Startseite Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children
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Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children

  • Stefanie Stasek ORCID logo , Frank Zaucke , Heike Hoyer-Kuhn , Julia Etich , Susanna Reincke ORCID logo , Isabell Arndt , Mirko Rehberg ORCID logo und Oliver Semler EMAIL logo
Veröffentlicht/Copyright: 16. Dezember 2024
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Journal of Pediatric Endocrinology and Metabolism
Aus der Zeitschrift Journal of Pediatric Endocrinology and Metabolism Band 38 Heft 1

Abstract

The formation of functional bone requires a delicate interplay between osteogenesis and osteolysis. Disturbances in this subtle balance result in an increased risk for fractures. Besides its mechanical function, bone tissue represents a key player in the regulation of calcium homeostasis. Impaired bone formation results in bone fragility, which is especially pronounced in osteogenesis imperfecta (OI). This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. The current classification of OI includes 23 distinct types. In recent years, several new mutations in different genes have been identified, although the exact pathomechanisms leading to the clinical presentation of OI often remain unclear. While bisphosphonates are still the standard of care, novel therapeutic approaches are emerging. Especially, targeted antibody therapies, originally developed for osteoporosis, are increasingly being investigated in children with OI and represent a promising approach to alleviate the consequences of impaired osteogenesis and improve quality of life in OI patients. This review aims to provide insight into the pathophysiology of OI and the consequences of distinct disease-causing mutations affecting the regulation of bone homeostasis. In this context, we describe the four most recently identified OI-causing genes and provide an update on current approaches for diagnosis and treatment.

Keywords: antisclerostin antibodies; bisphosphonates; COL1A1 mutations; denosumab

Introduction

Although typically regarded as a rare condition, the prevalence of osteogenesis imperfecta (OI) is estimated to be 1:10.000, making it one of the most common skeletal diseases in children [1]. The clinical picture was already documented in 1788 by the Swedish physician Olaus Jakob Ekman [2]. However, significant advances in understanding the pathophysiology of OI were first made in the 1980s, when mutations in COL1A1 and COL1A2, coding for the distinct chains of the triple helical collagen type I, were identified as the primary disease-causing genes [3]. Quantitative and structural defects of collagen type I, the critical component of the bone matrix, result in increased bone fragility and a predisposition to fractures after minor trauma. Initially thought to be a monogenic disorder, it is now known that OI involves a broad spectrum of genes, most of them involved in the synthesis of collagen I. The original classification of OI, introduced by David Sillence in 1979, categorized the disease into four types based on clinical severity: Type I (mild), Type II (perinatal lethal), Type III (severe with significant skeletal deformities), and Type IV (moderate severity) [4]. An alternative, genetic classification was implemented in the last years that defined each OI type based on the affected gene. This classification includes to date 23 different types, which reflects the complexity of this continuously growing field [5]. This review will give a brief overview of the underlying pathophysiology including the four most recently identified OI-causing genes. The focus, however, will be on the clinical aspects of OI, including the clinical presentation, diagnostic approaches, and management strategies.

Pathophysiology of OI

The human skeleton is a dynamic organ, constantly undergoing remodeling through the coordinated actions of bone formation and resorption. This remodeling process allows bones to repair microdamage, respond to changes in mechanical load, and ensure that old or damaged bone is replaced by new, stronger bone tissue [6]. Additionally, dynamic remodeling is essential for maintaining stable extracellular calcium levels needed for various physiological functions such as muscle contraction, enzymatic activity, and neuronal signaling.

Bone metabolism is regulated by three cell types: osteoblasts, osteoclasts, and osteocytes. Osteoblasts, derived from mesenchymal stem cells, are responsible for synthesizing new bone matrix and facilitating mineralization. Once osteoblasts become embedded in the matrix, they differentiate into osteocytes, which act as mechanosensors and regulate bone remodeling. Osteoclasts, on the other hand, are derived from hematopoietic stem cells and resorb bone [7].

The bone forming activity of osteoblasts and bone resorption by osteoclasts is tightly regulated. Mechanical loading, hormones (e.g., growth hormone, PTH, and estrogen), nutritional factors, along with local cytokines and growth factors, regulate this complex balance. Muscle activity plays a critical role in bone remodeling by generating mechanical forces that stimulate bone formation. Osteocytes detect mechanical strain through their dendritic processes within the bone matrix and transduce these signals into biochemical responses [8].

The signaling pathways regulating bone metabolism are highly complex, and a comprehensive discussion is beyond the scope of this review. However, some are essential to understand, as they have already been targeted by pharmacological therapies currently under investigation for the use in OI. These pathways include the Wnt/β-catenin, RANK/RANKL/OPG, and TGF-β pathway.

The Wnt/β-catenin signaling pathway is crucial for promoting osteoblast differentiation and activity. Wnt ligands bind to the transmembrane receptor “Frizzled” and its coreceptor, the low-density lipoprotein receptor–related protein −5 or −6 (LRP5/6) receptors on osteoblasts, leading to β-catenin stabilization and translocation to the nucleus, stimulating the transcription of genes involved in bone formation [9]. Sclerostin, a protein produced by osteocytes, binds to the LRP5/6 receptor and disrupts its interaction with Wnt proteins, thereby acting as a negative regulator of osteoblast activity and bone formation [10]. The RANK/RANKL/OPG pathway plays a key role in osteoclast regulation. RANKL (Receptor Activator of Nuclear Factor κB Ligand), produced by osteoblasts and osteocytes, binds to its receptor RANK on osteoclast precursors, promoting their maturation and activation [11], 12]. Osteoprotegerin (OPG), a secreted decoy receptor for RANKL, is produced by osteoblasts and can inhibit this interaction. TGF-β has a context-dependent effect on bone formation and absorption and interacts with the RANKL pathway. Upon binding to its receptors on osteoblast precursors, TGF-β triggers SMAD proteins, which translocate to the nucleus to upregulate expression of collagen and other components of the extracellular matrix. However, in certain conditions where increased bone resorption is required, TGF-β can enhance the expression of RANK on the surface of osteoclasts and bone marrow stromal cells, thereby promoting osteoclast differentiation and activity [13], 14].

A disruption of this complexly balanced system of bone formation and resorption can cause various bone disorders characterized by impaired bone stability. In osteoporosis, a condition which is commonly seen in elderly woman, a decline in estrogen levels after menopause causes an increased osteoclast activity and loss of bone mass [15]. Conversely, disturbances of the structural composition of bone can also impair its stability. OI is a genetic disorder, primarily caused by quantitative or qualitative defects of collagen I, the main structural protein of most connective tissue in the human body, making OI a multisystemic disease.

OI as a collagen I–related disorder

Collagen I is the primary organic component of bone matrix. It provides a scaffold for mineral deposition and imparts tensile strength to the bone. Collagen I is primarily synthesized by osteoblasts and fibroblasts and undergoes extensive post-translational modifications within the endoplasmic reticulum (ER). Assembled into a stable triple-helical structure, the procollagen chains are secreted into the extracellular matrix. Intra- and intermolecular crosslinks provide mechanical strength of collagen fibers [16].

Mutations in COL1A1 and COL1A2 can lead to OI with a broad phenotypic variety, ranging from mild to perinatal lethal, depending on the specific type of mutation. Mutations such as stop mutations or frameshift mutations can introduce a premature stop codon into the mRNA. In many cases, this leads to nonsense-mediated decay, and no collagen is produced from the mutated allele, resulting in a quantitative collagen deficiency. However, in heterozygous patients, the presence of one normal allele allows for partial compensation, typically leading to a milder phenotype [4].

In contrast, missense mutations that affect glycine residues essential for the proper folding of the triple-helix cause a more severe phenotype. Misfolded collagen is incorporated into the extracellular matrix, where it forms defective collagen fibrils that stimulate bone resorption by osteoclasts. Furthermore, intracellular accumulation of structurally abnormal collagen causes cellular stress, chronic low-grade inflammation, and osteoblast apoptosis [17].

While mutations in COL1A1 and COL1A2 are the most common causes of OI, there are several other genes involved in various processes related to collagen production, post-translational modification, bone formation, and mineralization that can lead to different forms and severities of OI when mutated. In addition to genes causing classical OI, some mutations result in phenotypes that exhibit bone fragility similar to OI, but these conditions may historically be categorized under other syndromes with overlapping features. These are often referred to as “OI-like phenotypes.” A detailed overview of all genes associated with OI and OI-like phenotypes is provided in Table 1.

Table 1:

Summary of genes and phenotypic characteristics of OI and OI-like phenotypes.

Category Affected pathway Affected gene (mode of inheritance) Protein Characteristics and phenotype Genetic OI type OMIM
Collagen synthesis and modifications Collagen synthesis COL1A1

COL1A2 (AD)		 Pro-alpha 1(I)/pro-alpha 2 (I) chain of type I collagen

  1. Up to 90 % of all OI cases

  2. Mild to moderately deforming to severe

  3. Perinatal lethal forms (type II) [4]

  4. Stop-mutations usually milder phenotype [5]

 I 166200
II 166210
III 259420
IV 166220
mRNA stabilization TENT5A (AR) Terminal nucleotidyl-transferase 5A (TENT5A)

alternative: family with sequence similarity 46, member A (FAM46A)

  1. Severe OI

  2. Decreased body length, skull deformities, reduced cortical thickness [18]

 XVIII 617952
Hydroxylation of proline and lysine residues P4HB (AR) Protein disulfide isomerase (PDI)

alternative: prolyl 4-hydroxylase subunit beta (P4HB)

  1. Cole–Carpenter syndromeb [19]

 Not classified 112240
CRTAP (AR) Cartilage-associated protein (CRTAP)

  1. Cole–Carpenter syndromeb [20]

  2. Severe to lethal OI[21]

VII 610682
P3H1

Alternative: LEPRE1 (AR)		 Prolyl-3-hydroxylase 1 (P3H1)

  1. Severe to lethal OI [22], 23]

 VIII 610915
PPIB (AR) Peptidyl-prolyl-cis-trans-isomerase B (PPIB)

alternative: cyclophilin B

  1. Moderate to severe OI [24], 25]

  2. Lethal [26]

 IX 259440
Chaperone-assisted formation of procollagen triple helix and quality control SERPINH1 (AR) Serpin peptidase inhibitor, clade H, member 1

alternative: heat shock protein 47 (HSP47)

