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New perspectives of therapies in osteogenesis imperfecta—a literature review.

1. Introduction

1.1. history, 1.2. pathophysiology, 1.3. classification.

Type of OI	Mode of Inheritance	Mutated Genes	Clinical Characteristics
I	AD	COL1A1 COL1A2	Mild form with increased bone fragility Non-deforming Normal stature Blue-gray sclerae Hearing-impaired
II	AD	COL1A1 COL1A2	Perinatal death
II	AR	CRTAP P3H1	Severe to lethal forms
III	AD	COL1A1 COL1A2 IFITM5	Progressive deformity
	AD	COL1A1 COL1A2 IFITM5	Mild-to-moderate form
	AR	SERPINF1 (type VI in the previous classifications)	Moderate to severe form; healthy at birth; no fracture until 6 months of age
		CRTAP P3H1 SERPINH1	Severe to lethal forms
		WNT1	Moderate to severe form
		BMP1	Fewer than 20 individuals were diagnosed with this mild-to-severe form; increased bone mineral density (BMD)
		FKBP10	Broad spectrum of disease includes a lethal form of OI previously classified as type IX, Kuskokwim syndrome, and Bruck syndrome
IV	AD	COL1A1 COL1A2	Moderately deforming
		WNT1	Moderately severe
		IFITM5	Mild-to-moderate form
	AR	FKBP10	Progressive form, deforming
	AR	SP7	Moderate form
V	AD	IFITM5	Moderately deforming; calcification of interosseous membranes

1.4. Current Treatment of OI

1.4.1. medical management or pharmacological treatment, 1.4.2. orthopedic treatment, 1.5. aim and scope, 2. materials and methods, 2.1. search strategies, 2.2. inclusion criteria, 2.3. data extraction, 3. discussions, 3.1. mesenchymal stem cells (mscs) ( table 2 ), 3.1.1. mechanism of action, 3.1.2. murine studies, 3.1.3. human studies, bone marrow mscs (bmscs).

Reference	Methods	Comments
Horwitz et al. 1999, 2001 [ , ]	Case series: 3 children with OI type III; duration: 2 years	They enrolled 3 children with OI type III and intravenously administered BMSCs from siblings, with reported improvements in bone density and growth velocity and reduced fracture frequency in the first 3 months. Two years later, they published a follow-up study comparing the evolution of the 3 children treated with 2 control patients. The growth rate declined or reached a plateau phase in time, but the BMD continued to increase at a similar rate to healthy children. No complications were reported.
Götherström et al. 2005, 2013 [ , ]	Case series: 2 fetuses with OI (type III and IV); duration: 10 years and 1 year	The study included OI patients transplanted with hfMSCs pre- and postnatal: No complications were reported.
Infante et al. 2021 [ ]	Clinical trial, phase 1, 2 children with OI	Two patients, a 6-year-old boy with a severe form of OI and an 8-year-old girl with a moderate form of OI, duration of 2.5 years. Both patients showed an increase in BMD and BV/TV, a decrease in fracture rates, and chronic pain. Benefits were observed after a 2-year follow-up visit after the ending of the therapy. No complications were reported.
Battle et al. 2021 [ ]	Meta-analysis of animal studies, control trials in OI mice models of stem cell therapy period: 13 years	Ten studies were reviewed. The authors found an increase in mechanical proprieties like maximum load (p = 0.02), a decrease in fracture incidence (p < 0.00001), and a beneficial effect on structural proprieties: cortical thickness and BV/TV, but without statistical significance (p = 0.4; respectively, p = 0.31). Also, the meta-analysis had data about cell engraftment in 5 studies with poor results.

3.2. Anti-RANKL Antibody ( Table 3 )

3.2.1. mechanism of action, 3.2.2. human studies.

Reference	Methods	Comments
Semler et al. 2012 [ ]	Case reports: 4 children with OI type VI (AR-SERPINF1); duration: 24 months	All of the subjects who were previously treated with bisphosphonates without response received Denosumab (1 mg/kg) every 3 months for 24 months. An increase in BMD and improvement in pain were noticed. One patient had mild hypocalcemia.
Hoyer-Kuhn et al. 2014 [ ]	Case reports: 2 children with OI (COL1A1/A2); duration: 36 weeks	They report 2 cases of children with poor responses to bisphosphonates for 4 years, who received 1 mg/kg Denosumab every 12 weeks (1 of them received 1 dose and 1 of them 3 doses). After treatment, an increase in metaphyseal density on X-rays was reported, with no complications.
Ward et al. 2016 [ ]	Case report: 23-month-old male patient with OI type VI; duration: 12 months	A 23-month-old male child with OI type VI, previously treated with 2 doses of Zolendronate at 4 months apart, was inefficient (the same rate of bone fractures, 3 fractures in 6 months). He received Denosumab, 1 mg/kg every 3 months for 12 months. The results were poor, the fracture rate continued to be high, and the bone sample obtained after 5 doses of treatment at 15 months showed no change in mineralization, with an increased number of osteoclasts in trabecular bone. No complications were reported.
Hoyer-Kuhn et al. 2016 [ ]	Prospective, single-arm, phase-2 trial: 10 children with OI, 8 type I and 2 type III; duration: 48 weeks (36 weeks administration and 12 weeks follow-up)	Ten children with OI who received at least 2 years of bisphosphonate, calcium, and vitamin D were included and treated with 4 doses of Denosumab (1 mg/kg every 12 weeks). An increase in the mean height was noticed but without a significant change in the z-score (p = 0.70). Four fractures occurred during this period. The treatment did not influence bone pain (p = 0.70) or mobility (p = 0.15), but the lumbar spine bone mineral density (LS-BMD) increased from −2.23 ± 2.03 to −1.27 ± 2.37 (p = 0.0006). Two patients reported arthralgia, and 1 child reported mild hypocalcemia.
Uehara et al. 2017 [ ]	Case reports: 3 females with OI type I, 2 adults (42 and 40 years), 1 adolescent of 14 years; duration: 30 months	All 3 patients were treated with 5 doses of Denosumab (1 dose every 6 months). The results consist of the enhancement of BMD during treatment, improved resorption markers and bone formation, and no new fractures. The adolescent had an increase in height of 2 cm during treatment. No complications were reported.
Trejo et al. 2018 [ ]	Case reports: 4 children with OI type V; duration variable from 1.3 years to 3.5 years.	The patients with bisphosphonate treatment failure received Denosumab 1 mg/kg every 3 months. The treatment increased spinal BMD, but not if the interval of administration was 6 months; as side effects, complications related to calcium levels were frequent.
Kobayashi et al. 2018 [ ]	Case series: 8 OI type I patients (5 adults, 3 children); duration: 54 months.	These patients received 60 mg of Denosumab every 6 months (from 1 to 9 doses), and calcium and cholecalciferol. The BMD generally increased in all patients and the fracture rate and bone turnover markers decreased in most of the patients. No complications were reported.
Maldonado et al. 2019 [ ]	Case report: a 9-year-old girl with OI type IV, cerebral palsy, and epilepsy; duration: 18 months	The child had a history of treatment with Pamindronate and Zolendronate with 40 fractures. She started Denosumab (3 doses of 60 mg, a dose every 6 months) with a decrease in bone resorption and an increase in quality of life; no fracture during the Denosumab treatment time, but hypercalcemia was reported.
Hoyer-Kuhn et al. 2019 [ ]	Prospective cohort study: 10 children with OI, 8 with type I, and 2 with type III; duration: 48 weeks treatment and 12 months follow-up	Ten children with OI received Denosumab at a mean interval of 20.33 weeks for 48 weeks (4 doses). BMDs had a significant reduction during the first follow-up year, but at the end of the follow-up, it was still higher than at the start of the trial. Vertebral shape improved further in the follow-up. Growth was not influenced, and mobility was not significantly different. As side effects, a decrease in the mean of serum calcium levels (p = 0.00039) and, for one child, symptomatic hypercalciuria with urolithiasis were reported in the first year of follow-up.

