Bone Fragility Research Articles

Adapting to Adulthood: A Review of Transition Strategies for Osteogenesis Imperfecta

AbstractOsteogenesis Imperfecta (OI), known as “brittle bone disease,” presents a rare genetic disorder characterized by bone fragility, often accompanied by skeletal deformities and extraskeletal complications. OI is primarily associated with collagen type I defects, responsible for the syndromic nature of the disease affecting a broad range of tissues. As such, its multisystemic complexity necessitates multidisciplinary care approaches in all patient life stages. OI treatment remains largely supportive, commonly including bisphosphonates and orthopedic surgeries, which show promise in children. Although rehabilitation programs for children exist, guidelines for adult care and especially the transition from pediatric to adult care, are lagging behind in OI care and research. The current systematic review summarizes the literature on OI patient pediatric to adult care transition experiences and compares OI transition approaches to other chronic diseases. The review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were conducted across multiple databases. Search terms encompassed synonyms and closely related phrases relevant to “OI” and “Transition to adult care”. The initial screening involved the evaluation of article titles, followed by a thorough review of abstracts to assess relevance for the purpose of the current review. Programs aimed at easing the transition from pediatric to adult OI care necessitate a multifaceted approach. Collaborative efforts between different medical disciplines including pediatricians, endocrinologists, orthopedics, cardiology, pulmonology, ophthalmology, otolaryngologists, maxillofacial specialists, psychologists and medical genetics, are crucial for addressing the diverse needs of OI patients during this critical life phase. Comprehensive education, readiness assessments, personalized transition plans, and further follow-up are essential components of a structured transition framework. Further research is warranted to evaluate the feasibility and efficacy of sequential stepwise transition systems tailored to individuals with OI.

REGγ is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis

Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a “silent disease” that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REGγ as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REGγ deficiency increased osteoclast activity and triggered bone mass loss in REGγ knockout (KO) and bone marrow-derive macrophage (BMM)-conditional REGγ KO mice. However, the osteoclast activity decreased in BMM-conditional REGγ overexpression mice. Mechanistically, we defined that REGγ-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin-independent pathway. More importantly, BMM-conditional Traf6 KO with REGγ KO mice could “rescue” the osteoporosis phenotypes. Based on NIP30 (a REGγ “inhibitor”) dephosphorylation by CKII inhibition activated the ubiquitin-independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REGγ/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis.

Abstract 4147633: Structural and Electrophysiological Cardiac Changes in Children with Osteogenesis Imperfecta (OI)

Introduction: Osteogenesis imperfecta (OI) is an inherited type 1 collagen disorder leading to bone fragility and increased fractures. Cardiovascular disease is the leading cause of death of adults with OI, but studies on cardiac changes from this collagen defect in children are sparse. We aim to fill this gap by assessing changes in EKG and echocardiogram (ECHO) variables in children with OI. Hypothesis: Children with OI will exhibit arrhythmogenic EKG changes and/or ECHO abnormalities which will precede changes that are documented in adults. Methods: 53 children with OI receiving care at Children’s Mercy-Kansas City were identified via ICD-10 codes. 64 with Duchenne Muscular Dystrophy (DMD, expected cardiac abnormalities) and 55 with non-accidental trauma (NAT, no expected cardiac abnormalities) served as controls. We specifically compared the most recent EKG and ECHO metrics extracted from medical charts by Kruskal-Wallis testing. Results: EKG: Children with OI differed from both NAT and DMD. OI had shorter median PR intervals (p<0.001) plus longer median QRS (p<0.001) and QTc intervals (p=0.002) than NAT. DMD had the shortest PR and longest QRS and QTc (see Table). Echo: The three groups showed no difference in systolic/diastolic BP or LV thickness. However, OI differed from NAT and/or DMD in other metrics. OI had higher end diastolic volume (p<0.001), end systolic volume (p<0.001) and stroke volume (p<0.05) than NAT, but lower values than the DMD group. Similarly, OI children had higher LV mass and LV internal diastolic and systolic diameters than NAT, but lower than DMD (p<0.001). OI LVOT diameter and Aortic root diameter were lower than NAT, but not as low as DMD (p<0.05 and p<0.001, respectively). Conclusion: Children with OI exhibit EKG and ECHO abnormalities that are similar to but less severe than for DMD, a group in which cardiovascular abnormalities are well documented. These abnormalities may be predictive of arrythmia/sudden cardiac death and/or functional decline in heart function. Our data suggest that OI children could benefit from ongoing routine cardiology studies along with orthopedic/metabolic management. Future studies would assess effects of age and OI treatments on cardiac abnormalities.

