type). Type I (the least severe) is the most common, with other types comprising a minority of cases.<ref name="Folkestad2016" /><ref name="Subramanian2020" /><ref name="Lindahl2015">{{cite journal | vauthors = Lindahl K, Åström E, Rubin CJ, Grigelioniene G, Malmgren B, Ljunggren Ö, Kindmark A | title = Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta | journal = European Journal of Human Genetics | volume = 23 | issue = 8 | pages = 1042–1050 | date = August 2015 | pmid = 25944380 | pmc = 4795106 | doi = 10.1038/ejhg.2015.81 }}</ref> Moderate-to-severe OI primarily affects mobility; if rodding surgery is performed during childhood, some of those with more severe types of OI may gain the ability to walk.<ref name="Rodriguez2020" /> The condition has been described since ancient history.<ref name="Kel2012" /> The [[Latinate]] term ''osteogenesis imperfecta'' was coined by Dutch anatomist [[Willem Vrolik]] in 1849; translated literally, it means "imperfect bone formation".<ref name="Kel2012">{{Cite book| vauthors = Kelly EB |title=Encyclopedia of Human Genetics and Disease|date=2012|publisher=ABC-CLIO|isbn=978-0-313-38713-5|page=613|url=https://books.google.com/books?id=gqMYt17klVIC&pg=PA613|url-status=live|archive-url=https://web.archive.org/web/20171105195021/https://books.google.com/books?id=gqMYt17klVIC&pg=PA613|archive-date=2017-11-05}}</ref><ref name="Dang2021" />{{rp|683}}

__TOC__

==Signs and symptoms==

=== Orthopedic ===
[[File:Osteogenesis Imperfecta 5.jpg|thumb|X-ray of the hips in osteogenesis imperfecta, showing low bone density]]
The main symptom of osteogenesis imperfecta is fragile, [[Bone density|low mineral density bones]]; all types of OI have some bone involvement.<ref name="Rowe2008" /> In moderate and especially severe OI, the long bones may be [[Genu varum|bowed]], sometimes extremely so.<ref>{{cite journal | vauthors = Johnson MT, Morrison S, Heeger S, Mooney S, Byers PH, Robin NH | title = A variant of osteogenesis imperfecta type IV with resolving kyphomelia is caused by a novel COL1A2 mutation | journal = Journal of Medical Genetics | volume = 39 | issue = 2 | pages = 128–132 | date = February 2002 | pmid = 11836364 | pmc = 1735034 | doi = 10.1136/jmg.39.2.128 }}</ref> The weakness of the bones causes them to [[Bone fracture|fracture]] easily—a study at the [[Endocrine disease|Endocrine Unit]] at the National Institute of Child Health in [[Karachi, Pakistan]] found an average of 5.8 fractures per year in untreated children.<ref>{{Cite journal |vauthors=Atta I, Iqbal F, Lone SW, et al. |date=2014 |title=Effect of Intravenous Pamidronate Treatment in Children with Osteogenesis Imperfecta |url=https://www.jcpsp.pk/archive/2014/Sep2014/11.pdf |url-status=live |journal=Journal of the College of Physicians and Surgeons Pakistan |location=Karachi |volume=24 |issue=9 |pages=653–657 |pmid=25233970 |archive-url=https://web.archive.org/web/20210817061150/https://www.jcpsp.pk/archive/2014/Sep2014/11.pdf |archive-date=17 August 2021 |access-date=12 December 2023}}</ref> Fractures typically occur much less after [[puberty]], but begin to increase again in women after [[menopause]] and in men between the ages of 60 and 80.<ref name="Shapiro2014" />{{rp|486}}

[[Joint hypermobility]] is also a common sign of OI, thought to be because the affected genes are the same as those that cause some types of [[Ehlers–Danlos syndrome]].<ref name="Rowe2008" />{{rp|1513}} <ref group="note">One OI mutation also causes combined Ehler–Danlos syndrome: "OIEDS1". ([[#{{harvid|Cabral|Makareeva|Colige|Letocha|2005}}|Cabral, ''et al.'' 2005]], [[#{{harvid|Rasmussen|2020}}|Rasmussen 2020]])</ref><ref name="Cabral2005">{{cite journal | vauthors = Cabral WA, Makareeva E, Colige A, Letocha AD, Ty JM, Yeowell HN, Pals G, Leikin S, Marini JC | display-authors = 6 | title = Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing | journal = The Journal of Biological Chemistry | volume = 280 | issue = 19 | pages = 19259–19269 | date = May 2005 | pmid = 15728585 | doi = 10.1074/jbc.m414698200 | doi-access = free }}</ref><ref name="Rasmussen2020">{{Cite web|vauthors=Rasmussen SA|date=2020-12-02|title=Combined osteogenesis imperfecta and Ehlers–Danlos syndrome 1; OIEDS1|url=https://omim.org/entry/619115|url-status=live|access-date=2021-08-17|website=[[Online Mendelian Inheritance in Man]]|publisher=[[Johns Hopkins University]]|id=619115|archive-date=20 September 2021|archive-url=https://web.archive.org/web/20210920212532/https://omim.org/entry/619115}}</ref>

=== Otologic ===
By the age of 50, about 50% of adults with OI experience significant [[hearing loss]], much earlier as compared to the general population.<ref name="Peterson2001">{{cite journal | vauthors = Paterson CR, Monk EA, McAllion SJ | title = How common is hearing impairment in osteogenesis imperfecta? | journal = The Journal of Laryngology and Otology | volume = 115 | issue = 4 | pages = 280–282 | date = April 2001 | pmid = 11276328 | doi = 10.1258/0022215011907442 | url = http://www.journals.cambridge.org/abstract_S0022215101000779 | access-date = 15 August 2021 | url-status = live | s2cid = 12303464 | archive-url = https://web.archive.org/web/20210920212539/https://www.cambridge.org/core/journals/journal-of-laryngology-and-otology/article/abs/how-common-is-hearing-impairment-in-osteogenesis-imperfecta/215FADBB8525BC47A658B98F4EE40730 | archive-date = 20 September 2021 | url-access = subscription }}</ref> Hearing loss in OI may or may not be associated with visible deformities of the [[ossicles]] and [[inner ear]].<ref>{{Cite web|date=2005-11-02|title=OI Issues: Hearing Loss|url=http://www.oif.org/site/PageServer?pagename=HearLoss|archive-url=https://web.archive.org/web/20120120093322/http://www.oif.org/site/PageServer?pagename=HearLoss|archive-date=2012-01-20|access-date=4 November 2018|vauthors=Vernick D}}</ref> Hearing loss frequently begins during the second, third, and fourth decades of life, and may be [[Conductive hearing loss|conductive]], [[Sensorineural hearing loss|sensorineural]], or a combination of both ("mixed").<ref>{{cite journal | vauthors = Santos F, McCall AA, Chien W, Merchant S | title = Otopathology in Osteogenesis Imperfecta | journal = Otology & Neurotology | volume = 33 | issue = 9 | pages = 1562–1566 | date = December 2012 | pmid = 22996160 | pmc = 3498599 | doi = 10.1097/MAO.0b013e31826bf19b }}</ref> If hearing loss does not occur by age 50, it is significantly less likely to occur in the years afterwards.<ref name="Peterson2001" /> Mixed hearing loss is most common among those with OI of all age groups, while conductive hearing loss is most likely to affect older people, with sensorineural hearing loss most likely to affect children.<ref name="Pillion2011">{{cite journal | vauthors = Pillion JP, Vernick D, Shapiro J | title = Hearing loss in osteogenesis imperfecta: characteristics and treatment considerations | journal = Genetics Research International | volume = 2011 | article-number = 983942 | date = 2011-12-14 | pmid = 22567374 | pmc = 3335494 | doi = 10.4061/2011/983942 | publisher = [[Hindawi (publisher)|Hindawi]] | doi-access = free }}</ref>

Although relatively rare, OI-related hearing loss can also begin in childhood; in a study of forty-five children aged four to sixteen, two were found to be affected, aged 11 and 15.<ref>{{cite journal | vauthors = Kuurila K, Grénman R, Johansson R, Kaitila I | title = Hearing loss in children with osteogenesis imperfecta | journal = European Journal of Pediatrics | volume = 159 | issue = 7 | pages = 515–519 | date = July 2000 | pmid = 10923226 | doi = 10.1007/s004310051322 | url = https://link.springer.com/article/10.1007%2Fs004310051322 | access-date = 15 August 2021 | url-status = live | s2cid = 8729406 | archive-url = https://web.archive.org/web/20210815205911/https://link.springer.com/article/10.1007%2Fs004310051322 | archive-date = 15 August 2021 | url-access = subscription }}</ref> In a different 2008 study, the hearing of 41 people with OI was checked. The results showed that 88% of those over 20 years of age had some form of hearing loss, while only 38% of those under 20 did.<ref>{{cite journal | vauthors = Pillion JP, Shapiro J | title = Audiological findings in osteogenesis imperfecta | journal = Journal of the American Academy of Audiology | volume = 19 | issue = 8 | pages = 595–601 | date = September 2008 | pmid = 19323351 | doi = 10.3766/jaaa.19.8.3 }}</ref>

Hearing loss is most common in type I OI; it is less common in types III and IV.<ref name="Shapiro2014" />{{rp|294–296}} Other parts of the inner ear may also be affected by OI. causing [[Balance (ability)|balance]] issues; however, only small studies have found links between [[vertigo]] and OI.<ref name="Shapiro2014" />{{rp|308}} OI may worsen the outcome of medical treatments which correct hearing loss.<ref name="Pillion2011" />

Besides OI's association with sensorineural hearing loss, OI is associated with several neurological abnormalities, usually involving the [[central nervous system]], due to [[deformities]] in the skeletal structures surrounding it. Neurological complications, especially [[basilar invagination]], may adversely affect life expectancy. In OI, this is most often due to upwards migration of the [[Axis (anatomy)#Dens|dens]],<ref name="Khandanpour2012" /><ref name="Wallace2017" />{{rp|106–107}} a feature of the [[C2 vertebra]]. [[Neurosurgery]] may be needed to correct severe abnormalities when they risk the patient's life or cause either great suffering or intolerable [[neurological deficit]]s.<ref name="Khandanpour2012">{{cite journal | vauthors = Khandanpour N, Connolly DJ, Raghavan A, Griffiths PD, Hoggard N | title = Craniospinal abnormalities and neurologic complications of osteogenesis imperfecta: imaging overview | journal = Radiographics | volume = 32 | issue = 7 | pages = 2101–2112 | date = 2012-12-01 | pmid = 23150860 | doi = 10.1148/rg.327125716 }}</ref><ref name="Wallace2017" />{{rp|106–107}}

=== Systemic ===
As its biological causes have been more precisely determined, it has become more widely recognized that while the primary disease process of OI happens in the bones, the most common [[Osteogenesis imperfecta#Classification|types of OI]]—those caused by type I collagen gene mutations—affect virtually all of the human body's [[organs]] in some way.<ref name="Folkestad2016" />

Type I collagen is present throughout the [[Circulatory system|circulatory]] and [[respiratory systems]]: from the [[Ventricle (heart)|ventricles]] of the heart itself, to the [[heart valves]], to the [[vasculature]],<ref name="Shapiro2014" />{{rp|329}} it is an integral part of the [[connective tissue]] of the [[lungs]].<ref name="Shapiro2014" />{{rp|336}} As such, cardiovascular complications, among them [[aortic insufficiency]], [[aortic aneurysm]], and [[arterial dissections]], are sometimes [[comorbid]] with OI,<ref name="Shapiro2014" />{{rp|333}} but not as frequently as they are comorbid with [[Marfan syndrome]].<ref name="Shapiro2014" />{{rp|332}}

Respiratory illnesses are a major cause of death in OI.<ref name="LoMauro2012" /><ref name="Shapiro2014" />{{rp|335}} The most obvious source of respiratory problems in OI is [[pulmonary insufficiency]] caused by problems in the architecture of the [[thoracic wall]].<ref name="Shapiro2014" />{{rp|341}} However, [[respiratory tract infections]], such as [[pneumonia]], are also more fatal among those with OI than the general population.<ref name="LoMauro2012" /><ref>{{Cite journal|vauthors=Turkalj M, Miranović V, Lulić-Jurjević R, Gjergja Juraški R, Primorac D|date=2017-09-25|title=Cardiorespiratory complications in patients with osteogenesis imperfecta|url=https://hrcak.srce.hr/201164|journal=Paediatria Croatica|language=en|volume=61|issue=3|pages=106–111|issn=1330-1403|access-date=29 August 2021|archive-date=20 September 2021|archive-url=https://web.archive.org/web/20210920212534/https://hrcak.srce.hr/201164|url-status=live}}</ref> Those with more severe [[ribcage]] deformities were found to have worse [[Restrictive lung disease|lung restriction]] in a small-scale 2012 study involving 22 Italian patients with OI types III and IV, plus 26 non-affected [[Treatment and control groups|controls]].<ref name="LoMauro2012" />

OI—especially its severe form, type III—also has effects on the gastrointestinal system. It was found to be associated with recurrent abdominal pain and chronic [[constipation]] in two studies on patients affected by OI.<ref>{{cite journal|vauthors=Violas P, Fassier F, Hamdy R, Duhaime M, Glorieux FH|date=September 2002|title=Acetabular protrusion in osteogenesis imperfecta|journal=Journal of Pediatric Orthopedics|volume=22|issue=5|pages=622–625|doi=10.1097/01241398-200209000-00010|pmid=12198464|s2cid=37895736}}</ref><ref name="Lee1995">{{cite journal|vauthors=Lee JH, Gamble JG, Moore RE, Rinsky LA|date=September 1995|title=Gastrointestinal problems in patients who have type-III osteogenesis imperfecta|journal=The Journal of Bone and Joint Surgery. American Volume|volume=77|issue=9|pages=1352–1356|doi=10.2106/00004623-199509000-00010|pmid=7673285}}</ref> Chronic constipation is especially common,<ref name="Shapiro2014" />{{rp|377}} and is thought to be aggravated by an asymmetric [[pelvis]] ([[Protrusio acetabuli|acetabular protrusion]]).<ref name="Shapiro2014" />{{rp|377}}<ref name="Lee1995" /> Especially in childhood, OI-associated constipation may cause a feeling of fullness and associated food refusal, leading to [[malnutrition]].<ref name="Shapiro2014" />{{rp|377}}

== Classification ==
There are two typing systems for OI in modern use. The first, created by [[David Sillence]] in 1979, classifies patients into four types, or [[syndromes]], according to their [[clinical presentation]], without taking into account the genetic cause of their disease.<ref name="Sillence1979">{{cite journal | vauthors = Sillence DO, Senn A, Danks DM | title = Genetic heterogeneity in osteogenesis imperfecta | journal = Journal of Medical Genetics | volume = 16 | issue = 2 | pages = 101–116 | date = April 1979 | pmid = 458828 | pmc = 1012733 | doi = 10.1136/jmg.16.2.101 }}</ref>{{rp|114–115}}<ref name="VanDijk2010">{{cite journal | vauthors = Van Dijk FS, Pals G, Van Rijn RR, Nikkels PG, Cobben JM | title = Classification of Osteogenesis Imperfecta revisited | journal = European Journal of Medical Genetics | volume = 53 | issue = 1 | pages = 1–5 | date = 2010-01-01 | pmid = 19878741 | doi = 10.1016/j.ejmg.2009.10.007 | url = https://www.sciencedirect.com/science/article/abs/pii/S1769721209001554 | access-date = 21 August 2021 | url-status = live | quote = In 1979 Sillence proposed a classification of Osteogenesis Imperfecta (OI) in OI types I, II, III and IV. In 2004 and 2007, this classification was expanded with OI types V–VIII because of distinct clinical features and/or different causative gene mutations. | archive-url = https://web.archive.org/web/20210821004559/https://www.sciencedirect.com/science/article/abs/pii/S1769721209001554 | archive-date = 21 August 2021 | url-access = subscription }}</ref> The second system expands on the Sillence model, but assigns new numbered types genetically as they are found.<ref name="Marini2013" /><ref name="VanDijk2010" /> Therefore, people with OI can be described as having both a ''clinical'' type and a ''genetic'' type, which may or may not be equivalent.<ref name="VanDijk2010" />

Type I is the most common, and 90% of cases result from mutations to either ''[[COL1A1]]'' or ''[[COL1A2]]''.<ref name="GHR2016" /> Symptoms vary widely between types, as well as vary from person to person, even in the same family.<ref>{{Cite web|vauthors=McKusick VA, Hamosh A|date=2018-10-23|title=Osteogenesis imperfecta, type I; OI1|url=https://omim.org/entry/166200|url-status=live|access-date=2021-08-17|website=[[Online Mendelian Inheritance in Man]]|publisher=[[Johns Hopkins University]]|language=en-us|id=166200|archive-date=26 March 2021|archive-url=https://web.archive.org/web/20210326192350/https://omim.org/entry/166200}}</ref>

As of 2021, 21 types of OI have been defined:<ref name="Marom2020">{{cite journal | vauthors = Marom R, Rabenhorst BM, Morello R | title = Osteogenesis imperfecta: an update on clinical features and therapies | journal = European Journal of Endocrinology | volume = 183 | issue = 4 | pages = R95–R106 | date = October 2020 | pmid = 32621590 | pmc = 7694877 | doi = 10.1530/EJE-20-0299 | url = https://eje.bioscientifica.com/view/journals/eje/183/4/EJE-20-0299.xml | access-date = 17 August 2021 | url-status = live | archive-url = https://web.archive.org/web/20210817052953/https://eje.bioscientifica.com/view/journals/eje/183/4/EJE-20-0299.xml | archive-date = 17 August 2021 }}</ref><ref name="VanDijk2020">{{cite journal | vauthors = van Dijk FS, Semler O, Etich J, Köhler A, Jimenez-Estrada JA, Bravenboer N, Claeys L, Riesebos E, Gegic S, Piersma SR, Jimenez CR, Waisfisz Q, Flores CL, Nevado J, Harsevoort AJ, Janus GJ, Franken AA, van der Sar AM, Meijers-Heijboer H, Heath KE, Lapunzina P, Nikkels PG, Santen GW, Nüchel J, Plomann M, Wagener R, Rehberg M, Hoyer-Kuhn H, Eekhoff EM, Pals G, Mörgelin M, Newstead S, Wilson BT, Ruiz-Perez VL, Maugeri A, Netzer C, Zaucke F, Micha D | display-authors = 6 | title = Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2 | journal = American Journal of Human Genetics | volume = 107 | issue = 5 | pages = 989–999 | date = November 2020 | pmid = 33053334 | pmc = 7675035 | doi = 10.1016/j.ajhg.2020.09.009 | hdl = 1887/3185060 }}</ref>