3.3. Sclerostin Inhibition ( Table 4 )

3.3.1. mechanism of action, 3.3.2. animal studies, 3.3.3. human studies.

Reference	Methods	Comments
Sinder et al. 2013 [ ]	Animal study: 8-week-old Brtl/+ mice; duration: 2 weeks	Randomized 8-week-old Brtl/+ mice and WT mice received 25 mg/kg Scl-Ab twice a week for 2 weeks. The body length was unchanged, but increased anabolic responses in the treated mice and an increase in BV/TV, cortical formation, and mechanical proprieties were reported.
Jacobsen et al. 2014 [ ]	Animal study: 6-week-old Col1a2 mice, model human OI type IV; duration: 6 weeks	Randomized OI type IV 6-week-old mice models received 25 mg/kg Scl-Ab twice a week for 6 weeks. At the end of the study, a significant rise in BV/TV, BMD, and bone strength was present in the treated mice compared with the OI model controller. The bone parameters were similar to or even greater than the wild-type mice without treatment. No complications were reported.
Sinder et al. 2014 [ ]	Animal study: 6-month-old Brtl/+ mice, model human OI type IV; duration: 5 weeks	Randomized OI type IV 6-month-old mice models received 25 mg/kg Scl-Ab twice a week for 5 weeks. An increase in bone formation rate and trabecular cortical bone mass were reported. Also, the mechanical tests and the strength and stiffness of the femoral bones increased. No complications were reported.
Roschger et al. 2014 [ ]	Animal study: growing (4 weeks) and adult (20 weeks) Col1a1 /+ mice, pediatric and adult model of severe OI; duration: 4 weeks	Growing (4 weeks) and adult (20 weeks) Col1a1 /+ mice, pediatric and adult models of severe OI, received 100 mg/kg Scl-Ab once a week for 4 weeks, with no significant changes in bone formation or resorption markers but higher trabecular volume and cortical thickness in growing mice, and no changes in the adult ones. The additional cortical formation reported in younger mice was located on the endocortical surface, with a minor effect on bone resistance to bending and the mechanical testing did not reveal a positive change in both growing and old OI mice. The authors concluded that this treatment was less effective in severe OI mouse models, pediatric or adult. No complications were reported.
Sinder et al. 2015 [ ]	Animal study: 3-week-old Brtl/+ mice, model human OI type IV; duration: 5 weeks	Randomized OI type IV 3-week-old mice models received 25 mg/kg Scl-Ab twice a week for 5 weeks, and an increase in bone formation, bone cortical mass, and improvements in mechanical strength in the models treated with Scl-Ab were noticed without complications.
Sinder et al. 2016 [ ]	Animal study: growing (3 weeks) and adult (6 months) Brtl/+ mice, pediatric and adult model of human OI type IV; duration: 5 weeks	Growing (3 weeks) and adult (6 months) Brtl/+ mice, pediatric and adult models of human OI type IV, received 25 mg/kg Scl-Ab twice a week for 5 weeks. The collected bone samples from the right femur showed the mineral matrix enhanced in the adult model but not significantly in the pediatric one. The elastic module was not increased in any model. No complications were reported.
Grafe et al. 2016 [ ]	Animal study: 1 and 6 weeks Crtap−/− mice, pediatric and young adult models of recessive OI; duration: 6 and 7 weeks	Crtap−/− mice models for recessive OI were treated with 25 mg/kg Scl-Ab twice a week for 6 weeks in the young adult model (6 weeks old) and for 7 weeks in the pediatric ones. The improvement in bone mass, bone formation, parameters of strength, and trabecular microarchitecture were reported, and there was a decrease in the number of osteoclasts without complications.
Glorieux et al. 2017 [ ]	Randomized, controlled human phase 2 study: 13 adults with moderate OI completed the study. They defined moderate OI as types I, III, or IV with a history of at least two fractures. In the control group (5), 2 had OI type I, and 3 had OI type III/IV. One of them was lost to follow-up and did not receive a DXA scan in the end. They do not specify what type this subject was. In the treatment group (9), 4 of them were type I, and 5 were type III/IV; duration: 21 weeks	The treatment group received 3 doses of Scl-Ab (BPS804) (day 1: 5 mg/kg; day 15: 10 mg/kg; day 29: 20 mg/kg) and was followed for 14 weeks. The biomarkers were significantly increased, and downregulation of the bone resorption marker (CTX-1) in the study drug group was noticed, compared to the control group (44% vs. 7%). The lumbar spine BMD (LsBMD) on day 141 was increased by 4% in the Scl-Ab group compared with only a 1% increase in the reference group. No serious adverse events were reported in the BPS804 treatment group (no abnormal calcium blood levels or other laboratory test abnormalities). Three fractures in the treatment group (2 on day 2 and 1 on day 48) were present, and none in the control group. The Scl-Ab increased the BMD, reduced resorption, and stimulated bone formation, and thus, the study opens the possibility of a phase 3 trial study.
Cardinal et al. 2019 [ ]	Animal study: 5-week-old B6C3Fe a/a-Col1a2 /J mice, model for OI type III; duration: 9 weeks	Wild-type and old mice were treated with Scl-Ab for 9 weeks, 50 mg/kg once a week, with an increase in BMD, ultimate load, stiffness, plastic energy, and elastic modulus, and significantly reduced long bone fractures, with no complications.
Uehara et al. 2021 [ ]	Case report: 64-year-old severe osteoporotic man with OI type I, previously treated with alendronate for 1 year, 8 years before this article; duration: 12 months	The subject received romosozumab, one dose of 210 mg monthly for 12 months, and vitamin D (eldecalcitol). The evaluation of BDM at 6 and 12 months of treatment revealed an improvement in BMD and in the turnover markers, with no fracture or other complications during the study time.
Wang et al. 2022 [ ]	Animal study: Col1a2+/G610C.ApoE−/− mice, OI mice with Ang II infusion; duration: 4 weeks	Col1a2+/G610C.ApoE−/− mice, OI mice with AngII infusion were treated with 25 mg/kg Apc001PE twice a week for 4 weeks. This model was used to assess the cardiovascular risk Apc001PE, a Scl-Ab that targets only loop 3 of sclerostin, theorizing that the inhibition of the first 2 loops increases the cardiovascular risk. Apc001PE promoted the formation of the bone, without an increase in the cardiovascular risk.
Dattagupta et al. 2023 [ ]	Case report: 52-year-old woman with type I OI; duration: 12 months	The patient received romosozumab, one dose of 210 mg monthly for 12 months, with improvements in BMD (10.3% in the spine and 5.4% in the right hip, p > 0.05) and no complications reported.

3.4. Recombinant Human Parathormone

3.4.1. mechanism of action, 3.4.2. human studies, 3.5. anti-transforming growth factor βeta (tgf-β) antibodies, 3.5.1. mechanism of action, 3.5.2. human studies, 3.6. genes therapy ( table 5 ), 3.6.1. mechanism of action, 3.6.2. animal studies, 3.6.3. cell studies.

Reference	Methods	Comments
Wang and Marini, 1996 [ ]	Cell study: fibroblasts from a patient with OI type IV (COL1A2 mutation heterozygous dominant)	The suppression of the mutant message is realized, but it was insufficient for clinical intervention (~50% suppression of the mutant chain).
Millington-Ward et al., 2004 [ ]	Cell study: MPCs with COL1A1 heterozygous dominant mutation	The mutation is downgraded successfully (up to 85%), but the study concluded the need for allele specificity.
Chamberlain et al., 2004 [ ]	Cell study: MSCs from 2 individuals with OI and COL1A1 heterozygous dominant mutation	The AAV-COLe1INpA gene-targeting vector was used to disrupt the exon 1 of the COL1A1 chromosome. The targeted cells showed an improvement in collagen stability, and the produced fibrils were closer to the wild-type mice, producing normal collagen.
Chamberlain et al., 2008 [ ]	Cell study: MSCs from patients with OI heterozygous dominant COL1A2 mutation	AAV, initially targeting exon 4, was used with unsuccessful results, so by targeting exon 2, the production of abnormal proα2(I) chains was eliminated, producing normal type I procollagen.
Lindahl et al., 2008 [ ]	Cell study: bone cells from OI heterozygous dominant COL1A2 mutation	siRNA could successfully silence COL1A2 (0.3 µg siRNA dosing, 71%; 0.45 µg, 77%; 0.6 µg, 82%) in bone cells from OI individuals.
Lindahl et al., 2013 [ ]	Cell study: bone cells from OI heterozygous dominant COL1A1 and COL1A2 mutations	Using siRNA, the average mRNA levels from both genes were successfully significantly reduced.
Rousseau et al., 2013 [ ]	Animal in vitro and in vivo study: Brtl OI mouse (Col1a1tm1.1 Jcm, MGI: 2158863)	With one siRNA (F-Mut) used in vivo, there was 52% suppression of the mutant allele with only 14% of the normal allele with a ~ 40% decrease in the mutant protein.

