Publications by authors named "Jay R Shapiro"

24 Publications

  • Page 1 of 1

ADULT OSTEOPOROSIS WITH A HISTORY OF CHILDHOOD-ONSET FRACTURE DUE TO AN LRP5 RECEPTOR VARIANT MUTATION.

AACE Clin Case Rep 2019 Nov-Dec;5(6):e362-e364. Epub 2019 Aug 15.

Objective: This case highlights the value of genetic screening for idiopathic osteoporosis with recurrent fractures.

Methods: Case report and review of the literature.

Results: A 52-year-old Caucasian female with idiopathic osteoporosis with recurrent fractures was identified with a heterozygous low-density lipoprotein receptor related protein 5 (LRP5) mutation.

Conclusion: This case highlights the variability in clinical expression of LRP5 polymorphisms and suggests that standard treatment in cases of recurrent fracture may be ineffective.
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http://dx.doi.org/10.4158/ACCR-2019-0219.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873838PMC
August 2019

Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study.

Am J Med Genet A 2020 04 26;182(4):697-704. Epub 2019 Dec 26.

Department of Pediatric Orthopedic Surgery, Hospital for Special Surgery, New York, New York.

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.
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http://dx.doi.org/10.1002/ajmg.a.61464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385724PMC
April 2020

A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta.

JBMR Plus 2019 May 7;3(5):e10118. Epub 2019 Jan 7.

Hospital for Special Surgery Dept of Orthopedic Surgery New York NY USA.

Osteogenesis imperfecta (OI) is characterized by low bone mass and bone fragility. Using data from a large cohort of individuals with OI from the Osteogenesis Imperfecta Foundation's linked clinical research centers, we examined the association between exposure to bisphosphonate (BPN) treatment (past or present) and lumbar spine (LS) areal bone mineral density (aBMD), fractures, scoliosis, and mobility. From 466 individuals, we obtained 1394 participant-age LS aBMD data points. Though all OI subtypes were examined, primary analyses were restricted to type I OI (OI-1). Using linear regression, we constructed expected OI-1 LS aBMD-for-age curves from the data from individuals who had never received BPN. LS aBMD in those who had been exposed to BPN was then compared with the computed expected aBMD. BPN exposure in preadolescent years (age <14 years) was associated with a LS aBMD that was 9% more than the expected computed values in BPN-naïve individuals ( < 0.01); however, such association was not observed across all ages. Exposure to i.v. BPN and treatment duration >2 years correlated with LS aBMD in preadolescent individuals. BPN exposure also had a significant association with non-aBMD clinical outcome variables. Logistic regression modeling predicted that with BPN exposure, a 1-year increase in age would be associated with an 8.2% decrease in fracture probability for preadolescent individuals with OI-1, compared with no decrease in individuals who had never received any BPN ( < 0.05). In preadolescent individuals with OI-1, a 0.1 g/cm increase in LS aBMD was associated with a 10.6% decrease in scoliosis probability, compared with a 46.8% increase in the BPN-naïve group ( < 0.01). For the same changes in age and LS aBMD in preadolescent individuals, BPN exposure was also associated with higher mobility scores ( < 0.01), demonstrating that BPN treatment may be associated with daily function. © 2018 The Authors. Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524673PMC
May 2019

Mobility in osteogenesis imperfecta: a multicenter North American study.

Genet Med 2019 10 28;21(10):2311-2318. Epub 2019 Mar 28.

Orthopaedic Rehabilitation and Engineering Center, Marquette University, Milwaukee, WI, USA.

Purpose: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes.

Methods: We collected mobility data at five clinical sites to analyze the largest cohort of individuals with OI (n = 491) to date. Linear mixed models were developed to explore relationships among subject demographics and mobility metrics.

Results: Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV).

Conclusion: These results are significant to understanding mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on prognosis for mobility.
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http://dx.doi.org/10.1038/s41436-019-0491-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401984PMC
October 2019

A multicenter study to evaluate pulmonary function in osteogenesis imperfecta.

