RARE DISEASE
Idiopathic juvenile osteoporosis
Idiopathic juvenile osteoporosis
Idiopathic juvenile osteoporosis
Synonyms: IJO, Juvenile osteoporosis
Synonyms: IJO, Juvenile osteoporosis
Synonyms: IJO, Juvenile osteoporosis
Drug discovery
1
drug
With orphan designation
Overview
Idiopathic juvenile osteoporosis (IJO) is a rare, self-limiting primary osteoporosis affecting prepubertal children (typically 8–14 years), characterized by vertebral/metaphyseal fractures, back pain, and gait abnormalities. Diagnosis requires exclusion of secondary causes and genetic disorders. Management focuses on fracture prevention, physical therapy, calcium/vitamin D supplementation, and bisphosphonates in severe cases. Most recover bone density post-puberty, though severe cases may result in permanent kyphoscoliosis or rib deformities [1][2][6][15].
Burden
90% achieve spontaneous remission post-puberty, but ~10% develop permanent spinal deformities [1][7]
Causes recurrent fractures (average 2–5 per year during active phase), impacting school attendance and quality of life [15][19]
Diagnostic delays common due to symptom overlap with rheumatic disorders [4][14]
Therapies
Conservative: Weight-bearing restrictions, calcium (1,000–1,300 mg/day), and vitamin D (600–1,000 IU/day) [3][8]
Pharmacologic: Off-label bisphosphonates (e.g., zoledronic acid) for vertebral fractures or severe bone loss [8][15]
Supportive: Physical therapy to maintain mobility and prevent disuse atrophy [7][11]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
66 drug discovery papers about Idiopathic juvenile osteoporosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
66 drug discovery papers about Idiopathic juvenile osteoporosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-23 | Effects of Puberty on Human Mesenchymal Stem Cells
Background/Objectives It is known that failure to gain sufficient bone during skeletal growth and maturation phases predisposes to the development of senile osteoporosis as age-related bone loss ensues. There is limited knowledge about factors that are necessary for the pubertal growth spurt and achievement of peak bone mass. Diminution or disappearance of Juvenile Protective Factors (JPFs) after a given maturational stage could contribute to the onset of age-related declines in a variety of physiological functions, including bone physiology. Methods With available pediatric platelet-poor plasma (PPP) and mesenchymal/skeletal stem cells (MSCs), we tested whether proteomics and RNA-seq methodology have potential for the discovery of novel regulators of pubertal skeletal growth. Results Our data demonstrate that pediatric PPP rejuvenates age-related compromised MSC functions; that Mass Spectrometry (MS)-based proteomics identified known and novel circulating tissue growth/trophic factors in human PPP of pubertal, as compared with pre-pubertal, and post-pubertal subjects; and that the unbiased RNA-Seq approach revealed new genes and networks of genes that are dramatically elevated or diminished in pubertal MSCs. Conclusions The findings support the hypothesis that the characterization of pro-osteogenic JPFs could lead to the identification of novel therapeutic approaches to promote bone health in the elderly and of potential treatment regimens for senile osteoporosis.