3.7. 4-Phenylbutiric Acid (4-PBA) ( Table 6 )

3.7.1. mechanism of action, 3.7.2. animal studies, 3.7.3. cell studies.

Reference	Methods	Comments
Gioia et al. 2017 [ ]	Animal study: Zebrafish larvae Chihuahua (Chi/+), model for OI. They had 6 groups of fish, 2 placebo groups (WT, Chihuahua) and 4 treated groups (WT, Chihuahua) with either 4-PBA or tauro-ursodeoxycholic acid (TUDCA); duration: 3.5 months	The authors found an enlargement of ER in fibroblasts and osteoblasts due to the mutant collagen retention. By reducing ER stress with 4-PBA, an amelioration of skeletal deformities and an increase in BMD was noticed in the treatment group with 4-PBA, so 4-PBA would be an effective treatment in OI trough reduction in ER stress.
Besio et al. 2018 [ ]	Human cells, fibroblast from 10 patients OI type II and III (5 with mutations in COL1A1 and 5 in COL1A2); duration: 15 h	In treated cells with mutations α2-G697C and α2-G745C, a decrease in stress and apoptotic markers are observed, and an increase in general protein secretion in all treated cells.
Takeyari et al. 2019 [ ]	Human cells: fibroblasts from 6 OI patients; duration: not specified	4-PBA improved overglycosylation, the capability of calcification, and decreased the production of excessive collagen type I and its accumulation in fibroblasts.
Takeyari et al. 2021 [ ]	Human cells: fibroblasts from 6 OI patients; duration: 28 days	Improvement in osteoblast mineralization reduced ER stress and normalization of the production of type I collagen was observed.
Duran et al. 2022 [ ]	Animal study: 2-month-old Aga2+/− mice, model for moderately severe OI; duration: 5 weeks	The mice were treated with 50 mg/day 4-PBA, and a reduction in ER stress and better bone quality in vivo was noticed, with an increase in growth and bone resistance in the study’s drug group.
Scheiber et al. 2022 [ ]	Animal study: 3-week-old OI model mice Col1a2(+/G610C) Four groups:	The treated mice displayed a reduction in growth deficiency, an improvement in the femur length, an improvement in BV/TV, trabecular BMD, and thickness, but without an amelioration in bone fragility, with no significant effect on biomechanical proprieties. No complications were reported.
Daponte et al. 2023 [ ]	Animal study: Zebrafish, 2 models, a dominant one (Chihuahua” (Chi/+)), and a recessive one (p3h1−/−). They had 4 groups of fish: 2 placebo groups (model WT/model Chihuahua) and 2 treatment groups (model WT/ model Chihuahua); duration: 14 days	The study was conducted on 5 groups of fish: 3 placebo groups (wild-type) and the 2 models; 2 treatment groups of the 2 models. They amputated the caudal fins and allowed them to grow back to investigate the synthesis of collagen and bone differentiation with a beneficial effect of 4-PBA in the recessive model. No complications were reported.

3.8. Inhibition of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphatase Enzymes (Salubrinal)

3.8.1. mechanism of action, 3.8.2. murine studies, 3.8.3. human studies, 5. conclusions, author contributions, acknowledgments, conflicts of interest.

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Dinulescu, A.; Păsărică, A.-S.; Carp, M.; Dușcă, A.; Dijmărescu, I.; Pavelescu, M.L.; Păcurar, D.; Ulici, A. New Perspectives of Therapies in Osteogenesis Imperfecta—A Literature Review. J. Clin. Med. 2024 , 13 , 1065. https://doi.org/10.3390/jcm13041065

Dinulescu A, Păsărică A-S, Carp M, Dușcă A, Dijmărescu I, Pavelescu ML, Păcurar D, Ulici A. New Perspectives of Therapies in Osteogenesis Imperfecta—A Literature Review. Journal of Clinical Medicine . 2024; 13(4):1065. https://doi.org/10.3390/jcm13041065

Dinulescu, Alexandru, Alexandru-Sorin Păsărică, Mădălina Carp, Andrei Dușcă, Irina Dijmărescu, Mirela Luminița Pavelescu, Daniela Păcurar, and Alexandru Ulici. 2024. "New Perspectives of Therapies in Osteogenesis Imperfecta—A Literature Review" Journal of Clinical Medicine 13, no. 4: 1065. https://doi.org/10.3390/jcm13041065

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Published: 18 August 2017

Osteogenesis imperfecta

Nature Reviews Disease Primers volume 3 , Article number: 17053 ( 2017 ) Cite this article

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Osteogenesis imperfecta — also known as brittle bone disease — is a phenotypically and genotypically heterogeneous group of inherited bone dysplasias. This PrimeView illustrates the key mechanisms involved.

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Osteogenesis imperfecta. Nat Rev Dis Primers 3 , 17053 (2017). https://doi.org/10.1038/nrdp.2017.53

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Published : 18 August 2017

DOI : https://doi.org/10.1038/nrdp.2017.53

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Animal models of osteogenesis imperfecta: applications in clinical research

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1 Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA, [email protected].
PMID: 30774469
PMCID: PMC6209373
DOI: 10.2147/ORR.S85198

Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a genetic disease characterized by extreme bone fragility and consequent skeletal deformities. This connective tissue disorder is caused by mutations in the quality and quantity of the collagen that in turn affect the overall mechanical integrity of the bone, increasing its vulnerability to fracture. Animal models of the disease have played a critical role in the understanding of the pathology and causes of OI and in the investigation of a broad range of clinical therapies for the disease. Currently, at least 20 animal models have been officially recognized to represent the phenotype and biochemistry of the 17 different types of OI in humans. These include mice, dogs, and fish. Here, we describe each of the animal models and the type of OI they represent, and present their application in clinical research for treatments of OI, such as drug therapies (ie, bisphosphonates and sclerostin) and mechanical (ie, vibrational) loading. In the future, different dosages and lengths of treatment need to be further investigated on different animal models of OI using potentially promising treatments, such as cellular and chaperone therapies. A combination of therapies may also offer a viable treatment regime to improve bone quality and reduce fragility in animals before being introduced into clinical trials for OI patients.

Keywords: OI; brittle bone; clinical research; dog; mouse; zebrafish.

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Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community

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Published: 06 September 2018
Volume 30 , pages 507–511, ( 2019 )

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T. Swezey 1 ,
B.B. Reeve 1 ,
T.S. Hart 2 ,
M.K. Floor 3 ,
C.M. Dollar 3 ,
A.P. Gillies 3 &
L.L. Tosi ORCID: orcid.org/0000-0001-8827-9883 3

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There is limited research which examines health concerns of individuals with osteogenesis imperfecta (OI). Discussion groups with leaders of the adult OI community identified a broad range of medical priorities beyond fractures and brittle bones. Our work underscores the need to include patient-reported outcomes in rare bone disease research.

Introduction

Osteogenesis imperfecta (OI) is a rare genetic disorder affecting collagen protein leading to brittle bones and a number of other medical complications. To date, there is limited research which examines the life-long process of aging with this rare disease, much less the perspective of individuals with OI.