Clin Genet 2018 12 24;94(6):502-511. Epub 2018 Sep 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.
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http://dx.doi.org/10.1111/cge.13440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235719PMC
December 2018

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.

Genet Med 2019 02 4;21(2):275-283. Epub 2018 Jul 4.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Purpose: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.

Methods: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.

Results: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05).

Conclusion: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.
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http://dx.doi.org/10.1038/s41436-018-0045-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320321PMC
February 2019

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations.

J Bone Miner Res 2017 Oct 16;32(10):1977-1980. Epub 2017 Aug 16.

New Mexico Clinical Research and Osteoporosis Center, Albuquerque, NM, USA.

Hypophosphatasia (HPP) is a rare inherited disorder of bone affecting approximately 500 to 600 known individuals in the United States. HPP is the result of mutations involving the gene for tissue nonspecific alkaline phosphatase. Five clinical types of HPP are recognized. The clinical presentation of HPP varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. In adults, main clinical involvement includes early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, and fractures. Treatment for HPP is limited. Asfotase alfa is a subcutaneously administered synthetic human alkaline phosphatase that is approved for treatment of patients, including adults, with perinatal/infantile- and juvenile-onset HPP. However, guidelines for the treatment of adults with HPP are not available. This discussion addresses diagnostic and treatment considerations for adults with HPP. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3226DOI Listing
October 2017

Zoledronic acid improves bone histomorphometry in a murine model of Rett syndrome.

Bone 2017 06 18;99:1-7. Epub 2017 Mar 18.

Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA. Electronic address:

Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT experience early onset osteoporosis, decreased bone mass and an increased fracture risk. There is no defined treatment for osteoporosis associated with RTT. The present study evaluated the effects of zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity, in a mouse model of MeCP2 deficiency. Mice received weekly injections of 20μg/kg ZA for six weeks. Due to the shortened lifespan of hemizygous male (Mecp2-null) mice, treatment began at 3weeks of age for this group and corresponding wildtype (WT) male mice. Treatment for heterozygous (HET) and WT female mice began at 8weeks of age. Micro-computed tomography (micro-CT) and dynamic analyses of bone turnover were performed. ZA treatment led to significant increases in bone volume fraction, number, connectivity density and apparent density of trabecular bone in all genotypes of mice. In contrast, cortical bone generally was unaffected by ZA injections. Parameters of bone turnover, including mineral apposition rate, labeled bone surface and bone formation rate decreased after treatment with ZA. Mecp2-null mice had reduced labeled bone surface and bone formation rate compared to WT male mice. The results indicate that ZA treatment significantly improved trabecular bone mass in a murine model of RTT with little effect on cortical bone.
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http://dx.doi.org/10.1016/j.bone.2017.03.040DOI Listing
June 2017

Health outcomes of neonates with osteogenesis imperfecta: a cross-sectional study.

J Matern Fetal Neonatal Med 2016 Dec 7;29(23):3889-93. Epub 2016 Mar 7.

a Bone and Osteogenesis Imperfecta Department, Kennedy Krieger Institute, Johns Hopkins School of Medicine , Baltimore , MD , USA and.

Objective: To assess at-birth health outcomes of neonates with osteogenesis imperfecta (OI).

Study Design: A total of 53 women who self-reported having had at least one child with OI completed the survey. We evaluated pregnancy length, neonatal intensive care unit (NICU) usage, at-birth complications, and the child's clinical information including OI type, height and weight.

Results: Information was gathered on a total of 77 children (60 type I, 4 type III and 13 type IV). Health conditions reported at birth included breech presentation (24%), prematurity (27%), fracture (18%), bone deformity (18%) and respiratory problems (22%). Approximately 31% (n = 24) received NICU care. There was a significant association between younger maternal age, preterm delivery and NICU admission.