2024-07-17 | BONE HEALTH SURVEILLANCE AMONG AT-RISK CHILDREN AND ADOLESCENTS IN KUCHING, SARAWAK, MALAYSIA
INTRODUCTION/BACKGROUNDChronic health conditions impose poor bone health due to underlying inflammatory conditions, reduced weightbearing activity and pubertal delay. METHODSThis prospective study was conducted as the pilot project for bone health surveillance among at-risk children and adolescents followed up by a multidisciplinary team from Paediatrics Department, Sarawak General Hospital from January to February 2024. A bone health screening questionnaire was administered, followed by a physical examination, and biochemical and radiological investigation. CASEA total of sixteen subjects (6 males, 10 females) with a mean age of 10.7 ± 2.74 years were recruited. Four subjects had primary bone disorders, while another 8 subjects (50.0%) had exposure to glucocorticoids for the management of various condition including systemic lupus erythematous (2 subjects, 12.5%), juvenile dermatomyositis (2 subjects, 12.5%), juvenile idiopathic arthritis (1 subjects, 6.3%), ANCA vasculitis (1 subject, 6.3%), autoimmune hepatitis (1 subject, 6.3%) and acute lymphoblastic leukaemia (1 subject, 6.3%). Only half of the subjects elicited adequate dairy consumption and took vitamin D supplements in the form of cholecalciferol or alfacalcidol. Sedentary lifestyle was observed in two thirds of the subjects. The physical stigmata of bone fragility disorders were present in 4 patients, and they had genetic confirmation of osteogenesis imperfecta. Five subjects (31.3%) had fracture of long bones, as well as osteoporosis. Bone-active therapy with bisphosphonate had commenced in three patients. Serum 25-hydroxy vitamin D and parathyroid level were examined in 5 subjects and 2 subjects were detected to have vitamin D deficiency. Four subjects (25.0%) displayed vertebral fractures. Overall, the mean areal bone mineral density Z- scores were -2.78 ± 1.74 for hip, -1.87 ± 1.71 for lumbar spines and -3.07 ± 2.16 for total body less head. CONCLUSIONBone health screening among the children and adolescents vulnerable to osteoporosis should be imparted as the standard of care.
2024-06-12 | High-molecular-weight Hyaluronan Administration Inhibits Bone Resorption and Promotes Bone Formation in Young-age Osteoporosis Rats.
Osteoporosis poses a significant global health concern, affecting both the elderly and young individuals, including athletes. Despite the development of numerous antiosteoporotic drugs, addressing the unique needs of young osteoporosis patients remains challenging. This study focuses on young rats subjected to ovariectomy (OVX) to explore the impact of high-molecular-weight hyaluronan (HA) on preventing OVX-induced osteoporosis. Twenty-four rats underwent OVX, while 12 underwent sham procedures (sham control group). Among the OVX rats, half received subcutaneous injections of HA (MW: 2700 kDa) at 10 mg/kg/week into their backs (OVX-HA group), whereas the other half received saline injections (0.5 ml/week) at the same site (OVX-saline group). OVX-HA group exhibited significantly higher percentages of osteoclast surface (Oc. S/BS), osteoblast surface per bone surface (Ob. S/BS), and bone volume/tissue volume (BV/TV) compared with OVX-saline group at the same age. The proportions of Ob. S/BS and BV/TV in the OVX-HA group closely resembled those of the sham control group, whereas the proportion of Oc. S/BS in the OVX-HA group was notably higher than that in the sham control group. In summary, the administration of HA significantly mitigated bone resorption and enhanced bone formation, suggesting a crucial role for HA in the treatment of young adult osteoporosis.
2024-02-26 | Effectiveness and safety of pamidronate treatment in nonambulatory children with low bone mineral density
Purpose: Nonambulatory pediatric patients may have low bone mineral density (BMD) and increased risk of pathologic fractures. Though bisphosphonate therapy is the mainstream medical intervention in these children, clinical data regarding this treatment are limited. Therefore, this study aimed to evaluate the effectiveness and safety of bisphosphonate therapy in such children.Methods: We conducted a retrospective study of 21 nonambulatory children (Gross Motor Function Classification System level V) with BMD z-score ≤ -2.0 who were treated with intravenous pamidronate for at least 1 year. These patients received pamidronate every 4 months at a dose of 1.0 to 3.0 mg/kg for each cycle and had regular follow-ups for at least 1 year. The main outcome measures were changes in BMD, risk rate of fracture, biochemical data, and adverse events.Results: The average duration of pamidronate treatment was 2.0±0.9 years, and the mean cumulative dose of pamidronate according to body weight was 7.7±2.5 mg/kg/yr. After treatment, the mean lumbar spine bone mineral content, BMD, and height-for-age-z-score-adjusted BMD z-score (BMDhazZ) significantly improved. The relative risk of fracture after treatment was 0.21 (<i>p</i>=0.0032), suggesting that pamidronate treatment reduced fracture incidence significantly. The increase in the average dose per body weight in each cycle significantly increased the changes in BMDhazZ.Conclusion: Pamidronate treatment improved the bone health of nonambulatory children with low bone density without any significant adverse events. Independent of cumulative dosage and duration of treatment, the effectiveness of pamidronate increased significantly with an increase in the average dose per body weight in subsequent cycles.