  1. Moderate to severe OI

  2. Blue sclerae

  3. Dentinogenesis imperfecta [27], 28]

 X 613848
FKBP10 (AR) Peptidyl-prolyl cis-trans isomerase FKBP10 (PPIase FKBP10)

alternative: 65 kDa FK506-binding protein (FKBP65)

  1. Bruck syndromee type 1 [29], [30], [31]

 XI 610968
KDELR2 (AR) (Lys-Asp-Glu-Leu) endoplasmic reticulum protein receptors 2 (KDELR2)

  1. Severe OI with perinatal fractures [32], 33]

 XXI 619131
ER homeostasis CREB3L1 (AR) Cyclic AMP-responsive element-binding protein 3-like protein 1 (CR3L1)

  1. Moderate to severe OI

  2. Prenatal fractures and shortening of long bones

  3. Milder phenotype in heterozygous forms [34]

XVI 616229
MBTPS2 (XLR) Membrane-bound transcription factor site-2 protease

alternative: endopeptidase S2P

  1. Moderate to severe OI [35]

  2. IFAP syndrome with or without BRESEK or BRESHECKa

  3. Olmsted syndromed

XIX 301014
TMEM38B (AR) Transmembrane protein 38B (TMEM38B)

alternative: trimeric intracellular cation channel type B (TRIC-B)

  1. Mild to severe OI

  2. Hypotonia

  3. Cardiac abnormalities [36]

 XIV 615066
Vesicular transport to Golgi apparatus and extracellular space SEC24D (AR) Selected protein acidic and rich in cysteine (SPARC)

  1. Cole–Carpenter syndromeb [37]

 Not classified 616294
Extracellular proteolytic processing and conversion into mature collagen BMP1 (AR) Bone morphogenic protein 1 (BMP1)

  1. Moderate to severe OI

  2. Macrocephaly

  3. High BMD, reduced trabecular numbers, and increased bone porosity [38], 39]

 XIII 614856
Collagen crosslinking PLOD2 (AR) Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)

alternative: lysyl hydroxylase 2 (LH2)

  1. Bruck syndrome type 2e [40], 41]

 Not classified 609220
Bone homeostasis ECM mineralization SPARC c Selected protein acidic and rich in cysteine (SPARC)

  1. Moderate to severe OI

  2. Delayed motor development

  3. Brain MRI abnormalities [42]

 XVII 616507
Transduction of mechanical stimuli on osteocytes PLS3 (XLD) Plastin-3 (PLS3)

  1. Low bone turnover OI

  2. Osteoarthritis

  3. X-linked osteoporosis in adults [43]

 Not classified 300910
Regulation of osteoblast differentiation or function and collagen synthesis WNT1 (AR) Proto-oncogene Wnt1 (wingless-type MMTV integration site family, member 1, WNT1)

  1. Severe OI

  2. Developmental disorders and cognitive impairment [44], [45], [46]

 XV 615220
MESD (AR) Mesoderm development LRP chaperone (MESD)

  1. Progressively deforming to lethal OI [47]

  2. Oligodontia

  3. Intellectual disability [48], 49]

 XX 618644
TAPT1 (AR) Transmembrane anterior posterior transformation 1 (TAPT1)

  1. Severe, progressively deforming OI [50]

  2. Lethal osteochondrodysplasia with ciliopathy [51]

 Not classified 616897
SP7 (AR, AD) Transcription factor Sp7

alternative: zinc finger protein osterix

  1. Moderate to severe OI [52]

  2. Sclerotic skeletal dysplasia with low bone turnover [53]

  3. Hearing impairment [54]

 XII 613849
Regulation of osteoclast differentiation or function SERPINF1 (AR) Pigment epithelium-derived factor (PEDF)

  1. Progressively deforming OI

  2. Increased osteoclastic activity with poor response to bisphosphonates [55], 56]

 VI 613982
IFITM5 (AR) Interferon-induced transmembrane protein 5 (IFITM5)

alternative: bone-restricted interferon-induced transmembrane protein-like protein (BRIL)

  1. Moderate to severe OI

  2. Hyperplastic callus formation

  3. Ossification of interosseous membrane of forearms and lower legs

  4. Radial head dislocation [57]

 V 610967
CCDC134 (AR) Secreted coiled-coil domain containing protein 134

  1. Severe OI

  2. Potential overlap with other skeletal dysplasias with dysregulated MAPK/ERK signaling (Noonan syndrome, neurofibromatosis type 1, cardiofaciocutaneous syndrome [58], 59]

  3. Poor response to bisphosphonate therapy [60]

 XXII 619795
Unknown Unknown PHLDB1 (AR) Pleckstrin homology-like domain, family B member 1

  1. Moderate to severe OI

  2. Platyspondyly

  3. Widened metaphyses

  4. Insulin resistance [61]

 XXIII 620639

  1. AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; XLD, X-linked dominant; BMD, bone mineral density. a IFAP: ichthyosis follicularis, alopecia, photophobia. BRESEK: bronchiectasis, restrictive pulmonary disease, encephalopathy, skeletal contractures, and ichthyosis. BRESHECK: brain anomalies, ectodermal dysplasia, skeletal malformations, and cryptorchidism. bCole–Carpenter syndrome is an OI-like syndrome with bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features (frontal bossing, midface hypoplasia, micrognathia) [20]. Type I and II exist, differentiation based on genetic findings. cSPARC has a function as a chaperone for collagen folding and is also involved in ECM mineralization. dOlmsted syndrome is a rare keratinization disorder characterized by palmoplantar keratoderma and perioral keratotic plaques [62], 63]. eBruck syndrome is characterized by bone fragility, osteoporosis, and congenital joint contractures. Two types exist classified based on genetic finding.

Novel genetic insights from inherited bone fragility syndromes

Over the last years, genetic analyses of patients with the clinical phenotype of OI led to the discovery of novel genes. The list of OI types has been updated accordingly and currently ends with type XXIII [5]. However, not all newly identified genes have been officially classified as distinct OI types. In the following section, the four latest described genes and the function of the encoded proteins are briefly summarized.

KDELR2 (OI type XXI)

In 2020, three different mutations in KDELR2 (KDEL receptor 2) were first identified in six affected individuals from four families [32]. Later, another two missense variants were reported. All affected individuals had been diagnosed with progressively deforming OI or OI type II; in the latter cases, additional neurodevelopmental features were reported [33]. KDELR2 encodes for a seven transmembrane domain receptor that localizes mainly to the ER, the intermediate ER–Golgi compartment, and the cis-Golgi complex indicating a crucial function in the secretion of proteins. KDELR2 binds proteins harboring a KDEL-like motif and regulates their trafficking between compartments. Interestingly, the collagen chaperone heat shock protein 47 (Hsp47) is one of the substrates and KDELR2 mutations lead to a reduction of intracellular levels and an increased secretion of Hsp 47. Finally, this results in impaired extracellular collagen fibril formation [32].

CCDC134 (OI type XXII)

Whole exome sequencing of three Moroccan patients from two families with severe OI identified a homozygous missense mutation in the first codon of CCDC134 [58]. Later, a male infant [60] and a Brazilian boy with severe OI harboring exactly the same mutation were described [59]. The gene encodes for the secreted coiled-coil domain containing protein 134 that is involved in the transcriptional regulation and signal transduction of MAP kinases. The mutation causes a loss of protein function and the pathomechanisms might involve a dysregulated MAPK/ERK signaling in osteoprogenitors. However, the exact mechanism as well as the overlap with other bone dysplasias with dysregulated MAPK/ERK signaling is not yet fully understood.

PHLDB1 (OI type XXIII)

In 2023, a new mild OI phenotype with regressive spondylometaphyseal alterations was reported in five infants from two unrelated families. In both families, the parents of the affected individuals were first cousins [61]. Two biallelic frameshift variants were identified in the candidate gene PHLDB1 that encodes the protein Pleckstrin homology-like domain, family B, member 1. The frameshift mutations lead to the loss of the C-terminal PH domain. The function of PHLDB1 is largely unknown. It interacts with and is a modulator of the Akt protein kinase [64], and it was suggested that this interaction might affect collagen biosynthesis or osteogenic differentiation [61].

TAPT1

Mutations in the gene TAPT1 were first reported to result in a complex and early osteochondrodysplasia with features of lethal OI in two consanguineous families from Morocco and Syria [51]. In 2023, two groups independently described novel homozygous mutations in TAPT1 in seven patients from consanguineous families that survived and were clinically diagnosed with OI [65], 66]. The function of the encoded protein TAPT1 (transmembrane anterior posterior transformation 1 protein) is not yet completely understood, but mutations led to a disrupted ciliogenesis and an altered morphology of the Golgi apparatus that might affect collagen secretion [51]. Molecular analysis also revealed an impaired collagen fibril formation that might explain brittle bones [66]. Currently TAPT1 is not yet classified as an OI-causing gene.

Clinical presentation

Osteogenesis imperfecta presents with a wide spectrum of clinical manifestations, ranging from mild to severe, depending on the specific type of OI and the underlying genetic mutations. While some infants present with multiple fractures already at birth, others remain asymptomatic until fractures occur later in childhood, often after they start walking. While early medical and physiotherapeutic interventions can help those with mild to moderate forms to maintain mobility, more severely affected individuals are typically wheelchair dependent throughout life.

Fractures occur typically in the long bones of the upper and lower extremities as well as in vertebrae and can lead to severe skeletal deformities, such as bowed limbs and scoliosis (Figure 1). Thorax deformities can restrict lung expansion and impair respiratory function [67]. In severe cases, scoliosis may cause neurological complications due to compression of the spinal cord [68], 69]. Basilar invagination is a condition more commonly observed in severe forms of OI, where recurrent microfractures cause the skull base to flatten, leading to spine migration into the skull [70]. This can compress the brainstem and cerebellum, causing hydrocephalus due to disrupted cerebrospinal fluid circulation and cranial nerve damage. Early screening for new neurological symptoms is crucial. Growth is often affected due to disruptions in the growth plates, reflecting the disease’s profound impact on bone development [71]. Repeated immobilization following fractures contributes to muscle atrophy and secondary bone loss, further aggravating bone fragility. Chronic pain is often underrecognized by parents and caregivers and consequently insufficiently managed [72]. This significantly impacts quality of life in children and adolescents with OI, as highlighted by the recently published IMPACT survey, which documented experiences of individuals with OI and their caregivers [73], 74].