Conclusion: Our findings suggest that newborns with OI appear to be at high risk of skeletal disorders, preterm delivery and breech presentation. Younger maternal age and preterm delivery seem to be strong predictors of the need for NICU care. Our data suggest that pregnant women with OI younger than 20 years of age may benefit from added clinical supervision in anticipation of adverse effects on their child.
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http://dx.doi.org/10.3109/14767058.2016.1151870DOI Listing
December 2016

Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.

PLoS One 2016 5;11(2):e0146824. Epub 2016 Feb 5.

Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, West Perth, Western Australia, Australia.

Objectives: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians.

Methods: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions.

Results: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended.

Conclusion: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743907PMC
July 2016

Cross-sectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care.

Pediatr Res 2016 Mar 5;79(3):489-95. Epub 2015 Nov 5.

Bone and Osteogenesis Imperfecta Department, Kennedy Krieger Institute, Baltimore, Maryland.

Background: There is strikingly limited information on linear growth and weight in the different types of osteogenesis imperfecta (OI). Here, we define growth patterns further with the intent of implementing appropriate adaptations proactively.

Methods: We report cross-sectional anthropometric data for 343 subjects with different OI types (144 children, 199 adults). Longitudinal height data for 36 children (18 girls, 18 boys) with OI type I and 10 children (8 girls, 2 boys) with OI type III were obtained.

Results: In all cases, the height Z-scores were negatively impacted, and final height Z-scores were impacted the most. In type I, the growth velocities taper near puberty, and there is a blunted pubertal growth spurt. The growth velocities of children with type III decelerate before age 5 y; poor growth continues without an obvious pubertal growth spurt. Obesity is a concern for all patients with OI, with type III patients being the most affected.

Conclusion: The linear growth patterns, in addition to the marked increase in weight over time, indicate a need for lifestyle modifications early in childhood, especially a need for weight control. Further definition of the anthropometric measures in OI enables patients to begin modifications as early as possible.
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http://dx.doi.org/10.1038/pr.2015.230DOI Listing
March 2016

Osteoblast function and bone histomorphometry in a murine model of Rett syndrome.

Bone 2015 Jul 10;76:23-30. Epub 2015 Mar 10.

Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA. Electronic address:

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder due to mutations affecting the neural transcription factor MeCP2. Approximately 50% of affected females have decreased bone mass. We studied osteoblast function using a murine model of RTT. Female heterozygote (HET) and male Mecp2-null mice were compared to wild type (WT) mice. Micro-CT of tibia from 5 week-old Mecp2-null mice showed significant alterations in trabecular bone including reductions in bone volume fraction (-29%), number (-19%), thickness (-9%) and connectivity density (-32%), and increases in trabecular separation (+28%) compared to WT. We also found significant reductions in cortical bone thickness (-18%) and in polar moment of inertia (-45%). In contrast, cortical and trabecular bone from 8 week-old WT and HET female mice were not significantly different. However, mineral apposition rate, mineralizing surface and bone formation rate/bone surface were each decreased in HET and Mecp2-null mice compared to WT mice. Histomorphometric analysis of femurs showed decreased numbers of osteoblasts but similar numbers of osteoclasts compared to WT, altered osteoblast morphology and decreased tissue synthesis of alkaline phosphatase in Mecp2-null and HET mice. Osteoblasts cultured from Mecp2-null mice, which unlike WT osteoblasts did not express MeCP2, had increased growth rates, but reductions in mRNA expression of type I collagen, Runx2 and Osterix compared to WT osteoblasts. These results indicate that MeCP2 deficiency leads to altered bone growth. Osteoblast dysfunction was more marked in Mecp2-null male than in HET female mice, suggesting that expression of MeCP2 plays a critical role in bone development.
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http://dx.doi.org/10.1016/j.bone.2015.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455889PMC
July 2015

Sandwich allografts for long-bone nonunions in patients with osteogenesis imperfecta: a retrospective study.