{| class="wikitable" 
! colspan="7" |[[Osteogenesis imperfecta#Sillence types|Sillence's four types]]
|-
! Type !! Description !! [[Gene]]!! [[OMIM]] !! [[Mendelian inheritance|Mode of inheritance]]!! Incidence
!Defined<ref group="note" name="OMIMNote">When year is uncited, OMIM is the source.</ref>
 |-
 | '''{{abbr|I|1}}'''  || mild || Null ''[[COL1A1]]'' allele ||{{OMIM|166200||none}} || autosomal dominant, 34% ''de novo''<ref name="Zhytnik2019">{{cite journal | vauthors = Zhytnik L, Maasalu K, Duy BH, Pashenko A, Khmyzov S, Reimann E, Prans E, Kõks S, Märtson A | display-authors = 6 | title = De novo and inherited pathogenic variants in collagen-related osteogenesis imperfecta | journal = Molecular Genetics & Genomic Medicine | volume = 7 | issue = 3 | article-number = e559 | date = March 2019 | pmid = 30675999 | pmc = 6418448 | doi = 10.1002/mgg3.559 }}</ref>|| 1 in 30,000<ref name="VanDijk2011">{{cite journal | vauthors = van Dijk FS, Cobben JM, Kariminejad A, Maugeri A, Nikkels PG, van Rijn RR, Pals G | title = Osteogenesis Imperfecta: A Review with Clinical Examples | journal = Molecular Syndromology | volume = 2 | issue = 1 | pages = 1–20 | date = December 2011 | pmid = 22570641 | pmc = 3343766 | doi = 10.1159/000332228 }}</ref>
| rowspan="4" |1979<ref name="VanDijk2010" />
 |-
 | '''{{abbr|II|2}}'''  || lethal in the perinatal period<ref name="Rowe2008" />{{rp|1511}} || ''COL1A1'', ''[[COL1A2]]'' || {{OMIM|166210||none}} || autosomal dominant, ≈100% ''de novo''<ref name="Zhytnik2019" />|| 1 in 40,000<ref name="Subramanian2020">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK536957/|title=Osteogenesis Imperfecta|website=StatPearls Publishing|vauthors=Subramanian S, Viswanathan VK|year=2021|publisher=StatPearls|pmid=30725642|access-date=30 July 2019|archive-date=21 October 2020|archive-url=https://web.archive.org/web/20201021085017/https://www.ncbi.nlm.nih.gov/books/NBK536957/|url-status=live}} Last Update: February 3, 2019.</ref> to 1 in 100,000<ref name="VanDijk2011" />
 |-
 | '''{{abbr|III|3}}''' || severe, progressive and deforming || ''COL1A1'', ''COL1A2'' || {{OMIM|259420||none}} || autosomal dominant, 85% ''de novo''<ref name="Zhytnik2019" />|| 1 in 60,000<ref name="VanDijk2011" />
 |-
 | '''{{abbr|IV|4}}''' || variable and deforming, but usually with normal [[sclera]]e<ref name="Shapiro2014" />{{rp|294–296}}<ref name="VanDijk2014" />|| ''COL1A1'', ''COL1A2'' || {{OMIM|166220||none}} || autosomal dominant, 50% ''de novo''<ref name="Zhytnik2019" />||1 in 30,000<ref name="Shapiro2014" />{{rp|21}}
|-
! colspan="7" style="border-top-width: 0px" |[[Osteogenesis imperfecta#Genetically defined types|Genetically defined types]]
|-
! Type 
! colspan="2" | Gene !! [[OMIM]] !! colspan="2" |[[Mendelian inheritance|Mode of inheritance]]<ref group="note">For references for genes for OI types {{Abbr|VII+|7+}}, see the types entry in {{Flr|#Genetically defined types}}.</ref>
!Defined<ref group="note" name="OMIMNote" />
|-
 | {{abbr|V|5}}
|colspan="2" |[[interferon induced transmembrane protein 5|''IFITM5'']]|| {{OMIM|610967||none}} ||colspan="2" | autosomal dominant<ref name="Steiner">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK1295/|title=GeneReviews [Internet]|vauthors=Steiner RD, Pepin MG, Byers PH, Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP|date=2021-05-06|publisher=University of Washington, Seattle|veditors=Adam MP, Ardinger HH, Pagon RA, etal|chapter=''COL1A1/2'' Osteogenesis Imperfecta|pmid=20301472|access-date=2021-08-26|archive-url=https://web.archive.org/web/20170118124154/https://www.ncbi.nlm.nih.gov/books/NBK1295/|archive-date=18 January 2017|url-status=live}}</ref><ref name="Shapiro_2013">{{cite journal | vauthors = Shapiro JR, Lietman C, Grover M, Lu JT, Nagamani SC, Dawson BC, Baldridge DM, Bainbridge MN, Cohn DH, Blazo M, Roberts TT, Brennen FS, Wu Y, Gibbs RA, Melvin P, Campeau PM, Lee BH | display-authors = 6 | title = Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation | journal = Journal of Bone and Mineral Research | volume = 28 | issue = 7 | pages = 1523–1530 | date = July 2013 | pmid = 23408678 | pmc = 3688672 | doi = 10.1002/jbmr.1891 }}</ref> 
|2000<ref name="Glorieux2000" /><ref group="note">Genetic cause not determined until 2012. ([[#{{harvid|Cho|Lee|Lee|Song|2012}}|Cho, ''et al.'' 2012]])</ref>
 |-
 | {{abbr|VI|6}}
|colspan="2" |''[[SERPINF1]]''|| {{OMIM|613982||none}}
|colspan="2" | autosomal recessive<ref name="Steiner" />
|2002
 |-
 | {{abbr|VII|7}}
|colspan="2" |''[[CRTAP]]''|| {{OMIM|610682||none}} 
|colspan="2" | autosomal recessive<ref name="Steiner" />
|2006
 |-
 | {{abbr|VIII|8}}
|colspan="2" |''[[LEPRE1]]''|| {{OMIM|610915||none}} 
|colspan="2" | autosomal recessive
|2007
 |-
 | {{abbr|IX|9}}
|colspan="2" |''[[PPIB]]''||{{OMIM|259440||none}}
|colspan="2" | autosomal recessive
|2009
 |-
 | {{abbr|X|10}}
|colspan="2" |''[[SERPINH1]]''||{{OMIM|613848||none}} 
| colspan="2" |autosomal recessive
|2010
 |-
 | {{abbr|XI|11}}
|colspan="2" |''[[FKBP10]]''||{{OMIM|610968||none}}|| colspan="2" |autosomal recessive
|2010
 |-
 | {{abbr|XII|12}}
|colspan="2" |''[[Sp7 transcription factor|SP7]]''||{{OMIM|613849||none}}
| colspan="2" |autosomal recessive
|2010
 |-
 | {{abbr|XIII|13}}
|colspan="2" |''[[Bone morphogenetic protein 1|BMP1]]''||{{OMIM|614856||none}}|| colspan="2" |autosomal recessive
|2012
 |-
 | {{abbr|XIV|14}}
|colspan="2" |''[[TMEM38B]]''||{{OMIM|615066||none}}
|colspan="2" |autosomal recessive
|2012
 |-
 | {{abbr|XV|15}}
|colspan="2" |''[[WNT1]]''||{{OMIM|615220||none}}
| colspan="2" |autosomal recessive
|2013
 |-
 | {{abbr|XVI|16}}
|colspan="2" |''[[CREB3L1]]''||{{OMIM|616229||none}}|| colspan="2" |autosomal recessive
|2013
 |-
 | {{abbr|XVII|17}}
|colspan="2" |''[[Osteonectin|SPARC]]''||{{OMIM|616507||none}}|| colspan="2" |autosomal recessive
|2015
 |-
 | {{abbr|XVIII|18}}
|colspan="2" |''[[TENT5A]]''||{{OMIM|617952||none}}|| colspan="2" |autosomal recessive
|2018
 |-
 | {{abbr|XIX|19}}
|colspan="2" |''[[MBTPS2]]''||{{OMIM|301014||none}}||colspan="2" | [[X-linked recessive]]
|2016
 |-
 | {{abbr|XX|20}}
|colspan="2" |''[[Mesoderm development LRP chaperone|MESD]]''||{{OMIM|618644||none}}|| colspan="2" |autosomal recessive
|2019
|-
|{{abbr|XXI|21}}
|colspan="2" |''[[KDELR2]]''
|{{OMIM|619131||none}}
|colspan="2" |autosomal recessive
|2020
|}

=== Sillence types ===
{{multiple image
| direction         = horizontal
| perrow            = 2
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| image1            = Jordanne Whiley Rio2016 cr.jpg
| image2            = AtticusShafferHWOFMay2012.jpg
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| image4            = Theresia Haidlmayr.jpg
| caption1          = [[Jordanne Whiley]]<ref>{{Cite news |date=2016-03-26 |title=Jordanne Whiley: 'To achieve perfection is impossible. You should be who you are because someone will find you attractive' |language=en |work=[[The Times]] |url=https://www.thetimes.com/sport/article/my-sporting-body-jordanne-whiley-wheelchair-tennis-player-hf0nq8xf2 |access-date=2022-03-26 |issn=0140-0460 |vauthors=Rudd A}}</ref>
| caption2          = [[Atticus Shaffer]]<ref>{{cite web |date=March 6, 2015 |title=''The Middle'' star says it's OK to be a nerd |url=https://www.stuff.co.nz/entertainment/tv-radio/tv-guide/66989441/the-middle-star-says-its-ok-to-be-a-nerd |access-date=May 25, 2018 |website=[[Stuff (website)|Stuff]] |publisher=[[Stuff (company)|Stuff Ltd]] |location=New Zealand |vauthors=Harvey K}}</ref>
| caption3          = [[Peter Radtke]]<ref>{{Cite news |date=2020-11-30 |title=Schauspieler und Kämpfer für Behindertenrechte: Peter Radtke ist tot |language=de-DE |trans-title=Actor and campaigner for disability rights Peter Radtke has died |work=Der Spiegel |url=https://www.spiegel.de/kultur/peter-radtke-ist-tot-schauspieler-und-kaempfer-fuer-behindertenrechte-a-08b81347-1d24-424a-8c96-9cfa26c8b0c0 |access-date=2022-03-26 |issn=2195-1349}}</ref>
| caption4          = [[Theresia Haidlmayr]]<ref>{{Cite web |title=Theresia Haidlmayr |url=http://www.smilerkreativ.at/bmin/Behinderte_Menschen_in_Not/Haidlmayr.html |access-date=2022-03-26 |website=Behinderte Menschen in Not |language=de-AT |archive-date=4 March 2016 |archive-url=https://web.archive.org/web/20160304025656/http://www.smilerkreativ.at/bmin/Behinderte_Menschen_in_Not/Haidlmayr.html }}</ref>
| footer            = Osteogenesis imperfecta is highly variable, affecting all those above.
}}

Sillence's four types have both a clinical and a genetic meaning; the descriptions below are clinical and can be applied to several genetic types of OI. When used to refer to a genetic as well as a clinical type, it indicates that the clinical symptoms are indeed caused by mutations in the ''COL1A1'' or ''COL1A2'' genes, which are inherited in an autosomal dominant fashion.<ref name="Marom2020" />

==== Type {{abbr|I|1}} ====
Collagen is of normal quality but is produced in insufficient quantities.<ref name="Rowe2008" />{{rp|1516}} Bones fracture more easily than in the general public, but not as easily as more severe types of OI; there might be [[scoliosis]], albeit mild compared to OI types III and IV, with a lower [[Cobb angle]]; the joints may be loose; blue sclerae may be apparent; hearing loss is likely to occur;<ref name="VanDijk2014" />{{rp|Table 1}} and there might be a slight decrease in height. Because cases exist missing one or more of these symptoms, OI type I in some cases goes undetected into adulthood.<ref name="Rowe2008" />{{rp|1513–1514}}

Some further split type I into types I–A and I–B, defined as being distinguished by the absence (I–A) or presence (I–B) of [[dentinogenesis imperfecta]] (opalescent teeth).<ref name="VanDijk2014" /><ref name="Singer2001">{{cite journal | vauthors = Singer RB, Ogston SA, Paterson CR | title = Mortality in various types of osteogenesis imperfecta | journal = Journal of Insurance Medicine | volume = 33 | issue = 3 | pages = 216–220 | date = 2001 | pmid = 11558400 }}</ref>{{rp|217}} People with type I generally have a normal lifespan.<ref>{{Cite web|date=2021-05-05|title=Osteogenesis Imperfecta: Types, Symptoms & Management|url=https://my.clevelandclinic.org/health/diseases/15807-osteogenesis-imperfecta-oi|url-status=live|access-date=2021-08-17|website=[[Cleveland Clinic]]|archive-date=17 August 2021|archive-url=https://web.archive.org/web/20210817052938/https://my.clevelandclinic.org/health/diseases/15807-osteogenesis-imperfecta-oi}}</ref>

==== Type {{abbr|II|2}} ====
Collagen is fatally defective at its [[C-terminus]].<ref name="Rowe2008" />{{rp|1512}} Most cases result in death shortly after birth, or within the first year of life, due to [[respiratory failure]]. Another common cause of death is [[intracranial bleeds]] from [[skull fractures]] present at, or sustained during or shortly after, birth.<ref name="Rowe2008" />{{rp|1511}} In many cases, the newborn already has multiple broken bones at the time of birth. Type II infants also exhibit severe [[Respiration (physiology)|respiratory]] problems and have severely deformed bones. Sixty percent of infants die less than 24 hours after being born, and survival after the first year is extremely unlikely and normally requires [[mechanical ventilation]].<ref name="Basel2009">{{cite journal | vauthors = Basel D, Steiner RD | title = Osteogenesis imperfecta: recent findings shed new light on this once well-understood condition | journal = Genetics in Medicine | volume = 11 | issue = 6 | pages = 375–385 | date = June 2009 | pmid = 19533842 | doi = 10.1097/GIM.0b013e3181a1ff7b | url = https://www.nature.com/articles/gim200954.pdf | access-date = 19 August 2021 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20210920212534/https://www.nature.com/articles/gim200954.pdf?origin=ppub&error=cookies_not_supported&code=25b1628f-762d-41d4-a9ed-906855f1314c | archive-date = 20 September 2021 }}</ref> In the rare cases of infants who survive their first year of life, severe [[Developmental delays|developmental and motor delays]] are seen; neither of two infants studied in 2019, both aged around two years, had achieved [[Child development stages#1–4 months|head control]], and both required a ventilator to breathe.<ref>{{Cite journal|vauthors=Nadar R, Saraff V, Hogler W, Desai M, Shaw N|date=2019-07-31|title=Determinants of survival in osteogenesis imperfecta (OI) Type II|url=http://www.bone-abstracts.org/ba/0007/ba0007p31.htm|journal=Bone Abstracts|volume=7|page=31|doi=10.1530/boneabs.7.P31|s2cid=208412310|issn=2052-1219|access-date=19 August 2021|archive-date=20 September 2021|archive-url=https://web.archive.org/web/20210920212536/https://www.bone-abstracts.org/ba/0007/ba0007p31.htm|url-status=live|url-access=subscription}}</ref>

Type II is also known as the "lethal [[perinatal]]" form of OI,<ref>{{cite journal | vauthors = Zisa D, Shabbir A, Mastri M, Suzuki G, Lee T | title = Intramuscular VEGF repairs the failing heart: role of host-derived growth factors and mobilization of progenitor cells | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 297 | issue = 5 | pages = R1503–R1515 | date = November 2009 | pmid = 19759338 | pmc = 2777764 | doi = 10.1152/ajpregu.00227.2009 }}</ref> and is not compatible with survival into adulthood.<ref name="Basel2009" /> Due to similarly severely deformed bones, sometimes infants with severe type III are wrongly initially classified as type II; once long-term survival is shown, they are considered as having type III instead.<ref name="Rowe2008" />{{rp|1511}}<ref>{{cite journal | vauthors = Ben Amor IM, Glorieux FH, Rauch F | title = Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta | journal = Journal of Osteoporosis | volume = 2011 | article-number = 540178 | date = 2011-09-06 | pmid = 21912751 | pmc = 3170785 | doi = 10.4061/2011/540178 | quote = For example, it can occur that a fetus is diagnosed with OI type II, the lethal form, on prenatal ultrasound, but after birth turns out to be less severely affected than initially thought and is eventually reclassified as OI type III or even type VI, if adequate management is initiated early on. | doi-access = free }}</ref>