Figure 1: Skeletal manifestations of OI. Series of X-rays from a young girl with severe OI type VIII. (A) X-ray of the lower body 3 days after birth showing multiple healed fractures, generalized osteopenia, bowing and shortening of the long bones. (B) Chest X-ray 3 days after birth. Notice the thin rips with irregularly shaped, thickened areas (arrow head) consistent with healed fractures. (C) Lateral X-ray of the spine in the age of 1.5 years reveals flattened, irregularly shaped vertebral bodies (arrow head), indicative of compression fractures, along with pronounced kyphosis. (D) X-ray of the lower extremity in the age of 5 years after surgical insertion of telescopic nails in the tibia and femur. Notice the generalized osteopenia, thin cortical bones, multiple fractures in the tibia and femur, and bowing of the thin fibula. The distal metaphyses of the femur appear wide and irregular.
Figure 1:

Skeletal manifestations of OI. Series of X-rays from a young girl with severe OI type VIII. (A) X-ray of the lower body 3 days after birth showing multiple healed fractures, generalized osteopenia, bowing and shortening of the long bones. (B) Chest X-ray 3 days after birth. Notice the thin rips with irregularly shaped, thickened areas (arrow head) consistent with healed fractures. (C) Lateral X-ray of the spine in the age of 1.5 years reveals flattened, irregularly shaped vertebral bodies (arrow head), indicative of compression fractures, along with pronounced kyphosis. (D) X-ray of the lower extremity in the age of 5 years after surgical insertion of telescopic nails in the tibia and femur. Notice the generalized osteopenia, thin cortical bones, multiple fractures in the tibia and femur, and bowing of the thin fibula. The distal metaphyses of the femur appear wide and irregular.

Extraskeletal manifestations

Due to the widespread role of collagen I in various tissues, OI also presents with different extraskeletal manifestations (Figure 2). Characteristic facial features like a triangular face shape, blue sclerae, and brittle and discolored teeth (dentinogenesis imperfecta) can provide diagnostic indicators [75], 76]. Neurodevelopmental delay indicate the possibility of OI type XV, a form associated with cognitive impairment caused by mutations in WNT1 [77].

Figure 2: Clinical manifestations of OI. (A) The phenotype of OI ranges from patients with mild forms who maintain full mobility, to those who rely on walking aids or are wheelchair dependent. Short stature is commonly present. (B) Skeletal manifestations of OI include fractures and deformities of the long bones, scoliosis, vertebral fractures, and craniofacial features like wormian bones, and a characteristic triangular face shape. (C) Extraskeletal manifestations occur due to the widespread presence of collagen I in various organ systems. Structural abnormalities in heart valves, blood vessels, and the lung parenchyma can restrict cardiopulmonary function and cause potentially lethal complications. Blue sclera and dentinogenesis imperfecta are characteristic facial features. Early-onset hearing loss and ligamentous laxity can also occur.
Figure 2:

Clinical manifestations of OI. (A) The phenotype of OI ranges from patients with mild forms who maintain full mobility, to those who rely on walking aids or are wheelchair dependent. Short stature is commonly present. (B) Skeletal manifestations of OI include fractures and deformities of the long bones, scoliosis, vertebral fractures, and craniofacial features like wormian bones, and a characteristic triangular face shape. (C) Extraskeletal manifestations occur due to the widespread presence of collagen I in various organ systems. Structural abnormalities in heart valves, blood vessels, and the lung parenchyma can restrict cardiopulmonary function and cause potentially lethal complications. Blue sclera and dentinogenesis imperfecta are characteristic facial features. Early-onset hearing loss and ligamentous laxity can also occur.

Other manifestations usually appear in adulthood and are, therefore, in most cases not relevant for the diagnosis but need to be considered by the medical team and care takers as they have significant impact on the patient’s quality of life. Fragility and deformation of the ossicles in the middle ear, as well as the abnormal remodeling of the otic capsule in the inner ear, can cause early hearing loss [78]. Abnormalities in collagen fibers can affect the structural integrity of heart valves and blood vessels, potentially leading to cardiovascular complications such as valve insufficiency and increased susceptibility to aortic dilation or rupture [79]. Thoracic deformities and intrinsic defects in the lung parenchyma restrict lung expansion and function [67]. In OI type II, the most severe type, prenatal rib fractures and underdeveloped lungs lead to respiratory failure and usually cause death in the perinatal period [80].

Diagnosis

To confirm the diagnosis of OI, a combination of clinical evaluation, imaging, and genetic testing is typically required. Importantly, not all patients exhibit the full spectrum of symptoms and individuals with milder forms may be misdiagnosed with conditions like juvenile osteoporosis or remain undiagnosed until adulthood. However, certain clinical signs should raise suspicion of OI. Children typically present with recurrent fractures without a clear cause or with an injury disproportionate to the reported trauma, a constellation of symptoms that often alerts clinicians and raises suspicion of child abuse.

Like other monogenetic diseases, a detailed family history might pave the way to the correct diagnosis. Recurrent fractures in one parent can guide the physician in the direction of OI, although not all patients have a positive family history, as spontaneous mutations are common [81].

Radiographic imaging is often the first diagnostic tool, revealing generalized osteopenia, multiple fractures at different stages of healing and bone deformities. Wormian bones are extra bone pieces that occur particularly along the lambdoid suture. So-called popcorn calcifications are disorganized hyperdense lines around the metaphyseal growth plates of long bones [82], 83]. The measurement of bone density via dual-energy X-ray absorptiometry (DXA) scans plays a supporting role in the diagnosis of OI. It does not help to differentiate OI from other bone diseases like osteoporosis, but it remains an important tool for monitoring effectiveness of antiresorptive treatments.

Laboratory diagnostics including measurements of calcium, phosphate, alkaline phosphatase (AP), vitamin D, and parathyroid hormone levels are recommended to exclude metabolic bone disorders associated with increased bone fragility, such as nutritional rickets or X-linked hypophosphatemia [81].

Genetic testing is currently gaining more and more relevance and the number of identified genes contributing to the OI phenotype is continuously growing. Genetic and phenotypical overlap with other connective tissue disorders, such as Ehlers–Danlos syndrome and Bruck syndrome, make the classification of patients into distinct diagnostic categories increasingly challenging [84]. For diagnosing OI, genetic testing is not mandatory. However, the deeper understanding of the genetic background and pathophysiology of OI resulted in a paradigm shift in the approach to manage this condition, as patients are no longer treated as one homogenous group. Instead, with the increasing knowledge of the disease’s pathophysiology, more targeted therapeutic strategies are currently investigated.

Management and therapy

The management of OI is primarily focused on symptomatic and supportive care, as there is currently no curative treatment available. A multidisciplinary approach (Figure 3) involving pediatricians, orthopedic surgeons, physiotherapists, and many other disciplines is essential to account for the complex needs of OI patients [81], 85]. Patients with OI and their caregivers, including health care professionals, often develop a fear of injuries and fractures [86]. Parents and hospital staff should, therefore, be trained how to handle OI patients safely from birth on. Overprotection due to fear of fractures impairs the social and motor development of the child. Therefore, education of the caregivers is a key component of the multidisciplinary treatment approach [87]. Psychological support and patient support groups can help patients and their families coping with fears and challenges of living with a chronic condition.

Figure 3: The three pillars of OI therapy. The multidisciplinary approach for OI patients includes physiotherapy, orthopedic management of acute fractures, and surgical correction of deformities and pharmacological therapy. Psychological support should always be provided to help the family managing a chronic, life-long condition.
Figure 3:

The three pillars of OI therapy. The multidisciplinary approach for OI patients includes physiotherapy, orthopedic management of acute fractures, and surgical correction of deformities and pharmacological therapy. Psychological support should always be provided to help the family managing a chronic, life-long condition.

Orthopedic management involves acute fracture treatment and the correction of chronic bone deformities. Fractures are usually treated by immobilization (casts, splints, bandages) while severe deformities and dislocated fractures require surgical interventions. Telescopic intramedullary rods, which prolong as the child grows, offer long-term stability and help maintain bone alignment [88]. Spinal surgery is indicated for progressive spinal deformities to correct misalignments, improve respiratory function, relieve pain through neural decompression, and enhance spinal stability [68], 69]. Concerns about potential side effects and lack of standardized pain assessment in young children often lead to insufficient pain management in chronically ill children [74], 89]. However, adequate pain management is essential to prevent immobilization due to fear of new fractures; therefore, its effectiveness should be evaluated regularly.

Physiotherapy plays a key role in enhancing mobility, motor function, and independence in daily activities [87]. Rehabilitation should aim to reduce the risk of fractures and deformities, while allowing the child to safely engage in activities that promote development. Especially after fractures, it is important to prevent contractures and joint misalignment and reduce secondary osteopenia from immobilization. Exercises focusing on improving muscle strength, coordination, and endurance are essential. Weight-bearing activities, isometric exercises, and functional training can significantly improve walking ability and bone mineral density (BMD) in OI patients [90]. Specific physiotherapy modalities exist for OI patients that provide a low-impact environment and minimize the risk of injury, such as whole-body vibration training and aquatic physiotherapy [87], 91].

Pharmacological treatment approaches

The pharmacological management of OI focuses on two primary therapeutic strategies: antiresorptive and osteoanabolic therapies. Both approaches have been adapted from treatments commonly used in adults with osteoporosis, although their application in OI and in children remains largely under investigation. An overview of the current medical treatment approaches is provided in Figure 4.