J Bone Joint Surg Am 2015 Feb;97(4):318-25

c/o Rachel Box, ELS, Senior Editor and Director, Editorial Services, Department of Orthopaedic Surgery, The Johns Hopkins University, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, #A665, Baltimore, MD 21224-2780. E-mail address:

Background: Patients with osteogenesis imperfecta often develop nonunions, as internal fixation has limited applicability in this condition. We report the outcomes of a modified "sandwich technique" in the treatment of long-bone nonunions in patients with osteogenesis imperfecta; this technique brings circumferential stabilization and normal collagen to the nonunion site.

Methods: From May 2003 through February 2012, twelve patients (eight females, four males; median age, 39.0 years; range, eleven to seventy-eight years) who had osteogenesis imperfecta (Sillence type I [three], type III [eight], and type IV [one]) and a combined total of thirteen nonunions (two humeral, two radial, three femoral, four tibial, and two ulnar; median duration, 15.0 months; range, six to 204 months) were treated at our institution with compressed sandwich allograft cortical struts. The struts were fashioned to be wide enough to allow for increased osteoconductive surface area and to approximate a hemicylindrical shape. Treatment history and demographics data were acquired through retrospective chart review. Follow-up radiographs were analyzed by two attending orthopaedic surgeons to determine radiographic findings. The median follow-up time was 4.6 years (range, 2.1 to 10.3 years).

Results: All thirteen nonunions, including one requiring a second graft procedure, healed with abundant, smooth allograft incorporation, resulting in an initial healing rate of 92% because of a refracture in one patient. This patient's nonunion ultimately healed with additional allograft struts and a new intramedullary rod. One patient required removal of prominent screws. The final follow-up examinations revealed no pain or refracture at the original nonunion site. All patients regained their prefracture level of function.

Conclusions: Sandwich allograft struts constitute a durable, safe method for the stabilization and healing of persistent long-bone nonunions in patients with osteogenesis imperfecta. All patients showed incorporation of the allograft to the native diaphysis.
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http://dx.doi.org/10.2106/JBJS.N.00584DOI Listing
February 2015

Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Nat Genet 2013 Sep 4;45(9):1050-4. Epub 2013 Aug 4.

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.
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http://dx.doi.org/10.1038/ng.2695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876926PMC
September 2013

Increased fracture risk and low bone mineral density in patients with loeys-dietz syndrome.

Am J Med Genet A 2013 Aug 4;161A(8):1910-4. Epub 2013 Jul 4.

Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD 21224-2780, USA.

Loeys-Dietz syndrome is a recently recognized connective tissue disorder with widespread systemic involvement. Little is known about its skeletal phenotype. Our goal was to investigate the risk of fracture and incidence of low bone mineral density in patients with Loeys-Dietz syndrome. We performed a cross-sectional, descriptive, survey-based study with subsequent chart review from July 2011 to April 2012. Fifty-seven patients (26 men, 31 women) with Loeys-Dietz syndrome confirmed by genetic testing completed the survey (average age, 25.3 years; range, 0.9-79.6 years). There were a total of 51 fractures (33 patients): 35 fractures in the upper extremities, 14 in the lower extremities, and two in the spine. Fourteen patients (24.6%) reported two or more fractures. There was a 50% risk of fracture by age 14 years. The incidence of any fracture in this cohort was 3.86 per 100 person-years. Seventeen patients had dual-energy X-ray absorptiometry scans available for review, 11 (64.7%) of whom had at least one fracture. Thirteen included lumbar spine absorptiometry reports; eight (61.5%) indicated low or very low bone mineral density. In the left hip, ten of 14 participants (71.4%) had low or very low bone mineral density. In the left femoral neck, nine of 13 participants (69.2%) had low or very low bone mineral density. The lowest Z- and T-scores were not associated with an increased number of fractures. Patients with Loeys-Dietz syndrome have a high risk of fracture and a high incidence of low bone mineral density.
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http://dx.doi.org/10.1002/ajmg.a.36029DOI Listing
August 2013

Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation.

J Bone Miner Res 2013 Jul;28(7):1523-30

Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institution, Johns Hopkins University, Baltimore, MD, USA.