2022-02-24 | Idiopathic juvenile osteoporosis in a child: a four-year follow-up with review of literature.
Childhood osteoporosis is an uncommon condition that usually develops secondary to underlying disease states. Idiopathic juvenile osteoporosis or early onset osteoporosis is a rare cause of primary osteoporosis in childhood associated with mutations in "bone fragility" genes. The index case presented with upper back pain and was detected to have multiple vertebral fractures. Further workup for the cause revealed a homozygous benign mutation in low-density lipoprotein receptor-related protein 5, which was also detected in the mother who remained asymptomatic till presentation. The child was successfully treated with intravenous zoledronate. The case report describes the management approach and four-year follow-up of the child.
proteins
2017-09-22 | PTH(1-34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology.
Treatment of secondary pediatric osteoporosis-particularly that due to chronic diseases, immobilization, and necessary medical treatments-is currently limited by a poor understanding of the long-term efficacy and safety of skeletal metabolism modifying drugs. This study aimed to characterize longitudinal effects of representative anabolic (parathyroid hormone, PTH) and anti-catabolic (zoledronic acid, ZA) drugs on skeletal morphology, mechanical strength, and growth in juvenile mice. BALB/cJ mice aged 4 weeks were given PTH(1-34) or vehicle (control) daily for 8 weeks, or 4 weekly doses of ZA, and evaluated at time points 0-26 weeks after treatment initiation. There were no enduring differences in body length or mass between treatment groups. ZA increased femur size as early as week 0, including increased distal femur bone volume and diaphyseal cross-sectional area, persisting through week 26. PTH treatment only transiently increased bone size, including distal femur volume at weeks 4-12. ZA decreased diaphyseal cortical tissue mineral density (TMD) at 12-26 weeks versus controls; PTH decreased TMD only at 2 weeks (vs. controls). ZA increased bending strength at 0-12 weeks and flexural strength at week 4 (vs. controls), but decreased flexural strength and modulus at week 26. PTH treatment increased bending strength only at 4 weeks, and did not affect flexural strength. Overall, ZA rapidly and persistently increased femur strength and size, but compromised bone material quality long-term. In healthy juvenile mice, limited-duration PTH treatment did not exert a strong anabolic effect, and had no adverse effects on femur strength, morphology, or growth. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1707-1715, 2017.
antibodies
2022-06-15 | Siglec-15-targeting therapy protects against glucocorticoid-induced osteoporosis of growing skeleton in juvenile rats.
Effective treatment of juvenile osteoporosis, which is frequently caused by glucocorticoid (GC) therapy, has not been established due to limited data regarding the efficacy and adverse effects of antiresorptive therapies on the growing skeleton. We previously demonstrated that sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) targeting therapy, which interferes with osteoclast terminal differentiation in the secondary, but not primary, spongiosa, increased bone mass without adverse effects on skeletal growth, whereas bisphosphonate, a first-line treatment for osteoporosis, increased bone mass but impaired long bone growth in healthy growing rats. In the present study, we investigated the efficacy of anti-Siglec-15 neutralizing antibody (Ab) therapy against GC-induced osteoporosis in a growing rat model. GC decreased bone mass and deteriorated mechanical properties of bone, due to a disproportionate increase in bone resorption. Both anti-Siglec-15 Ab and alendronate (ALN) showed protective effects against GC-induced bone loss by suppressing bone resorption, which was more pronounced with anti-Siglec-15 Ab treatment, possibly due to a reduced negative impact on bone formation. ALN induced histological abnormalities in the growth plate and morphological abnormalities in the long bone metaphysis but did not cause significant growth retardation. Conversely, anti-Siglec-15 Ab did not show any negative impact on the growth plate and preserved normal osteoclast and chondroclast function at the primary spongiosa. Taken together, these results suggest that anti-Siglec-15 targeting therapy could be a safe and efficacious prophylactic therapy for GC-induced osteoporosis in juvenile patients.