==== Type {{abbr|III|3}} ====
Collagen quantity is sufficient, but is not of a high enough quality.<ref name="Rowe2008" />{{rp|1512}} [[Differential diagnosis|Clinical differentiation]] between types III and IV is not always simple, and is further confounded by the fact that an untreated adult with type IV may have worse symptoms than a treated adult with type III;<ref name="Rowe2008" />{{rp|1511}}<ref>{{cite journal | vauthors = Georgescu I, Vlad C, Gavriliu TŞ, Dan S, Pârvan AA | title = Surgical treatment in Osteogenesis Imperfecta - 10 years experience | journal = Journal of Medicine and Life | volume = 6 | issue = 2 | pages = 205–213 | date = June 2013 | pmid = 23904885 | pmc = 3725451 }}</ref> features only found in type III are its [[Progressive disease|progressively deforming]] nature<ref name="Rowe2008" />{{rp|1511–1512}} and the presence of a face with a "triangular" appearance.<ref>{{Cite book|title=Atlas of genetic diagnosis and counseling|vauthors=Chen H|publisher=Humana Press|year=2006|isbn=978-1-58829-681-8|location=Totowa, NJ|page=771|chapter=Triangular face|chapter-url=https://books.google.com/books?id=2VcdAXJ_dZkC&pg=PA771|archive-url=https://web.archive.org/web/20130608031238/http://books.google.com/books?id=2VcdAXJ_dZkC&pg=PA771|archive-date=8 June 2013}}</ref> Another differentiating factor between type III and IV is blue sclerae; in type III, infants commonly have blue sclerae that gradually turn white with age, but blue sclerae are not commonly seen in type IV,<ref name="Shapiro2014">{{Cite book|title=Osteogenesis imperfecta: a translational approach to brittle bone disease|vauthors=Shapiro JR, Byers PH, Glorieux FH, Sponseller PD|publisher=[[Elsevier Inc.]]|year=2014|isbn=978-0-12-397165-4|edition=2nd|location=London|oclc=876364090}}</ref>{{rp|294–296}} although they are seen in 10% of cases.<ref name="Johnson2002">{{cite journal | vauthors = Johnson MT, Morrison S, Heeger S, Mooney S, Byers PH, Robin NH | title = A variant of osteogenesis imperfecta type IV with resolving kyphomelia is caused by a novel COL1A2 mutation | journal = Journal of Medical Genetics | volume = 39 | issue = 2 | pages = 128–132 | date = February 2002 | pmid = 11836364 | pmc = 1735034 | doi = 10.1136/jmg.39.2.128 | quote = The persistent pale blue sclera is uncommon in OI type IV, but can be seen in up to 10% of affected subjects. }}</ref>

OI type III causes [[Osteopenia|osteopenic]] bones that fracture very easily, sometimes even ''in [[utero]]'', often leading to hundreds of fractures during a lifetime;<ref name="Lindahl2015" /> early scoliosis that progresses until puberty; [[dwarfism]] (a final adult height frequently less than {{Convert|4|ft|cm|disp=or}}); loose joints; and possible respiratory problems due to low [[rib cage]] volume causing low [[lung volumes]].<ref name="Rowe2008" />{{rp|1512}}

Due to the severity of the issues with the bones, neurological and [[seizure disorders]] are more likely to develop in type III.<ref name="Rowe2008" />{{rp|1512}} [[Basilar invagination]], which puts pressure on the [[brainstem]], may cause or contribute to early death; surgical treatment of it is more complex in OI cases.<ref name="Rowe2008" />{{rp|1512}}<ref name="Wallace2017" />{{rp|106–107}}

==== Type {{abbr|IV|4}} ====
Collagen quantity is sufficient, but it is not of a high enough quality.<ref name="Rowe2008" />{{rp|1512}} Type IV is for cases of variable severity, which do not fit into either types III or I.<ref name="VanDijk2014">{{cite journal | vauthors = Van Dijk FS, Sillence DO | title = Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment | journal = American Journal of Medical Genetics. Part A | volume = 164A | issue = 6 | pages = 1470–1481 | date = June 2014 | pmid = 24715559 | pmc = 4314691 | doi = 10.1002/ajmg.a.36545 }}</ref> While one of Sillence's required characteristics for type IV was having normal sclerae,<ref name="Shapiro2014" />{{rp|294–296}}<ref name="Sillence1979" />{{rp|114}} modern classification allows even those with blue sclerae to fit the criteria for type IV if they meet the other clinical requirements of the type.<ref name="Johnson2002" />

In type IV, bone deformity can be mild to severe, bones fracture easily (especially before puberty), dwarfism is common, [[vertebral collapse]] and scoliosis are evident, and hearing loss is possible,<ref name="NIH2015" /> although uncommon.<ref name="VanDijk2014" /><ref name="VanDijk2011" /> Type IV OI is mostly defined in contrast to type III and type I, being the clinical classification for patients somewhere in the middle ground between the two.<ref name="Rowe2008" />{{rp|1511}} As such, type IV OI is often termed "variable" OI,<ref name="Sillence1979" />{{rp|111}} with the severity of even those in the same family (so, with the same genetic mutation) differing.<ref name="VanDijk2014" />

Prepubertal bone fracture rates are another way of clinically assessing type IV OI—those with it tend to have fracture rates of ≈1 per year, compared to ≈3 per year for severe OI (type III).<ref name="VanDijk2014" />

As in type I, some further split type IV into types IV–A and IV–B, defined again by the absence (IV–A) or presence (IV–B) of [[dentinogenesis imperfecta]].<ref name="VanDijk2014" /><ref name="Singer2001" />{{rp|217}}

=== Genetically defined types (types {{abbr|V|5}}–{{abbr|XXI|21}}) ===
{{anchor|Genetically defined types}}As of 2020, fifteen types of OI are defined genetically:<ref name="Marom2020" />

{{Multiple image
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| footer            = [[Projectional radiography|X-ray]]s of three people with OI type V: a newborn, a child, and an adult. Evident are somewhat deformed long bones with widened [[metaphysis|metaphyses]].
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* '''Type {{abbr|V|5}}''' &ndash; Having the same clinical features as type IV, it can be clinically distinguished by observing a "mesh-like" appearance to a [[bone biopsy]] under a microscope. Type V can be further distinguished from other types of OI by the "V triad": an opaque band (visible on X-ray) adjacent to the [[growth plates]]; [[hypertrophic]] [[calluses]] (abnormally large masses of bony repair tissue) which form at fracture sites during the healing process; and calcification of the [[interosseous membrane of the forearm]],<ref name="Glorieux2000">{{cite journal | vauthors = Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, Lalic L, Glorieux DF, Fassier F, Bishop NJ | display-authors = 6 | title = Type V osteogenesis imperfecta: a new form of brittle bone disease | journal = Journal of Bone and Mineral Research | volume = 15 | issue = 9 | pages = 1650–1658 | date = September 2000 | pmid = 10976985 | doi = 10.1359/jbmr.2000.15.9.1650 | s2cid = 13748803 }}</ref> which may make it difficult to turn the wrist.<ref name="Shapiro2014" />{{rp|429}} {{pb}} Other features of this condition may include [[pulled elbow]], and, as in other types of OI, long bone bowing and hearing loss.<ref name="Cho2012">{{cite journal | vauthors = Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D, Lee G, Kim HN, Lee HR, Eom HH, Lee ZH, Kim OH, Park WY, Park SS, Ikegawa S, Yoo WJ, Choi IH, Kim JW | display-authors = 6 | title = A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V | journal = American Journal of Human Genetics | volume = 91 | issue = 2 | pages = 343–348 | date = August 2012 | pmid = 22863190 | pmc = 3415533 | doi = 10.1016/j.ajhg.2012.06.005 }}</ref> {{pb}} Cases of this type are caused by mutations in the ''[[interferon induced transmembrane protein 5|IFITM5]]'' gene on [[chromosome 11]]<nowiki/>p15.5.<ref name="Cho2012" /><ref name="Shapiro_2013" /> The separation of type V from type IV OI, its clinical type, was initially suggested even before its genetic cause was known, by Glorieux ''et al''. in 2000.<ref name="Glorieux2000" /><ref>{{cite journal | vauthors = Cao YJ, Wei Z, Zhang H, Zhang ZL | title = Expanding the Clinical Spectrum of Osteogenesis Imperfecta Type V: 13 Additional Patients and Review | journal = Frontiers in Endocrinology | volume = 10 | page = 375 | date = 2019-06-12 | pmid = 31244780 | pmc = 6581704 | doi = 10.3389/fendo.2019.00375 | doi-access = free }}</ref> Type V is relatively common compared to other genetically defined types of OI—4% of OI patients at the genetics department of the Brazilian [[Hospital de Clínicas de Porto Alegre]] were found to have it.<ref>{{cite journal | vauthors = Brizola E, Mattos EP, Ferrari J, Freire PO, Germer R, Llerena JC, Félix TM | title = Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V | language = english | journal = Molecular Syndromology | volume = 6 | issue = 4 | pages = 164–172 | date = October 2015 | pmid = 26648832 | pmc = 4662268 | doi = 10.1159/000439506 }}</ref>
* '''Type {{abbr|VI|6}}''' &ndash; With the same clinical features as type III, it is distinguished by bones which have an appearance similar to that seen in [[osteomalacia]].<ref name="Shapiro2014" />{{rp|168}} Type VI is caused by a [[loss-of-function mutation]] in the ''[[SERPINF1]]'' gene on [[chromosome 17]]<nowiki/>p13.3.<ref name="Shapiro2014" />{{rp|170}}
* '''Type {{abbr|VII|7}}''' &ndash; OI caused by a mutation in the gene ''[[CRTAP]]'' on [[chromosome 3]]<nowiki/>p22.3; clinically similar to OI types II and III, depending on affected individual. Type VII was the first recessive OI type confirmed, initially found among [[First Nations in Canada|First Nations]] people in [[Quebec]].<ref name="Morello2006">{{cite journal | vauthors = Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bächinger HP, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B | display-authors = 6 | title = CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta | journal = Cell | volume = 127 | issue = 2 | pages = 291–304 | date = October 2006 | pmid = 17055431 | doi = 10.1016/j.cell.2006.08.039 | s2cid = 8123837 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundaram UT, Lee B, Marini JC | display-authors = 6 | title = Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta | journal = The New England Journal of Medicine | volume = 355 | issue = 26 | pages = 2757–2764 | date = December 2006 | pmid = 17192541 | pmc = 7509984 | doi = 10.1056/NEJMoa063804 }}</ref>
* '''Type {{abbr|VIII|8}}''' &ndash; OI caused by a mutation in the gene ''[[LEPRE1]]'' on [[chromosome 1]]<nowiki/>p34.2; clinically similar to OI types II and III, depending on affected individual.<ref>{{cite journal | vauthors = Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, Makareeva E, Kuznetsova NV, Rosenbaum KN, Tifft CJ, Bulas DI, Kozma C, Smith PA, Eyre DR, Marini JC | display-authors = 6 | title = Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta | journal = Nature Genetics | volume = 39 | issue = 3 | pages = 359–365 | date = March 2007 | pmid = 17277775 | pmc = 7510175 | doi = 10.1038/ng1968 }}</ref>
* '''Type {{abbr|IX|9}}''' &ndash; OI caused by homozygous or compound heterozygous mutation in the ''[[PPIB]]'' gene on [[chromosome 15]]<nowiki/>q22.31.<ref>{{cite journal | vauthors = van Dijk FS, Nesbitt IM, Zwikstra EH, Nikkels PG, Piersma SR, Fratantoni SA, Jimenez CR, Huizer M, Morsman AC, Cobben JM, van Roij MH, Elting MW, Verbeke JI, Wijnaendts LC, Shaw NJ, Högler W, McKeown C, Sistermans EA, Dalton A, Meijers-Heijboer H, Pals G | display-authors = 6 | title = PPIB mutations cause severe osteogenesis imperfecta | journal = American Journal of Human Genetics | volume = 85 | issue = 4 | pages = 521–527 | date = October 2009 | pmid = 19781681 | pmc = 2756556 | doi = 10.1016/j.ajhg.2009.09.001 }}</ref>
* '''Type {{abbr|X|10}}''' &ndash; OI caused by homozygous mutation in the ''[[SERPINH1]]'' gene on chromosome 11q13.<ref>{{cite journal | vauthors = Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, Pepin MG, Weis MA, Eyre DR, Byers PH | display-authors = 6 | title = Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta | journal = American Journal of Human Genetics | volume = 86 | issue = 3 | pages = 389–398 | date = March 2010 | pmid = 20188343 | pmc = 2833387 | doi = 10.1016/j.ajhg.2010.01.034 }}</ref>
* '''Type {{abbr|XI|11}}''' &ndash; OI caused by mutations in ''[[FKBP10]]'' on chromosome 17q21. The mutations cause a decrease in the secretion of [[Trimer (chemistry)|trimeric]] procollagen molecules. Other mutations in this gene can cause autosomal recessive [[Bruck syndrome]], which is similar to OI.<ref>{{cite journal | vauthors = Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, Aktas D, Alikasifoglu M, Tuncbilek E, Orhan D, Bakar FT, Zabel B, Superti-Furga A, Bruckner-Tuderman L, Curry CJ, Pyott S, Byers PH, Eyre DR, Baldridge D, Lee B, Merrill AE, Davis EC, Cohn DH, Akarsu N, Krakow D | display-authors = 6 | title = Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta | journal = American Journal of Human Genetics | volume = 86 | issue = 4 | pages = 551–559 | date = April 2010 | pmid = 20362275 | pmc = 2850430 | doi = 10.1016/j.ajhg.2010.02.022 }}</ref>
* '''Type {{abbr|XII|12}}''' &ndash; OI caused by a [[frameshift mutation]] in ''[[Sp7 transcription factor|SP7]]'' on [[chromosome 12]]<nowiki/>q13.13. This mutation causes bone deformities, fractures, and delayed [[tooth eruption]].<ref>{{cite journal | vauthors = Sam JE, Dharmalingam M | title = Osteogenesis Imperfecta | journal = Indian Journal of Endocrinology and Metabolism | volume = 21 | issue = 6 | pages = 903–908 | date = 2017 | pmid = 29285457 | pmc = 5729682 | doi = 10.4103/ijem.IJEM_220_17 | doi-access = free }}</ref>
* '''Type {{abbr|XIII|13}}''' &ndash; OI caused by a mutation in the [[bone morphogenetic protein 1]] (''BMP1'') gene on [[chromosome 8]]<nowiki/>p21.3.<ref>{{Cite book| vauthors = Shapiro JR |chapter=Clinical and Genetic Classification of Osteogenesis Imperfecta and Epidemiology|date=2014|pages=15–22|publisher=Elsevier|isbn=978-0-12-397165-4|doi=10.1016/b978-0-12-397165-4.00002-2|title=Osteogenesis Imperfecta}}</ref> This mutation causes recurrent fractures, high bone mass, and [[Hypermobility (joints)|hypermobile joints]].<ref name="Sam2017">{{cite journal | vauthors = Sam JE, Dharmalingam M | title = Osteogenesis Imperfecta | journal = Indian Journal of Endocrinology and Metabolism | volume = 21 | issue = 6 | pages = 903–908 | date = 2017-11-01 | pmid = 29285457 | pmc = 5729682 | doi = 10.4103/ijem.IJEM_220_17 | doi-access = free }}</ref>
* '''Type {{abbr|XIV|14}}''' &ndash; OI caused by mutations in the ''[[TMEM38B]]'' gene on [[chromosome 9]]<nowiki/>q31.2. This mutation causes recurrent fractures and [[osteopenia]], although the disease trajectory is highly variable.<ref>{{cite journal | vauthors = Shaheen R, Alazami AM, Alshammari MJ, Faqeih E, Alhashmi N, Mousa N, Alsinani A, Ansari S, Alzahrani F, Al-Owain M, Alzayed ZS, Alkuraya FS | display-authors = 6 | title = Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation | journal = Journal of Medical Genetics | volume = 49 | issue = 10 | pages = 630–635 | date = October 2012 | pmid = 23054245 | doi = 10.1136/jmedgenet-2012-101142 | s2cid = 35542661 }}</ref>
* '''Type {{abbr|XV|15}}''' &ndash; OI caused by homozygous or compound heterozygous mutations in the ''WNT1'' gene on chromosome 12q13.12. It is autosomal recessive.<ref name="Sam2017" />
* '''Type {{abbr|XVI|16}}''' &ndash; OI caused by mutations in the ''[[CREB3L1]]'' gene on chromosome 11p11.2. The homozygous mutation causes prenatal onset of recurrent fractures of the ribs and long bones, demineralization, decreased ossification of the skull, and blue sclerae; it is clinically type II or type III.<ref name="Lindahl2018">{{cite journal | vauthors = Lindahl K, Åström E, Dragomir A, Symoens S, Coucke P, Larsson S, Paschalis E, Roschger P, Gamsjaeger S, Klaushofer K, Fratzl-Zelman N, Kindmark A | display-authors = 6 | title = Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy | journal = Bone | volume = 114 | pages = 268–277 | date = September 2018 | pmid = 29936144 | doi = 10.1016/j.bone.2018.06.019 | url = https://www.sciencedirect.com/science/article/abs/pii/S8756328218302515 | access-date = 29 August 2021 | url-status = live | s2cid = 49406925 | archive-url = https://web.archive.org/web/20210829024252/https://www.sciencedirect.com/science/article/abs/pii/S8756328218302515 | archive-date = 29 August 2021 | url-access = subscription }}</ref> Family members who are heterozygous for OI XVI may have recurrent fractures, osteopenia and blue sclerae.<ref name="Lindahl2018" /><ref>{{cite journal | vauthors = Keller RB, Tran TT, Pyott SM, Pepin MG, Savarirayan R, McGillivray G, Nickerson DA, Bamshad MJ, Byers PH | display-authors = 6 | title = Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively | journal = Genetics in Medicine | volume = 20 | issue = 4 | pages = 411–419 | date = April 2018 | pmid = 28817112 | pmc = 5816725 | doi = 10.1038/gim.2017.115 }}</ref>
* '''Type {{abbr|XVII|17}}''' &ndash; OI caused by homozygous mutation in the ''[[SPARC (gene)|SPARC]]'' gene on [[chromosome 5]]<nowiki/>q33, causing a defect in the protein [[osteonectin]], which leads to severe disease characterized by generalized [[platyspondyly]], dependence on a wheelchair, and recurrent fractures.<ref>{{cite journal | vauthors = Mendoza-Londono R, Fahiminiya S, Majewski J, Tétreault M, Nadaf J, Kannu P, Sochett E, Howard A, Stimec J, Dupuis L, Roschger P, Klaushofer K, Palomo T, Ouellet J, Al-Jallad H, Mort JS, Moffatt P, Boudko S, Bächinger HP, Rauch F | display-authors = 6 | title = Recessive osteogenesis imperfecta caused by missense mutations in SPARC | journal = American Journal of Human Genetics | volume = 96 | issue = 6 | pages = 979–985 | date = June 2015 | pmid = 26027498 | pmc = 4457955 | doi = 10.1016/j.ajhg.2015.04.021 }}</ref>
* '''Type {{abbr|XVIII|18}}''' &ndash; OI caused by homozygous mutation in the ''[[FAM46A]]'' gene on [[chromosome 6]]<nowiki/>q14.1. Characterized by congenital bowing of the long bones, [[Wormian bones]], blue sclerae, [[vertebral collapse]], and multiple fractures in the first years of life.<ref>{{cite journal | vauthors = Doyard M, Bacrot S, Huber C, Di Rocco M, Goldenberg A, Aglan MS, Brunelle P, Temtamy S, Michot C, Otaify GA, Haudry C, Castanet M, Leroux J, Bonnefont JP, Munnich A, Baujat G, Lapunzina P, Monnot S, Ruiz-Perez VL, Cormier-Daire V | display-authors = 6 | title = ''FAM46A'' mutations are responsible for autosomal recessive osteogenesis imperfecta | journal = Journal of Medical Genetics | volume = 55 | issue = 4 | pages = 278–284 | date = April 2018 | pmid = 29358272 | doi = 10.1136/jmedgenet-2017-104999 | url = https://jmg.bmj.com/content/55/4/278 | access-date = 29 August 2021 | publisher = [[The BMJ]] | url-status = live | s2cid = 4283476 | archive-url = https://web.archive.org/web/20210829024310/https://jmg.bmj.com/content/55/4/278 | archive-date = 29 August 2021 | url-access = subscription }}</ref>
*'''Type {{abbr|XIX|19}}''' &ndash; OI caused by hemizygous mutation in the ''[[MBTPS2]]'' gene on [[chromosome X]]<nowiki/>p22.12. Thus far, OI type XIX is the only known type of OI with an [[X-linked recessive]] pattern of inheritance, making it the only type that is more common in males than females. OI type XIX disrupts [[regulated intramembrane proteolysis]], which is critical for healthy bone formation.<ref name="Lindert2016" />
*'''Type {{abbr|XX|20}}''' &ndash; OI caused by homozygous mutation in the ''[[Mesoderm development LRP chaperone|MESD]]'' gene on chromosome 15q25.1. Initial studies of type XX indicate that it may cause [[global developmental delay]], a first among OI types. OI type XX disrupts the [[Wnt signaling pathway]], which is thought to have a role in bone development.<ref name="Moosa2019">{{cite journal | vauthors = Moosa S, Yamamoto GL, Garbes L, Keupp K, Beleza-Meireles A, Moreno CA, Valadares ER, de Sousa SB, Maia S, Saraiva J, Honjo RS, Kim CA, Cabral de Menezes H, Lausch E, Lorini PV, Lamounier A, Carniero TC, Giunta C, Rohrbach M, Janner M, Semler O, Beleggia F, Li Y, Yigit G, Reintjes N, Altmüller J, Nürnberg P, Cavalcanti DP, Zabel B, Warman ML, Bertola DR, Wollnik B, Netzer C | display-authors = 6 | title = Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta | journal = American Journal of Human Genetics | volume = 105 | issue = 4 | pages = 836–843 | date = October 2019 | pmid = 31564437 | pmc = 6817720 | doi = 10.1016/j.ajhg.2019.08.008 }}</ref>
*'''Type {{abbr|XXI|21}}''' – OI caused by homozygous mutation in the ''[[KDELR2]]'' gene on [[chromosome 7]]<nowiki/>p22.1. Causes disease clinically similar to types II and III, thought to be related to inability of chaperone protein HP47 to unbind from collagen type I, as to do so it needs to bind to the missing [[ER lumen protein retaining receptor 2]] protein encoded by ''KDELR2''.<ref name="VanDijk2020" />