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5' untranslated region (5'UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.-14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.
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http://dx.doi.org/10.1002/jbmr.1891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688672PMC
July 2013

Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations.

Pediatr Res 2010 Nov;68(5):446-51

Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institution, Johns Hopkins University, Baltimore, Maryland 21205, USA.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. In 49 female RTT children, aged 1.9-17 y, bone mass was assessed and correlated with clinical parameters and mutations involving the MECP2 gene. We also studied five adult females, aged 20-33 y, and one male child, aged 6 y. Lumbar spine bone mineral content (BMC) and bone mineral density (BMD) were correlated with weight, height, BMI, clinical severity, degree of scoliosis, use of anticonvulsants, and ambulatory status. L1-L4 BMD and BMC showed that 48.9% of them had BMD values >2 SD below age-related norms. BMD values were in the osteoporotic range in the five adult females with RTT. Eleven percent of the children and adults with RTT experienced fractures. Low bone mass was correlated with marginal significance to clinical severity and ambulation but not to scoliosis or anticonvulsant use. Lowest bone mass occurred in patients with T158M or R270X mutations but without statistical significance. Studies in a murine model of RTT confirmed low bone mass as an inherent component of this syndrome. MECP2 mutations and clinical parameters impact bone mass in RTT, but an association with a specific mutation was not demonstrable.
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http://dx.doi.org/10.1203/PDR.0b013e3181f2edd2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074246PMC
November 2010

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta.

Calcif Tissue Int 2010 Aug 11;87(2):120-9. Epub 2010 Jun 11.

Osteogenesis Imperfecta Program, Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA.

The effect of bisphosphonate treatment on bone mineral density (BMD) and fracture rates was assessed in adults with osteogenesis imperfecta (OI). This observational nonrandomized study included 90 OI adults treated with intravenous pamidronate (n = 28), oral alendronate (n = 10), or oral residronate (n = 17) or not treated (n = 35). There were 63 type I, 15 type III, and 12 type IV OI patients. BMD results were observed for up to 161 months and an average of 52 months of treatment. For type I and grouped type III/IV patients, treatment with pamidronate showed an increasing rate in L1-L4 BMD from baseline (0.006 [P = 0.03] and 0.016 [P < 0.001] gm/cm(2)/year, respectively); oral bisphosphonate treatment showed a significant increasing rate in L1-L4 BMD (0.004 gm/cm(2)/year [P = 0.047]) for type I patients. Pamidronate-treated type III/IV and oral bisphosphonate-treated type I patients showed significant increases in total-hip BMD (0.006 [P = 0.003] and 0.011 [P = 0.046] gm/cm(2)/year, respectively). Bisphosphonate effect on fracture rate was assessed for 5-year periods before and after treatment in 51 treated and 22 nontreated individuals matched for age at which bisphosphonate was first administered to the treated group. Bisphosphonate treatment did not decrease fracture rate in type I OI patients. Fracture rate decreased in type III/IV patients following pamidronate but not following oral bisphosphonate treatment. These results underscore a need to consider whether bisphosphonate treatment is appropriate for all adults with OI.
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http://dx.doi.org/10.1007/s00223-010-9383-yDOI Listing
August 2010

Osteogenesis imperfecta: questions and answers.

Curr Opin Pediatr 2009 Dec;21(6):709-16

Department Physical Medicine and Rehabilitation, Johns Hopkins University, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA.

Purpose Of Review: Considerable attention has recently been focused on the pathogenesis, diagnosis and treatment of osteogenesis imperfecta. Two new genes have been defined in patients with recessive severe or lethal osteogenesis imperfecta types. Diagnostic concerns involve testing procedures, either skin biopsies or DNA analysis. Bisphosphonates have been accepted as 'standard of care' for children with osteogenesis imperfecta. However, questions remain as to the selection of patients for treatment, effectiveness in fracture prevention, which bisphosphonates should be used and the duration of treatment. Orthopedic intervention occurs on several levels: including the immediate treatment of fractures, the treatment of scoliosis and the use of intramedullary rods.