Height prediction of individuals with osteogenesis imperfecta by machine learning

BackgroundOsteogenesis imperfecta (OI) is a genetic disorder characterized by low bone mass, bone fragility and short stature. There is a significant gap in knowledge regarding the growth patterns across different types of OI, and the prediction of height in individuals with OI was not adequately addressed. In this study, we described the growth patterns and predicted the height of individuals with OI employing multiple machine learning (ML) models. Accurate height prediction enables effective monitoring and facilitates the development of personalized intervention plans for managing OI.MethodThis study included cross-sectional data for 323 participants with OI, and the median height Z-score for OI types I, III and IV were − 0.62 (-5.93 ~ 3.24), -3.97 (-10.44 ~ -0.02) and − 1.64 (-6.67 ~ 2.44), respectively. Based on the cross-sectional data of participants, the height curves across different gender and OI types were plotted and compared. Subsequently, feature selection techniques, specifically the filter and wrapper methods, were employed to identify predictive factors for the height of participants. Finally, multiple machine learning (ML) models were constructed for height prediction, and the performance of each model was systematically evaluated.ResultsThe analysis of height curves revealed that male with OI are significantly taller than female with OI from the age of 14 (p = 0.045), individuals with OI type III are statistically shorter than those with OI types I and IV starting from 3 years old (p = 0.006), and those with OI type IV are statistically shorter than those with OI type I from the age of 10 (p = 0.028). The application of filter and wrapper methods identified gender (p = 0.001), age (p < 0.001), Sillence types (p = 0.007), weight Z-score (p < 0.001) and aBMD Z-score (p = 0.021) as significant predictive factors for height. The optimal performance of predictive models was registered by gradient boosting classifier (GB) (bias = 5.783, accuracy = 92.59%, R2 = 0.828), random forest (RF) (bias = 6.155, accuracy = 90.12%, R2 = 0.788), ensemble machine learning (EML) (bias = 6.250, accuracy = 91.36%, R2 = 0.825) and deep neuron networks (DNNs) (bias = 6.223, accuracy = 90.12%, R2 = 0.821).ConclusionThis study analyzed a large cohort of individuals with OI and provided detailed height patterns across different gender and OI types that are crucial for assessing overall growth. Gender, age, Sillence types, weight Z-score and aBMD Z-score were identified as predictive factors for height. The predictive models of GB, RF, EML and DNNs had higher accuracy to evaluate the height of individuals with OI. This study allows guardians and physicians to timely monitor the height parameters, and facilitate the creation of personalized intervention schedules tailored to the needs of individuals with OI.

Prediction of Fragility Fractures and Mortality in a Cohort of Geriatric Patients.

Risk factors of refracture after fragility fractures include osteoporosis, female gender and advanced age among others. We hypothesized that the assessment of functionality, muscle health and nutrition status contribute to the risk prediction for further fractures and death. We assessed 334 patients admitted to the department of acute geriatrics for sociodemographic data, bone fragility, selected laboratory tests, body composition and data on functionality using the comprehensive geriatric assessment. Patients had follow-ups until the occurrence of further fractures or death. Dual-energy X-ray absorptiometry and pulse echo measurements were performed to assess bone mineral density. Fracture risk was assessed using the FRAX score and muscle strength according to published guidelines on sarcopenia. The mean age was 81 years (70-95), and 82.3% (275/334) were women. An incidence of 10.4% (35/334) new fragility fractures was observed within 24 months, and the mortality rate was 12.2% (41/334). A significantly higher rate of further fractures was associated with lower BMI (body mass index) (HR 0.925, CI 0.872-0.98; p = 0.009), lower parathyroid hormone levels (HR 0.986, CI 0.973-0.998; p = 0.026) and with the diagnosis of osteoporosis (HR 2.546, CI 1.192-5.438; p = 0.016). No significant associations were present in patients with previous fractures, with higher age, higher FRAX scores, sarcopenia, in women, sarcopenic obesity, frail patients, lower grip strength, lower walking speed, lower Barthel index or lower DI (density index) values. The predictive power for further fractures was 10.7% higher adding osteosarcopenia, BMI and parathyroid hormone levels to standard assessment parameters osteoporosis, age and the status of previous fractures. Mortality was significantly higher with advanced age (HR 1.101, CI 1.052-1.151; p < 0.001), in men (HR 6.464, CI 3.141-13.305; p < 0.001), in smokers (p = 0.002), higher FRAX score (HR 1.039, CI 1.009-1.070; p = 0.010), lower renal function (HR 0.987, CI 0.976-0.997; p = 0.010), lower Tinetti test scores (HR 0.943, CI 0.900-0.987; p = 0.012), lower walking speed (HR 0.084, CI 0.018-0.382; p = 0.001), lower hand grip (HR 0.876, CI 0.836-0.919; p < 0.001) and lower Barthel index scores (HR 0.984, CI 0.971-0.997; p = 0.015). In a cohort of geriatric patients, the addition of BMI, low parathyroid hormone levels and osteosarcopenia increases the predictive power for further fractures by 10.7%. These parameters are a valuable addition to the standard assessment parameters age and history of sustained fractures. Mortality is partly associated with potentially treatable functional parameters.