Given the rapid rate of type discovery, it is extremely likely that there are other genes associated with OI that have yet to be reported.<ref name=":0">{{Cite journal|vauthors=Byers PH, Pyott SM|date=2012-12-15|title=Recessively Inherited Forms of Osteogenesis Imperfecta|url=https://www.annualreviews.org/doi/10.1146/annurev-genet-110711-155608|journal=[[Annual Review of Genetics]]|language=en|volume=46|issue=1|pages=475–497|doi=10.1146/annurev-genet-110711-155608|pmid=23145505|issn=0066-4197|url-access=subscription}}</ref>{{Rp|pages=491–492}}

== Genetics ==
[[File:COL1A1 protein - PDB rendering based on 1y0f.jpg|thumb|An [[Collagen, type I, alpha 1|α1 type I collagen]] [[protein]]]]
Osteogenesis imperfecta is a group of genetic disorders, all of which cause bone fragility. OI has high [[genetic heterogeneity]], that is, many different genetic [[mutations]] lead to the same or similar sets of observable symptoms ([[phenotypes]]).<ref>{{cite journal | vauthors = Ho Duy B, Zhytnik L, Maasalu K, Kändla I, Prans E, Reimann E, Märtson A, Kõks S | display-authors = 6 | title = Mutation analysis of the COL1A1 and COL1A2 genes in Vietnamese patients with osteogenesis imperfecta | journal = Human Genomics | volume = 10 | issue = 1 | article-number = 27 | date = August 2016 | pmid = 27519266 | pmc = 4983065 | doi = 10.1186/s40246-016-0083-1 | doi-access = free }}</ref>

The main causes for developing the disorder are a result of mutations in the ''COL1A1'' and/or ''COL1A2'' genes which are jointly responsible for the production of [[collagen type I]].<ref>{{cite journal | vauthors = Palomo T, Vilaça T, Lazaretti-Castro M | title = Osteogenesis imperfecta: diagnosis and treatment | journal = Current Opinion in Endocrinology, Diabetes and Obesity | volume = 24 | issue = 6 | pages = 381–388 | date = December 2017 | pmid = 28863000 | doi = 10.1097/MED.0000000000000367 | s2cid = 4555427 }}</ref> Approximately 90% of people with OI are [[heterozygous]] for mutations in either the ''COL1A1'' or ''COL1A2'' genes.<ref>{{cite journal | vauthors = Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B | title = What is new in genetics and osteogenesis imperfecta classification? | journal = Jornal de Pediatria | volume = 90 | issue = 6 | pages = 536–541 | date = 18 July 2014 | pmid = 25046257 | doi = 10.1016/j.jped.2014.05.003 | doi-access = free }}</ref> There are several biological factors that are results of the dominant form of OI. These factors include: intracellular stress; abnormal tissue mineralization; abnormal cell-to-cell interactions; abnormal cell-[[Extracellular matrix|matrix]] interactions; a compromised cell matrix structure; and, abnormal interaction between non-collagenous [[proteins]] and collagen.<ref name="Forlino2011">{{cite journal | vauthors = Forlino A, Cabral WA, Barnes AM, Marini JC | title = New perspectives on osteogenesis imperfecta | journal = Nature Reviews. Endocrinology | volume = 7 | issue = 9 | pages = 540–557 | date = June 2011 | pmid = 21670757 | pmc = 3443407 | doi = 10.1038/nrendo.2011.81 }}</ref>

Previous research led to the belief that OI was an [[autosomal dominant]] disorder with few other variations in genomes.<ref name="Forlino2016">{{cite journal | vauthors = Forlino A, Marini JC | title = Osteogenesis imperfecta | journal = Lancet | volume = 387 | issue = 10028 | pages = 1657–1671 | date = April 2016 | pmid = 26542481 | pmc = 7384887 | doi = 10.1016/S0140-6736(15)00728-X }}</ref> However, with the lowering of the cost of [[DNA sequencing]] in the wake of 2003's [[Human Genome Project]], autosomal recessive forms of the disorder have been identified.<ref>{{cite journal | vauthors = Koromani F, Trajanoska K, Rivadeneira F, Oei L | title = Recent Advances in the Genetics of Fractures in Osteoporosis | language = English | journal = Frontiers in Endocrinology | volume = 10 | page = 337 | date = 2019-06-04 | pmid = 31231309 | pmc = 6559287 | doi = 10.3389/fendo.2019.00337 | doi-access = free }}</ref> Recessive forms of OI relate heavily to defects in the collagen chaperones responsible for the production of [[procollagen]] and the assembly of the related proteins.<ref>{{cite journal | vauthors = Rohrbach M, Giunta C | title = Recessive osteogenesis imperfecta: clinical, radiological, and molecular findings | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 160C | issue = 3 | pages = 175–189 | date = August 2012 | pmid = 22791419 | doi = 10.1002/ajmg.c.31334 | s2cid = 28592112 | doi-access = free }}</ref> Examples of [[Chaperone (protein)|collagen chaperones]] that are defective in patients with recessive forms of OI include [[Heat shock protein 47|chaperone HSP47]] ([[Cole-Carpenter syndrome]]) and [[FKBP65]].<ref name="Marini2013">{{cite journal | vauthors = Marini JC, Blissett AR | title = New genes in bone development: what's new in osteogenesis imperfecta | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 8 | pages = 3095–3103 | date = August 2013 | pmid = 23771926 | pmc = 3733862 | doi = 10.1210/jc.2013-1505 }}</ref> Mutations in these chaperones result in an improper [[Protein folding|folding]] pattern in the collagen 1 proteins, which causes the recessive form of the disorder.<ref name="Marini2013" /> There are three significant types of OI that are a result of mutations in the collagen [[Leprecan|prolyl 3-hydroxylation complex]] (components CRTAP, P3H1, and CyPB).<ref name="Marini2013" /> These components are responsible for the modification of collagen α1(l)Pro986.<ref name="Marini2013" /> Mutations in other genes such as ''SP7'', ''SERPINF1'', ''[[TMEM38B]]'' and ''BMP1'' can also lead to irregularly formed proteins and [[enzymes]] that result in other recessive types of osteogenesis imperfecta.<ref name="Marini2013" />

Defects in the proteins [[pigment epithelium-derived factor]] (PEDF) and [[bone-restricted interferon-induced transmembrane protein]] (BRIL) are the causes of type V and VI osteogenesis imperfecta.<ref name="Marini2014">{{cite journal | vauthors = Marini JC, Reich A, Smith SM | title = Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation | journal = Current Opinion in Pediatrics | volume = 26 | issue = 4 | pages = 500–507 | date = August 2014 | pmid = 25007323 | pmc = 4183132 | doi = 10.1097/MOP.0000000000000117 }}</ref> Defects in these proteins lead to defective [[bone mineralization]] which causes the characteristic brittle bones of osteogenesis imperfecta.<ref name="Marini2014" /> A [[single point mutation]] in the [[5′ untranslated region]] (5′ UTR) of the ''IFITM5'' gene, which encodes BRIL, is linked directly to OI type V.<ref name="Cho2012" /><ref name="Hanagata2016">{{cite journal | vauthors = Hanagata N | title = IFITM5 mutations and osteogenesis imperfecta | journal = Journal of Bone and Mineral Metabolism | volume = 34 | issue = 2 | pages = 123–131 | date = March 2016 | pmid = 26031935 | doi = 10.1007/s00774-015-0667-1 | s2cid = 3173191 }}</ref>

In the rare case of type XIX, first discovered in 2016, OI is inherited as an [[X-linked recessive inheritance|X-linked genetic disorder]], with its detrimental effects resulting ultimately from a mutation in the gene ''[[MBTPS2]].''<ref name="Lindert2016">{{cite journal | vauthors = Lindert U, Cabral WA, Ausavarat S, Tongkobpetch S, Ludin K, Barnes AM, Yeetong P, Weis M, Krabichler B, Srichomthong C, Makareeva EN, Janecke AR, Leikin S, Röthlisberger B, Rohrbach M, Kennerknecht I, Eyre DR, Suphapeetiporn K, Giunta C, Marini JC, Shotelersuk V | display-authors = 6 | title = MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta | journal = Nature Communications | volume = 7 | issue = 1 | article-number = 11920 | date = July 2016 | pmid = 27380894 | pmc = 4935805 | doi = 10.1038/ncomms11920 | bibcode = 2016NatCo...711920L }}</ref> Genetic research is ongoing, and it is uncertain when all the genetic causes of OI will be identified, as the number of genes that need to be tested to rule out the disorder continue to increase.<ref name=":0" />{{Rp|pages=491–492}}

In a study of 37 families, a 1.3% chance was found that OI recurs in multiple siblings born to two unaffected parents—this is a much higher rate than would be expected if all such recurrences were ''de novo''.<ref name="Pyott2011">{{cite journal | vauthors = Pyott SM, Pepin MG, Schwarze U, Yang K, Smith G, Byers PH | title = Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance | journal = Genetics in Medicine | volume = 13 | issue = 2 | pages = 125–130 | date = February 2011 | pmid = 21239989 | doi = 10.1097/GIM.0b013e318202e0f6 | doi-access = free }}</ref> The cause is [[genetic mosaicism]]; that is, some of, or most of, the [[germ cells]] of one parent have a dominant form of OI, but not enough of their [[somatic cells]] do to cause symptoms or obvious disability in the parent—the parent's different cells have two (or more) sets of slightly different DNA.<ref name="Pyott2011" /><ref name="Rowe2008" />{{rp|1513}} It has been clinically observed that ≈5–10% of cases of OI types II and III are attributable to genetic mosaicism.<ref name="Shapiro2014" />{{rp|532}}

==Pathophysiology==
People with OI are either born with defective [[connective tissue]], born without [[Collagen#Collagen I formation|the ability to make it]] in sufficient quantities, or, in the rarest genetic types, born with deficiencies in other aspects of [[bone formation]] such as [[chaperone proteins]], the [[Wnt signaling pathway]], the [[BRIL]] protein, et cetera.<ref name="Marom2020" /> In type I the collagen's structure itself is normal, it is just its quantity that is low.<ref name="Rowe2008" />{{rp|1516}} Types II, III and IV are usually, but not always, related to a deficiency of [[type I collagen]].<ref name="Rauch F, Glorieux FH 2004 1377–85">{{cite journal | vauthors = Rauch F, Glorieux FH | title = Osteogenesis imperfecta | journal = Lancet | volume = 363 | issue = 9418 | pages = 1377–1385 | date = April 2004 | pmid = 15110498 | doi = 10.1016/S0140-6736(04)16051-0 | s2cid = 24081895 }}</ref> One possible deficiency arises from an [[amino acid]] substitution of [[glycine]] to a bulkier amino acid, such as [[alanine]], in the [[collagen]] protein's [[triple helix]] structure. The larger amino acid side-chains lead to [[steric effects]] that creates a bulge in the collagen [[Molecular complex|complex]], which in turn influences both the molecular [[nanomechanics]] and the [[interaction between molecules]], which are both compromised.<ref name="Gautieri A, Uzel S, Vesentini S, Redaelli A, Buehler MJ 2009 857–865">{{cite journal | vauthors = Gautieri A, Uzel S, Vesentini S, Redaelli A, Buehler MJ | title = Molecular and mesoscale mechanisms of osteogenesis imperfecta disease in collagen fibrils | journal = Biophysical Journal | volume = 97 | issue = 3 | pages = 857–865 | date = August 2009 | pmid = 19651044 | pmc = 2718154 | doi = 10.1016/j.bpj.2009.04.059 | bibcode = 2009BpJ....97..857G }}</ref><ref name="Xiao2011">{{cite journal | vauthors = Xiao J, Cheng H, Silva T, Baum J, Brodsky B | title = Osteogenesis imperfecta missense mutations in collagen: structural consequences of a glycine to alanine replacement at a highly charged site | journal = Biochemistry | volume = 50 | issue = 50 | pages = 10771–10780 | date = December 2011 | pmid = 22054507 | pmc = 3292618 | doi = 10.1021/bi201476a }}</ref> Depending on both the location of the substitution and the amino acid being used instead, different effects are seen which account for the type diversity in OI despite the same two collagen genes being responsible for most cases.<ref name="Nijhuis2019">{{cite journal | vauthors = Nijhuis WH, Eastwood DM, Allgrove J, Hvid I, Weinans HH, Bank RA, Sakkers RJ | title = Current concepts in osteogenesis imperfecta: bone structure, biomechanics and medical management | journal = Journal of Children's Orthopaedics | volume = 13 | issue = 1 | pages = 1–11 | date = February 2019 | pmid = 30838070 | pmc = 6376438 | doi = 10.1302/1863-2548.13.180190 }}</ref><ref name="Xiao2011" /> Replacements of glycine with [[serine]] or [[cysteine]] are seen less often in fatal type II OI, while replacements with [[valine]], [[aspartic acid]], [[glutamic acid]], or [[arginine]] are seen more often.<ref name="Xiao2011" />

At a larger scale, the relationship between the collagen [[fibrils]] and [[hydroxyapatite]] crystals to form bone is altered, causing brittleness.<ref name="Nijhuis2019" /> Bone fractures occur because the stress state within collagen fibrils is altered at the locations of mutations, where locally larger [[shear forces]] lead to rapid failure of fibrils even at moderate loads because the [[wikt:homogeneous#English|homogeneous]] stress state normally found in healthy collagen fibrils is lost.<ref name="Gautieri A, Uzel S, Vesentini S, Redaelli A, Buehler MJ 2009 857–865" /> OI is therefore a multi-scale phenomenon, where defects at the smallest levels of tissues (genetic, nano, micro) [[Domino effect|domino]] to affect the macro level of [[Tissue (biology)|tissues]].<ref name="Gautieri A, Uzel S, Vesentini S, Redaelli A, Buehler MJ 2009 857–865" />