Recent Findings: The discovery of mutations involving CRTAP and LEPRE1 genes in severe/lethal and recessively inherited osteogenesis imperfecta has provided partial answers to questions about 'other' osteogenesis imperfecta genes in patients with an osteogenesis imperfecta phenotype but no COL1A1 and COL1A2 mutations. Current experience suggests that DNA analysis is a better test for diagnosis as compared with dermal biopsy. There are no standardized guidelines for initiating bisphosphonate treatment in children. Recent data suggest either intravenous or oral bisphosphonates are effective, but differences exist between different bisphosphonates. Two recent reports document the paucity of evidence-based data regarding the effectiveness of bisphosphonate treatment in fracture prevention.

Summary: This report will update the medical and orthopedic approaches to care for children with osteogenesis imperfecta.
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http://dx.doi.org/10.1097/MOP.0b013e328332c68fDOI Listing
December 2009

Osteogenesis imperfecta:epidemiology and pathophysiology.

Curr Osteoporos Rep 2007 Sep;5(3):91-7

The Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA.

Osteogenesis imperfecta (OI) is the most common of the inherited connective tissue disorders that primarily affect bone. However, it is a systemic disorder, as evidenced by the occurrence of ocular complications, dentinogenesis imperfecta, hearing loss, joint laxity, restrictive pulmonary disease, and short stature. The OI classification initially included four phenotypes (I-IV) involving COL1A1 and COL1A2 mutations. Three new phenotypes have been added, of which one, type VII, is the result of mutations of the cartilage-associated protein (CRTAP) gene. Investigation of recessive forms of OI particularly reported among South African blacks have revealed mutations involving both the CRTAP gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, each involved in collagen proline-3 hydroxylation. Issues related to the treatment of OI with bisphosphonates involve patient selection, evaluation of the results of treatment, and the duration of treatment. Also, questions exist regarding the difference in treatment response between children and adults with OI. Other treatment options, such as recombinant human parathyroid hormone (1-34), Rank ligand inhibitors, and stem cell technology, are being evaluated or are of future investigative interest.
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http://dx.doi.org/10.1007/s11914-007-0023-zDOI Listing
September 2007

Genetic and environmental influences on bone mineral density in pre- and post-menopausal women.

Osteoporos Int 2005 Dec 5;16(12):1849-56. Epub 2005 Jul 5.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Genetic factors influencing acquisition of peak bone mass account for a substantial proportion of the variation in bone mineral density (BMD), although the extent to which genes also contribute to variation in bone loss is debatable. Few prospective studies of related individuals have been carried out to address this issue. To gain insights into the nature of the genetic factors contributing to variation in BMD, we studied 570 women from large Amish families. We evaluated and compared the genetic contributions to BMD in pre- and post-menopausal women, with the rationale that genetic variation in pre-menopausal women is due primarily to genetic determinants of peak bone mass, while genetic variation in post-menopausal women is due to the combined genetic effects of peak bone mass and bone loss. Bone mineral density was measured at one point in time at the hip and spine by dual energy X-ray absorptiometry (DXA). We used variance decomposition procedures to partition variation in BMD into genetic and environmental effects common to both groups and to pre- and post-menopausal women separately. Total variation in BMD was higher in post- compared to pre-menopausal women. Genes accounted for 58-88% of the total variation in BMD in pre-menopausal women compared to 37-54% of the total variation in post-menopausal women. In absolute terms, however, the genetic variance was approximately similar between the two groups because the environmental variance was 3 1/2- to 4-fold larger in the post-menopausal group. The genetic correlation in total hip BMD was 0.81 between pre- and post-menopausal women and differed significantly from one, consistent with the presence of at least some non-overlapping genetic effects in the two groups for BMD at this site. Overall, these analyses suggest that many, but not all, of the genetic factors influencing variation in BMD are common to both pre- and post-menopausal women.
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http://dx.doi.org/10.1007/s00198-005-1948-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049290PMC
December 2005

Reduced incidence of hip fracture in the Old Order Amish.

