RARE DISEASE
Osteopetrosis and related disorders
Osteopetrosis and related disorders
Osteopetrosis and related disorders
Drug discovery
1
drug
With orphan designation
Overview
Osteopetrosis is a group of rare genetic disorders characterized by defective osteoclast-mediated bone resorption, leading to abnormally dense, brittle bones and complications such as fractures, bone marrow failure, and cranial nerve compression. Major types include autosomal dominant (ADO, Albers-Schönberg disease), autosomal recessive (ARO), and intermediate forms, with severity ranging from asymptomatic to life-threatening manifestations in infancy [1][3][7][12].
Burden
Mortality: Untreated ARO is fatal in infancy/early childhood due to marrow failure or infections [3][7].
Morbidity: Chronic pain, recurrent fractures, vision/hearing loss, and growth retardation [1][12].
Healthcare costs: High due to complex management, HSCT, and lifelong multidisciplinary care [5][15].
Therapies
Severe ARO: Hematopoietic stem cell transplantation (HSCT) to address bone marrow failure and metabolic defects; limited efficacy in neurodegenerative subtypes [5][9].
Mild/ADO: Supportive care (fracture management, physical therapy), calcium/vitamin D supplementation, interferon gamma-1b to enhance osteoclast activity [2][9][15].
Complications: Surgery for fractures/deformities, antibiotics for osteomyelitis, and multidisciplinary care for neurological, dental, and hematological issues [2][12].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare transplant-related disorders
Research Papers
1,713 drug discovery papers about Osteopetrosis and related disorders, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,713 drug discovery papers about Osteopetrosis and related disorders, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-15 | PIDDosome deficiency impairs bone remodeling by increasing osteoclast ploidy and function.
Osteoporosis is a chronic disease driven by an imbalance between bone-building osteoblasts and bone-resorbing osteoclasts, whose hyperactivation can promote this condition. Osteoclasts are multinucleated cells, and their activity directly correlates with their ploidy level. Multinucleation associates with the accumulation of extra centrosomes that can activate the PIDDosome pathway. Depending on cell type, this can lead to a p53/p21-mediated cell cycle arrest, or BCL2-regulated apoptosis. Here, we report that the PIDDosome controls polyploidization in osteoclasts and its absence triggers bone erosion in mice. PIDDosome activation in osteoclasts depends on the presence of extra centrosomes bearing the distal appendage protein ANKRD26. Consistently, loss of Ankrd26 phenocopies PIDDosome-deficiency in osteoclasts. Surprisingly, p53 and p21, which restrict cell cycle progression in the presence of extra centrosomes, are not involved in limiting osteoclast polyploidization and function. In support of this notion, bones from p53-/- mice display a higher trabecular bone mass phenotype, and osteoclasts generated from p21-/- mice show normal OC ploidy and function. Altogether, we document that the PIDDosome regulates bone homeostasis by regulating osteoclast polyploidization and their bone-resorbing function independently of the canonical p53/p21 axis, hinting towards unknown downstream effectors. We propose that modulation of PIDDosome activation might be therapeutically exploited for osteoporosis treatment, while its inhibition may ameliorate osteopetrosis symptoms.
2026-08-14 | Neonatal hypocalcemia and hydrocephalus as early manifestations of intermediate osteopetrosis: successful hematopoietic stem cell transplantation despite negative genetic testing: a case report.
Osteopetrosis is a rare genetic skeletal disorder caused by defective osteoclast-mediated bone resorption, leading to increased bone density and complications including hypocalcemia, pancytopenia, cranial nerve compression, and, more rarely, hydrocephalus. We report a rare case of intermediate osteopetrosis presenting with neonatal hypocalcemia and progressive macrocephaly. Brain magnetic resonance imaging confirmed obstructive hydrocephalus, which was treated with ventriculoperitoneal shunting. Clinical and radiological findings supported the diagnosis of osteopetrosis, although targeted genetic testing and whole exome sequencing did not identify a causative variant. The patient was treated with calcium gluconate and vitamin D supplementation, followed by hematopoietic stem cell transplantation from an HLA-matched unrelated donor using peripheral blood stem cells. This case highlights the importance of early recognition and timely hematopoietic stem cell transplantation to promote successful engraftment and improve long-term outcomes, even in the absence of molecular confirmation.