Structural Variants in COL1A1 and COL1A2 in Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a heterogeneous skeletal dysplasia characterized by bone fragility, skeletal deformities, and short stature. Most commonly, it is caused by autosomal dominant variants in the type I collagen genes, COL1A1 or COL1A2. Type I collagen is the main protein of the extracellular matrix in the skeleton and changes in its structure or quantity may lead to OI. 85%-90% of OI cases occur due to sequence variants in type I collagen genes, while OI caused by structural abnormalities in type I collagen genes is less common. In most cases, haploinsufficiency of type I collagen is associated with a milder OI phenotype. Large genomic deletions often involve several genes within the same chromosomal region, leading to microdeletion syndromes with OI features. Here, we report eight Swedish patients from five unrelated families with OI due to structural variants in the COL1A1 and COL1A2 genes. One patient with OI type III had a complex rearrangement with a deletion and duplication event in COL1A2, leading to reduced COL1A2 expression. Three other patients from two different families with OI type I had whole gene deletions involving COL1A1. In one family, three affected individuals with OI type I had a small intragenic deletion of exons 11-12 in COL1A2. One patient had a 2.1 Mb de novo deletion encompassing COL1A1 and DLX3 genes and features of OI and tricho-dento-osseous syndrome. Overall, this study highlights the importance of investigating gene dosage abnormalities in patients with OI and further delineates clinical and genetic variability of OI caused by structural variants in type I collagen genes.

F2-Isoprostanes Are Associated With Increased Fracture Risk in Type 2 Diabetes.

Fracture risk is higher in type 2 diabetes (T2D) for a given bone mineral density (BMD) level. Increased oxidative stress in T2D induces diabetic complications and may affect T2D bone fragility. To investigate whether the levels of plasma F2-isoprostanes, a reliable oxidative stress marker, are associated with incident clinical fracture risk in older adults with diabetes. An observational cohort study was conducted in a well-characterized cohort from Health, Aging, and Body Composition study. Older black and white ambulatory adults with baseline plasma F2-isoprostanes measurements (baseline age 70-79 years, T2D: N=132; non-diabetes: N=571) were selected from the study cohort of 3075 individuals. Incident clinical fractures. In the Cox proportional hazard model with multivariate adjustments (including BMD, medications, and other risk factors), a 93% increase in incident clinical fracture risk was significantly associated with each SD increase in log plasma F2-isoprostanes in the T2D group (HR: 1.93, 95% CI 1.26-2.95, p=0.002), but there was no evidence of an association in the non-diabetes group (HR: 0.98, 95% CI 0.81-1.18, p=0.79, p for interaction < 0.001). Log plasma F2-isoprostanes were moderately correlated with a decline in baseline total hip BMD (r=-0.25, p=0.003), and with a 4-year decrease in total hip BMD (r=-0.28, p=0.008) in T2D. There was no evidence of correlation between log plasma F2-isoprostanes and circulating glycoxidation markers or bone turnover markers in either group. Plasma F2-isoprostanes levels in individuals with diabetes are associated with increased incident clinical fracture risk independently of baseline BMD.

Effects of COVID-19 on bone fragility: a new perspective from osteoimmunological biomarkers

Effects of COVID-19 on bone fragility: a new perspective from osteoimmunological biomarkers

Association between theSp1-binding-site polymorphism in the collagen type I alpha 1 (COLIA1) gene and bone phenotypes: the Dubbo Osteoporosis Epidemiology Study.