In order to explore and prioritize health concerns that adults with OI feel have been inadequately addressed in health care and research, investigators held discussions with leaders from the global adult OI community. The meetings were held in August 2017 at the 13th International Conference on OI in Oslo, Norway as part of the preconference seminar “Patient Participation in OI Research”. Investigators were part of the Brittle Bone Disease Consortium (BBDC), a multicenter research program devoted to the study of OI, and their focus was on patient-reported outcomes (PRO).

Participants noted that while fractures and brittle bones are the most common feature of OI, a number of body systems are under-studied in this disorder. They particularly emphasized breathing, hearing, and the effects of aging as primary concerns that researchers and physicians may not fully understand or address. Other areas included pain, gastrointestinal problems, mental health, nutrition, menopause/pregnancy, and basilar invagination. Participants also emphasized that they must be informed of study results. They underscored that outcome measures incorporated into future drug trials must look beyond fractures and consider the whole patient.

Conclusions

This work will help guide the incorporation of PROs into the next phase of the BBDC Natural History Study of OI and underscores the importance of including PROs in the study of rare diseases.

Avoid common mistakes on your manuscript.

Osteogenesis imperfecta (OI) is a group of rare genetic disorders related to connective tissue dysfunction. OI manifests clinically with increased fracture rates and bone fragility, as well as a wide range of non-skeletal issues which may include blue sclerae, joint laxity, impaired dentition, cardiopulmonary deficits, and hearing loss [ 1 , 2 , 3 , 4 , 5 ]. Treatment for OI has generally been focused on reducing fractures, alleviating pain, and increasing mobility. However, due to the complex nature of the disease, patients often have a much wider range of health care needs [ 6 , 7 , 8 ]. At present, beyond a handful of morbidity and mortality studies, little work has been done to explore the changes faced by children and adults with OI as they age.

The Brittle Bone Disease Consortium (BBDC) is leading a longitudinal study of individuals with OI and now seeks to expand the assessment of patient-reported outcomes (PROs) [ 9 , 10 ]. In August 2017, PRO-focused investigators of the Consortium attended the 13th International Conference on OI in Oslo, Norway. With the help of the Norwegian Osteogenesis Imperfecta Association (NFOI), stakeholder meetings with international OI organization representatives were conducted during the pre-conference seminar on the topic of “Patient Participation in OI Research.” These stakeholders explored and prioritized the health concerns individuals with OI feel are not being addressed in health care and research, with a focus on issues that impact adults with OI.

This paper seeks to describe the critical gaps in disease knowledge and care that were underscored by stakeholders from across the globe, in an effort to expand the BBDC’s PRO efforts in a manner that is reflective of the myriad concerns of adults with OI. Although the focus of the meeting was on adults, the concerns of children and their parents were also included as health issues in OI occur across the age span, include a wide variety of body systems, and often differ by OI type. This short communication highlights what patient leaders from the OI community expressed should be our greatest priorities in developing PRO measures.

Two approximately 1-hour discussions were held with 15 adult individuals (4 men, 11 women) with OI, primarily representing OI support groups from Europe, Asia, Australia, and the USA. Two investigators from our group (Laura Tosi and Teresa Swezey) moderated the discussions and focused on three core subjects: key health issues, gaps in knowledge, and research priorities for adults with OI. The sessions adhered to an open forum format in which participants could answer directly to a question or respond to comments made by other participants. Notes summarized key points from each participant stakeholder; topics that were repeatedly emphasized will be highlighted in this report.

Key health issues for adults with OI

Participants in the group discussions identified a range of health concerns for adults with OI. Although brittle bones are a daily worry for the OI community, fracture and fracture risk received less attention, as the community seems well versed in handling fracture issues. Participants noted that, in adulthood, fractures become less frequent, but fracture non-union and complications posed additional problems with age. In fact, the topics of highest concern included breathing, hearing, and aging-related issues, rather than fractures.

Previous research in the OI community has shown pulmonary disease to be highly correlated with morbidity and mortality [ 11 ]. Reported manifestations include higher rates of asthma and pneumonia in both children and adults, as well as exercise intolerance and sleep apnea. Discussion group participants expressed anxiety about their breathing, but were often unable to articulate specific concerns, besides their general understanding of the possibility of respiratory health issues associated with severe cases of OI. Participants were also concerned with exercise and weight maintenance, which can be impacted by decreased pulmonary function [ 12 ]. Since pulmonary function also impacts quality of life (QoL) and daily activities, the participants felt that addressing this concern is essential to providing comprehensive care for the spectrum of OI symptoms [ 13 ].

Participants who had experienced hearing loss felt that they had become socially isolated and withdrawn as a result, which led to significant diminution of their QoL. Prior studies have suggested as many as 50% of OI patients who experience some degree of hearing loss [ 4 , 14 , 15 ]. This aspect of the OI experience has far reaching consequences and highlights a greater need to understand what might predispose specific individuals with OI (beyond OI type) to hearing loss. Other hearing concerns were related to career obstacles, and how an individual with OI’s height variability and unassisted mobility restrictions might be impeded in their ability to hear or reposition themselves for workplace conversations.

The many challenges faced while aging were a reoccurring topic among participants, and presented different challenges across different stages of life. Participants noted that younger individuals with OI wear a “mask to pass,” and try to live as if they do not have OI. This may have far reaching impact on perceptions of QoL and mental health. Maintenance of independence and avoidance of functional decline was repeatedly discussed as a crucial drive for OI patients. The pivotal role of support groups in providing encouragement and access to resources was consistently underscored. While fracture care and prevention were not an issue, generally, concerns regarding skeletal health were paramount when the discussion turned to the effects of aging with OI, especially regarding increased risk of fracture and age-related changes to mobility and independence. It was emphasized that postmenopausal women with OI likely have different skeletal health concerns from men as they age, and that this represents a topic urgently in need of more research.

Additional concerns

Topics of next highest concern included gastrointestinal (GI) issues, mental health, and pain, areas that have been largely undocumented or under-investigated in OI research. Participants note that GI issues affect the community widely, but are rarely talked about. In addition to the various anatomical differences that can cause GI issues, participants emphasized that use of pain medications is another cause of constipation, while other individuals face frequent diarrhea. The group emphasized that serious GI-related issues are common, can interfere with social interactions, school, and employment, and thus deserve careful attention.

The topic of mental health was discussed in relation to the constant fears of falling, fracture, and the stress that recurrent injury, pain, and trips to the hospital can place on a child/family and adults. Participants suggested that individuals with OI may be subjected to significant traumatic events starting as early as infancy due to their high rate of injury and challenges with pain relief. In a previous study, adults with OI had poorer overall mental health scores as well as higher depression and anxiety scores when compared to the representative US population, as measured by the Patient-Reported Outcomes Measurement Information System® (PROMIS ®) [ 10 , 16 ]. This suggests that the cumulative traumatic experiences of individuals with OI may have lasting and previously unrecognized consequences.

Pain was cited as an ever present burden in daily life. Since opioids and chronic pain medication use can impair GI function, individuals with OI are often conflicted between living with pain or accepting constipation and diarrhea [ 17 ]. Living with pain was also described as impacting sleep and mental health, demonstrating the overlap of many of the issues discussed. Participants also described confusion or dismissiveness among healthcare providers in addressing incidents of “microfracture,” commonly described as bone injuries that are not visible on X-ray but cause pain and disability. Discussion group participants expressed concern that doctors overlook and undertreat these injuries as they cannot be confirmed by X-ray.

Gaps in knowledge

During the discussions, participants suggested that some care providers are not always in tune with the realities of the OI patient experience, or might not address all the concerns of their patient. Perceptions of access to quality of care varied widely among the meeting attendees. However, it was the consensus of the participants that most primary care doctors lack comprehensive knowledge about OI at a system level; physicians regularly think of OI as simply a “brittle bone” disorder and frequently do not appreciate the complex effects of collagen mutations throughout the body.