2018-08-01 | Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth
The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups: control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4 mg/kg every 3 weeks), and alendronate (ALN) (0.028 or 0.14 mg/kg twice per week). Treatment commenced at 6 weeks of age and continued for the next 6 weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis.
small molecules
2026-04-23 | Effects of Puberty on Human Mesenchymal Stem Cells
Background/Objectives It is known that failure to gain sufficient bone during skeletal growth and maturation phases predisposes to the development of senile osteoporosis as age-related bone loss ensues. There is limited knowledge about factors that are necessary for the pubertal growth spurt and achievement of peak bone mass. Diminution or disappearance of Juvenile Protective Factors (JPFs) after a given maturational stage could contribute to the onset of age-related declines in a variety of physiological functions, including bone physiology. Methods With available pediatric platelet-poor plasma (PPP) and mesenchymal/skeletal stem cells (MSCs), we tested whether proteomics and RNA-seq methodology have potential for the discovery of novel regulators of pubertal skeletal growth. Results Our data demonstrate that pediatric PPP rejuvenates age-related compromised MSC functions; that Mass Spectrometry (MS)-based proteomics identified known and novel circulating tissue growth/trophic factors in human PPP of pubertal, as compared with pre-pubertal, and post-pubertal subjects; and that the unbiased RNA-Seq approach revealed new genes and networks of genes that are dramatically elevated or diminished in pubertal MSCs. Conclusions The findings support the hypothesis that the characterization of pro-osteogenic JPFs could lead to the identification of novel therapeutic approaches to promote bone health in the elderly and of potential treatment regimens for senile osteoporosis.
2024-07-17 | BONE HEALTH SURVEILLANCE AMONG AT-RISK CHILDREN AND ADOLESCENTS IN KUCHING, SARAWAK, MALAYSIA
INTRODUCTION/BACKGROUNDChronic health conditions impose poor bone health due to underlying inflammatory conditions, reduced weightbearing activity and pubertal delay. METHODSThis prospective study was conducted as the pilot project for bone health surveillance among at-risk children and adolescents followed up by a multidisciplinary team from Paediatrics Department, Sarawak General Hospital from January to February 2024. A bone health screening questionnaire was administered, followed by a physical examination, and biochemical and radiological investigation. CASEA total of sixteen subjects (6 males, 10 females) with a mean age of 10.7 ± 2.74 years were recruited. Four subjects had primary bone disorders, while another 8 subjects (50.0%) had exposure to glucocorticoids for the management of various condition including systemic lupus erythematous (2 subjects, 12.5%), juvenile dermatomyositis (2 subjects, 12.5%), juvenile idiopathic arthritis (1 subjects, 6.3%), ANCA vasculitis (1 subject, 6.3%), autoimmune hepatitis (1 subject, 6.3%) and acute lymphoblastic leukaemia (1 subject, 6.3%). Only half of the subjects elicited adequate dairy consumption and took vitamin D supplements in the form of cholecalciferol or alfacalcidol. Sedentary lifestyle was observed in two thirds of the subjects. The physical stigmata of bone fragility disorders were present in 4 patients, and they had genetic confirmation of osteogenesis imperfecta. Five subjects (31.3%) had fracture of long bones, as well as osteoporosis. Bone-active therapy with bisphosphonate had commenced in three patients. Serum 25-hydroxy vitamin D and parathyroid level were examined in 5 subjects and 2 subjects were detected to have vitamin D deficiency. Four subjects (25.0%) displayed vertebral fractures. Overall, the mean areal bone mineral density Z- scores were -2.78 ± 1.74 for hip, -1.87 ± 1.71 for lumbar spines and -3.07 ± 2.16 for total body less head. CONCLUSIONBone health screening among the children and adolescents vulnerable to osteoporosis should be imparted as the standard of care.