Polymorphisms within the collagen 1 alpha 1 gene (COLIA1) have been shown to be associated with bone mineral density (BMD). This study aimed to test the hypothesis that COLIA1 polymorphisms are associated with bone loss and fragility fractures. The study involved 809 postmenopausal women aged 60years and above in the Dubbo Osteoporosis Epidemiology Study who had COLIA1 genotypes and at least two BMD measurements over a 30-year period. BMD at the lumbar spine (LSBMD) and femoral neck (FNBMD) was measured biennially by dual-energy X-ray absorptiometry (GE-Lunar Prodigy). Fragility fracture has been ascertained by X-ray reports between 1990 and 2020. The G-> T polymorphism at the Sp1-binding site in the COLIA1 gene (rs1800012) was determined by the PCR-based method, and coded as GG, GT, and TT. Women homozygous for the minor allele (TT) tended to have greater bone loss (-0.72%/year) than those with GT (-0.58%/year) or GG (-0.56%/year) though the difference did not achieve statistical significance (P = 0.84). Women of the TT genotype were associated with a two-fold greater risk of any fracture (adjusted hazard ratio: 2.21; 95%CI 1.42-3.46) and almost fourfold greater risk of hip fracture (3.78; 1.83-7.82) than those with either GG or GT genotype. Polymorphisms at the Sp1 site in the COLIA1 gene are associated with fracture risk, independent of bone loss.

Possible role of bone turnover markers in the diagnosis of adult hypophosphatasia.

Hypophosphatasia (HPP) is a rare disorder of the bone metabolism, characterized by genetically-determined low alkaline phosphatase (ALP) activity. Low ALP may also be observed in some common causes of bone fragility, such as in osteoporosis treated with antiresorptive drugs. This study aimed to verify whether differences in bone turnover markers (BTMs) could help differentiate adult patients with HPP from those with osteoporosis undergoing antiresorptive treatment. In this multicenter study, we enrolled 23 adult patients with a diagnosis of HPP and compared them with 46 osteoporotic subjects previously treated with zoledronic acid or denosumab. BTMs such as C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I procollagen (P1NP), total ALP, and bone ALP (bALP) were measured, and ratios between BTMs were also calculated. Considering that the control group included only females, in the primary analysis we compared their characteristics with that of the 16 female patients with HPP. Both individual BTMs (CTX and P1NP) and four BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an AUC of 0.962 with a cut-off of 32μg/L, while as for the BTMs ratios, the ALP/P1NP ratio had an AUC of 0.964 with a cut-off of 1.114. Similar results were confirmed when including male HPP patients, when adjusting for age and sex, and finally when performing a sensitivity analysis only in patients with ALP less than or equal to 32U/L (i.e., the median of the distribution of the entire population). In cases of low ALP and bone fragility, BTM and their ratios could help distinguish HPP patients from osteoporotic individuals treated with antiresorptive drugs, aiding in accurate diagnosis and reducing the risk of inappropriate treatment.

Shen Gu An Capsule Inhibition of Postmenopausal Osteoporosis in Ovariectomized Mice Using Network Pharmacology-Based Mechanism Prediction and Pharmacological Validation

Background Postmenopausal osteoporosis (PMOP) is characterized by low bone mass and increased bone fragility in postmenopausal women. Shen Gu An capsule (SGA) has been clinically used to treat bone diseases, especially PMOP with kidney Yang deficiency. Objectives We aimed to study the effect of SGA on the treatment of PMOP. Methodology The key candidate targets and pathways of SGA for treating PMOP were predicted by Network pharmacology analysis. Then, in vivo validation using bilaterally ovariectomized C57BL/6 mice was performed, and the bone quality was analyzed by Micro-CT and histological analysis. Results In this study, we obtained 113 active compounds and 82 targets via the database of Traditional Chinese Medicine Systems Pharmacology. Subsequently, compound-target and protein−protein interaction networks were constructed. Then GO and KEGG analysis revealed that NF-κB signaling pathway might be the underlying mechanism as its well-known function in osteoclastogenesis. Furthermore, the in vivo experiments using ovariectomized mice demonstrated that SGA could decrease the number of osteoclasts and preserve bone mass through inhibiting the NF-κB signaling pathway. Conclusions SGA could prevent postmenopausal osteoporosis in ovariectomized mice through inhibiting NF-κB signaling pathway. The finding of this study provides more evidence for the clinical application of SGA to treat osteoporosis.

Osteoclast indices in osteogenesis imperfecta: systematic review and meta-analysis.

Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes encoding collagen type I or that affect its processing. Alterations in osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. The systematic search of Medline, Ovid, and Web of Science identified 798 unique studies. After screening, we included 23 studies for meta-analysis, reporting osteoclast parameters in 310 patients with OI of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference with 95% confidence interval (CI) was used as the effect size, and random-effects meta-analysis was performed. In patients with OI, collagen degradation markers were significantly higher compared with age-matched controls, with an effect size of 1.23 (CI: 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3- to 7-year-old age group and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers (1.16; CI: -0.22, 2.55) and osteoclast surface (0.43; CI: -0.63, 1.49), and significantly higher eroded surface (3.24; CI: 0.51, 5.96) compared with age-matched controls. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers (1.59; CI: 1.07, 2.11), in osteoclast numbers (0.94; CI: 0.50, 1.39), osteoclast surface (0.73; CI: 0.22, 1.23), and eroded surface (1.31; CI: 0.54, 2.08). The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.