Endocrine-related issues were at the forefront of conversations related to gaps in knowledge about adults with OI. For example, many clinical providers advise individuals with OI to reduce their bodyweight for both heart-health and diabetes prevention, but provide little advice related to exercise and diet. Often, GI or orthopedic ailments directly impede a patient’s ability to eat correctly and stay active. Peri- and postmenopausal women with OI feel that they receive inadequate guidance regarding the maintenance of their bone density; similarly, pregnant women with OI lack clarity on the effects of breastfeeding, as well as pregnancy itself, on their bone density.

Great concern was expressed about the risk of basilar invagination. This rare, serious condition presents in individuals with OI due to connective tissue laxity near the base of the skull and can result in life-threatening complications [ 8 , 18 , 19 , 20 ]. The literature regarding this condition in OI is sparse, and both patients and providers are largely unaware of occurrence rates, diagnostic criteria, and/or risk factors. Participants discussed this topic largely as a fear of the unknown, and urged that steps be taken to address this knowledge gap.

Future avenues for research

Research was of particular interest to participants, as many had participated in studies or completed questionnaires in the past. Many participants expressed frustration that they had been involved in studies for which they never saw the results. They underscored that researchers must strive to inform participants of study findings. While participants acknowledged that there may be challenges to presenting results and conclusions in an accessible manner, it is crucial for researchers to seek out forums to present their results. The many newsletters offered by the international OI patient support groups offer an easy platform both to inform the OI community of new findings and prevent misunderstanding of results.

Topics of high research priority to the attendees, beyond what has already been discussed, included the following: transition of care, long-term effects of bisphosphonate use, and determinants of QoL. Although not stated specifically as a research concern, many respondents mentioned how their QoL was impacted by their disorder. The group thought that more research should be conducted in older adults with OI, and expressed concern that the long-term effects of OI have not been adequately explored.

As the need to compare and contrast results of new therapies continues to evolve, improving measures for assessing drug impact will be essential. The group also brought up the potential long-term effects of bisphosphonate use, which has not been thoroughly studied. Since this class of drugs has been primarily prescribed for elderly patients with osteoporosis, individuals who received bisphosphonate therapy at a young age worry about the long-term consequences of their treatment.

Our team was grateful for the extensive insights provided by discussion group participants. It is our goal to continue to engage this patient community to identify research priorities and to oversee the conduct of studies and dissemination and implementation of findings in practice and policy. At the same time, we will strive to reach out to other individuals with OI who can provide diverse perspectives based on their gender, age, disease type, culture and racial perspective, access to resources, and living conditions.

Limitations

The recommendations from our stakeholder group are limited to those 15 adult patients with OI who were motivated and had the resources and the capability to attend the 13th International Conference on OI. However, these individuals have been living with OI for many years and are well connected with the broader OI community and therefore serve as excellent representatives.

Moving forward

Our next step will be to work with the broader membership of the BBDC to incorporate additional PRO measures into the existing longitudinal study of OI. The longitudinal study offers the unique opportunity to incorporate and validate existing and novel PRO instruments for under-appreciated/under-studied aspects of OI into the existing research framework. Similarly, the longitudinal study will allow us to explore how PRO measures compare with traditional clinical measures such as audiometry, spirometry, mobility functional tests, and legacy questionnaires in eliciting and quantifying health concerns. This will be essential to meeting our long-term goal of creating web-based tools which assist the OI community in understanding changes in their health status and articulating them to caregivers. It is our firm belief that the improvement of OI care requires an expanded research agenda that incorporates the health concerns articulated by the OI community and includes patient-reported outcomes in measuring the success of diagnostic and treatment strategies.

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Acknowledgments

The authors would like to thank Ingunn Westerheim and Inger-Margrethe Stavdal Paulsen who helped us organize discussion groups as part of the preconference “Patient Participation in OI Research” and Karen Braitmeyer for her meticulous note-taking. We also would like to thank the participants in the discussion groups and the many stakeholders who are invested in OI.

Funding for Teresa Swezey’s conference travel to attend the 13th International Conference on Osteogenesis Imperfecta in Oslo, Sweden, was provided by the Osteogenesis Imperfecta Foundation, Gaithersburg, MD, USA. No other funds were acquired.

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Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA

T. Swezey & B.B. Reeve

The Osteogenesis Imperfecta Foundation, Gaithersburg, MD, USA

Division of Orthopaedic Surgery and Sports Medicine, Children’s National Health System, Washington, DC, USA

M.K. Floor, C.M. Dollar, A.P. Gillies & L.L. Tosi

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Correspondence to L.L. Tosi .

Ethics declarations

The stakeholder meeting plan was reviewed by the Children’s National Health System IRB and this research was determined to be exempt from IRB review. For this type of study, formal consent is not required.

Conflict of interest

Tracy S. Hart serves as the CEO of the Osteogenesis Imperfeta Foundation. We do not believe that this represents a conflict of interest. As noted in her conflict of interest disclosure, Teresa Swezey received travel funds to attend the OI conference. Bryce B. Reeve, Marianne K. Floor, Christina M. Dollar, Austin P. Gillies, and Laura L. Tosi declare that they have no disclosures.

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Swezey, T., Reeve, B., Hart, T. et al. Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community. Osteoporos Int 30 , 507–511 (2019). https://doi.org/10.1007/s00198-018-4690-7

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Accepted : 26 August 2018

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Issue Date : 05 February 2019

DOI : https://doi.org/10.1007/s00198-018-4690-7

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Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease

J. Shapiro , P. Byers , +1 author Paul Sponsellor
Published 1 September 2013

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Int J Clin Pediatr Dent
v.13(4); Jul-Aug 2020

Fragile and Brittle Bone Disease or Osteogenesis Imperfecta: A Case Report

Navin h krishnamurthy.

1–4 Department of Pedodontics and Preventive Dentistry, RajaRajeswari Dental College and Hospital, Bengaluru, Karnataka, India

Nagarathna Chikkanarasaiah

Aishwarya nanjappa, nimishabalakrishnan vathariparambath, aim and objective.

The aim and objective of this report is to describe the dental management of 11-year-old patient with type III osteogenesis imperfecta (OI).

Osteogenesis imperfecta or brittle bone disease is caused by mutations in the collegen type I gene which is a heterogeneous rare connective tissue disorder. Dentinogenesis imperfecta, hearing impairment, scoliosis, sclera is blue, hyperlaxity of ligaments, and fragile skin are other common features. Individuals having positive family history suggest a straightforward diagnosis of OI but can be difficult in the absence of affected family.

Case description

We report a case of 11-year-old boy, with a chief complaint of pain and swelling on the lower left back tooth region which was associated with extraoral draining sinus. His medical history revealed multiple fractures sustained during routine handling. On examination, the child was pale, dyspneic, with rhizomelic dwarfism, and relative macrocephaly with frontal bossing. On the grounds of history taken, clinical examination and respective investigations carried out, we came to a conclusion of osteogenesis imperfect type III. As the child needs a special care, we planned for a conservative treatment approach.

The craniofacial abnormalities in OI-III affected person's impact on their dentofacial appearance and masticatory function. A detailed dental and craniofacial investigation is necessary in affected persons in order to identify any primary or secondary abnormalities. As soon as the deciduous teeth erupt, patients with OI should be evaluated with adequate dental treatment and oral hygiene instructions in order to reduce the need for extensive treatment.

Clinical significance

Although oral manifestations are seldom seen, dentist should be extremely alert while managing this fragile bone disease. Early diagnosis, increased awareness, and effective treatment plan will reduce the effects of this debilitating disease. An ounce of prevention is worth a pound of cure, especially when something has no cure.

How to cite this article

Krishnamurthy NH, Chikkanarasaiah N, Nanjappa A, et al. Fragile and Brittle Bone Disease or Osteogenesis Imperfecta: A Case Report. Int J Clin Pediatr Dent 2020;13(4):425–428.