Figure 4: Pharmacological treatment approaches for OI. Most of these approaches are currently being investigated in clinical trials and are not yet approved for OI. Antiresorptive drugs primarily inhibit bone resorption. Denosumab, an anti-RANKL antibody, prevents RANKL-induced osteoclast proliferation and differentiation. Anti-TGF-β antibodies reduce TGF-β-stimulated osteoclastogenesis and expression of RANK on osteoclast precursors. Bisphosphonates (zoledronic acid, neridronate), the current standard of care for OI, induce apoptosis of osteoclasts. Osteoanabolic drugs primarily promote bone formation. Antisclerostin antibodies (romosozumab, setrusumab) inhibit sclerostin, leading to activation of the Wnt signaling pathway and subsequently stimulation of osteoblast activity. Additionally, antisclerostin antibodies exert antiresorptive effects by promoting the secretion of osteoprotegerin (OPG), which inhibits the RANK–RANKL interaction.
Figure 4:

Pharmacological treatment approaches for OI. Most of these approaches are currently being investigated in clinical trials and are not yet approved for OI. Antiresorptive drugs primarily inhibit bone resorption. Denosumab, an anti-RANKL antibody, prevents RANKL-induced osteoclast proliferation and differentiation. Anti-TGF-β antibodies reduce TGF-β-stimulated osteoclastogenesis and expression of RANK on osteoclast precursors. Bisphosphonates (zoledronic acid, neridronate), the current standard of care for OI, induce apoptosis of osteoclasts. Osteoanabolic drugs primarily promote bone formation. Antisclerostin antibodies (romosozumab, setrusumab) inhibit sclerostin, leading to activation of the Wnt signaling pathway and subsequently stimulation of osteoblast activity. Additionally, antisclerostin antibodies exert antiresorptive effects by promoting the secretion of osteoprotegerin (OPG), which inhibits the RANK–RANKL interaction.

Antiresorptive drugs

Bisphosphonates

Bisphosphonates, first introduced as a pharmacological treatment for children with OI in the 1980s, still remain the standard of care [81], 92]. These compounds bind to hydroxyapatite crystals in bone and are internalized by osteoclasts upon their activation and attachment to the bone surface. Once internalized, bisphosphonates disrupt key metabolic pathways within the osteoclasts, leading to functional inhibition or apoptosis, thereby reducing bone resorption. This results in increases of bone mass, reduced incidence of vertebral compression fractures and bone pain, and vertebral remodeling [93]. While generally well tolerated, short-term side effects include flu-like symptoms, such as fever, bone pain, and fatigue [94]. Oral administration of bisphosphonates may cause gastrointestinal irritation; therefore, intravenous application is usually preferred [95]. Since mild hypocalcemia can occur due to decreased bone resorption 24–48 h after administration of bisphosphonates, calcium and vitamin D status should be assessed before initiating therapy [96]. Osteonecrosis of the jaw is a serious side effect documented in adult patients treated with bisphosphonates. However, there is no evidence of an increased risk of bisphosphonate-related osteonecrosis in children with OI [97], 98]. The response to bisphosphonates in children with OI is variable and seems to be related to the underlying genetic mutation: Children with structural collagen defects or nonautosomal-dominant inheritance showed less increase of BMD with zoledronic acid therapy [99] and also type VI OI is characterized by a poor response to bisphosphonates [55]. This highlights the limitations of bisphosphonate therapy and the need for tailored therapeutic approaches for certain genetic subtypes.

Anti-RANKL antibodies

Denosumab is a monoclonal antibody administered via subcutaneous injection every 3 to 6 months. It specifically targets and inhibits the receptor activator of nuclear factor kappa-B ligand (RANKL), thereby inhibiting RANKL-induced differentiation of osteoclast precursors to mature bone resorbing cells. Furthermore, denosumab reduces activity and survival time of mature osteoclasts [100], [101], [102], [103]. In contrast to bisphosphonates, which remain in the organism for decades [104], denosumab is fully metabolized after a few months [105].

Denosumab effectively increased bone mass and areal BMD measured by DXA and reduced fracture incidence in osteoporosis patients [106], 107]. A single-center, 1-year study by Liu et al. (2024) showed previously denosumab to be as effective as the bisphosphonate zoledronic acid in increasing aBMD in children with OI [108]. However, large-scale studies investigating the effects of denosumab in OI are currently lacking due to safety concerns about calcium-related side effects. A pronounced rebound effect 3–7 months after denosumab injections was reported in children and adults [109], 110]. This rebound is associated with excessive bone resorption, leading to a loss of bone mass to pretreatment levels, increased calcium mobilization to the circulation, and an increased risk of fractures [111]. Case reports have described severe hypercalcemia requiring acute hospital admission with hydration and antiresorptive therapy to prevent acute kidney failure [108], 112], 113]. These safety concerns led to the early termination of a large multicenter study that aimed to investigate denosumab in children with OI [114]. Denosumab is, therefore, currently not recommended for the treatment of pediatric OI patients.

Anti-TGF-β antibodies

Excessive TGF-β signaling has been identified in both dominant and recessive forms of OI [115], 116]. Anti-TGF-β treatment using neutralizing antibodies increased bone mass and improved bone architecture in OI mouse models [115] and in adults receiving fresolimumab [117]. A phase 1 clinical study is currently investigating the safety and tolerability of a single dose of SAR439459, another human anti-TGF-β monoclonal antibody, in adult participants with OI [118].

Osteoanabolic drugs

Recombinant human PTH

Parathyroid hormone (PTH) regulates bone metabolism by stimulating osteoclast activity to increase calcium release into the bloodstream. However, when administered intermittently, PTH stimulates bone formation [119]. In adults with OI, particularly patients with OI type I, teriparatide, a recombinant human PTH, has shown significant increases in BMD compared to placebo and bisphosphonates [120], 121]. However, preclinical studies in rodents receiving high-dose PTH treatment raised concerns about an increased risk of osteosarcoma with long-term use [122]. Therefore, this therapy is not used in children. The TOPaZ trial is currently investigating whether a 2-year treatment with teriparatide followed by a single infusion of zoledronic acid can reduce fracture risk in adult patients with OI compared to standard therapy with zoledronic acid alone [123].

Antisclerostin antibodies

Sclerostin, a glycoprotein predominantly expressed by osteocytes, regulates bone formation by binding to the LRP5/6 receptors on osteoblasts. It inhibits the Wnt/β-catenin signaling pathway, which is essential for osteoblast proliferation, differentiation, and activity. Inhibiting sclerostin reduces β-catenin degradation, thereby enhancing osteoblast activity and bone formation [124], 125]. In murine OI models, treatment with an antisclerostin antibody decreased fracture rates and increased cortical bone thickness and BMD [126], 127]. The effectiveness of the antisclerostin antibody setrusumab was already shown in adult osteoporosis and OI patients [128]. Currently, two antisclerostin antibodies are investigated in phase 3 multicenter studies in pediatric patients with OI to evaluate their effectiveness compared to bisphosphonates: Romosozumab, a monoclonal antibody, which is injected subcutaneously monthly [129], and setrusumab, which is administered monthly via intravenous infusion [130].

Future therapy approaches

Emerging therapies such as mesenchymal stem cell (MSC) therapy and gene therapy offer promising new avenues for treating OI. These approaches aim to address the underlying genetic and cellular defects of the disease, potentially providing long-term or even curative effects.

MSC therapy involves the use of multipotent stromal cells that can differentiate into osteoblasts and chondrocytes. Preclinical studies with animal models have shown that human fetal MSCs can target bone lesions, reduce brittleness, and increase bone thickness and collagen content in OI mice [131]. In humans, bone marrow transplants from siblings have increased growth rates and reduced fractures in children with OI type III [132]. Prenatal MSC transplantation followed by additional postnatal treatments improved growth and fracture reduction in severe OI types III and IV [133]. Challenges include ensuring the effective integration and long-term viability of transplanted MSCs, along with risks such as immune rejection and potential malignant transformation. The BOOSTB4 clinical trial is currently evaluating the long-term safety and efficacy of postnatal vs. prenatal and postnatal administration of fetal MSCs in severe OI [134].

Gene therapy aims to treat OI by directly addressing its genetic defect. Techniques like CRISPR/Cas9 are being explored for precise gene editing in other genetic diseases [135]. However, challenges include developing effective delivery systems and avoiding potential off-target effects.

Summary

OI is one of the most common inherited skeletal disorders. Over the past decades, there has been substantial progress in understanding its genetic background and underlying molecular mechanisms, as well as in improving treatment strategies. Nevertheless, current treatment for OI remains primarily supportive. Future approaches may focus increasingly on personalized, gene-targeted therapies to offer long-term solutions for even the most severe cases. As our understanding of the molecular mechanisms in this disease deepens, we are moving closer to curative therapies that could transform patient care in the future.

Corresponding author: Prof. Dr. med. Oliver Semler, Department of Pediatrics, Children’s Hospital, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany, E-mail:

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: FOR2722

Acknowledgments

Figures were created in BioRender. Metz, M. (2024) https://BioRender.com/q44t448.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: All authors were involved in structuring and preparation of the manuscript. SS wrote the manuscript and prepared the figures. FZ contributed by describing the four new genes. JE, FZ, and IA proofread the biochemical section. OS, SR, and HH provided critical revisions and contributed to the clinical section. All authors reviewed and approved the final manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: All other authors state no conflict of interest.

  6. Research funding: Parts of this work were supported by DFG funding FOR 2722 (SE2373/1–2384170921; ZA 561/3–2407168728; ET 144/3–2384170921). SS and HH work as Clinician Scientists within the project.