==Diagnosis==
[[File:Blue sclerae.jpg|thumb|Blue sclerae in a person with osteogenesis imperfecta]]
Diagnosis is typically based on [[medical imaging]], including plain [[X-rays]], and symptoms. In severe OI, signs on medical imaging include abnormalities in all extremities and the spine.<ref name="elsobky2017">{{Cite journal| vauthors = El-Sobky TA, Shawky RM, Sakr HM, Elsayed SM, Elsayed NS, Ragheb SG, Gamal R |title=A systematized approach to radiographic assessment of commonly seen genetic bone diseases in children: A pictorial review.|journal= J Musculoskelet Surg Res|volume=1|issue=2|page=25|date=15 November 2017|doi=10.4103/jmsr.jmsr_28_17|s2cid=79825711 |doi-access=free }}</ref> As X-rays are often insensitive to the comparatively smaller bone density loss associated with type I OI, [[DEXA scans]] may be needed.<ref name="Rowe2008" />{{rp|page=1514}}

An OI diagnosis can be confirmed through DNA or collagen [[protein analysis]], but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue [[sclerae]] are sufficient for a diagnosis. A [[skin biopsy]] can be performed to determine the structure and quantity of type I collagen. While DNA testing can confirm the diagnosis, it cannot absolutely exclude it because not all mutations causing OI are yet known and/or tested for.<ref name=":0" />{{Rp|pages=491–492}} OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be visible. Relative to control, OI [[cortical bone]] shows increased porosity, canal diameter, and connectivity in micro-computed tomography.<ref>{{Cite book |chapter=3D micron-scale imaging of the cortical bone canal network in human osteogenesis imperfecta (OI) |vauthors=Jameson JR, Albert CI, Busse B, Smith PA, Harris GF |veditors=Weaver JB, Molthen RC |title=Medical Imaging 2013: Biomedical Applications in Molecular, Structural, and Functional Imaging |date=March 29, 2013 |publisher=International Society for Optics and Photonics |volume=8672 |pages=86721L |doi=10.1117/12.2007209 |s2cid=13876569 |url=https://epublications.marquette.edu/bioengin_fac/470 |access-date=26 August 2020 |archive-date=7 June 2020 |archive-url=https://web.archive.org/web/20200607062934/https://epublications.marquette.edu/bioengin_fac/470/ |url-status=live }}</ref> OI can also be detected before birth by using an ''in vitro'' genetic testing technique such as [[amniocentesis]].<ref>{{cite journal | vauthors = Westgren M, Götherström C | title = Stem cell transplantation before birth - a realistic option for treatment of osteogenesis imperfecta? | journal = Prenatal Diagnosis | volume = 35 | issue = 9 | pages = 827–832 | date = September 2015 | pmid = 25962526 | doi = 10.1002/pd.4611 | s2cid = 10640427 }}</ref>

=== Genetic testing ===
To determine whether osteogenesis imperfecta is present, genetic sequencing of the most common problematic genes, ''COL1A1'', ''COL1A2'', and ''IFITM5'', may be done;<ref name="Pepin2015">{{cite journal | vauthors = Pepin MG, Byers PH | title = What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 169 | issue = 4 | pages = 307–313 | date = December 2015 | pmid = 26566591 | doi = 10.1002/ajmg.c.31459 | s2cid = 26045033 }}</ref> if no mutation is found yet OI is still suspected, the other 10+ genes known to cause OI may be tested.<ref name="Marom2020" /> Duplication and deletion testing is also suggested to parents who suspect their child has OI.<ref name="Pepin2015" /> The presence of [[frameshift mutations]] caused by duplications and deletions is generally the cause of increased severity of disease.<ref name="Pepin2015" />

===Differential diagnosis===
An important differential diagnosis of OI is [[child abuse]], as both may present to a clinician with multiple fractures in various stages of healing.<ref name="Rowe2008" />{{rp|1514}} Differentiating them can be difficult, especially when no other characteristic features of OI are present.<ref name="Shapiro2014" />{{Rp|page=391}} This can become an issue in court; in the United States, several child abuse cases were resolved with a finding that osteogenesis imperfecta was the true cause of a child's fractures, leading to lawsuits seeking redress such as ''Alice Velasquez, et al. v. United States''.<ref name="Shapiro2014" />{{Rp|page=391}}<ref>{{Cite news|date=2005-10-25|title=Parents Get $1 Million in False Abuse Case|language=en-US|newspaper=Washington Post|url=https://www.washingtonpost.com/archive/local/2005/10/25/parents-get-1-million-in-false-abuse-case/c2537488-ab8c-4c5e-8a94-299280b6c5fd/|access-date=2022-02-04|issn=0190-8286|vauthors=Castaneda R}}</ref>

Other differential diagnoses include [[rickets]] and [[osteomalacia]], both caused by [[malnutrition]], as well as rare skeletal syndromes such as [[Bruck syndrome]], [[hypophosphatasia]], [[geroderma osteodysplasticum]], and [[Ehlers–Danlos syndrome]].<ref name="Rowe2008" />{{rp|1513}}<ref name="Shapiro2014" />{{rp|253–256}} Various forms of [[osteoporosis]], such as [[iatrogenic]] osteoporosis, [[idiopathic juvenile osteoporosis]], disuse osteoporosis and exercise-related osteoporosis should also be considered as explanations when OI is suspected.<ref name="Shapiro2014" />{{rp|255–256}}

==Treatment==
There is no cure for osteogenesis imperfecta.<ref name=NIH2015/> Maintaining a healthy lifestyle by exercising and avoiding smoking can help prevent fractures.<ref name=NIH2014Tx>{{cite web|title=What Is Osteogenesis Imperfecta? Fast Facts: An Easy-to-Read Series of Publications for the Public|url=http://www.niams.nih.gov/Health_Info/Bone/Osteogenesis_Imperfecta/osteogenesis_imperfecta_ff.asp|website=NIAMS|access-date=15 October 2016|date=November 2014|archive-url=https://web.archive.org/web/20161018215941/http://www.niams.nih.gov/Health_Info/Bone/Osteogenesis_Imperfecta/osteogenesis_imperfecta_ff.asp|archive-date=18 October 2016}}</ref> Treatment may include care of broken bones, pain medication, [[physical therapy]], mobility aids such as braces or wheelchairs, and surgery.<ref name="NIH2014Tx" />

Judging the success or failure of treatment can be difficult in OI patients, as decreased bone fracture rates may just be coincidental. While these rates are often used in medical studies to judge treatment efficacy, a Norwegian study of fifteen people with OI emphasized that they feel doctors should consider the whole patient and not just fracture rates.<ref>{{cite journal | vauthors = Swezey T, Reeve BB, Hart TS, Floor MK, Dollar CM, Gillies AP, Tosi LL | title = Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community | journal = Osteoporosis International | volume = 30 | issue = 2 | pages = 507–511 | date = February 2019 | pmid = 30191258 | pmc = 6449303 | doi = 10.1007/s00198-018-4690-7 }}</ref>

=== Acute bone fracture care ===
Bone fractures are treated in individuals with osteogenesis imperfecta in much the same way as they are treated in the general population; OI bone heals at the same rate as non-OI bone.<ref name="Shapiro2014" />{{rp|431}} A greater emphasis is placed on using lightweight materials to immobilize the fracture, as in moderate or severe types of OI, using heavy [[Orthopedic cast|casts]], such as [[hip spica]] casts, can cause fractures at the bones at the boundaries of the cast, as well as generalized [[osteopenia]].<ref name="Shapiro2014" />{{rp|431}} The lightweight cast or splint is then replaced with a removable [[orthosis]] after a few weeks and once evidence of union is seen on X-ray.<ref name="Shapiro2014" />{{rp|431}} To prevent a [[nonunion]] or [[malunion]], all fractures should be immobilized, even if the fracture seems trivial ([[Bone fracture|microfracture]]),<ref name="Shapiro2014" />{{rp|439}} as people with OI are at greater risk of nonunion.<ref name="Shapiro2014" />{{rp|438}}

Bone [[infection]]s secondary to fractures are treated as and when they occur with the appropriate [[antibiotics]] and [[antiseptics]], as in the general population.<ref name="Shapiro2014" />{{rp|424}}

=== Medications ===

====Bisphosphonates====
[[File:Pamidronate2DACS.svg|thumb|[[Pamidronate]]]]
In 1998, an initial observational trial demonstrated the effectiveness of intravenous [[pamidronate]], a [[bisphosphonate]] which had previously been used in adults to treat [[osteoporosis]]. In severe OI, this trial showed that pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of long-bone fractures.<ref>{{cite journal | vauthors = Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R | title = Cyclic administration of pamidronate in children with severe osteogenesis imperfecta | journal = The New England Journal of Medicine | volume = 339 | issue = 14 | pages = 947–952 | date = October 1998 | pmid = 9753709 | doi = 10.1056/NEJM199810013391402 | s2cid = 19316414 | doi-access = free }}Free full text</ref>

Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and intravenous bisphosphonates are generally more effective, although this is under study. Some studies have found oral and intravenous bisphosphonates, such as oral [[alendronate]] and intravenous pamidronate, equivalent.<ref>{{cite journal | vauthors = DiMeglio LA, Peacock M | title = Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta | journal = Journal of Bone and Mineral Research | volume = 21 | issue = 1 | pages = 132–140 | date = January 2006 | pmid = 16355282 | doi = 10.1359/JBMR.051006 | s2cid = 12996685 | doi-access = free }}</ref> In a 2013 [[double-blind trial]] of children with mild OI, oral [[risedronate]] increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures.<ref>{{cite journal | vauthors = Bishop N, Adami S, Ahmed SF, Antón J, Arundel P, Burren CP, Devogelaer JP, Hangartner T, Hosszú E, Lane JM, Lorenc R, Mäkitie O, Munns CF, Paredes A, Pavlov H, Plotkin H, Raggio CL, Reyes ML, Schoenau E, Semler O, Sillence DO, Steiner RD | display-authors = 6 | title = Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial | journal = Lancet | volume = 382 | issue = 9902 | pages = 1424–1432 | date = October 2013 | pmid = 23927913 | doi = 10.1016/S0140-6736(13)61091-0 | s2cid = 25559791 }}</ref><ref>{{cite journal | vauthors = Ward LM, Rauch F | title = Oral bisphosphonates for paediatric osteogenesis imperfecta? | journal = Lancet | volume = 382 | issue = 9902 | pages = 1388–1389 | date = October 2013 | pmid = 23927912 | doi = 10.1016/S0140-6736(13)61531-7 | s2cid = 5872511 }}</ref> A [[Cochrane review|''Cochrane'' review]] in 2016 concluded that though bisphosphonates seem to improve bone mineral density, it is uncertain whether this leads either to a reduction in [[bone fractures]] or improvement in the [[quality of life]] of individuals with osteogenesis imperfecta.<ref name=Phi2016/> Even in trials with as many as 125 children, no causal link has been found between bisphosphonates and decreased fracture rates; [[placebo controlled trials]] were also unable to prove that they brought about increased strength, [[motor control]] or lower pain levels.<ref name="Forlino2011" />

Bisphosphonates are not as effective at increasing the bone mineral density of adults.<ref name="Chevrel2006">{{cite journal | vauthors = Chevrel G, Schott AM, Fontanges E, Charrin JE, Lina-Granade G, Duboeuf F, Garnero P, Arlot M, Raynal C, Meunier PJ | display-authors = 6 | title = Effects of oral alendronate on BMD in adult patients with osteogenesis imperfecta: a 3-year randomized placebo-controlled trial | journal = Journal of Bone and Mineral Research | volume = 21 | issue = 2 | pages = 300–306 | date = February 2006 | pmid = 16418786 | doi = 10.1359/JBMR.051015 | s2cid = 34089615 | doi-access = free }}</ref>

==== Nutritional supplements ====
OI is a genetic disorder and is not caused by insufficient intake of any vitamin or mineral; [[Multivitamin|supplementation]] cannot cure OI. Nevertheless, people with OI tend to be severely deficient in [[vitamin D]] at much higher rates than the general population, and the cause of this is not well understood.<ref name=":1">{{Cite journal|vauthors=Meena BL, Panigrahi I, Marwaha RK|date=2014-10-01|title=PO-0077 Vitamin D Deficiency In Children With Osteogenesis Imperfecta|url=https://adc.bmj.com/content/99/Suppl_2/A275.1|journal=Archives of Disease in Childhood|language=en|volume=99|issue=Suppl 2|page=A275|doi=10.1136/archdischild-2014-307384.747|s2cid=72491188|issn=0003-9888|access-date=18 September 2021|archive-date=18 September 2021|archive-url=https://web.archive.org/web/20210918102054/https://adc.bmj.com/content/99/Suppl_2/A275.1|url-status=live|doi-access=free}}</ref><ref name="Edouard2011">{{cite journal | vauthors = Edouard T, Glorieux FH, Rauch F | title = Predictors and correlates of vitamin D status in children and adolescents with osteogenesis imperfecta | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 10 | pages = 3193–3198 | date = October 2011 | pmid = 21832107 | doi = 10.1210/jc.2011-1480 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Zambrano MB, Brizola E, Pinheiro B, Vanz AP, Mello ED, Félix TM | title = Study of the Determinants of Vitamin D Status in Pediatric Patients With Osteogenesis Imperfecta | journal = Journal of the American College of Nutrition | volume = 35 | issue = 4 | pages = 339–345 | date = 2016-05-18 | pmid = 26709914 | doi = 10.1080/07315724.2015.1057776 | s2cid = 45930763 }}</ref> The severity of the deficiency and the likelihood of its occurrence is thought to be related to severity of OI.<ref name="Edouard2011" /> Vitamin D supplementation may be recommended, at least until levels of [[Calcifediol|25(OH)D<sub>3</sub>]] in a patient's blood return to normal.<ref name=":1" /> [[Vitamin D deficiency]] is also a concern as it may decrease the benefit of [[Osteogenesis imperfecta#Bisphosphanates|bisphosphanates]].<ref name=":1" />

===Surgery===
A [[surgery]] of any type inherently carries more risks when done on a patient who has (especially moderate to severe) OI. Skeletal deformities and dentinogenesis imperfecta may hinder [[Airway access|access to the airway]].<ref name="Shapiro2014" />{{rp|333}} Use of, and [[Ventilator weaning|weaning]] off of, [[mechanical ventilation]] is also more challenging to carry out on patients with OI.<ref name="Shapiro2014" />{{rp|333}} During the procedure itself or the healing process, defective OI collagen may lead to [[bleeding diatheses]].<ref name="Shapiro2014" />{{rp|333}}

The [[safety of anesthesia]] is also of more concern among patients with OI,<ref name="Shapiro2014" />{{rp|333}} with anesthetic complications 5.6x more likely to occur when the patient has OI type III.<ref>{{cite journal | vauthors = Rothschild L, Goeller JK, Voronov P, Barabanova A, Smith P | title = Anesthesia in children with osteogenesis imperfecta: Retrospective chart review of 83 patients and 205 anesthetics over 7 years | journal = Pediatric Anesthesia | volume = 28 | issue = 11 | pages = 1050–1058 | date = November 2018 | pmid = 30295359 | doi = 10.1111/pan.13504 | url = https://onlinelibrary.wiley.com/doi/10.1111/pan.13504 | access-date = 29 August 2021 | url-status = live | s2cid = 52929810 | archive-url = https://web.archive.org/web/20210829064208/https://onlinelibrary.wiley.com/doi/10.1111/pan.13504 | archive-date = 29 August 2021 | url-access = subscription }}</ref> A unique concern of anesthesia in OI is [[perioperative]] fracture—fractures sustained due to patient transfer and airway access techniques that, while routine when a patient's bones are strong, may cause injury with brittle OI bones.<ref>{{Cite book|title=Handbook of Pediatric Anesthesia|vauthors=Houck JP|publisher=[[McGraw-Hill Education]]|year=2014|isbn=978-0-07-176935-8|veditors=Houck JP, Hache M, Sun LS|location=New York|chapter=Osteogenesis imperfecta|chapter-url=https://accessanesthesiology.mhmedical.com/content.aspx?sectionid=70364025&bookid=1189|access-date=29 August 2021|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829064222/https://accessanesthesiology.mhmedical.com/content.aspx?sectionid=70364025&bookid=1189|url-status=live}}</ref> As an example, due to a 1972 report of a [[humerus]] fracture from a [[sphygmomanometer]] cuff sustained in an OI patient during surgery, [[Blood pressure measurement|blood pressure monitoring]] protocols are often modified for patients with OI, with [[neonatal]] size cuffs and machine settings being used even in adults;<ref>{{Citation|title=Anesthetic and Post-operative Pain Management|date=2020|work=Osteogenesis Imperfecta: A Case-Based Guide to Surgical Decision-Making and Care|pages=111–125|publisher=Springer International Publishing|language=en|doi=10.1007/978-3-030-42527-2_8|isbn=978-3-030-42527-2|vauthors=Goeller JK, Rothschild L|s2cid=219515776|veditors=Kruse RW}}</ref>{{rp|¶11.72}} further, the least deformed of the patient's limbs is preferred to receive the cuff.<ref name="Esposito2020">{{Citation|title=Osteogenesis Imperfecta Surgical Management of the Femur and Knee|date=2020|work=Osteogenesis Imperfecta: A Case-Based Guide to Surgical Decision-Making and Care|pages=147–182|publisher=Springer International Publishing|language=en|doi=10.1007/978-3-030-42527-2_10|isbn=978-3-030-42527-2|veditors=Kruse RW|vauthors=Esposito P, Wallace MJ|s2cid=219515805}}</ref>{{rp|¶14.23}}