B ackground

Osteogenesis imperfecta (OI) is a rare inherited disorder affecting connective tissue integrity, which is characterized by bone fragility of varying severity ranging from lethal forms to those with very minimal features. 1 The incidence is between 10,000 and 20,000 live births. The craniofacial abnormalities in affected persons can also impact on their dentofacial appearance and masticatory function. Care should be taken while managing such patients, as there is increase chance of bone fracture, and early diagnosis and effective treatment plan will reduce the effects of this debilitating disease.

C ase D escription

Here, we are presenting a rare case of a 11-year-old boy referred to our Department of Pediatric and Preventive Dentistry with the chief complaint of pain and swelling on the lower left back tooth region from the past 20 days ( Fig. 1 ). Swelling was initially small in size gradually progressed to present size and associated with extraoral draining sinus for which he consulted a private dental clinic. Although he was under medication for past 1 week, there was no reduction in the size of the swelling ( Fig. 2 ). His medical history revealed multiple fractures sustained during routine handling with difficulty in walking. His birth and neonatal period were uneventful. Family history revealed a positive finding of the same illness in his elder sibling. On examination, child was sick looking, pale, dyspneic, with rhizomelic dwarfism, and relative macrocephaly with frontal bossing. There was bilateral bowing of lower limbs with varus deformity and flexion deformity of the thumb. Patient profile was concave with typical triangular faces with fragile skin ( Fig. 1 ). He had white sclera with narrow thoracic cage. Abdomen was protuberant with marked kyphosis. Patient had undergone surgery for impaired vision and hearing was normal. There was marked scoliosis with convexity toward left. Asymmetry was seen on the left side of the face with palpable submandibular lymph nodes, which was mobile and tender on palpation. On inspection, a solitary diffuse swelling was present on the left side of the face measuring 2 × 3 cm, extending from the corner of the mouth to middle third of the mandible anteroposteriorly, and from ala-tragal line to the base of the mandible superior-inferiorly, associated with draining sinus. The swelling was soft in consistency, fluctuant, mild-tender on palpation, and there was a localized rise in temperature. On intraoral examination, swelling present in relation to 75 extending from attached gingiva up to buccal vestibule ( Fig. 3 ). Deep dentinal caries was present in relation to mandibular left primary second molar which was tender on percussion and presented with vestibular tenderness and obliteration. The intraoral lesion was rubbery and fluctuant on palpation. Tooth present was 15 53 12 11 21 22 25 84 42 41 31 32 75. Dental caries with respect to 11, 21, 15 and 25, caries with pulp exposure with respect to 75, 84. Intraoral periapical radiograph and orthopantomograph and cone-beam computed tomography were taken ( Fig. 4 ), and finally, diagnosis has arrived as dentoalveolar abscess with respect to 75 associated with extraoral draining sinus and pathological fracture of body of mandible on the left side. Investigation with hemogram revealed microcytic hypochromic anemia with relative lymphocytosis, echocardiography showed mild pulmonic regurgitation renal function test, and electrolytes were normal. Reduced Serum calcium level. Alkaline phosphatase was significantly raised, bilateral pneumonitic patches and haziness with lack of air spaces seen in chest X-ray. Hip X-ray revealed protrusion acetabulum. X-ray of the extremities showed thinned cortices ( Figs 5 and and6). 6 ). X-ray spine shows platyspondyly. Owing to his physician's high index of suspicion, a diagnosis of OI-III was pursued, which is the non-lethal form of the disease.

An external file that holds a picture, illustration, etc.
Object name is ijcpd-13-425-g001.jpg

Patient photograph showing typical features of osteogenesis imperfect

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Object name is ijcpd-13-425-g002.jpg

Preoperative photograph showing extraoral draining sinus

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Object name is ijcpd-13-425-g003.jpg

Intraoral photograph showing submerged 75 with deep dental caries and obliteration in the vestibule

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Cone-beam computed tomography image showing lingually tilted 75 associated bone resorption and pathological fracture of body of mandible and thinning of lower border of mandible

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X-ray of long bones showing multiple healed and healing fractures with reduced trabecular pattern with thinning of the cortex

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Object name is ijcpd-13-425-g006.jpg

X-ray showing AP spine, platyspondyly and scoliosis and chest showing multiple pneumonitic patches. Hip X-ray revealed protrusion acetabulum

Calcium and vitamin D therapy was initiated, and an in-depth discussion regarding bisphosphonates was pursued. Advised oral prophylaxis and oral hygiene instructions, lesion sterilization and tissue repair were done in relation to 75, pulp therapy with respect to 84, and restoration in relation to 15, 11, 21, and 25 were done. Tablet Augmentin 375 mg, Soframycin ointment, and tablet Metrogyl–200 mg were prescribed for 5 days. Patient was recalled after 3 days, 10 days, 15 days, 1 month, 3 months, and 4 months. Clinically healing extraoral sinus was noticed, and intraorally the findings were satisfactory and erupting 43 was noted ( Fig. 7 ).

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Object name is ijcpd-13-425-g007.jpg

Followup photograph after 4 months

D iscussion

On the grounds of history taken, clinical examination and respective investigations carried out, we came to a conclusion of OI-III. Our patient presented with short stature, significant bowing, recurrent fractures, typical triangular facies, hypermobile joints, skeletal deformities, cardiac abnormalities, hearing loss, hematopoietic changes, respiratory difficulty due to rib cage deformities, and fragile skin except for blue sclera which all are the classic features 2 of OI-type III. This condition may or may not be associated with dentinogenesis imperfecta leads to enamel breakage due to abnormal collagen. The lower teeth are more severely affected than the upper teeth. 1 According to Sillence classification, 3 this is constituted by four types (I to IV) based on clinical and radiological features without the possibility of curative clinical treatment. 4 Novel types V, VI, and VII in which type I collagen genes were not involved were later added. The sillence classification is universally accepted to classify the degree of OI. 5 Reasonable therapeutic possibilities are capable to improve the course of the disease and quality of life. 6 , 7

C onclusion

In order to identify primary and secondary abnormalities in individual, detailed dental and craniofacial investigation is necessary.
Multispecialty approach is necessary in the management of individuals with OI type III.
Adequate dental treatment and oral hygiene instructions are necessary in order to reduce the need for extensive treatment.

C linical S ignificance

Although oral manifestations are seldom seen, dentist should be extremely alert while managing this fragile bone disease and sometimes pedodontist are the first identifier of such rare diseases. Early diagnosis, increased awareness, and effective treatment plan will reduce the effects of this debilitating disease. “An ounce of prevention is worth a pound of cure … especially when something has no cure”.

ACKNOWLEDGMENTS

We would like to extend our sincere thanks to staffs and postgraduate students, Department of Pediatrics, RajaRajeswari Medical College and Hospital, Bengaluru, for their most valuable contribution. We also extent our gratitude to the management of RajaRajeswari Dental College and Hospital, Bengaluru, Karnataka, India, for their constant encouragement and support.

Source of support: Nil

Conflict of interest: None

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Florida International University (FIU) - College of Law

Date Written: 2004

In child abuse cases involving multiple fractures, prosecutors and investigators are increasingly facing a relatively new defense. In some jurisdictions, judges are allowing defense medical experts to testify that infants have not been abused, but instead suffer from a mild form of Osteogenesis Imperfecta (OI) or a purported variant of OI, Temporary Brittle Bone Disease (TBBD). These diagnoses are offered in cases where the injuries are highly specific for abuse because they involve: (1) fractures typical of abuse in different stages of healing; (2) infants who have tested negative for conventionally diagnosable metabolic bone diseases (including OI); and (3) infants whose bones do not continue to fracture after they are placed in protective custody. 2 It is critically important for doctors, investigators and prosecutors to be able to distinguish bone disease from abuse because OI is the most frequent medical/legal defense in suspected cases of child abuse.3 This article will provide a brief and general overview of what is currently known and accepted in the medical literature about OI, and then examine more controversial diagnoses such as TBBD. Finally, strategies for prosecutors will be discussed for dealing with bone disease defenses.