2026-08-13 | Osteopetrorickets and calcium homeostasis in children with osteopetrosis: an endocrinological single-center study
Background Osteopetrosis is a rare inherited disorder caused by impaired osteoclast number or function, leading to increased bone density, fractures, neurologic complications, and disturbances in calcium-phosphate homeostasis. This study aimed to describe the endocrine manifestations of childhood osteopetrosis, particularly osteopetrorickets, and to evaluate treatment responses and post-transplant calcium disorders. Methods We retrospectively reviewed 17 children diagnosed with osteopetrosis at a single tertiary center between 2015 and 2025. Clinical, biochemical, radiologic, genetic, and treatment data were analyzed. Results The median age at diagnosis was 14 months (range, 15 days–130 months), and short stature was observed in 13 of 17 patients (76.4%). Ophthalmologic abnormalities were present in 10 patients (58.8%), hearing loss in 7 patients (41.1%), and hepatosplenomegaly in 7 patients (41.1%). TCIRG1 was the most frequent mutation, followed by CLCN7, TNFSF11, TNFRSF11A , and CA2 . Osteopetrorickets was identified in 13 of 17 patients (76.4%); among these patients, hypocalcemia occurred in 11 of 13, hypophosphatemia in 8 of 13, and vitamin D deficiency in 4 of 13. Generalized osteosclerosis was observed in all patients, whereas classic osteopetrosis-associated radiographic findings, including bone-in-bone appearance, sandwich vertebrae, and Erlenmeyer flask deformity, were identified only in a subset of patients. Hematopoietic stem cell transplantation was performed in 11 of 13 patients with osteopetrorickets. Four of these 11 patients died during the early post-transplant period. Among patients with osteopetrorickets who underwent hematopoietic stem cell transplantation (HSCT) (n=11), seven surviving patients achieved complete resolution of rickets (7/11, 63.6%), allowing discontinuation of replacement therapy within 15 days to 8 months. Post-transplant hypercalcemia developed in 4 of 13 transplant recipients (30.8%). Conclusions Osteopetrorickets is a frequent and clinically significant complication of pediatric osteopetrosis. Early recognition of mineral disturbances, genotype-based treatment planning, and close surveillance for rebound hypercalcemia after transplantation are essential to improve outcomes.
2026-07-27 | OSTM1 SUPPRESSES B-CELL MALIGNANCY THROUGH GLYCOSYLATION REGULATED UBIQUITIN E3 LIGASE ACTIVITY
Osteopetrosis-associated transmembrane protein 1 (OSTM1) is a glycosylated membrane protein essential for lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Using a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a previously unrecognized tumor suppressor in B-cell malignancies. Consistently, OSTM1 is frequently deleted or downregulated across diverse human B-cell lymphomas. In mice, B-cell specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a deletion to drive lymphomagenesis with near-complete penetrance. Mechanistically, we identify a cytosolic, non-glycosylated pool of OSTM1 that functions as a ubiquitin E3 ligase, promoting proteasomal degradation of phosphodiesterase 3B (PDE3B). As PDE3B hydrolyzes cAMP, loss of OSTM1 stabilizes PDE3B, attenuates the tumor suppressive cAMP/PKA/CREB/CREBBP signaling, and enhances oncogenic transformation. Notably, genetic or pharmacological inhibition of PDE3B limits tumor cell growth and sensitizes cells to PI3K inhibition. Together, these findings establish OSTM1 as a tumor suppressor and reveal PDE3B signaling as a therapeutic vulnerability in B-cell lymphoma.
2026-06-29 | A Novel Homozygous T-Cell Immune Regulator 1 (TCIRG1) Stop-Gain Variant Causing Malignant Infantile Osteopetrosis
Malignant infantile osteopetrosis (MIOP) is a rare life-threatening autosomal recessive disorder characterized by defective osteoclast-mediated bone resorption, most commonly caused by pathogenic variants in the TCIRG1 gene. Without hematopoietic stem cell transplantation (HSCT), the disease is associated with severe morbidity and early mortality. We report a 15-month-old Moroccan girl born to first-cousin consanguineous parents who initially presented during infancy with failure to thrive, persistent bicytopenia, developmental delay, axial hypotonia, divergent strabismus with nystagmus, and facial dysmorphism. Skeletal radiographs demonstrated diffuse osteosclerosis, obliteration of medullary cavities, and characteristic Erlenmeyer flask deformities, strongly suggestive of MIOP. Whole-exome sequencing identified a novel homozygous pathogenic variant in T-cell immune regulator 1 (TCIRG1) (NM_006019.4:c.1897C>T; p.Gln633Ter). The variant is absent from the gnomAD database and was classified as pathogenic according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. To the best of our knowledge, this variant has not previously been reported in affected individuals. The patient is currently undergoing evaluation for HSCT. This case expands the mutational spectrum of TCIRG1-associated MIOP and highlights the importance of early genomic testing in infants from consanguineous families presenting with unexplained cytopenias, growth failure, and characteristic skeletal abnormalities.