==== Rodding ====
{{Multiple image
|direction=horizontal
|image1=Tip of a Fassier–Duval intramedullary rod manufactured by Pega Medical.png
|caption1=The tip of a modern Fassier–Duval telescoping [[intramedullary rod]], manufactured by Pega Medical for use in osteogenesis imperfecta.<ref name="Behera2020">{{Cite journal|vauthors=Behera P, Santoshi JA, Geevarughese NM, Meena UK, Selvanayagam R|date=2020-02-28|title=Dislodgement of Telescopic Nail from the Epiphysis: A Case Report with an Analysis of Probable Mechanism|journal=[[Cureus]]|volume=12|issue=2|article-number=e7130|language=en|doi=10.7759/cureus.7130|doi-access=free |issn=2168-8184|pmc=7105006|pmid=32257675}}</ref><!-- Warning: Open access journal. Do not use cite outside of image sourcing. -->
|image2=Two postoperative radiographs of a patient who underwent rodding surgery for osteogenesis imperfecta.png
|caption2=The right [[femur]] (2A) and [[tibia]] (2B) of a 10-year-old girl immediately after her rodding surgery, which involved implantation of the same type of telescoping [[intramedullary rod]] photographed at left.<ref name="Behera2020"/> Note the bone fragmentation, an important step in the procedure, clearly visible on the X-ray of the femur.
|total_width=500
}}
Metal rods can be [[surgery|surgically]] inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield when he was Chief of Staff at Chicago's [[Shriners Hospitals for Children]], a hospital that offers [[orthopedic surgery|orthopedic care and surgery]] to children regardless of their family's ability to pay.<ref>{{Cite web|title=Financial Assistance|url=https://www.shrinershospitalsforchildren.org/shc/financial-assistance|url-status=live|archive-url=https://web.archive.org/web/20210303085312/https://www.shrinershospitalsforchildren.org/shc/financial-assistance|archive-date=2021-03-03|access-date=2021-08-21|website=[[Shriners Hospitals for Children]]|quote=Shriners Hospitals for Children is committed to providing specialized care to children with orthopaedic conditions [...] regardless of the families' ability to pay.}}</ref> Large numbers of children with OI came to Shriners, and Sofield experimented with various methods to strengthen their bones.<ref>{{Cite web|title=A Leader in the Treatment of Osteogensis Imperfecta (OI)|url=http://www.shriners.com/Hospitals/Chicago/conditions/OI.aspx|archive-url=https://web.archive.org/web/20070928140354/http://www.shriners.com/Hospitals/Chicago/conditions/OI.aspx|archive-date=2007-09-28|access-date=2007-07-05|work=[[Shriners International]]}}</ref> In 1959, with Edward A. {{Sic|Mill|ar}}, Sofield wrote a seminal article describing a three-part surgery that seemed radical at the time: [[Osteotomy|precisely breaking the bones]] ("fragmentation"), putting the resulting bone fragments in a straight line ("realignment"), then placing metal rods into the [[intramedullary]] canals of the long bones to stabilize and strengthen them ("rod fixation").<ref>{{Cite journal| vauthors = Sofield HA, Millar EA |date=1959-12-01|title=Fragmentation, Realignment, and Intramedullary Rod Fixation of Deformities of the Long Bones in Children: A Ten-Year Appraisal |journal=[[The Journal of Bone and Joint Surgery]]|language=en-US|volume=41|issue=8|pages=1371–1391|doi=10.2106/00004623-195941080-00001|issn=0021-9355}}</ref> His treatment proved useful for increasing the mobility of people with OI, and it has been adopted throughout the world—it became standard surgical treatment for severe OI by 1979, in which year [[David Sillence]] found that ≈{{frac|2|3}} of the patients he surveyed with OI type III had undergone at least one rodding surgery.<ref name="Sillence1979" />{{rp|108}}

Rodding surgery is often done with the hope that it will offer a path to ambulation, [[walking]], to patients with moderate or severe OI. A 2020 review in ''[[The Journal of Bone and Joint Surgery]]'' (''JB&JS'') found it remains broadly popular: ≈{{frac|2|3}} of people with OI types III and IV (severe OI) have undergone some form of rodding surgery in their lives, at a mean age of {{frac|4|1|10}} and {{frac|7|1|2}} years respectively;<ref name="Rodriguez2020">{{cite journal | vauthors = Rodriguez Celin M, Kruger KM, Caudill A, Nagamani SC, Harris GF, Smith PA | title = A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta | journal = JB & JS Open Access | volume = 5 | issue = 3 | article-number = e20.00031 | date = 2020-09-11 | pmid = 32984750 | pmc = 7489747 | doi = 10.2106/JBJS.OA.20.00031 }}</ref>{{rp|Table I}} one possible explanation for a tendency towards earlier intervention in type III is that one half of affected children could not walk at all without the surgery, as their limbs were more bowed, so surgery was sought sooner.<ref name="Rodriguez2020" />

In those with type III OI who had undergone rodding surgery, 79.5% had the femurs and tibias of both legs rodded.<ref name="Rodriguez2020" />{{rp|Table I}} The most common form of rods used are [[Intramedullary rod|intramedullary (IM) rods]], some of which, such as the Fassier–Duval IM rod, are [[Telescopic cylinder|telescoping]], meaning that they are designed to grow as the child grows, in an attempt to avoid the necessity of revision surgeries.<ref>{{Cite web|title=The Fassier-Duval Telescopic IM System|url=https://www.pegamedical.com/en/products/the-fassier-duval-telescopic-im-system|url-status=live|access-date=2021-08-15|website=Pega Medical|location=[[Laval, Quebec]]|language=en|archive-date=15 August 2021|archive-url=https://web.archive.org/web/20210815171101/https://www.pegamedical.com/en/products/the-fassier-duval-telescopic-im-system}}</ref> Telescoping IM rods are widely used,<ref name="Sterian2015">{{cite journal | vauthors = Sterian A, Balanescu R, Barbilian A, Ulici A | title = Osteosynthesis in Osteogenesis Imperfecta, telescopic versus non-telescopic nailing | journal = Journal of Medicine and Life | volume = 8 | issue = 4 | pages = 563–565 | date = 2015 | pmid = 26664490 | pmc = 4656972 }}</ref> and the common Fassier–Duval IM rod is designed to be used to rod the femur, tibia, and humerus.<ref name="Frassier2021">{{Cite web|vauthors=Frassier F, Duval P, Paley D|year=2021|title=Fassier–Duval Telescopic IM System Surgical Technique|url=https://www.pegamedical.com/medias/iw/FD-ST-EN-RevK_1.pdf|url-status=live|access-date=2021-08-15|website=Pega Medical|location=[[Laval, Quebec]]|id=FD-ST-EN Revision K|archive-date=15 August 2021|archive-url=https://web.archive.org/web/20210815171101/https://www.pegamedical.com/medias/iw/FD-ST-EN-RevK_1.pdf}}</ref>{{rp|1}} The surgery involves breaking the long bones in between one and three (or more)<ref name="Sterian2015" />{{rp|Figure 4}} places, then fixing the rod alongside the bone to keep it straight.<ref name="Frassier2021" />{{rp|11}}

While telescoping IM rods are intended to grow along with both the femur and tibia in developing children; surgeons have a preference to use non-telescoping IM rods, such as Rush rods, in the tibia, which grows less comparatively—the ''JB&JS'' review found that while 69.7% of femurs were treated with telescoping IM rods, only 36.9% of tibiae were.<ref name="Rodriguez2020" />{{rp|Table IV}}

While the review in the ''JB&JS'' was able to correlate receiving rodding surgery with greater mobility across all types of OI, in patients with type IV, the surgery did not decrease the incidence of broken bones as compared to non-rodded patients—while type IV patients with rodded tibiae experienced 0.93 tibia fractures per year, patients with natural tibiae experienced only 0.81. However, in patients with type III, rodding surgery decreased the average number of tibia fractures per year from 0.84 to 0.57.<ref name="Rodriguez2020" />{{rp|Table V}}

==== Spinal ====
[[Spinal fusion]] can be performed either as a preventative measure or to correct existing [[scoliosis]], although the inherent fragility of OI bone makes this operation more complex in OI patients than it does with patients who have adolescent [[Idiopathic disease|idiopathic]] scoliosis, but normal bone density.<ref>{{Cite journal| vauthors = Belyea CM, Knox JB |date=2020-01-01|title=Spinal fusion in children with osteogenesis imperfecta: A nationwide retrospective comparative cohort study over a 12-year period|journal=Current Orthopaedic Practice|language=en-US|volume=31|issue=1|pages=72–75|doi=10.1097/BCO.0000000000000805|s2cid=209229412|issn=1940-7041}}</ref> Despite the risks, however, three [[Nemours Alfred I. duPont Hospital for Children|Nemours–duPont]] orthopedic surgeons who specialize in surgical intervention for osteogenesis imperfecta recommend operating if the curve is greater than 50° after a child is past [[peak height velocity]], as the spine's curve can continue to worsen even into adulthood.<ref name="Wallace2017">{{cite journal | vauthors = Wallace MJ, Kruse RW, Shah SA | title = The Spine in Patients With Osteogenesis Imperfecta | journal = The Journal of the American Academy of Orthopaedic Surgeons | volume = 25 | issue = 2 | pages = 100–109 | date = February 2017 | pmid = 28009707 | doi = 10.5435/JAAOS-D-15-00169 }}</ref>{{rp|104}}

Due to the risk involved, the same surgeons recommend that surgery for basilar impressions and [[basilar invagination]]s should only be carried out if the pressure being exerted on the [[spinal cord]] and [[brain stem]] is causing actual neurological symptoms.<ref name="Wallace2017" />{{rp|106–107}} Once basilar invagination has become symptomatic, only surgery can halt or reverse the progression of [[neurological deficits]].<ref name="Shapiro2014" />{{rp|345}}

===Physical therapy===
[[Physical therapy]] is generally recommended, however individualized protocols are required due to the variability of OI.<ref name="Shapiro2014" />{{rp|378}} Physical therapy is used to strengthen muscles, improve [[motility]], improve [[Flexibility (anatomy)|flexibility]], and help with [[weight maintenance]], although it must be done in a gentle manner to minimize the risk of bone fracture.<ref name="Shapiro2014" />{{rp|378}} In people with OI, exercise often involves [[water aerobics]], light [[Strength training|resistance exercises]], and walking, if the patient is able.<ref name="Shapiro2014" />{{rp|378}} However, even in patients with mild OI, [[contact sports]], as well as activities likely to put unnecessary stress on the joints, such as [[jumping]], are contraindicated due to the risks they pose.<ref name="Shapiro2014" />{{rp|378}}

Individuals with more limited mobility are encouraged to change positions regularly throughout the day; people who sit in a wheelchair most or all of the day are recommended to get out of it every two hours, as a form of exercise, to decrease stiffness, and to prevent [[pressure ulcers]].<ref name="Shapiro2014" />{{rp|378}}

Individuals with moderate to severe OI, who require assistive mobility devices and [[adapted vehicles]], face significant barriers to access [[wheelchair-accessible]] pools or gyms—they either may not have any in their area, nor the means to get there.<ref name="Shapiro2014" />{{rp|378}} [[Obesity]] may be more likely to present among those with severe OI, (especially after the age of 20,) and can, in some, cause further declines in mobility.<ref>{{cite journal | vauthors = Zani A, Ford-Adams M, Ratcliff M, Bevan D, Inge TH, Desai A | title = Weight loss surgery improves quality of life in pediatric patients with osteogenesis imperfecta | journal = Surgery for Obesity and Related Diseases | volume = 13 | issue = 1 | pages = 41–44 | date = January 2017 | pmid = 26948942 | pmc = 5965274 | doi = 10.1016/j.soard.2015.11.029 | publisher = [[Elsevier Inc.]] }}</ref><ref name="Shapiro2014" />{{rp|371,373}}

[[Tilt table]] [[whole body vibration]] may also be done to increase the mobility of long-term immobilized ([[bedridden]]) patients with OI; in at least two cases, it helped bedridden children to be able to sit upright.<ref>{{cite journal | vauthors = Semler O, Fricke O, Vezyroglou K, Stark C, Schoenau E | title = Preliminary results on the mobility after whole body vibration in immobilized children and adolescents | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 7 | issue = 1 | pages = 77–81 | date = 2007-01-01 | pmid = 17396011 }}</ref><ref name="Forlino2011" />

=== Teeth ===
{{See also|Dentinogenesis imperfecta}}
More than 1 in 2 people with OI also have dentinogenesis imperfecta (DI)—a congenital abnormality in the formation of [[dentin]], one of the four major components of the [[human tooth]].<ref name="Biria2012">{{cite journal | vauthors = Biria M, Abbas FM, Mozaffar S, Ahmadi R | title = Dentinogenesis imperfecta associated with osteogenesis imperfecta | journal = Dental Research Journal | volume = 9 | issue = 4 | pages = 489–494 | date = July 2012 | pmid = 23162594 | pmc = 3491340 }}</ref> Dental treatment may pose a challenge as a result of the various deformities, skeletal and dental, due to OI. Children with OI should go for a dental check-up as soon as their [[Tooth eruption|teeth erupt]]; this may minimize tooth structure loss as a result of abnormal dentine, and they should be monitored regularly to preserve their teeth and oral health.<ref name="Biria2012" />

Many people with OI are treated with bisphosphonates, and there are several possible related complications with dental procedures, for example, [[medication-related osteonecrosis of the jaw]] (MRONJ). However, no report of bisphosphonate-related MRONJ in either a child or adult with OI was found in a 2016 ''Cochrane'' review of the safety and efficacy of bisphosphonates for OI.<ref name="Phi2016" />

=== In development ===

==== Monoclonal antibodies ====
[[Monoclonal antibodies]] have long been considered for OI, but as of 2021, such therapy has not been approved for OI, neither in the European Union nor in the United States. Thus, it is unclear whether they are safe or effective. Among the monoclonal antibodies that have been studied are [[romosozumab]] (targets [[sclerostin]], by [[Amgen]]), [[fresolimumab]] ([[TGF-β]], [[Sanofi]]), [[blosozumab]] (sclerostin, [[Eli Lilly and Company|Lilly]]), and [[setrusumab]] (sclerostin, begun by [[Novartis]]).<ref name="Plieth2020">{{Cite web|date=2020-12-18|title=Recycling pays off for Mereo|url=https://www.evaluate.com/vantage/articles/news/deals/recycling-pays-mereo|url-status=live|access-date=2021-09-18|website=Evaluate Vantage|language=en|vauthors=Plieth J|archive-date=18 September 2021|archive-url=https://web.archive.org/web/20210918091906/https://www.evaluate.com/vantage/articles/news/deals/recycling-pays-mereo}}</ref>

Setrusumab, formerly known as BPS-804, is a monoclonal antibody that targets [[sclerostin]], and has been studied in OI specifically more than any of the others. In the body, sclerostin binds to the [[LRP5]] and [[LRP6]] receptors, resulting in inhibition of the [[Wnt signaling pathway]]. This decreases bone formation, and is not a problem when a person has healthy bones.<ref>{{cite journal | vauthors = Delgado-Calle J, Sato AY, Bellido T | title = Role and mechanism of action of sclerostin in bone | journal = Bone | volume = 96 | pages = 29–37 | date = March 2017 | pmid = 27742498 | pmc = 5328835 | doi = 10.1016/j.bone.2016.10.007 }}</ref> It is thought, though, that decreasing the concentration of sclerostin in the body may lead to the formation of more bone, and that is the premise as to why monoclonal antibodies that reduce the concentrations of naturally occurring sclerostin may help strengthen OI bone.<ref>{{cite journal | vauthors = Glorieux FH, Devogelaer JP, Durigova M, Goemaere S, Hemsley S, Jakob F, Junker U, Ruckle J, Seefried L, Winkle PJ | display-authors = 6 | title = BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial | journal = Journal of Bone and Mineral Research | volume = 32 | issue = 7 | pages = 1496–1504 | date = July 2017 | pmid = 28370407 | doi = 10.1002/jbmr.3143 | s2cid = 4432023 | doi-access = free | hdl = 2078.1/203752 | hdl-access = free }}</ref> While setrusumab was first developed at the pharmaceutical company Novartis, Novartis sold its rights to patent the drug to Mereo Biopharma in 2015, who has continued its development in conjunction with [[Ultragenyx]].<ref name="Plieth2020" /><ref>{{Cite web|date=2020-12-17|title=Ultragenyx and Mereo BioPharma Announce Collaboration and License Agreement for Setrusumab in Osteogenesis Imperfecta|url=https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-and-mereo-biopharma-announce-collaboration-and|url-status=live|access-date=2021-09-18|website=[[Ultragenyx Pharmaceutical Inc.]]|language=en|archive-date=18 September 2021|archive-url=https://web.archive.org/web/20210918094909/https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-and-mereo-biopharma-announce-collaboration-and}}</ref> In 2019, Mereo announced that it had concluded collecting data for its [[Phase II trial|phase II-B trial]] of setrusumab; the study was completed on 12 November 2020.<ref name="Plieth2020" /><ref>{{Cite journal|date=2021-04-01 |title=A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804 (ASTEROID)|url=https://clinicaltrials.gov/ct2/show/results/NCT03118570|access-date=2021-09-18|website=[[ClinicalTrials.gov]]|publisher=[[United States National Library of Medicine]]|id=NCT03118570}}</ref> Despite the trial data failing to show improvements in bone density on [[QCT]] scans, its primary goal, there were improvements on [[DXA]] scans.<ref>{{Cite web|date=2019-11-25|title=Setrusumab ready to advance into pivotal studies|url=https://www.trinitydelta.org/research-notes/setrusumab-ready-to-advance-into-pivotal-studies/|url-status=live|access-date=2021-09-18|website=Trinity Delta|language=en-US|vauthors=Cooper M, Gregorek L|archive-date=18 September 2021|archive-url=https://web.archive.org/web/20210918104032/https://www.trinitydelta.org/research-notes/setrusumab-ready-to-advance-into-pivotal-studies/}}</ref> In a September 2020 press release, Mereo said it was seeking to do a [[phase III trial]] in 2021, and had received a Rare Pediatric Disease (RPD) designation from the US [[Food and Drug Administration]] (FDA).<ref>{{Cite web|date=2020-09-24|title=Mereo setrusumab gets FDA rare pediatric disease designation for osteogenesis imperfecta|url=https://biotuesdays.com/2020/09/24/mereo-setrusumab-gets-fda-rare-pediatric-disease-designation-for-osteogenesis-imperfecta/|url-status=live|access-date=2021-09-18|website=BioTuesdays|language=en-CA|vauthors=Hardy A|archive-date=18 September 2021|archive-url=https://web.archive.org/web/20210918090404/https://biotuesdays.com/2020/09/24/mereo-setrusumab-gets-fda-rare-pediatric-disease-designation-for-osteogenesis-imperfecta/}}</ref>