Keywords: Temporary Brittle Bone Disease, Child Abuse, Expert Testimony, Medical Witnesses, Radiology

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Joelle Anne Moreno (Contact Author)

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Rare Research Report: May 2024

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Brittle Bone Disorders Consortium (BBDC)

Frontiers in congenital disorders of glycosylation consortium (fcdgc), global leukodystrophy initiative clinical trials network (glia-ctn), lysosomal disease network (ldn).

Nephrotic Syndrome Study Network (NEPTUNE)

Primary Immune Deficiency Treatment Consortium (PIDTC)

Listen to these summaries on the Rare Research Report podcast .

Discussing Genetic Testing for Monogenic Disorders of Osteoporosis

Monogenic disorders of osteoporosis are characterized by low bone mass, increased bone fragility, and increased risk of fractures. There are currently over 50 different known types of these disorders, which are each caused by variations in a single gene. Widespread availability of clinical genetic testing offers an opportunity to correctly diagnose individuals with these disorders.

In this review paper, researchers discuss genetic testing for patients with suspected monogenic forms of osteoporosis. The team outlines the principles of clinical genetic testing and provides practical guidance for clinicians to navigate the process.

Authors note that clinicians should be aware of how to incorporate genetic testing into their practices, as these techniques could help identify the appropriate diagnosis for patients with low bone mass, multiple or unusual fractures, and severe or early-onset osteoporosis.

Busse E, Lee B, Nagamani SCS. Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know. Curr Osteoporos Rep. 2024 Apr 11. doi: 10.1007/s11914-024-00870-6. Epub ahead of print. PMID: 38600318.

Investigating the Effects of Glycan Extension Deficiency in ALG3-CDG

ALG3-CDG is a rare congenital disorder of glycosylation (CDG) characterized by neurological symptoms, transaminitis (elevated liver enzymes), and frequent infections. When the endoplasmic reticulum—a network of membranes inside a cell that plays a major role in protein synthesis and transport—is under stress, one of the earliest and fastest responses in cells is glycan extension. The first step of this process is catalyzed by the ALG3 enzyme, which is deficient in patients with ALG3-CDG.

In this study, researchers investigated the effects of glycan extension deficiency in ALG3-CDG. The team explored the biochemical consequences of this deficiency and associated response to endoplasmic reticulum stress.

These results provide a better understanding of how glycan extension deficiency affects patients with ALG3-CDG. Authors note that these findings also have important implications for the development of personalized medicine for other types of CDG.

Daniel EJP, Edmondson AC, Argon Y, Alsharhan H, Lam C, Freeze HH, He M. Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG. J Inherit Metab Dis. 2024 Apr 10. doi: 10.1002/jimd.12739. Epub ahead of print. PMID: 38597022.

Exploring Potential Biomarkers for Alexander Disease

Alexander disease is a rare disorder of the nervous system characterized by leukodystrophy, or the destruction of myelin (the fatty coating surrounding nerve fibers). Biomarkers are needed to help researchers monitor the progression of the disease and response to treatments. Elevated levels of the GFAP protein in the blood of patients with Alexander disease could serve as a possible biomarker. However, therapies currently in development involve targeting GFAP for treatment, highlighting a critical need for additional biomarkers.

In this study, researchers explored the potential of biomarkers used in other neurodegenerative diseases for Alexander disease. The team measured concentrations of GFAP, neurofilament light, and tau in blood samples from individuals with Alexander disease and healthy controls.

Results show significant changes in these levels in individuals with Alexander disease, especially those with infantile onset.

Ashton NJ, Di Molfetta G, Tan K, Blennow K, Zetterberg H, Messing A. Plasma concentrations of glial fibrillary acidic protein, neurofilament light, and tau in Alexander disease. Neurol Sci. 2024 Apr 1. doi: 10.1007/s10072-024-07495-8. Epub ahead of print. PMID: 38558318.

Exploring Management Approaches for High-Sustained Anti-rhGAA IgG Antibody Titers in Patients with Pompe Disease

Pompe disease is an inherited lysosomal disorder caused by an abnormal enzyme that cannot break down glycogen. Patients with infantile-onset Pompe disease often experience high-sustained anti-rhGAA IgG antibody titers (HSAT), which can lower the efficacy of enzyme replacement therapy and lead to health complications.

In this study, researchers explored management approaches for HSAT in patients with Pompe disease. The team compared the disease course of eight patients with infantile-onset Pompe who were treated with the drug bortezomib. Researchers tracked differences in timing, dosage, and outcomes among these patients.

Results suggest that bortezomib should be initiated at the earliest sign of HSAT with a minimum of two consecutive treatment cycles to achieve optimal outcomes. Authors recommend close monitoring of HSAT and early intervention as soon as significantly elevated levels are noted.

Desai AK, Shrivastava G, Grant CL, Wang RY, Burt TD, Kishnani PS. An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation. Front Immunol. 2024 Mar 8;15:1360369. doi: 10.3389/fimmu.2024.1360369. PMID: 38524130; PMCID: PMC10959098.

Nephrotic Syndrome Study Network (NEPTUNE)

Investigating the Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies

Primary proteinuric glomerulopathies are a group of kidney disorders characterized by dysfunction of the glomeruli (kidney structures responsible for filtering the blood and removing waste in urine), leading to elevated protein in the urine. Elevated levels of fibroblast growth factor 23 (FGF23), a hormone that helps regulate kidney function, are a risk factor for cardiovascular disease. However, not much is known about how FGF23 impacts cardiovascular health in proteinuric glomerulopathies.

In this study, researchers investigated the association of FGF23 levels with resting blood pressure and lipids over time in patients with proteinuric glomerulopathies. The team analyzed data from 204 adults and 93 children using generalized estimating equation regression techniques.

Results showed that higher baseline FGF23 levels were significantly associated with hypertensive blood pressure over time. Authors note that FGF23 should be investigated further as a potential therapeutic target for reducing cardiovascular disease in proteinuric glomerulopathies.

Pfaff M, Denburg MR, Meyers KE, Brady TM, Leonard MB, Hoofnagle AN, Sethna CB. Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies. Am J Nephrol. 2024;55(2):187-195. doi: 10.1159/000535092. Epub 2023 Dec 21. PMID: 38128487; PMCID: PMC10987260.

Exploring the Impact of Various Methods for Measuring PHA-Based T Cell Growth in Patients with Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) is a genetic disorder characterized by very low T cell numbers, leading to frequent infections and abnormal (low) function of the immune system. Phytohemagglutinin (PHA), a lectin found in red kidney beans, stimulates T cell growth. Several methods can be used to measure PHA-stimulated T cell growth. However, interpretation of results can vary based on the method used.

In this study, researchers explore how different methods of measuring PHA-stimulated T cell growth affects test results and interpretation in patients with SCID. The team analyzed data collected from 307 participants with SCID for PHA-based T cell growth, using either a radioactive or flow cytometry method.

Results showed a more accurate analysis from the flow cytometry method—especially in patients with severely low T cell numbers—suggesting that the method used to measure PHA growth impacts the interpretation of results. Authors note that this test is not essential for the diagnosis of typical SCID and should only be considered as a supportive test.

Abraham RS, Basu A, Heimall JR, Dunn E, Yip A, Kapadia M, Kapoor N, Satter LF, Buckley R, O'Reilly R, Cuvelier GDE, Chandra S, Bednarski J, Chaudhury S, Moore TB, Haines H, Dávila Saldaña BJ, Chellapandian D, Rayes A, Chen K, Caywood E, Chandrakasan S, Lugt MTV, Ebens C, Teira P, Shereck E, Miller H, Aquino V, Eissa H, Yu LC, Gillio A, Madden L, Knutsen A, Shah AJ, DeSantes K, Barnum J, Broglie L, Joshi AY, Kleiner G, Dara J, Prockop S, Martinez C, Mousallem T, Oved J, Burroughs L, Marsh R, Torgerson TR, Leiding JW, Pai SY, Kohn DB, Pulsipher MA, Griffith LM, Notarangelo LD, Cowan MJ, Puck J, Dvorak CC, Haddad E. Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia. Clin Immunol. 2024 Apr;261:109942. doi: 10.1016/j.clim.2024.109942. Epub 2024 Feb 15. PMID: 38367737; PMCID: PMC11018339.