2024-06-12 | High-molecular-weight Hyaluronan Administration Inhibits Bone Resorption and Promotes Bone Formation in Young-age Osteoporosis Rats.
Osteoporosis poses a significant global health concern, affecting both the elderly and young individuals, including athletes. Despite the development of numerous antiosteoporotic drugs, addressing the unique needs of young osteoporosis patients remains challenging. This study focuses on young rats subjected to ovariectomy (OVX) to explore the impact of high-molecular-weight hyaluronan (HA) on preventing OVX-induced osteoporosis. Twenty-four rats underwent OVX, while 12 underwent sham procedures (sham control group). Among the OVX rats, half received subcutaneous injections of HA (MW: 2700 kDa) at 10 mg/kg/week into their backs (OVX-HA group), whereas the other half received saline injections (0.5 ml/week) at the same site (OVX-saline group). OVX-HA group exhibited significantly higher percentages of osteoclast surface (Oc. S/BS), osteoblast surface per bone surface (Ob. S/BS), and bone volume/tissue volume (BV/TV) compared with OVX-saline group at the same age. The proportions of Ob. S/BS and BV/TV in the OVX-HA group closely resembled those of the sham control group, whereas the proportion of Oc. S/BS in the OVX-HA group was notably higher than that in the sham control group. In summary, the administration of HA significantly mitigated bone resorption and enhanced bone formation, suggesting a crucial role for HA in the treatment of young adult osteoporosis.
2024-02-26 | Effectiveness and safety of pamidronate treatment in nonambulatory children with low bone mineral density
Purpose: Nonambulatory pediatric patients may have low bone mineral density (BMD) and increased risk of pathologic fractures. Though bisphosphonate therapy is the mainstream medical intervention in these children, clinical data regarding this treatment are limited. Therefore, this study aimed to evaluate the effectiveness and safety of bisphosphonate therapy in such children.Methods: We conducted a retrospective study of 21 nonambulatory children (Gross Motor Function Classification System level V) with BMD z-score ≤ -2.0 who were treated with intravenous pamidronate for at least 1 year. These patients received pamidronate every 4 months at a dose of 1.0 to 3.0 mg/kg for each cycle and had regular follow-ups for at least 1 year. The main outcome measures were changes in BMD, risk rate of fracture, biochemical data, and adverse events.Results: The average duration of pamidronate treatment was 2.0±0.9 years, and the mean cumulative dose of pamidronate according to body weight was 7.7±2.5 mg/kg/yr. After treatment, the mean lumbar spine bone mineral content, BMD, and height-for-age-z-score-adjusted BMD z-score (BMDhazZ) significantly improved. The relative risk of fracture after treatment was 0.21 (<i>p</i>=0.0032), suggesting that pamidronate treatment reduced fracture incidence significantly. The increase in the average dose per body weight in each cycle significantly increased the changes in BMDhazZ.Conclusion: Pamidronate treatment improved the bone health of nonambulatory children with low bone density without any significant adverse events. Independent of cumulative dosage and duration of treatment, the effectiveness of pamidronate increased significantly with an increase in the average dose per body weight in subsequent cycles.
2022-02-24 | Idiopathic juvenile osteoporosis in a child: a four-year follow-up with review of literature.