  7. Data availability: Not applicable.

References

1. Orioli, IM, Castilla, EE, Barbosa-Neto, JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986;23:328–32. https://doi.org/10.1136/jmg.23.4.328.Suche in Google Scholar PubMed PubMed Central

2. Olaus, JE, Acrel, JG. Dissertatio medica descriptionem et casus aliquot osteomalaciæ sistens. Uppsala: Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine; 1788.Suche in Google Scholar

3. Marini, JC, Forlino, A, Bächinger, HP, Bishop, NJ, Byers, PH, De Paepe, A, et al.. Osteogenesis imperfecta. Nat Rev Dis Prim 2017;3:1–19. https://doi.org/10.1038/nrdp.2017.52.Suche in Google Scholar PubMed

4. Shapiro, JR. Clinical and genetic classification of osteogenesis Imperfecta and epidemiology. London: Academic Press; 2014:15–22 pp.10.1016/B978-0-12-397165-4.00002-2Suche in Google Scholar

5. Jovanovic, M, Marini, JC. Update on the genetics of osteogenesis imperfecta. Calcif Tissue Int 2024;115:891–914. https://doi.org/10.1007/s00223-024-01266-5.Suche in Google Scholar PubMed PubMed Central

6. Kenkre, JS, Bassett, JHD. The bone remodelling cycle. Ann Clin Biochem 2018;55:308–27. https://doi.org/10.1177/0004563218759371.Suche in Google Scholar PubMed

7. Mohamed, AMFS. An overview of bone cells and their regulating factors of differentiation. Malays J Med Sci 2008;15:4.Suche in Google Scholar

8. Qin, L, Liu, W, Cao, H, Xiao, G. Molecular mechanosensors in osteocytes. Bone Res 2020;8:1–24. https://doi.org/10.1038/s41413-020-0099-y.Suche in Google Scholar PubMed PubMed Central

9. Ozhan, G, Iscan, E, Schambony, A, Liu, Y, Ren, Q, Chen, J. LRP5 and LRP6 in Wnt signaling: similarity and divergence. Front Cell Dev Biol 2021;9. https://doi.org/10.3389/FCELL.2021.670960.Suche in Google Scholar

10. Marini, F, Giusti, F, Palmini, G, Brandi, ML. Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders. Osteoporos Int 2023;34:213–38. https://doi.org/10.1007/s00198-022-06523-7.Suche in Google Scholar PubMed

11. Boyce, BF, Xing, L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008;473:139–46. https://doi.org/10.1016/j.abb.2008.03.018.Suche in Google Scholar PubMed PubMed Central

12. Anandarajah, AP. Role of RANKL in bone diseases. Trends Endocrinol Metab 2009;20:88–94. https://doi.org/10.1016/j.tem.2008.10.007.Suche in Google Scholar PubMed

13. Rahman, MS, Akhtar, N, Jamil, HM, Banik, RS, Asaduzzaman, SM. TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res 2015;3:15005. https://doi.org/10.1038/boneres.2015.5.Suche in Google Scholar PubMed PubMed Central

14. Yan, T, Riggs, BL, Boyle, WJ, Khosla, S. Regulation of osteoclastogenesis and RANK expression by TGF‐β1. J Cell Biochem 2001;83:320–5. https://doi.org/10.1002/jcb.1200.Suche in Google Scholar PubMed

15. Buckley, L, Humphrey, MB. Glucocorticoid-induced osteoporosis. N Engl J Med 2018;379:2547–56. https://doi.org/10.1056/NEJMcp1800214.Suche in Google Scholar PubMed

16. Forlino, A, Cabral, WA, Barnes, AM, Marini, JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 2011;7:540–57. https://doi.org/10.1038/nrendo.2011.81.Suche in Google Scholar PubMed PubMed Central

17. Lisse, TS, Thiele, F, Fuchs, H, Hans, W, Przemeck, GKH, Abe, K, et al.. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genet 2008;4:e7. https://doi.org/10.1371/journal.pgen.0040007.Suche in Google Scholar PubMed PubMed Central

18. Doyard, M, Bacrot, S, Huber, C, Di Rocco, M, Goldenberg, A, Aglan, MS, et al.. FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. J Med Genet 2018;55:278–84. https://doi.org/10.1136/JMEDGENET-2017-104999.Suche in Google Scholar

19. Rauch, F, Fahiminiya, S, Majewski, J, Carrot-Zhang, J, Boudko, S, Glorieux, F, et al.. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am J Hum Genet 2015;96:425–31. https://doi.org/10.1016/J.AJHG.2014.12.027.Suche in Google Scholar PubMed PubMed Central

20. Balasubramanian, M, Pollitt, RC, Chandler, KE, Mughal, MZ, Parker, MJ, Dalton, A, et al.. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A 2015;167:587–91. https://doi.org/10.1002/AJMG.A.36916.Suche in Google Scholar PubMed

21. Valli, M, Barnes, AM, Gallanti, A, Cabral, WA, Viglio, S, Weis, MA, et al.. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix. Clin Genet 2012;82:453–9. https://doi.org/10.1111/J.1399-0004.2011.01794.X.Suche in Google Scholar

22. Cabral, WA, Chang, W, Barnes, AM, Weis, M, Scott, MA, Leikin, S, et al.. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 2007;39:359–65. https://doi.org/10.1038/ng1968.Suche in Google Scholar PubMed PubMed Central

23. Willaert, A, Malfait, F, Symoens, S, Gevaert, K, Kayserili, H, Megarbane, A, et al.. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J Med Genet 2009;46:233–41. https://doi.org/10.1136/JMG.2008.062729.Suche in Google Scholar PubMed

24. Barnes, AM, Carter, EM, Cabral, WA, Weis, M, Chang, W, Makareeva, E, et al.. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. N Engl J Med 2010;362:521–8. https://doi.org/10.1056/nejmoa0907705.Suche in Google Scholar PubMed PubMed Central

25. van Dijk, FS, Nesbitt, IM, Zwikstra, EH, Nikkels, PGJ, Piersma, SR, Fratantoni, SA, et al.. PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 2009;85:521–7. https://doi.org/10.1016/j.ajhg.2009.09.001.Suche in Google Scholar PubMed PubMed Central

26. Pyott, SM, Schwarze, U, Christiansen, HE, Pepin, MG, Leistritz, DF, Dineen, R, et al.. Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Hum Mol Genet 2011;20:1595–609. https://doi.org/10.1093/HMG/DDR037.Suche in Google Scholar

27. Marshall, C, Lopez, J, Crookes, L, Pollitt, RC, Balasubramanian, M. A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly. Gene 2016;595:49–52. https://doi.org/10.1016/J.GENE.2016.09.035.Suche in Google Scholar

28. Christiansen, HE, Schwarze, U, Pyott, SM, AlSwaid, A, Al Balwi, M, Alrasheed, S, et al.. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet 2010;86:389–98. https://doi.org/10.1016/j.ajhg.2010.01.034.Suche in Google Scholar PubMed PubMed Central

29. Duran, I, Nevarez, L, Sarukhanov, A, Wu, S, Lee, K, Krejci, P, et al.. HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. Hum Mol Genet 2015;24:1918–28. https://doi.org/10.1093/HMG/DDU608.Suche in Google Scholar

30. Shaheen, R, Al-Owain, M, Sakati, N, Alzayed, ZS, Alkuraya, FS. FKBP10 and bruck syndrome: phenotypic heterogeneity or call for reclassification? Am J Hum Genet 2010;87:306–7. https://doi.org/10.1016/j.ajhg.2010.05.020.Suche in Google Scholar PubMed PubMed Central

31. Alanay, Y, Avaygan, H, Camacho, N, Utine, GE, Boduroglu, K, Aktas, D, et al.. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 2010;86:551–9. https://doi.org/10.1016/j.ajhg.2010.02.022. 20362275.Suche in Google Scholar PubMed PubMed Central

32. Van Dijk, FS, Semler, O, Etich, J, Köhler, A, Jimenez-Estrada, JA, Bravenboer, N, et al.. Interaction between KDELR2 and HSP47 as a key determinant in osteogenesis imperfecta caused by Bi-allelic variants in KDELR2. Am J Hum Genet 2020;107:989–99. https://doi.org/10.1016/j.ajhg.2020.09.009.Suche in Google Scholar PubMed PubMed Central

33. Efthymiou, S, Herman, I, Rahman, F, Anwar, N, Maroofian, R, Yip, J, et al.. Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. Am J Med Genet A 2021;185:2241–9. https://doi.org/10.1002/AJMG.A.62221.Suche in Google Scholar

34. Keller, RB, Tran, TT, Pyott, SM, Pepin, MG, Savarirayan, R, Mcgillivray, G, et al.. Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet Med 2017;20. https://doi.org/10.1038/gim.2017.115.Suche in Google Scholar PubMed PubMed Central

35. Lindert, U, Cabral, WA, Ausavarat, S, Tongkobpetch, S, Ludin, K, Barnes, AM, et al.. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun 2016;7. https://doi.org/10.1038/NCOMMS11920.Suche in Google Scholar

36. Webb, EA, Balasubramanian, M, Fratzl-Zelman, N, Cabral, WA, Titheradge, H, Alsaedi, A, et al.. Phenotypic spectrum in osteogenesis imperfecta due to mutations in TMEM38B: unraveling a complex cellular defect. J Clin Endocrinol Metab 2017;102:2019–28. https://doi.org/10.1210/JC.2016-3766.Suche in Google Scholar PubMed PubMed Central

37. Garbes, L, Kim, K, Rieß, A, Hoyer-Kuhn, H, Beleggia, F, Bevot, A, et al.. Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta. Am J Hum Genet 2015;96:432. https://doi.org/10.1016/J.AJHG.2015.01.002.Suche in Google Scholar

38. Valencia, M, Caparrós-Martin, JA, Sirerol-Piquer, MS, García-Verdugo, JM, Martínez-Glez, V, Lapunzina, P, et al.. Report of a newly identified patient with mutations in BMP1 and underlying pathogenetic aspects. AJMG 2014;164A:1143–50. https://doi.org/10.1002/AJMG.A.36427.Suche in Google Scholar PubMed

39. Xu, X-J, Lv, F, Song, Y-W, Li, L-J, Asan, Wei, X-X, et al.. Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta. Clin Chim Acta 2019;489:21–8. https://doi.org/10.1016/j.cca.2018.11.004. 30408480.Suche in Google Scholar PubMed

40. Puig-Hervás, MT, Temtamy, S, Aglan, M, Valencia, M, Martínez-Glez, V, Ballesta-Martínez, MJ, et al.. Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome—osteogenesis imperfecta phenotypic spectrum. Hum Mutat 2012;33:1444–9. https://doi.org/10.1002/HUMU.22133.Suche in Google Scholar

41. Ha-Vinh, R, Alanay, Y, Bank, RA, Campos-Xavier, AB, Zankl, A, Superti-Furga, A, et al.. Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. Am J Med Genet A 2004;131A:115–20. https://doi.org/10.1002/AJMG.A.30231.Suche in Google Scholar

42. Durkin, A, DeVile, C, Arundel, P, Bull, M, Walsh, J, Bishop, NJ, et al.. Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review. J Med Genet 2022;59:810–6. https://doi.org/10.1136/JMEDGENET-2021-107942.Suche in Google Scholar PubMed

43. Zhong, W, Pathak, JL, Liang, Y, Zhytnik, L, Pals, G, Eekhoff, EMW, et al.. The intricate mechanism of PLS3 in bone homeostasis and disease. Front Endocrinol 2023;14. https://doi.org/10.3389/FENDO.2023.1168306.Suche in Google Scholar PubMed PubMed Central