The Rare Diseases Clinical Research Network (RDCRN) is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). Now in its fourth five-year funding cycle, RDCRN is a partnership with funding and programmatic support provided by Institutes, Centers, and Offices across NIH, including the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, the National Institute of Mental Health, and the Office of Dietary Supplements.

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(PDF) Clinical features of temporary brittle bone disease
Brittle bone disease
SOLUTION: Osteogenesis imperfecta brittle bone disease
Brittle Bone Disease
(PDF) Brittle bone disease (osteogenesis imperfecta): a rare condition
SOLUTION: Osteogenesis imperfecta brittle bone disease

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COMMENTS

Current Overview of Osteogenesis Imperfecta
Abstract. Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild ...
Osteogenesis Imperfecta
Osteogenesis imperfecta (OI) (brittle bone disease) is the most common heritable disorder of connective tissue. [ 1] Major clinical forms of OI represent quantitative and qualitative abnormalities of Type I collagen, the most abundant protein in bone. [ 1]
Osteogenesis Imperfecta
Osteogenesis imperfecta (OI) is a genetic disorder of connective tissues caused by an abnormality in the synthesis or processing of type I collagen.[1][2] It is also called brittle bone disease. It is characterized by an increased susceptibility to bone fractures and decreased bone density. Other manifestations include blue sclerae, dentinogenesis imperfecta, short stature, as well as deafness ...
Osteogenesis Imperfecta: A Case Report and Review of Literature
Discussion/Literature Review. OI is a rare disorder. It has variously been called "osteopsathyrosis idiopathica" by Lobstein, "fragilitus osseum", hereditary fragility of bone, later brittle bone disease and fragile bone disease, but the current name "OI" was coined by Vrolik in 1845.[11,12] The disorder was first brought to the limelight by the Swede, Olof Jakob Ekman in his ...
Research Publications
Epub ahead of print. PMID: 38472351. Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know. Busse E, Lee B, Nagamani SCS. Curr Osteoporos Rep. 2024 Apr 11. doi: 10.1007/s11914-024-00870-6. Epub ahead of print. PMID: 38600318.
Osteogenesis imperfecta
Introduction. Osteogenesis imperfecta — also known as brittle bone disease — is a phenotypically and genetically heterogeneous group of inherited bone dysplasias 1. Although the primary ...
Osteogenesis imperfecta
Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare genetic multisystem disorder of Type I collagen associated with bone fragility, fractures and connective tissue abnormalities, with highly heterogeneous phenotypic features and varying genetic basis. It has an incidence of one in 15-20,000 births.1 Greater incidence is within populations with a higher level of ...
New Perspectives of Therapies in Osteogenesis Imperfecta—A ...
Osteogenesis imperfecta (OI), also called brittle bone disease, Lobstein disease, or Vrolik syndrome, is a rare genetic disorder of the connective tissues characterized by skeletal dysplasia with bone fragility, caused by an abnormality in the metabolism of type I collagen, with a reported incidence of 1 in 15,000 to 20,000 births [ 1, 2, 3 ].
Osteogenesis imperfecta
Nature Reviews Disease Primers 3, Article number: 17053 ( 2017 ) Cite this article. Osteogenesis imperfecta — also known as brittle bone disease — is a phenotypically and genotypically ...
PDF Osteogenesis imperfecta: potential therapeutic approaches
This research paper serves as a guideline for health practitioners involved in the care of patients with osteogenesis imperfecta (OI). Since there is currently no cure for OI, disease severity is addressed with symptomatic treatment. Treatment guidelines in this research paper address the following areas: • Dental manifestations and treatments
Animal models of osteogenesis imperfecta: applications in clinical research
Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a genetic disease characterized by extreme bone fragility and consequent skeletal deformities. This connective tissue disorder is caused by mutations in the quality and quantity of the collagen that in turn affect the overall m …
Current OI Studies and Publications
Participation in OI research helps advance the scientific understanding of OI so that more and better treatments can be made available to the OI community. ... Dollar CM, Gillies AP; Members of the Brittle Bone Disease Consortium, Hart TS, Cuthbertson DD, Sutton VR, Krischer JP. Orphanet Journal of Rare Diseases. 2019 Jan 29;14:23. https://doi ...
Incorporating the patient perspective in the study of rare bone disease
Summary There is limited research which examines health concerns of individuals with osteogenesis imperfecta (OI). Discussion groups with leaders of the adult OI community identified a broad range of medical priorities beyond fractures and brittle bones. Our work underscores the need to include patient-reported outcomes in rare bone disease research. Introduction Osteogenesis imperfecta (OI ...
Brittle Bone Disease: A Case Report
Introduction. Osteogenesis imperfecta (OI) or brittle bone disease is a rare genetic disorder occurring in 1 in 15,000 to 20,000 births and is characterized by bone fragility and osteopenia [ 1 ]. Due to considerable phenotypic variability, a classification of OI types was developed based on clinical features and disease severity.
Research Studies
The Brittle Bone Disorders Consortium (BBDC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). BBDC is funded under grant number U54AR068069 as a collaboration between NCATS, the ...
Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease
Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. F. Van Dijk D. Sillence. Medicine. American journal of medical genetics. Part A. 2014. TLDR. The new OI nomenclature and the pre‐and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify ...
Home
The Brittle Bone Disorders Consortium (BBDC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). BBDC is funded under grant number U54AR068069 as a collaboration between NCATS, the ...
OI Research Update: New Medical Treatments
OI Research Update: New Medical Treatments. Posted on March 18, 2022 by OI Foundation. On March 15, 2022, the OI Foundation spoke with Dr. Brendan Lee, Principal Investigator for the Brittle Bone Disease Consortium (BBDC). In this interview, they discussed new drugs being studied to treat osteogenesis imperfecta, and the drug development process.
Fragile and Brittle Bone Disease or Osteogenesis Imperfecta: A Case
B ackground. Osteogenesis imperfecta (OI) is a rare inherited disorder affecting connective tissue integrity, which is characterized by bone fragility of varying severity ranging from lethal forms to those with very minimal features. 1 The incidence is between 10,000 and 20,000 live births. The craniofacial abnormalities in affected persons can also impact on their dentofacial appearance and ...
Osteogenesis Imperfecta
The Brittle Bone Disorders Consortium (BBDC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). BBDC is funded under grant number U54AR068069 as a collaboration between NCATS, the ...
A Courtroom Diagnosis: Countering the Defense of Temporary Brittle Bone
A Courtroom Diagnosis: Countering the Defenses of Temporary Brittle Bone Disease and Mild Osteogenesis Imperfecta in Child Abuse Cases,American Prosecutors Research Institute, 16 Update 8 (2004) Florida International University Legal Studies Research Paper No. 16-13
Resources for Patients and Families
The Brittle Bone Disorders Consortium (BBDC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). BBDC is funded under grant number U54AR068069 as a collaboration between NCATS, the ...
Rare Research Report: May 2024
Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below. Jump to: Brittle Bone Disorders Consortium (BBDC) Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

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1.4. Current Treatment of OI

3.2. Anti-RANKL Antibody ( Table 3 )

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3.4. Recombinant Human Parathormone

3.7. 4-Phenylbutiric Acid (4-PBA) ( Table 6 )

3.8. Inhibition of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphatase Enzymes (Salubrinal)

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Animal models of osteogenesis imperfecta: applications in clinical research

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Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease

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Human dentin characteristics of patients with osteogenesis imperfecta: insights into collagen-based biomaterials.

Fragile and Brittle Bone Disease or Osteogenesis Imperfecta: A Case Report

Nagarathna Chikkanarasaiah

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A Courtroom Diagnosis: Countering the Defense of Temporary Brittle Bone Disease and Mild OI

Joelle Anne Moreno

Joelle Anne Moreno (Contact Author)

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Criminal Law eJournal

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Rare Research Report: May 2024

Brittle Bone Disorders Consortium (BBDC)

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