2026-08-15 | PIDDosome deficiency impairs bone remodeling by increasing osteoclast ploidy and function.
Osteoporosis is a chronic disease driven by an imbalance between bone-building osteoblasts and bone-resorbing osteoclasts, whose hyperactivation can promote this condition. Osteoclasts are multinucleated cells, and their activity directly correlates with their ploidy level. Multinucleation associates with the accumulation of extra centrosomes that can activate the PIDDosome pathway. Depending on cell type, this can lead to a p53/p21-mediated cell cycle arrest, or BCL2-regulated apoptosis. Here, we report that the PIDDosome controls polyploidization in osteoclasts and its absence triggers bone erosion in mice. PIDDosome activation in osteoclasts depends on the presence of extra centrosomes bearing the distal appendage protein ANKRD26. Consistently, loss of Ankrd26 phenocopies PIDDosome-deficiency in osteoclasts. Surprisingly, p53 and p21, which restrict cell cycle progression in the presence of extra centrosomes, are not involved in limiting osteoclast polyploidization and function. In support of this notion, bones from p53-/- mice display a higher trabecular bone mass phenotype, and osteoclasts generated from p21-/- mice show normal OC ploidy and function. Altogether, we document that the PIDDosome regulates bone homeostasis by regulating osteoclast polyploidization and their bone-resorbing function independently of the canonical p53/p21 axis, hinting towards unknown downstream effectors. We propose that modulation of PIDDosome activation might be therapeutically exploited for osteoporosis treatment, while its inhibition may ameliorate osteopetrosis symptoms.
2026-08-14 | Neonatal hypocalcemia and hydrocephalus as early manifestations of intermediate osteopetrosis: successful hematopoietic stem cell transplantation despite negative genetic testing: a case report.
Osteopetrosis is a rare genetic skeletal disorder caused by defective osteoclast-mediated bone resorption, leading to increased bone density and complications including hypocalcemia, pancytopenia, cranial nerve compression, and, more rarely, hydrocephalus. We report a rare case of intermediate osteopetrosis presenting with neonatal hypocalcemia and progressive macrocephaly. Brain magnetic resonance imaging confirmed obstructive hydrocephalus, which was treated with ventriculoperitoneal shunting. Clinical and radiological findings supported the diagnosis of osteopetrosis, although targeted genetic testing and whole exome sequencing did not identify a causative variant. The patient was treated with calcium gluconate and vitamin D supplementation, followed by hematopoietic stem cell transplantation from an HLA-matched unrelated donor using peripheral blood stem cells. This case highlights the importance of early recognition and timely hematopoietic stem cell transplantation to promote successful engraftment and improve long-term outcomes, even in the absence of molecular confirmation.