[[Romosozumab]], which is also a monoclonal antibody targeting sclerostin, is an approved drug in the US and EU for the treatment of [[osteoporosis]]. The pharmaceutical industry analyst [[Evercore]] has remarked that "it could wipe out setrusumab's [[Cost of drug development|economics]]", as romosozumab is priced more cheaply than a drug for a rare disease would be, claiming that it will be "vital" to Ultragenyx's [[profit margins]] to prove its setrusumab is more efficacious than romosozumab for OI.<ref name="Plieth2020" /> A clinical trial evaluating romosozumab's efficacy in OI began in September 2020 and as of September 2021 is ongoing.<ref>{{Cite journal|date=2021-07-23 |title=Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta|url=https://clinicaltrials.gov/ct2/show/NCT04545554|url-status=live|access-date=2021-09-18|website=[[ClinicalTrials.gov]]|publisher=United States National Library of Medicine|id=NCT04545554|archive-date=18 September 2021|archive-url=https://web.archive.org/web/20210918105332/https://clinicaltrials.gov/ct2/show/NCT04545554}}</ref> Ultragenyx predicts that its [[Phase III trial|phase 2/3 trials]] for setrusumab will be completed in 2026.<ref>{{Cite web |last=Out of Ignorance |date=2022-09-02 |title=Ultragenyx Stock: Downward Trajectory Likely to Continue |url=https://seekingalpha.com/article/4538584-ultragenyx-pharmaceuticals-stock-downward-trajectory-likely-continue |access-date=2022-09-24 |website=[[Seeking Alpha]] |language=en}}</ref><ref>{{Cite web |last1=Carpenter |first1=Thomas |last2=Gulanski |first2=Barbara |last3=Barros |first3=Julio Sotto |name-list-style=vanc |date=2023-04-21 |title=Study to Assess the Efficacy and Safety of Setrusumab in Participants With Osteogenesis Imperfecta |url=https://www.yalemedicine.org/clinical-trials/efficacy-and-safety-of-setrusumab-in-subjects-with-osteogenesis-imperfecta-1 |archive-url=https://web.archive.org/web/20230726062924/https://www.yalemedicine.org/clinical-trials/efficacy-and-safety-of-setrusumab-in-subjects-with-osteogenesis-imperfecta-1 |archive-date=2023-07-26 |access-date=2023-12-16 |website=Yale Medicine |language=en}}</ref>

== Prevention ==
[[File:Preimplantation genetic diagnosis.svg|275px|thumb|[[Preimplantation genetic diagnosis]] is a medical procedure that families with OI can undergo to guarantee non-affected offspring.]]
{{See also|Introduction to genetics|bioethics}}
As a genetic disorder, the mainstay of twenty-first-century prevention of osteogenesis imperfecta is based on [[Prenatal testing|preventing affected individuals from being born in the first place]]. [[Genetic counseling]] can help patients and their families determine what types of screening, if any, are right for their situation. Patients can consider [[preimplantation genetic diagnosis]] after [[in vitro fertilization]] to select fertilized embryos that are not affected.<ref name="Shapiro2014" />{{Rp|247–248}} Common mutations which cause OI may be caught by [[exome sequencing]] and [[whole genome sequencing]]. If a pregnancy is already in progress, the procedure of [[amniocentesis]] may be undergone to see if the fetus is affected.<ref name="Shapiro2014" />{{Rp|247}} If affected, it is up to the family to consider whether or not they want to [[Abortion|terminate the pregnancy]] and try again—raising questions of [[medical ethics]] and a [[woman's right to choose]].<ref>{{cite web | vauthors = Green R |date=2012-03-11|title=Brittle Bone Disease Forced Mother Into 'No Easy Choice'|url=https://www.courant.com/news/connecticut/hc-xpm-2012-03-11-hc-green-reproduction-abortion-0307-20120311-story.html|access-date=2021-09-16|website=[[Hartford Courant]]|language=en-US}}</ref><ref>{{cite news | vauthors = Hopper T |date=2013-02-06|title='Incompatible with life': Mother's account of her difficult decision to request a late-term abortion sheds light on 'live-born' debate|url=https://nationalpost.com/news/canada/incompatible-with-life-one-mothers-account-of-her-difficult-decision-to-request-a-rare-late-term-abortion|access-date=2021-09-16|website=[[National Post]]|language=en-CA}}</ref>

Without intervention, patients with the most common mutations causing osteogenesis imperfecta have a 50% chance per [[gestation]] of passing on the disorder, as these mutations are inherited in an [[autosomal dominant]] pattern of [[Mendelian inheritance]].<ref name="Shapiro2014" />{{Rp|247}} Those with the rare [[autosomal recessive]] forms of OI have a 25% chance of passing on the disorder. Genetic testing of the affected members of the family can be used to determine which inheritance pattern applies.<ref name="Shapiro2014" />{{Rp|101}}

As OI type I may be difficult to detect in a newborn child, the [[cord blood]] of the child can be tested to determine if it has been passed on, if the family has already rejected the more invasive genetic screening methods.<ref name="Shapiro2014" />{{Rp|247}} In more severe cases, the diagnosis may be able to be done via ultrasound, especially if OI is already a possibility.<ref name="Shapiro2014" />{{Rp|248}} An ethical concern with prenatal screening for OI often arises when parents inquire as to how severely affected their child will be—such questions are as yet difficult to answer conclusively.<ref name="Shapiro2014" />{{Rp|382}}

If a non-affected person has already had a child with OI, there is a greater likelihood (although still quite remote) that their future children will have OI due to [[genetic mosaicism]].<ref name="Pyott2011" /><ref name="Shapiro2014" />{{rp|100,1513}}

The [[disability rights]] critique of prenatal screening for OI, held by some [[bioethicists]] and some affected individuals, negatively compares it to [[eugenics]], with even those not opposed to abortion opposing selective abortions on the ethical ground that their existence betrays the belief that the lives of those with OI are "less worth living [and] less valuable".<ref name="Shapiro2014" />{{Rp|388}}

== Prognosis ==
The [[prognosis]] of osteogenesis imperfecta depends entirely on its type (see {{Format link|#Classification}}).

=== Life expectancy ===
In the mild form of the disorder, type I, the [[life expectancy]] of patients is near that of the general population.<ref name="Shapiro2014" />{{rp|461}} In type II, however, patients only very rarely live past the age of two, and typically die in their first weeks of life.<ref name="Rowe2008" />{{rp|1511}} Assessment of the life expectancy of patients with types III and IV is more complicated, as lifestyle choices can cause fatally [[Major trauma|traumatic]] injuries that would not have otherwise occurred, or not been fatal in the general population. Life expectancy in type IV OI is thought to be close to normal, but in type III it is lower than in the general population.<ref name="Steiner" />

A 2016 study of data in Denmark's {{ill|National Patient Register|da|Nationalt patientindex}} found that across all types of OI, [[all-cause mortality]] was three times higher, leading to a loss of around seven years in females and nine years in males.<ref name="Folkestad2016">{{cite journal | vauthors = Folkestad L, Hald JD, Canudas-Romo V, Gram J, Hermann AP, Langdahl B, Abrahamsen B, Brixen K | display-authors = 6 | title = Mortality and Causes of Death in Patients With Osteogenesis Imperfecta: A Register-Based Nationwide Cohort Study | journal = Journal of Bone and Mineral Research | volume = 31 | issue = 12 | pages = 2159–2166 | date = December 2016 | pmid = 27345018 | doi = 10.1002/jbmr.2895 | s2cid = 32196304 | doi-access = free }}</ref> A 1996 study published in the ''[[British Medical Journal]]'' found that mortality in type III OI is significantly higher, with many patients dying in their 20's, 30's, and 40's; patients who survive to the age of 10 were further found to have longer life expectancy than newborns.<ref>{{cite journal | vauthors = Paterson CR, Ogston SA, Henry RM | title = Life expectancy in osteogenesis imperfecta | journal = BMJ | volume = 312 | issue = 7027 | page = 351 | date = February 1996 | pmid = 8611834 | pmc = 2350292 | doi = 10.1136/bmj.312.7027.351 }}</ref>

===Mobility===
People with mild (type I) OI as adults need few pieces of [[adaptive equipment]], although in infancy they reach motor milestones at a significant delay compared to the general population.<ref name="Shapiro2014" />{{rp|477}}

With adaptive equipment such as [[crutches]], [[motorized wheelchair]]s, [[Splint (medicine)|splints]], [[reach extender]]s, and/or modifications to the home, many individuals with moderate to severe OI can achieve or maintain a significant degree of [[Autonomy#Medicine|independence]].<ref name="Donohoe2020">{{cite book | vauthors = Donohoe M |title=Osteogenesis Imperfecta|chapter=Therapy, Orthotics and Assistive Devices for Osteogenesis Imperfecta|date=2020|chapter-url=http://link.springer.com/10.1007/978-3-030-42527-2_3|work=Osteogenesis Imperfecta: A Case-Based Guide to Surgical Decision-Making and Care|pages=21–37|  veditors = Kruse RW |publisher=Springer International Publishing|language=en|doi=10.1007/978-3-030-42527-2_3|isbn=978-3-030-42526-5|s2cid=219518604}}</ref><ref name="Shapiro2014" />{{rp|488}} With treatment and physical therapy, the maximum levels of mobility are expected to be unassisted community walking for type I, household or exercise walking for type III, and household or community walking for type IV; due to the variability of OI between individuals, mobility achieved varies and may be below this expected maximum.<ref name="Shapiro2014" />{{rp|476}}

==Epidemiology==
In the United States, the [[Incidence (epidemiology)|incidence]] of osteogenesis imperfecta is estimated to be one per 20,000 live births.<ref name=Plotkin>{{Cite web| url = http://emedicine.medscape.com/article/947588-overview | title = Genetics of Osteogenesis Imperfecta | archive-url = https://web.archive.org/web/20101230211602/http://emedicine.medscape.com/article/947588-overview | archive-date=2010-12-30 | vauthors = Plotkin H | date = 29 February 2016 }}</ref> An estimated 20,000 to 50,000 people are affected by OI in the United States.<ref>{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf|title=Bone Health and Osteoporosis: A Report of the Surgeon General|publisher=Office of the [[Surgeon General of the United States]], [[U.S. Department of Health and Human Services]]|year=2004|location=[[Rockville, Maryland]]|page=68|language=en|chapter=2.4: The Frequency of Bone Disease|id=WE 225 B71259 2004|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK45515/}}</ref>

The most common types are I, II, III, and IV, while the rest are very rare.<ref>{{Cite web|title=Osteogenesis Imperfecta Panel|url=https://www.unmc.edu/mmi/geneticslab/catalog/postnatal-testing/post-p-oi.html|access-date=2019-07-30|website=[[University of Nebraska Medical Center]]|archive-date=30 July 2019|archive-url=https://web.archive.org/web/20190730080719/https://www.unmc.edu/mmi/geneticslab/catalog/postnatal-testing/post-p-oi.html}}</ref> Type I is the most common and has been reported to be around three times more common than type II. The prevalence of types III and IV is less certain.<ref name="Subramanian2020" /> In a 1989 study in Denmark, type I was found to comprise 71% of cases and type II 12% of cases, with other types comprising the other 17%.<ref name="Folkestad2016" /> In a 2015 study in Sweden, type I was nearly six times more common than type III and nearly four times more common than type IV.<ref name="Lindahl2015" />

Most people with OI receive it from a parent, but in many cases, it is a brand new (''de novo'' or "sporadic") mutation in a family. Among a study of patients with survivable types of OI, OI type III is most often ''de novo'' (85%), followed by type IV (50%) and type I (34%).<ref name="Zhytnik2019" />{{rp|Table 1}}

Some populations can have a higher incidence of OI than would be otherwise expected if they have a larger-than-average number of carriers of the recessive forms of the disease.<ref name="Shapiro2014" />{{rp|20–21}}<ref>{{Cite journal|display-authors=6|vauthors=Abali S, Arman A, Atay Z, Bereket A, Bas S, Haliloglu B, Guran T, Gormez Z, Demirci H, Akarsu N, Turan S|date=2016-08-19|title=Frequency of Recessive Osteogenesis Imperfecta in a Turkish Cohort and Genetic Causes|url=https://abstracts.eurospe.org/hrp/0086/hrp0086p1-p131|journal=ESPE Abstracts|language=en|publisher=Bioscientifica|volume=86|page=131|access-date=26 August 2021|archive-date=26 August 2021|archive-url=https://web.archive.org/web/20210826081612/https://abstracts.eurospe.org/hrp/0086/hrp0086p1-p131|url-status=live}}</ref>

==History==
{{Multiple image| perrow = 3
| align = right
| direction = horizontal
| total_width = 383
| image1 = Vrolik, W..jpg
| image2 = Nicolas Malebranche.jpg
| image3 = Jean Georges Chrétien Frédéric Martin Lobstein (portrait, cropped).jpg
| caption1 = Dr. [[Willem Vrolik]] (born 1801) coined the term "osteogenesis imperfecta" in 1849.<ref name="Dang2021"/>{{rp|683}}
| caption2 = [[Nicolas de Malebranche]] (born 1638) is thought to be the first person to attempt to describe the clinical features of OI.<ref name="Dang2021"/>{{rp|683}}
| caption3 = Where Vrolik would describe what is now type II OI, in 1833 Dr. [[Jean Lobstein]] (born 1777) was the first to describe what is now called type I OI.<ref name="Davel1956"/>{{rp|347}}
}}
The condition, or types of it, has had various other names over the years and in different nations; "[[wikt:ὀστέον#Ancient Greek|osteo]][[wikt:genesis#Latin|genesis]] [[wikt:imperfectus#Latin|imperfecta]]" has, however, been the most widely accepted name for the condition since the late 20th century. Among some of the most common alternatives are "[[wikt:fragilitas#Latin|fragilitas]] [[wikt:os#Latin etymology 2|ossium]]";<ref name="Roger1983">{{Cite book|title=The brittle bone syndrome: osteogenesis imperfecta|vauthors=Roger S, Francis MJ, Houghton GR|publisher=[[Butterworth-Heinemann]]|year=1983|isbn=978-0-407-00211-1|location=London|page=4|oclc=9784850}}</ref> "Ekman–Lobstein syndrome", and "Vrolik syndrome", both [[Eponymous disease|eponyms]]; and, the [[colloquialism]], "brittle bone disease".<ref name="Shapiro2014" />

=== Earliest recorded cases ===
OI has been identified in an [[ancient Egypt]]ian infant [[mummy|mummified]] in around 1000 BC, originally dismissed by archaeologists as containing the remains of a [[monkey]].<ref>{{cite journal | vauthors = Lowenstein EJ | title = Osteogenesis imperfecta in a 3,000-year-old mummy | journal = Child's Nervous System | volume = 25 | issue = 5 | pages = 515–516 | date = May 2009 | pmid = 19212769 | doi = 10.1007/s00381-009-0817-7 | doi-access = free }}</ref><ref name="Tainmont2007">{{cite journal | vauthors = Tainmont J | title = History of osteogenesis imperfecta or brittle bone disease: a few stops on a road 3000 years long | journal = B-Ent | volume = 3 | issue = 3 | pages = 157–173 | year = 2007 | pmid = 17970442 | url = http://www.b-ent.be/en/a-historical-vignette-be-proud-of-yourself-you-have-a-history-history-of-osteogenesis-imperfecta-or-brittle-bone-disease-a-few-stops-on-a-road-3000-years-long-16829 | access-date = 29 August 2021 | url-status = live | archive-url = https://web.archive.org/web/20210829002652/http://www.b-ent.be/en/a-historical-vignette-be-proud-of-yourself-you-have-a-history-history-of-osteogenesis-imperfecta-or-brittle-bone-disease-a-few-stops-on-a-road-3000-years-long-16829 | archive-date = 29 August 2021 }}</ref>{{rp|161}} The [[Norsemen|Norse]] king [[Ivar the Boneless]], who lived {{Circa|800 [[Common Era|CE]]}},<ref>{{Cite web| vauthors = Groeneveld E|date=2018-11-12|title=Ivar the Boneless|url=https://www.worldhistory.org/Ivar_the_Boneless/|url-status=live|archive-url=https://web.archive.org/web/20210821165537/https://www.worldhistory.org/Ivar_the_Boneless/|archive-date=2021-08-21|access-date=2021-08-21|website=[[World History Encyclopedia]]|publisher=Ancient History Encyclopedia Limited|language=en}}</ref> is speculated to have had OI as well.<ref>{{Cite web| vauthors = Lewis R, Lotha G, Gaur A|date=2019-01-08|title=Ivar the Boneless|url=https://www.britannica.com/biography/Ivar-the-Boneless|url-status=live|access-date=2021-08-21|website=[[Encyclopedia Britannica]]|language=en|archive-date=24 June 2021|archive-url=https://web.archive.org/web/20210624065051/https://www.britannica.com/biography/Ivar-the-Boneless}}</ref>

[[Nicolas de Malebranche]] is often credited as being the first person to describe the physical characteristics of OI in his 1688 book {{ill|The Search after Truth|lt=''The Search after Truth''|fr|De la recherche de la vérité}}, in which he describes a man who has had his "bones broken in the places a murderer's would be" all his life. His confident description of the [[pathology]] of the disorder, however, which creates what he termed «{{lang|fr|enfants monstrueux}}» ("monstrous children"), is scientifically void—he wrote that it was due to the mother's [[antepartum]] viewership of a [[public execution]] by [[breaking wheel]].<ref name="Dang2021">{{Cite book|url=|title=Cassidy and Allanson's Management of Genetic Syndromes|vauthors=Dang Do AN, Marini JC|date=2021-01-27|publisher=John Wiley & Sons|isbn=978-1-119-43267-8|veditors=Carey JC, Cassidy SB, Battaglia A, Viskochil D|pages=683–705|language=en|chapter=Osteogenesis imperfecta|chapter-url=https://books.google.com/books?id=B7cAEAAAQBAJ&pg=PA683|access-date=29 August 2021|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829002647/https://books.google.com/books?id=B7cAEAAAQBAJ&pg=PA683&lpg=PA683|url-status=live}}</ref>{{rp|683}}<ref name="Tainmont2007" />{{rp|165–168}}<ref>{{Cite wikisource|title=De la recherche de la vérité| vauthors = Malebranche N |author-link=Nicolas Malebranche|year=1688|wslink=Page:Malebranche_-_De_la_recherche_de_la_vérité.djvu/140|wslanguage=fr|page=119|edition=1842}}</ref>