44. Fahiminiya, S, Majewski, J, Mort, J, Moffatt, P, Glorieux, FH, Rauch, F. Mutations in WNT1 are a cause of osteogenesis imperfecta. J Med Genet 2013;50:345–8. https://doi.org/10.1136/jmedgenet-2013-101567.Suche in Google Scholar PubMed

45. Lu, Y, Ren, X, Wang, Y, Bardai, G, Sturm, M, Dai, Y, et al.. Novel WNT1 mutations in children with osteogenesis imperfecta: clinical and functional characterization. Bone 2018;114:144–9. https://doi.org/10.1016/J.BONE.2018.06.018.Suche in Google Scholar

46. Kuptanon, C, Srichomthong, C, Sangsin, A, Kovitvanitcha, D, Suphapeetiporn, K, Shotelersuk, V. The most 5’ truncating homozygous mutation of WNT1 in siblings with osteogenesis imperfecta with a variable degree of brain anomalies: a case report. BMC Med Genet 2018;19:117. https://doi.org/10.1186/s12881-018-0639-0. 30012084.Suche in Google Scholar PubMed PubMed Central

47. Moosa, S, Yamamoto, GL, Garbes, L, Keupp, K, Beleza-Meireles, A, Moreno, CA, et al.. Autosomal recessive mutations in MESD cause osteogenesis imperfecta. Am J Hum Genet 2019;105:836–43. https://doi.org/10.1016/J.AJHG.2019.08.008.Suche in Google Scholar

48. Stürznickel, J, Jähn-Rickert, K, Zustin, J, Hennig, F, Delsmann, MM, Schoner, K, et al.. Compound heterozygous frameshift mutations in MESD cause a lethal syndrome suggestive of osteogenesis imperfecta type XX. J Bone Miner Res 2021;36:1077–87. https://doi.org/10.1002/JBMR.4277.Suche in Google Scholar PubMed

49. Uludağ Alkaya, D, Uyguner, ZO, Güneş, N, Tüysüz, B. Long‐term follow‐up findings in a Turkish girl with osteogenesis imperfecta type XX caused by a homozygous MESD variant. Am J Med Genet A 2022;188:1639–46. https://doi.org/10.1002/AJMG.A.62664.Suche in Google Scholar PubMed

50. Etich, J, Semler, O, Stevenson, NL, Stephan, A, Besio, R, Garibaldi, N, et al.. TAPT1 —at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta. EMBO Mol Med 2023;15. https://doi.org/10.15252/emmm.202317528.Suche in Google Scholar PubMed PubMed Central

51. Symoens, S, Barnes, AM, Gistelinck, C, Malfait, F, Guillemyn, B, Steyaert, W, et al.. Genetic defects in TAPT1 disrupt ciliogenesis and cause a complex lethal osteochondrodysplasia. Am J Hum Genet 2015;97:521–34. https://doi.org/10.1016/j.ajhg.2015.08.009.Suche in Google Scholar PubMed PubMed Central

52. Gauthier, LW, Fontanges, E, Chapurlat, R, Collet, C, Rossi, M. Long-term follow-up of severe autosomal recessive SP7-related bone disorder. Bone 2024;179:116953. https://doi.org/10.1016/J.BONE.2023.116953.Suche in Google Scholar PubMed

53. Ludwig, K, Ward, LM, Khan, N, Robinson, ME, Miranda, V, Bardai, G, et al.. Dominant osteogenesis imperfecta with low bone turnover caused by a heterozygous SP7 variant. Bone 2022;160:116400. https://doi.org/10.1016/J.BONE.2022.116400.Suche in Google Scholar

54. Al-Mutairi, DA, Jarragh, AA, Alsabah, BH, Wein, MN, Mohammed, W, Alkharafi, L. A homozygous SP7/OSX mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies. JBMR Plus 2024;8. https://doi.org/10.1093/JBMRPL/ZIAE026.Suche in Google Scholar PubMed PubMed Central

55. Land, C, Rauch, F, Travers, R, Glorieux, FH. Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone 2007;40:638–44. https://doi.org/10.1016/j.bone.2006.10.010.Suche in Google Scholar PubMed

56. Ward, L, Bardai, G, Moffatt, P, Al-Jallad, H, Trejo, P, Glorieux, FH, et al.. Osteogenesis imperfecta type VI in individuals from northern Canada. Calcif Tissue Int 2016;98:566–72. https://doi.org/10.1007/s00223-016-0110-1.Suche in Google Scholar PubMed

57. Glorieux, FH, Rauch, F, Plotkin, H, Ward, L, Travers, R, Roughley, P, et al.. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000;15:1650–8. https://doi.org/10.1359/JBMR.2000.15.9.1650.Suche in Google Scholar PubMed

58. Dubail, J, Brunelle, P, Baujat, G, Huber, C, Doyard, M, Michot, C, et al.. Homozygous loss‐of‐function mutations in CCDC134 are responsible for a severe form of osteogenesis imperfecta. J Bone Miner Res 2020;35:1470–80. https://doi.org/10.1002/JBMR.4011.Suche in Google Scholar

59. Ali, TM, Linnenkamp, BDW, Yamamoto, GL, Honjo, RS, Cabral de Menezes Filho, H, Kim, CA, et al.. The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non‐Morrocan ancestry. Am J Med Genet A 2022;188:1545–9. https://doi.org/10.1002/AJMG.A.62651.Suche in Google Scholar

60. Holick, MF, Shirvani, A, Charoenngam, N. Fetal fractures in an infant with maternal ehlers-danlos syndrome, CCDC134 pathogenic mutation and a negative genetic test for osteogenesis imperfecta. Children 2021;8. https://doi.org/10.3390/CHILDREN8060512.Suche in Google Scholar

61. Tuysuz, B, Uludag Alkaya, D, Geyik, F, Alaylloǧlu, M, Kasap, B, Kurugoǧlu, S, et al.. Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes. J Med Genet 2023;60:819–26. https://doi.org/10.1136/JMG-2022-108763.Suche in Google Scholar

62. Ma, DL, Hu, J, Fang, K. Olmsted syndrome. J Clin Dermatol 2012;35:637–9. https://doi.org/10.1155/2012/927305.Suche in Google Scholar PubMed PubMed Central

63. Elise Tonoli, R, De Villa, D, Hübner Frainer, R, Pizzarro Meneghello, L, Ricachnevsky, N, de Quadros, M. Olmsted syndrome. Case Rep Dermatol Med 2012;2012:927305. https://doi.org/10.1155/2012/927305. 23320205.Suche in Google Scholar PubMed PubMed Central

64. Zhou, QL, Jiang, ZY, Mabardy, AS, Del Campo, CM, Lambright, DG, Holik, J, et al.. A novel Pleckstrin homology domain-containing protein enhances insulin-stimulated Akt phosphorylation and GLUT4 translocation in adipocytes. JBC 2010;285:27581–9. https://doi.org/10.1074/jbc.M110.146886.Suche in Google Scholar PubMed PubMed Central

65. Nabavizadeh, N, Bressin, A, Shboul, M, Moreno Traspas, R, Chia, PH, Bonnard, C, et al.. A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing. EMBO Mol Med 2023;15. https://doi.org/10.15252/EMMM.202216478.Suche in Google Scholar PubMed PubMed Central

66. Etich, J, Semler, O, Stevenson, NL, Stephan, A, Besio, R, Garibaldi, N, et al.. TAPT1 – at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta. EMBO Mol Med 2023;15. https://doi.org/10.15252/emmm.202317528.Suche in Google Scholar PubMed PubMed Central

67. Khan, SI, Yonko, EA, Carter, EM, Dyer, D, Sandhaus, RA, Raggio, CL. Cardiopulmonary status in adults with osteogenesis imperfecta: intrinsic lung disease may contribute more than scoliosis. Clin Orthop Relat Res 2020;478:2833–43. https://doi.org/10.1097/CORR.0000000000001400.Suche in Google Scholar PubMed PubMed Central

68. Wallace, MJ, Kruse, RW, Shah, SA. The spine in patients with osteogenesis imperfecta. J Am Acad Orthop Surg 2017;25:100–9. https://doi.org/10.5435/JAAOS-D-15-00169.Suche in Google Scholar PubMed

69. Sienko, S, Tucker, C, Welborn, MC. Surgical outcomes for spinal deformity in osteogenesis imperfecta. Spine Deform 2023;11:391–8. https://doi.org/10.1007/S43390-022-00600-X.Suche in Google Scholar

70. Frank, E, Berger, T, Tew, JM. Basilar impression and platybasia in osteogenesis imperfecta tarda. Surg Neurol 1982;17:116–9. https://doi.org/10.1016/S0090-3019(82)80033-5.Suche in Google Scholar

71. Scheiber, AL, Wilkinson, KJ, Suzuki, A, Enomoto-Iwamoto, M, Kaito, T, Cheah, KSE, et al.. 4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts. JCI Insight 2022;7. https://doi.org/10.1172/jci.insight.149636.Suche in Google Scholar PubMed PubMed Central

72. Rodriguez Celin, M, Kruger, KM, Caudill, A, Murali, CN, Nagamani, SCS, Smith, PA, et al.. A multicenter study to evaluate pain characteristics in osteogenesis imperfecta. Am J Med Genet A 2023;191:160–72. https://doi.org/10.1002/ajmg.a.63009.Suche in Google Scholar PubMed PubMed Central

73. Zack, P, Franck, L, Devile, C, Clark, C. Fracture and non‐fracture pain in children with osteogenesis imperfecta. Acta Paediatr 2005;94:1238–42. https://doi.org/10.1111/j.1651-2227.2005.tb02082.x.Suche in Google Scholar PubMed

74. Westerheim, I, Hart, T, van Welzenis, T, Wekre, LL, Semler, O, Raggio, C, et al.. The IMPACT survey: a mixed methods study to understand the experience of children, adolescents and adults with osteogenesis imperfecta and their caregivers. Orphanet J Rare Dis 2024;19:128. https://doi.org/10.1186/s13023-024-03126-9.Suche in Google Scholar PubMed PubMed Central