2026-08-13 | Osteopetrorickets and calcium homeostasis in children with osteopetrosis: an endocrinological single-center study
Background Osteopetrosis is a rare inherited disorder caused by impaired osteoclast number or function, leading to increased bone density, fractures, neurologic complications, and disturbances in calcium-phosphate homeostasis. This study aimed to describe the endocrine manifestations of childhood osteopetrosis, particularly osteopetrorickets, and to evaluate treatment responses and post-transplant calcium disorders. Methods We retrospectively reviewed 17 children diagnosed with osteopetrosis at a single tertiary center between 2015 and 2025. Clinical, biochemical, radiologic, genetic, and treatment data were analyzed. Results The median age at diagnosis was 14 months (range, 15 days–130 months), and short stature was observed in 13 of 17 patients (76.4%). Ophthalmologic abnormalities were present in 10 patients (58.8%), hearing loss in 7 patients (41.1%), and hepatosplenomegaly in 7 patients (41.1%). TCIRG1 was the most frequent mutation, followed by CLCN7, TNFSF11, TNFRSF11A , and CA2 . Osteopetrorickets was identified in 13 of 17 patients (76.4%); among these patients, hypocalcemia occurred in 11 of 13, hypophosphatemia in 8 of 13, and vitamin D deficiency in 4 of 13. Generalized osteosclerosis was observed in all patients, whereas classic osteopetrosis-associated radiographic findings, including bone-in-bone appearance, sandwich vertebrae, and Erlenmeyer flask deformity, were identified only in a subset of patients. Hematopoietic stem cell transplantation was performed in 11 of 13 patients with osteopetrorickets. Four of these 11 patients died during the early post-transplant period. Among patients with osteopetrorickets who underwent hematopoietic stem cell transplantation (HSCT) (n=11), seven surviving patients achieved complete resolution of rickets (7/11, 63.6%), allowing discontinuation of replacement therapy within 15 days to 8 months. Post-transplant hypercalcemia developed in 4 of 13 transplant recipients (30.8%). Conclusions Osteopetrorickets is a frequent and clinically significant complication of pediatric osteopetrosis. Early recognition of mineral disturbances, genotype-based treatment planning, and close surveillance for rebound hypercalcemia after transplantation are essential to improve outcomes.
2026-07-27 | OSTM1 SUPPRESSES B-CELL MALIGNANCY THROUGH GLYCOSYLATION REGULATED UBIQUITIN E3 LIGASE ACTIVITY
Osteopetrosis-associated transmembrane protein 1 (OSTM1) is a glycosylated membrane protein essential for lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Using a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a previously unrecognized tumor suppressor in B-cell malignancies. Consistently, OSTM1 is frequently deleted or downregulated across diverse human B-cell lymphomas. In mice, B-cell specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a deletion to drive lymphomagenesis with near-complete penetrance. Mechanistically, we identify a cytosolic, non-glycosylated pool of OSTM1 that functions as a ubiquitin E3 ligase, promoting proteasomal degradation of phosphodiesterase 3B (PDE3B). As PDE3B hydrolyzes cAMP, loss of OSTM1 stabilizes PDE3B, attenuates the tumor suppressive cAMP/PKA/CREB/CREBBP signaling, and enhances oncogenic transformation. Notably, genetic or pharmacological inhibition of PDE3B limits tumor cell growth and sensitizes cells to PI3K inhibition. Together, these findings establish OSTM1 as a tumor suppressor and reveal PDE3B signaling as a therapeutic vulnerability in B-cell lymphoma.
2026-06-29 | A Novel Homozygous T-Cell Immune Regulator 1 (TCIRG1) Stop-Gain Variant Causing Malignant Infantile Osteopetrosis
Malignant infantile osteopetrosis (MIOP) is a rare life-threatening autosomal recessive disorder characterized by defective osteoclast-mediated bone resorption, most commonly caused by pathogenic variants in the TCIRG1 gene. Without hematopoietic stem cell transplantation (HSCT), the disease is associated with severe morbidity and early mortality. We report a 15-month-old Moroccan girl born to first-cousin consanguineous parents who initially presented during infancy with failure to thrive, persistent bicytopenia, developmental delay, axial hypotonia, divergent strabismus with nystagmus, and facial dysmorphism. Skeletal radiographs demonstrated diffuse osteosclerosis, obliteration of medullary cavities, and characteristic Erlenmeyer flask deformities, strongly suggestive of MIOP. Whole-exome sequencing identified a novel homozygous pathogenic variant in T-cell immune regulator 1 (TCIRG1) (NM_006019.4:c.1897C>T; p.Gln633Ter). The variant is absent from the gnomAD database and was classified as pathogenic according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. To the best of our knowledge, this variant has not previously been reported in affected individuals. The patient is currently undergoing evaluation for HSCT. This case expands the mutational spectrum of TCIRG1-associated MIOP and highlights the importance of early genomic testing in infants from consanguineous families presenting with unexplained cytopenias, growth failure, and characteristic skeletal abnormalities.
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Drug Discovery Landscape
1 orphan drug designation for Osteopetrosis and related disorders.
1 orphan drug designation for Osteopetrosis and related disorders.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous haematopoietic stem and progenitor cell population containing CD34+ cells transduced with a lentiviral vector encoding the TCIRG1 cDNA ex vivo expanded | gene therapies | EMA | 2021-10-15 | — | Fondazione Telethon Ets |
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