Childhood osteoporosis is an uncommon condition that usually develops secondary to underlying disease states. Idiopathic juvenile osteoporosis or early onset osteoporosis is a rare cause of primary osteoporosis in childhood associated with mutations in "bone fragility" genes. The index case presented with upper back pain and was detected to have multiple vertebral fractures. Further workup for the cause revealed a homozygous benign mutation in low-density lipoprotein receptor-related protein 5, which was also detected in the mother who remained asymptomatic till presentation. The child was successfully treated with intravenous zoledronate. The case report describes the management approach and four-year follow-up of the child.
proteins
2017-09-22 | PTH(1-34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology.
Treatment of secondary pediatric osteoporosis-particularly that due to chronic diseases, immobilization, and necessary medical treatments-is currently limited by a poor understanding of the long-term efficacy and safety of skeletal metabolism modifying drugs. This study aimed to characterize longitudinal effects of representative anabolic (parathyroid hormone, PTH) and anti-catabolic (zoledronic acid, ZA) drugs on skeletal morphology, mechanical strength, and growth in juvenile mice. BALB/cJ mice aged 4 weeks were given PTH(1-34) or vehicle (control) daily for 8 weeks, or 4 weekly doses of ZA, and evaluated at time points 0-26 weeks after treatment initiation. There were no enduring differences in body length or mass between treatment groups. ZA increased femur size as early as week 0, including increased distal femur bone volume and diaphyseal cross-sectional area, persisting through week 26. PTH treatment only transiently increased bone size, including distal femur volume at weeks 4-12. ZA decreased diaphyseal cortical tissue mineral density (TMD) at 12-26 weeks versus controls; PTH decreased TMD only at 2 weeks (vs. controls). ZA increased bending strength at 0-12 weeks and flexural strength at week 4 (vs. controls), but decreased flexural strength and modulus at week 26. PTH treatment increased bending strength only at 4 weeks, and did not affect flexural strength. Overall, ZA rapidly and persistently increased femur strength and size, but compromised bone material quality long-term. In healthy juvenile mice, limited-duration PTH treatment did not exert a strong anabolic effect, and had no adverse effects on femur strength, morphology, or growth. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1707-1715, 2017.
antibodies
2022-06-15 | Siglec-15-targeting therapy protects against glucocorticoid-induced osteoporosis of growing skeleton in juvenile rats.
Effective treatment of juvenile osteoporosis, which is frequently caused by glucocorticoid (GC) therapy, has not been established due to limited data regarding the efficacy and adverse effects of antiresorptive therapies on the growing skeleton. We previously demonstrated that sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) targeting therapy, which interferes with osteoclast terminal differentiation in the secondary, but not primary, spongiosa, increased bone mass without adverse effects on skeletal growth, whereas bisphosphonate, a first-line treatment for osteoporosis, increased bone mass but impaired long bone growth in healthy growing rats. In the present study, we investigated the efficacy of anti-Siglec-15 neutralizing antibody (Ab) therapy against GC-induced osteoporosis in a growing rat model. GC decreased bone mass and deteriorated mechanical properties of bone, due to a disproportionate increase in bone resorption. Both anti-Siglec-15 Ab and alendronate (ALN) showed protective effects against GC-induced bone loss by suppressing bone resorption, which was more pronounced with anti-Siglec-15 Ab treatment, possibly due to a reduced negative impact on bone formation. ALN induced histological abnormalities in the growth plate and morphological abnormalities in the long bone metaphysis but did not cause significant growth retardation. Conversely, anti-Siglec-15 Ab did not show any negative impact on the growth plate and preserved normal osteoclast and chondroclast function at the primary spongiosa. Taken together, these results suggest that anti-Siglec-15 targeting therapy could be a safe and efficacious prophylactic therapy for GC-induced osteoporosis in juvenile patients.
2018-08-01 | Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth
The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups: control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4 mg/kg every 3 weeks), and alendronate (ALN) (0.028 or 0.14 mg/kg twice per week). Treatment commenced at 6 weeks of age and continued for the next 6 weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Idiopathic juvenile osteoporosis.
1 orphan drug designation for Idiopathic juvenile osteoporosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Teriparatide | proteins | FDA | 1999-10-28 | — | Biomeasure, Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.