75. Treurniet, S, Burger, P, Ghyczy, EAE, Verbraak, FD, Curro‐ Tafili, KR, Micha, D, et al.. Ocular characteristics and complications in patients with osteogenesis imperfecta: a systematic review. Acta Ophthalmol 2022;100. https://doi.org/10.1111/aos.14882.Suche in Google Scholar PubMed PubMed Central

76. Forlino, A, Marini, JC. Osteogenesis imperfecta. Lancet 2016;387:1657–71. https://doi.org/10.1016/S0140-6736(15)00728-X.Suche in Google Scholar PubMed PubMed Central

77. Kuptanon, C, Srichomthong, C, Sangsin, A, Kovitvanitcha, D, Suphapeetiporn, K, Shotelersuk, V. The most 5′ truncating homozygous mutation of WNT1 in siblings with osteogenesis imperfecta with a variable degree of brain anomalies: a case report. BMC Med Genet 2018;19. https://doi.org/10.1186/S12881-018-0639-0.Suche in Google Scholar PubMed PubMed Central

78. Ugarteburu, M, Cardoso, L, Richter, C-P, Carriero, A. Treatments for hearing loss in osteogenesis imperfecta: a systematic review and meta-analysis on their efficacy. Sci Rep 2022;12:17125. https://doi.org/10.1038/s41598-022-20169-9.Suche in Google Scholar PubMed PubMed Central

79. Folkestad, L, Hald, JD, Gram, J, Langdahl, BL, Hermann, AP, Diederichsen, AC, et al.. Cardiovascular disease in patients with osteogenesis imperfecta — a nationwide, register-based cohort study. Int J Cardiol 2016;225:250–7. https://doi.org/10.1016/j.ijcard.2016.09.107.Suche in Google Scholar PubMed

80. Gatto, G, et al.. Osteogenesis imperfecta and related diseases: collagen I alterations in skeletal and extraskeletal tissues. In: Rossi, A, Zaucke, F, editors. The extracellular matrix in genetic skeletal disorders. Cham: Springer; 2025. In press.10.1007/978-3-031-70835-0_2Suche in Google Scholar

81. Hoyer-Kuhn, H, Bartz-Seel, J, Blickheuser, R, Deimling, U, Stücker, R, Wirth, T, et al.. Diagnostik und Therapie der Osteogenesis imperfecta. Monatsschr Kinderh 2017;165:333–46. https://doi.org/10.1007/s00112-016-0189-5.Suche in Google Scholar

82. Renaud, A, Aucourt, J, Weill, J, Bigot, J, Dieux, A, Devisme, L, et al.. Radiographic features of osteogenesis imperfecta. Insights Imag 2013;4:417–29. https://doi.org/10.1007/s13244-013-0258-4.Suche in Google Scholar PubMed PubMed Central

83. Obafemi, AA, Bulas, DI, Troendle, J, Marini, JC. Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet A 2008;146A:2725. https://doi.org/10.1002/AJMG.A.32508.Suche in Google Scholar

84. Morlino, S, Micale, L, Ritelli, M, Rohrbach, M, Zoppi, N, Vandersteen, A, et al.. COL1‐related overlap disorder: a novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers‐Danlos syndrome overlap. Clin Genet 2020;97:396–406. https://doi.org/10.1111/cge.13683.Suche in Google Scholar PubMed

85. Semler, O, Hoyer-Kuhn, H, Netzer, C. Osteogenesis imperfecta. Med Genet 2012;24:297–311. https://doi.org/10.1007/s11825-012-0358-4.Suche in Google Scholar

86. Tsimicalis, A, Denis-Larocque, G, Michalovic, A, Lepage, C, Williams, K, Yao, T-R, et al.. The psychosocial experience of individuals living with osteogenesis imperfecta: a mixed-methods systematic review. Qual Life Res 2016;25:1877–96. https://doi.org/10.1007/s11136-016-1247-0.Suche in Google Scholar PubMed

87. Mueller, B, Engelbert, R, Baratta-Ziska, F, Bartels, B, Blanc, N, Brizola, E, et al.. Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J Rare Dis 2018;13:1–14. https://doi.org/10.1186/S13023-018-0905-4/FIGURES/3.Suche in Google Scholar

88. Antičević, D, Jeleč, Ž, Zagreb, H. Osteogenesis imperfecta: surgical treatment options with emphasis on today’s orthopedic approach. Paediatr Croat 2017;61:129–62. https://doi.org/10.13112/PC.2017.18.Suche in Google Scholar

89. Kasahun, AE, Sendekie, AK, Abebe, RB. Assessment of pain management adequacy among hospitalized pediatric patients: institutional-based cross-sectional study. Front Pediatr 2023;11:1195416. https://doi.org/10.3389/FPED.2023.1195416.Suche in Google Scholar

90. Hoyer-Kuhn, H, Semler, O, Stark, C, Struebing, N, Goebel, O, Schoenau, E. A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta. J Musculoskelet Neuronal Interact 2014;14:445–53.Suche in Google Scholar

91. Semler, O, Fricke, O, Vezyroglou, K, Stark, C, Stabrey, A, Schoenau, E. Results of a prospective pilot trial on mobility after whole body vibration in children and adolescents with osteogenesis imperfecta. Clin Rehabil 2008;22:387–94. https://doi.org/10.1177/0269215507080763.Suche in Google Scholar PubMed

92. Glorieux, FH, Bishop, NJ, Plotkin, H, Chabot, G, Lanoue, G, Travers, R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998;339:947–52. https://doi.org/10.1056/NEJM199810013391402.Suche in Google Scholar PubMed

93. Land, C, Rauch, F, Munns, CF, Sahebjam, S, Glorieux, FH. Vertebral morphometry in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate treatment. Bone 2006;39:901–6. https://doi.org/10.1016/j.bone.2006.04.004.Suche in Google Scholar PubMed

94. Ott, SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005;90:1897–9. https://doi.org/10.1210/jc.2005-0057.Suche in Google Scholar PubMed

95. Dwan, K, Phillipi, CA, Steiner, RD, Basel, D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev 2016;2016. https://doi.org/10.1002/14651858.CD005088.pub4.Suche in Google Scholar PubMed PubMed Central

96. Maines, E, Tadiotto, E, Morandi, G, Fedrizzi, M, Gaudino, R, Cavarzere, P, et al.. Hypocalcemia following neridronate administration in pediatric patients with osteogenesis imperfecta: a prospective observational study. J Pediatr Genet 2020;09:093–100. https://doi.org/10.1055/s-0039-1700972.Suche in Google Scholar PubMed PubMed Central

97. Hennedige, AA, Jayasinghe, J, Khajeh, J, Macfarlane, TV. Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta. J Oral Maxillofac Res 2013;4. https://doi.org/10.5037/jomr.2013.4401.Suche in Google Scholar PubMed PubMed Central

98. Duarte, NT, Rech, Bde O, Martins, IG, Franco, JB, Ortega, KL. Can children be affected by bisphosphonate-related osteonecrosis of the jaw? A systematic review. Int J Oral Maxillofac Surg 2020;49:183–91. https://doi.org/10.1016/j.ijom.2019.08.004.Suche in Google Scholar PubMed

99. Sun, L, Hu, J, Liu, J, Zhang, Q, Wang, O, Jiang, Y, et al.. Relationship of pathogenic mutations and responses to zoledronic acid in a cohort of osteogenesis imperfecta children. J Clin Endocrinol Metab 2022;107:2571–9. https://doi.org/10.1210/clinem/dgac366.Suche in Google Scholar PubMed

100. Lacey, DL, Tan, HL, Lu, J, Kaufman, S, Van, G, Qiu, W, et al.. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 2000;157:435–48. https://doi.org/10.1016/S0002-9440(10)64556-7.Suche in Google Scholar PubMed PubMed Central

101. Feng, X. RANKing intracellular signaling in osteoclasts. IUBMB Life 2005;57:389–95. https://doi.org/10.1080/15216540500137669.Suche in Google Scholar PubMed

102. Burgess, TL, Qian, Y, Kaufman, S, Ring, BD, Van, G, Capparelli, C, et al.. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 1999;145:527–38. https://doi.org/10.1083/jcb.145.3.527.Suche in Google Scholar PubMed PubMed Central

103. Jimi, E, Akiyama, S, Tsurukai, T, Okahashi, N, Kobayashi, K, Udagawa, N, et al.. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol 1999;163:434–42. https://doi.org/10.4049/jimmunol.163.1.434.Suche in Google Scholar

104. Papapoulos, SE, Cremers, SCLM. Prolonged bisphosphonate release after treatment in children. N Engl J Med 2007;356:1075–6. https://doi.org/10.1056/NEJMc062792.Suche in Google Scholar PubMed

105. Chen, Q, Hu, C, Liu, Y, Song, R, Zhu, W, Zhao, H, et al.. Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: a randomized, single-blind, placebo-controlled study. PLoS One 2018;13:e0197984. https://doi.org/10.1371/journal.pone.0197984.Suche in Google Scholar PubMed PubMed Central

106. Cummings, SR, Martin, JS, McClung, MR, Siris, ES, Eastell, R, Reid, IR, et al.. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. https://doi.org/10.1056/NEJMOA0809493.Suche in Google Scholar PubMed

107. Gnant, M, Pfeiler, G, Dubsky, PC, Hubalek, M, Greil, R, Jakesz, R, et al.. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;386:433–43. https://doi.org/10.1016/S0140-6736(15)60995-3.Suche in Google Scholar PubMed

108. Liu, J, Lin, X, Sun, L, Zhang, Q, Jiang, Y, Wang, O, et al.. Safety and efficacy of denosumab in children with osteogenesis imperfecta—the first prospective comparative study. J Clin Endocrinol Metab 2024;109:1827–36. https://doi.org/10.1210/CLINEM/DGAD732.Suche in Google Scholar

109. Horiuchi, K, Kobayashi, E, Mizuno, T, Susa, M, Chiba, K. Hypercalcemia following discontinuation of denosumab therapy: a systematic review. Bone Rep 2021;15:101148. https://doi.org/10.1016/j.bonr.2021.101148.Suche in Google Scholar PubMed PubMed Central

110. Anastasilakis, AD, Evangelatos, G, Makras, P, Iliopoulos, A. Rebound-associated vertebral fractures may occur in sequential time points following denosumab discontinuation: need for prompt treatment re-initiation. Bone Rep 2020;12:100267. https://doi.org/10.1016/j.bonr.2020.100267.Suche in Google Scholar PubMed PubMed Central