J Bone Miner Res 2004 Feb 16;19(2):308-13. Epub 2003 Dec 16.

Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Unlabelled: The incidence of hip fracture was estimated in a community of Old Order Amish and compared with available data from non-Amish whites. Hip fracture rates were 40% lower in the Amish, and the Amish also experienced higher BMD.

Introduction: Understanding the patterns of fracture risk across populations could reveal insights about bone health and lead to the earlier detection and prevention of osteoporosis. Toward this aim, we compared hip fracture incidence and bone mineral density (BMD) between an Old Order Amish (OOA) community, characterized by a rural and relatively active lifestyle, and non-Amish U.S. whites.

Materials And Methods: All hospital admissions for hip fracture among OOA individuals in Lancaster County, PA, were identified between 1995 and 1998 from four area hospitals. Hip fracture incidence was calculated by cross-referencing an available Anabaptist genealogy database with communities located within these hospital service areas and compared with non-Amish whites obtained from National Hospital Discharge data. Additionally, BMD at the hip was compared between 287 Amish subjects and non-Amish whites from the National Health and Nutrition Examination Survey III survey.

Results And Conclusions: OOA experienced 42% fewer hip fractures than would be expected had they experienced the same rate of hip fracture as observed in non-Amish whites (p < 0.01) and a higher mean BMD that was significant in women (p < 0.05) but not men. Further evaluation of lifestyle and/or genetic differences between Amish and non-Amish populations may shed insights into etiologic factors influencing hip fracture risk.
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http://dx.doi.org/10.1359/JBMR.0301223DOI Listing
February 2004

Bisphosphonates in children with bone diseases.

N Engl J Med 2003 Nov;349(21):2068-71; author reply 2068-71

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November 2003

Age-related changes in human bone proteoglycan structure. Impact of osteogenesis imperfecta.

J Biol Chem 2002 Nov 6;277(46):43638-47. Epub 2002 Sep 6.

Dental Research Center, School of Dentistry, University of North Carolina, Chapel Hill, 27599-7455, USA.

Proteoglycans (PGs) are a family of molecules that undergo extensive post-translational modifications that include addition of glycosaminoglycan (GAG) chains as well as N- and O-linked oligosaccharides to the protein core. PG composition and structure have been reported to alter with age. To test whether the post-translational modifications to PGs can serve as in vitro surrogate end point markers for chronological age, the extent of GAG modifications was determined for PGs derived from normal human bone cells of 14 donors (age range, fetal to 60 years). Isolated cells were steady state radiolabeled with (35)SO(4)(2-) and [(3)H]GlcN. For biglycan and decorin, iduronate content was linearly correlated with age (increased 1.5x between fetal and age 60 years). For the syndecan-like heparan sulfate PG, the N-sulfation of post-natal cells increased over 3.5-fold until reaching a plateau during the 4th decade of life. The amount of O-linked oligosaccharides was also found to decrease as a function of increasing normal donor age, whereas the specific activity of the metabolic precursor pool remained constant regardless of donor age. These age-related changes in post-translational modifications were then used to demonstrate that osteoblasts derived from patients with osteogenesis imperfecta did not exhibit facets of a pre-mature aging, but rather were arrested in a fetal-like phenotypic state. A growth matrix rich in thrombospondin altered PG metabolism in osteoblastic cells, resulting in the production and secretion of the fetal-like (rich in O-linked oligosaccharides) forms of decorin and biglycan. This effect was qualitatively different from the effect of transforming growth factor-beta, which predominantly altered GAGs rather than O-linked oligosaccharides. No other Arg-Gly-Asp protein (fibronectin, vitronectin, type I collagen, osteopontin, and bone sialoprotein) showed any detectable effect on PG metabolism in bone cells. These results indicate that a proper matrix stoichiometry is critical for metabolism of PGs.
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http://dx.doi.org/10.1074/jbc.M202124200DOI Listing
November 2002