The earliest modern scientific studies of OI began in 1788 by Olof Jakob Ekman, who described the condition, which he termed "[[osteomalacia]] congenital", in his [[doctoral thesis]] and mentioned cases of it going back to 1678, all in the same family, through three generations.<ref>{{cite journal | vauthors = Edelu B, Ndu I, Asinobi I, Obu H, Adimora G | title = Osteogenesis imperfecta: a case report and review of literature | journal = Annals of Medical and Health Sciences Research | volume = 4 | issue = Suppl 1 | pages = S1–S5 | date = March 2014 | pmid = 25031897 | pmc = 4083720 | doi = 10.4103/2141-9248.131683 | publisher = [[Nigerian Medical Association]] | doi-broken-date = 12 July 2025 | doi-access = free }}</ref> Ekman's description of the condition mentioned dwarfism, bone fragility, and bowing of the long bones.<ref>{{Cite journal|vauthors=Hektoen L|date=May 1903|title=Anatomical Study of a Short-Limbed Dwarf, With Special Reference To Osteogenesis Imperfecta and Chondrodystrophia Foetalis|url=https://books.google.com/books?id=DOxGAQAAMAAJ&pg=PA763|journal=[[The American Journal of the Medical Sciences]]|publisher=[[J. B. Lippincott & Co.]]|volume=125|issue=5|pages=751–769|doi=10.1097/00000441-190305000-00001|isbn=978-0-243-38392-4|s2cid=71836609|access-date=16 August 2021|archive-date=16 August 2021|archive-url=https://web.archive.org/web/20210816123354/https://books.google.com/books?id=DOxGAQAAMAAJ&pg=PA763|url-status=live}}</ref>{{rp|763}} In 1831, Edmund Axmann gave a detailed description of it in himself and his two brothers, being the first to mention blue sclerae as a characteristic sign of OI.<ref name="Dang2021" />{{rp|683}} [[Jean Lobstein]] first described the mild form of the condition, today known as type I, in 1833, calling it "osteo[[:wikt:ψαθυρός|psathyrosis]] [[idiopathic]]a".<ref name="Davel1956">{{cite journal | vauthors = Davel JG, Fichardt T, Van Der Spuy D | title = Osteogenesis imperfecta | journal = Archives of Disease in Childhood | volume = 31 | issue = 159 | pages = 346–353 | date = October 1956 | pmid = 13363481 | pmc = 2011939 | doi = 10.1136/adc.31.159.346 }}</ref>{{rp|347}}

It was not until 1912 that [[hearing loss]] was positively recognized as a symptom of OI, first mentioned in a brief paper by the English physician Charles Allen Adair-Dighton.<ref>{{Cite journal|vauthors=Adair-Dighton CA|year=1912|title=Four generations of blue sclerotics|url=https://archive.org/details/ophthalmoscope10londuoft/page/188/mode/2up|journal=The Ophthalmoscope|location=London|publisher=[[George Pulman]] & Sons, Ltd|volume=10|pages=188–189|oclc=1049881577|via=[[Internet Archive]]}}</ref><ref name="Tainmont2007" />{{rp|168–169}}

=== Of the term ===
{{Multiple image| perrow = 1
| header = Excerpts from [[#{{harvid|Vrolik|1849}}|Vrolik W (1849)]]:
| align = right
| direction = vertical
| total_width = 250
| image1 = Willem Vrolik's specimen of an infant with osteogenesis imperfecta.jpg
| image2 = First appearance in print of «osteogenesis imperfecta» (header only).jpg
| caption1 = {{small|A drawing of the remains Vrolik examined while describing what he called "osteogenesis imperfecta".}}
| caption2 = {{small|The [[neologism|first appearance]] of "osteogenesis imperfecta" in print appears on the page afterwards.}}
}}
[[Willem Vrolik]], a Dutch [[anatomist]] who was also [[curator]] of the "Museum Vrolikianum", which made him privy to many specimens of bodies having [[birth defects]], coined the term "osteogenesis imperfecta"<ref name="Dang2021"/>{{rp|683}} in his [[Parallel text|bilingual]] [[Latin]] and [[Dutch language]] book on [[teratology]], ''Illustrations of Human and Mammalian [[Embryogenesis]]'', first published in 1849.<ref name="Vrolik1849">{{Cite book|url=https://objects.library.uu.nl/reader/index.php?obj=1874-282727&lan=en#page//13/18/68/131868320076759297610882234672017577930.jpg/mode/1up|title={{lang|nocat=true|la|Tabulae ad illustrandam embryogenesin hominis et mammalium, tam naturalem quam abnormem}} — {{lang|nocat=true|nl|De Vrucht van den Mensch en van de Zoogdieren afgebeeld en beschreven in hare regelmatige en onregelmatige Ontwikkeling}}|vauthors=Vrolik W|publisher=G.M.P. Londonck|year=1849|location=Amsterdam|pages=562–566|language=la, nl|trans-title=Illustrations of human and mammalian [[embryogenesis]], both normal and abnormal|oclc=489920691|access-date=29 August 2021|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829002655/https://objects.library.uu.nl/reader/index.php?obj=1874-282727&lan=en#page//13/18/68/131868320076759297610882234672017577930.jpg/mode/1up|url-status=live}}</ref>

Included is a description of the remains of an infant who had what is now known as [[perinatally]] fatal OI type II<ref name="Davel1956" />{{rp|347}}<ref name="Shapiro2014" />{{rp|5}} (as verified in a 1998 re-examination of the remains by Baljet ''et al.'').<ref name="Baljet2002">{{cite journal | vauthors = Baljet B | title = Aspects of the history of osteogenesis imperfecta (Vrolik's syndrome) | journal = Annals of Anatomy - Anatomischer Anzeiger | volume = 184 | issue = 1 | pages = 1–7 | date = January 2002 | pmid = 11876477 | doi = 10.1016/S0940-9602(02)80023-1 | url = https://linkinghub.elsevier.com/retrieve/pii/S0940960202800231 | access-date = 29 August 2021 | url-status = live | archive-url = https://web.archive.org/web/20180612014557/https://linkinghub.elsevier.com/retrieve/pii/S0940960202800231 | archive-date = 12 June 2018 | url-access = subscription }}</ref> The remains were first given to Vrolik's father, who could not make sense of them. Vrolik described poorly mineralized bones, bowed long bones, and fractures in various states of healing.<ref>{{Cite book|vauthors=Baljet B|title=Geschichte der Grenzgebiete der Orthopädie |publisher=[[Verlag Theodor Steinkopff]]|year=2002|isbn=978-3-642-57510-5|veditors=Rauschmann MA, Thomann KD, Zichner, L|volume=4|location=Heidelberg|pages=133–144|chapter=Willem Vrolik and "his" Syndrome|doi=10.1007/978-3-642-57510-5_15|chapter-url=https://link.springer.com/chapter/10.1007/978-3-642-57510-5_15|access-date=29 August 2021|archive-date=8 June 2018|archive-url=https://web.archive.org/web/20180608065057/https://link.springer.com/chapter/10.1007%2F978-3-642-57510-5_15|url-status=live}}</ref> Vrolik correctly determined that what he termed OI in the infant was not caused by secondary [[rickets]], but a congenital abnormality causing primary [[osteopenia]]; he theorized this was due to a lack of "intrinsic generative energy".<ref name="Baljet2002" />

=== Of its classification ===
[[Osteogenesis imperfecta#Classification|Classification of OI]] has also evolved as scientific understanding of it has improved. Before the advent of modern genetic testing, OI was classified in two broad groups: ''osteogenesis imperfecta [[Congenital|congenita]]'', and ''osteogenesis imperfecta [[wikt:tardus#Latin|tarda]]'', a division first proposed by the German [[physician]] E. Looser in 1906.<ref name="Roger1983" /><ref>{{Cite journal|vauthors=Looser E|year=1906|title=Zur Kenntnis der Osteogenesis Imperfecta Congenita et Tarda (sogenannte idiopathische Osteopsatyrosis)|trans-title=On awareness of osteogenesis imperfecta ''congenita'' and ''tarda'' (so-called "idiopathic osteopsatyrosis")|url=https://books.google.com/books?id=gSQCAAAAYAAJ&pg=PA161|journal=Mitteilungen aus den Grenzgebieten der Medizin und Chirurgie (Dispatches from the Frontier of Medicine and Surgery)|volume=15|pages=161–207|language=de|access-date=21 August 2021|archive-date=21 August 2021|archive-url=https://web.archive.org/web/20210821080919/https://books.google.com/books?hl=en&lr=&id=gSQCAAAAYAAJ&oi=fnd&pg=PA161|url-status=live}}</ref> ''Congenita'' was used to describe the modern clinical types II, III, and some cases of IV, where upon birth the condition was obvious, either due to bowing of the limbs or due to fractures sustained ''in [[utero]]''.<ref name="Sillence1979" /> ''Tarda'' was used to classify the modern OI type I and some cases of type IV, where the inherent fragility of the bones did not become clear until long after birth.<ref name="Roger1983" /> The idea that these "late" and "prenatal" forms were manifestations of the same disorder was first proposed in 1897 by [[Martin Benno Schmidt]];<ref name="WhoNamedIt">{{WhoNamedIt|synd|1743}}</ref> by the 1950s this fact was well accepted.<ref name="Davel1956" />{{rp|346}}

The modern system of four types (I, II, III, IV), meanwhile, were introduced in a paper by [[David Sillence]], Alison Senn, and [[David Danks]] in the ''[[Journal of Medical Genetics]]'' in 1979,<ref name="Sillence1979" /><ref>{{Cite book|url=https://books.google.com/books?id=L-BlM8uD6SYC&pg=PA116|title=Double helix, double joy: David Danks, the father of clinical genetics in Australia|vauthors=Rasmussen C, Danks A|date=2010|publisher=Melbourne University Press|isbn=978-0-522-85799-3|location=[[Carlton, Victoria]]|page=116|language=English|oclc=906592657|access-date=28 August 2021|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828174208/https://books.google.com/books?id=L-BlM8uD6SYC&pg=PA116&lpg=PA116|url-status=live}}</ref> and have since become standard terms among doctors, patients, and researchers.<ref name="VanDijk2010" /><ref name="VanDijk2014" /><ref name="Warman2011" /> The modern genetic types, (those with numbers greater than IV,) have come into use as more and more recessively inherited forms of OI have been discovered since the discovery of the first one by Roy Morello ''et al.'' in 2006.<ref name="VanDijk2011" /><ref name="Forlino2016" /><ref name="Morello2006" /> In 2010, the International Nomenclature Group for Constitutional Disorders of the Skeleton (INCDS) "freed" the Sillence types from [[Pathophysiology|molecular reference]], acquiescing to their new clinical-first role in the wake of what was to them a "surprising" increase in the number of genetic causes of OI.<ref name="Warman2011">{{cite journal | vauthors = Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A | display-authors = 6 | title = Nosology and classification of genetic skeletal disorders: 2010 revision | journal = American Journal of Medical Genetics. Part A | volume = 155A | issue = 5 | pages = 943–968 | date = May 2011 | pmid = 21438135 | pmc = 3166781 | doi = 10.1002/ajmg.a.33909 }}</ref><ref name="VanDijk2014" />

Writing for the ''[[Annual Review of Genetics]]'' in 2012, Drs. Peter Byers and Shawna M. Pyott lamented how the expansion of the number of types to include genetic types has created a system that "[[grew like Topsy]]".<ref name=":0" />{{Rp|page=492}} They suggest that it may indeed be impossible to create a system which is useful for clinicians and which accurately describes the genetic cause of a person's OI, with attempts always prioritizing one use at the expense of the other.<ref name=":0" />{{Rp|page=492}}

==Society and culture==
{{See also|List of people with osteogenesis imperfecta|Osteogenesis imperfecta in popular culture}}Much [[medical research]] has been done into the causes of osteogenesis imperfecta, benefiting not only those with OI but medicine more broadly; in the ten years between 2006 and 2016, the many discoveries of non-collagen related recessive gene mutations, which still led in those who have them to the clinical signs of OI, led to numerous breakthroughs in medical understanding of the process of healthy bone development.<ref name="Forlino2016" />

==Other animals==

In dogs, OI is an [[autosomal recessive]] condition, meaning that dogs with two copies of the allele will be affected.<ref name="UCDavisVetLab">{{Cite web|title=Osteogenesis Imperfecta (OI) in Dachshunds|url=https://vgl.ucdavis.edu/test/oi-dachshund|url-status=live|access-date=2021-08-28|website=UC Davis Veterinary Genetics Laboratory|publisher=[[UC Davis School of Veterinary Medicine]]|language=en|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828110155/https://vgl.ucdavis.edu/test/oi-dachshund}}</ref> Many breed organizations and veterinarians offer OI tests to tell if a dog is a carrier of OI.<ref name="UCDavisVetLab" /><ref name="Generatio">{{Cite news|title=Osteogenesis Imperfecta (OI Dachsund)|work=Center for Animal Genetics|publisher=Generatio GmbH|url=https://www.centerforanimalgenetics.com/services/dog-genetic-testing/hereditary-disease-testing-for-dogs/osteogenesis-imperfecta/|access-date=2018-11-07|archive-url=https://web.archive.org/web/20181108074324/https://www.centerforanimalgenetics.com/services/dog-genetic-testing/hereditary-disease-testing-for-dogs/osteogenesis-imperfecta/|archive-date=2018-11-08}}</ref> To prevent OI, dogs who are [[heterozygous]] for OI should not be bred.<ref name="Generatio" />

Naturally occurring mutations causing OI have been found in [[Golden Retrievers]], [[Dachshunds]], and [[Beagles]]. OI has also been identified in [[zebrafish]] and [[mice]].<ref name="Enderli2016">{{cite journal | vauthors = Enderli TA, Burtch SR, Templet JN, Carriero A | title = Animal models of osteogenesis imperfecta: applications in clinical research | journal = Orthopedic Research and Reviews | volume = 8 | pages = 41–55 | date = September 2016 | pmid = 30774469 | pmc = 6209373 | doi = 10.2147/ORR.S85198 | doi-access = free }}</ref>

Although dogs, mice, fish, and humans are not genetically identical, some of these [[animal models]] have been officially recognized to represent the varying types of OI in humans. For example, homozygous ''oim''/''oim'' mice experience spontaneous bone fractures, small body size, and kyphosis, making them a model of OI type III. Meanwhile, heterozygous ''oim''<sup>/+</sup> mice appear normal but have bones which are quite a bit weaker than wild mice, making them a model for OI type I.<ref name="Enderli2016" /><ref>{{cite journal | vauthors = Saban J, Zussman MA, Havey R, Patwardhan AG, Schneider GB, King D | title = Heterozygous oim mice exhibit a mild form of osteogenesis imperfecta | journal = Bone | volume = 19 | issue = 6 | pages = 575–579 | date = December 1996 | pmid = 8968022 | doi = 10.1016/S8756-3282(96)00305-5 | url = https://linkinghub.elsevier.com/retrieve/pii/S8756328296003055 | access-date = 28 August 2021 | url-status = live | archive-url = https://web.archive.org/web/20180630183333/https://linkinghub.elsevier.com/retrieve/pii/S8756328296003055 | archive-date = 30 June 2018 | url-access = subscription }}</ref> As in human OI, the location on the gene which is mutated affects the severity of resulting disease—the G859C ''Col1a1'' mouse is a model for OI type II as affected mice all die in the perinatal period.<ref name="Enderli2016" />

[[Animal testing]] on identified animal models may lead to human therapies for OI.<ref name="Enderli2016" />

== Explanatory notes ==
{{NoteFoot}}

== References ==
{{Reflist}}

== External links ==
{{Commons category|Osteogenesis imperfecta}}
* {{Cite web| url = https://www.bones.nih.gov/health-info/bone/osteogenesis-imperfecta | archive-url = https://web.archive.org/web/20171004203117/https://www.bones.nih.gov/health-info/bone/osteogenesis-imperfecta | archive-date = 4 October 2017 | title = Osteogenesis Imperfecta Overview | work = NIH Osteoporosis and Related Bone Diseases — National Resource Center | date = 8 May 2023 | publisher = National Institutes of Health, U.S. Department of Health and Human Services }}

<!-- Do not add OMIM or MeSH ID's to below {{Medical condition classification and resources}} template without seeking talk page consensus, as such ID's can only refer to one type of OI and not the group of disorders, creating confusion. All OMIM ID's are already listed in § Classification. -->
{{Medical condition classification and resources| ICD10          = {{ICD10|Q|78|0|q|65}}
| ICD9           = {{ICD9|756.51}}
| MedlinePlus    = 001573
| eMedicineSubj  = ped
| eMedicineTopic = 1674
| DiseasesDB     = 9342
| Orphanet        = 666
|ICD11={{ICD11|LD24.K0}}|ICD10CM={{ICD10CM|Q78.0}}}}
{{Collagen disease|state=expanded}}
{{Osteochondrodysplasia|state=expanded}}
{{Authority control}}

{{DEFAULTSORT:Osteogenesis Imperfecta}}
[[Category:Abnormalities of dermal fibrous and elastic tissue]]
[[Category:Skeletal disorders]]
[[Category:Collagen disease]]
[[Category:Rare diseases]]
[[Category:Wikipedia medicine articles ready to translate]]