111. Cummings, SR, Ferrari, S, Eastell, R, Gilchrist, N, Jensen, JEB, McClung, M, et al.. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled freedom trial and its extension. J Bone Miner Res 2018;33:190–8. https://doi.org/10.1002/JBMR.3337.Suche in Google Scholar PubMed

112. Raux, S, Bouhamama, A, Gaspar, N, Brugières, L, Entz-Werlé, N, Mallet, C, et al.. Denosumab for treating aneurysmal bone cysts in children. Orthop Traumatol Surg Res 2019;105:1181–5. https://doi.org/10.1016/J.OTSR.2019.04.028.Suche in Google Scholar PubMed

113. Grasemann, C, Schündeln, MM, Hövel, M, Schweiger, B, Bergmann, C, Herrmann, R, et al.. Effects of RANK-ligand antibody (denosumab) treatment on bone turnover markers in a girl with juvenile paget’s disease. J Clin Endocrinol Metab 2013;98:3121–6. https://doi.org/10.1210/JC.2013-1143.Suche in Google Scholar

114. Multicenter, single-arm study to evaluate efficacy, safety, & pharmacokinetics of denosumab in children w/OI. n.d. https://clinicaltrials.gov/study/NCT02352753 [Accessed 6 Oct 2024].Suche in Google Scholar

115. Grafe, I, Yang, T, Alexander, S, Homan, EP, Lietman, C, Jiang, MM, et al.. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med 2014;20:670–5. https://doi.org/10.1038/nm.3544.Suche in Google Scholar PubMed PubMed Central

116. Infante, A, Cabodevilla, L, Gener, B, Rodríguez, CI. Circulating TGF-β pathway in osteogenesis imperfecta pediatric patients subjected to MSCs-based cell therapy. Front Cell Dev Biol 2022;10. https://doi.org/10.3389/FCELL.2022.830928.Suche in Google Scholar PubMed PubMed Central

117. Song, I-W, Nagamani, SCS, Nguyen, D, Grafe, I, Sutton, VR, Gannon, FH, et al.. Targeting TGF-β for treatment of osteogenesis imperfecta. J Clin Invest 2022;132. https://doi.org/10.1172/JCI152571.Suche in Google Scholar PubMed PubMed Central

118. Single ascending dose study of SAR439459 in adults with osteogenesis imperfecta (OI). n.d. https://clinicaltrials.gov/study/NCT02352753 [Accessed 6 Oct 2024].Suche in Google Scholar

119. Rubin, MR, Cosman, F, Cosman, F, Lindsay, R, Lindsay, R, Bilezikian, JP, et al.. The anabolic effects of parathyroid hormone. Clin Geriatr Med 2002;13:267–77. https://doi.org/10.1007/s001980200026.Suche in Google Scholar PubMed

120. Orwoll, ES, Shapiro, J, Veith, S, Wang, Y, Lapidus, J, Vanek, C, et al.. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest 2014;124:491–8. https://doi.org/10.1172/JCI71101.Suche in Google Scholar PubMed PubMed Central

121. Leali, PT, Balsano, M, Maestretti, G, Brusoni, M, Amorese, V, Ciurlia, E, et al.. Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study. Clin Cases Miner Bone Metab 2017;14:153–6. https://doi.org/10.11138/CCMBM/2017.14.1.153.Suche in Google Scholar

122. Vahle, JL, Sato, M, Long, GG, Young, JK, Francis, PC, Engelhardt, JA, et al.. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 Years and relevance to human safety. Toxicol Pathol 2002;30:312–21. https://doi.org/10.1080/01926230252929882.Suche in Google Scholar PubMed

123. Hald, JD, Keerie, C, Weir, CJ, Javaid, MK, Lam, W, Osborne, P, et al.. Protocol: protocol of a randomised trial of teriparatide followed by zoledronic acid to reduce fracture risk in adults with osteogenesis imperfecta. BMJ Open 2023;13:78164. https://doi.org/10.1136/BMJOPEN-2023-078164.Suche in Google Scholar PubMed PubMed Central

124. Poole, KES, Van Bezooijen, RL, Loveridge, N, Hamersma, H, Papapoulos, SE, Löwik, CW, et al.. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 2005;19:1842–4. https://doi.org/10.1096/fj.05-4221fje.Suche in Google Scholar PubMed

125. Lewiecki, EM, Shah, A, Shoback, D. Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis. Int J Womens Health 2015;565. https://doi.org/10.2147/IJWH.S73244.Suche in Google Scholar PubMed PubMed Central

126. Cardinal, M, Dessain, A, Roels, T, Lafont, S, Ominsky, MS, Devogelaer, J-P, et al.. Sclerostin-antibody treatment decreases fracture rates in axial skeleton and improves the skeletal phenotype in growing oim/oim mice. Calcif Tissue Int 2020;106:494–508. https://doi.org/10.1007/s00223-019-00655-5.Suche in Google Scholar PubMed

127. Ominsky, MS, Niu, Q-T, Li, C, Li, X, Ke, HZ. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res 2014;29:1424–30. https://doi.org/10.1002/jbmr.2152.Suche in Google Scholar PubMed

128. Glorieux, FH, Langdahl, B, Chapurlat, R, De Beur, SJ, Sutton, VR, Poole, KES, et al.. Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study. J Bone Miner Res 2024;39:1215–28. https://doi.org/10.1093/jbmr/zjae112.Suche in Google Scholar PubMed PubMed Central

129. Study to evaluate efficacy and safety of Romosozumab compared with bisphosphonates in children and adolescents with osteogenesis imperfecta. n.d. https://clinicaltrials.gov/study/NCT05972551 [Accessed 7 Oct 2024).Suche in Google Scholar

130. Setrusumab vs bisphosphonates in pediatric subjects with osteogenesis imperfecta. n.d. https://clinicaltrials.gov/study/NCT05768854 [Accessed 7 Oct 2024].Suche in Google Scholar

131. Jones, GN, Moschidou, D, Abdulrazzak, H, Kalirai, BS, Vanleene, M, Osatis, S, et al.. Potential of human fetal chorionic stem cells for the treatment of osteogenesis imperfecta. Stem Cells Dev 2014;23:262. https://doi.org/10.1089/SCD.2013.0132.Suche in Google Scholar PubMed PubMed Central

132. Horwitz, EM, Gordon, PL, Koo, WKK, Marx, JC, Neel, MD, McNall, RY, et al.. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci U S A 2002;99:8932–7. https://doi.org/10.1073/pnas.132252399.Suche in Google Scholar PubMed PubMed Central

133. Götherström, C, Westgren, M, Shaw, SWS, Åström, E, Biswas, A, Byers, PH, et al.. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl Med 2014;3:255. https://doi.org/10.5966/SCTM.2013-0090.Suche in Google Scholar PubMed PubMed Central

134. Sagar, RL, Åström, E, Chitty, LS, Crowe, B, David, AL, Devile, C, et al.. An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol. BMJ Open 2024;14. https://doi.org/10.1136/BMJOPEN-2023-079767.Suche in Google Scholar

135. Schindeler, A, Lee, LR, O’Donohue, AK, Ginn, SL, Munns, CF. Curative cell and gene therapy for osteogenesis imperfecta. J Bone Miner Res 2020;37:826–36. https://doi.org/10.1002/jbmr.4549.Suche in Google Scholar PubMed PubMed Central

Received: 2024-10-25
Accepted: 2024-11-19
Published Online: 2024-12-16
Published in Print: 2025-01-29

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Frontmatter
  2. Review
  3. Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children
  4. Opinion Paper
  5. CRH receptor antagonist crinecerfont – a promising new treatment option for patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  6. Original Articles
  7. Age and sex mark clinical differences in the presentation of pediatric type 1 diabetes mellitus
  8. Geographic information system mapping and predictors of glycemic control in children and youth with type 1 diabetes: a study from Western India
  9. Body composition assessment measured via bioelectrical impedance analysis in euthyroid children with newly diagnosed Hashimoto’s thyroiditis
  10. Outcomes of newborns screened for congenital hypothyroidism in Turkey – a single center experience
  11. High yield of congenital hypothyroidism among infants attending Children Hospital, Nairobi, Kenya. Facility based study in the absence of newborn screening
  12. Immune checkpoint inhibitors and endocrinopathies in pediatric brain tumor patients
  13. Assessment of quality of life in families affected by maple syrup urine disease: a cross sectional study
  14. Case Reports
  15. Reninoma: an unusual cause of growth failure
  16. Persistent hypoglycemia in congenital syphilis: hyperinsulinemic hypoglycemia with a focal pancreatic lesion
  17. Diagnostic challenges in pediatric Cushing’s disease associated with chronic renal failure: a report of three patients
  18. A novel de novo missense OTC mutation in an Iranian girl: a case report
https://doi.org/10.1515/jpem-2024-0512
Schlagwörter für diesen Artikel
antisclerostin antibodies; bisphosphonates; COL1A1 mutations; denosumab
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Review
  3. Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children
  4. Opinion Paper
  5. CRH receptor antagonist crinecerfont – a promising new treatment option for patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  6. Original Articles
  7. Age and sex mark clinical differences in the presentation of pediatric type 1 diabetes mellitus
  8. Geographic information system mapping and predictors of glycemic control in children and youth with type 1 diabetes: a study from Western India
  9. Body composition assessment measured via bioelectrical impedance analysis in euthyroid children with newly diagnosed Hashimoto’s thyroiditis
  10. Outcomes of newborns screened for congenital hypothyroidism in Turkey – a single center experience
  11. High yield of congenital hypothyroidism among infants attending Children Hospital, Nairobi, Kenya. Facility based study in the absence of newborn screening
  12. Immune checkpoint inhibitors and endocrinopathies in pediatric brain tumor patients
  13. Assessment of quality of life in families affected by maple syrup urine disease: a cross sectional study
  14. Case Reports
  15. Reninoma: an unusual cause of growth failure
  16. Persistent hypoglycemia in congenital syphilis: hyperinsulinemic hypoglycemia with a focal pancreatic lesion
  17. Diagnostic challenges in pediatric Cushing’s disease associated with chronic renal failure: a report of three patients
  18. A novel de novo missense OTC mutation in an Iranian girl: a case report
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