Growth hormone and bone: a basic perspective.

Growth hormone is fundamental for growth during childhood and for maintaining bone mass and homeostasis in the adults. GH deficiency causes decreased bone growth and osteopenia, whereas GH excess causes increased bone fragility and decreased bone quality. In the past, it was common knowledge that GH effects on the skeletal system were due to the production of IGF1 from the liver, which has a huge bone anabolic effect per se. However, with the progress of basic research techniques new light has been shed on the mechanisms underlying GH effect in bone, and it is now clear that GH has effects that go beyond the downstream activation of liver IGFs. Therefore, the purpose of this review is to summarize the milestones in basic research that led to the discovery of GH local activity on bone.

Modulation of biomineralization morphology by phosphorylated collagen peptides: insights into osteogenesis imperfecta pathophysiology.

Osteogenesis imperfecta (OI) is a hereditary skeletal disorder characterized by bone fragility and deformities, primarily attributed to defects in type I collagen, the most abundant structural protein in humans. Multiple phosphorylation sites have been detected within collagen, suggesting that phosphorylation may influence mineralization processes, thereby impacting the development of OI. In this study, we investigated the modulation of biomineralization morphology by phosphorylated collagen peptides mimicking Gly-Ser mutations in osteogenesis imperfecta. A series of collagen peptide sequences, including GPO13S, GPO13pS, GPO12S, GPO12pS, GPO11S, and GPO11pS, were synthesized to explore the role of phosphorylation in peptide stability and its templating effect on biomineralization. The CD results indicated that the phosphorylation of Gly-pSer mutants reduces the stability of collagen peptides. SEM images revealed that phosphorylated peptides acted as templates, guiding the morphology of calcium carbonate into either olive-like or spherical structures, depending on their conformational state of the peptides. Non-phosphorylated peptides maintained a calcite crystal structure. The XRD patterns predominantly exhibited peaks associated with calcite and vaterite for GPO13pS-CaCO3, GPO12pS-CaCO3, and GPO11pS-CaCO3, and peaks associated with calcite for GPO13S-CaCO3, GPO12S-CaCO3, and GPO11S-CaCO3, indicating a transformation of mesocrystals influenced by peptide phosphorylation. Our findings elucidate the crucial role of phosphorylated collagen peptides in mediating biomineralization morphology and polymorph selection, offering insights into the complex pathophysiology of OI.

Reduced Graphene Oxide-Substituted Nanohydroxyapatite: Rejuvenating Bone-Nerve Crosstalk with Electrical Cues in a Fragility Fracture Rat Model under Hyperglycemia.

Diabetes has currently acquired the status of epidemic worldwide, and among its various pathological consequences like retinopathy and nephropathy, bone fragility fractures from diabetic osteopathy occurs in later stages and is equally destructive. Chronic hyperglycemia culminates into deteriorating microvasculature and quality of bone, making it prone to fractures. Among these, hip fractures are most common, especially in older diabetic patients apart from underlying neuropathy. Our study is an attempt to ameliorate hip fragility fracture and nerve trauma with electrical stimulation as an interface in a chronic diabetic rat model. We have fabricated reduced graphene oxide-substituted hydroxyapatite as an electroactive bone substitute and incorporated it into chitosan gelatin cryogels. The in situ reduction of graphene oxide during sintering of hydroxyapatite imparts higher potential to the fabricated composite in dealing with problem at question. The cryogels depicted optimum in vitro biocompatibility and enhanced mineralization after ectopic subcutaneous implantation in rats. The therapeutic potency of composite cryogels was evaluated in a hip fracture model with compression to the sciatic nerve in diabetic rats, mimicking the severe clinical trauma. The presence of cryogels in the femoral neck canal coupled with electrical stimulation and biochemical factors significantly improved bone regeneration in diabetic rats as depicted with microcomputed tomography analysis and histology images. The application of electrical stimulation also ameliorated the nerve trauma observed with 70% improvement in electrophysiological parameters such as the compound muscle action potential with combinatorial therapy. We therefore report the successful implication of a multitarget therapy in a chronic diabetic rat model unraveling the bone-nerve crosstalk with electroactive smart cryogels.

HR-pQCT reveals marked trabecular and cortical structural deficits in women with pregnancy and lactation associated osteoporosis (PLO).

Pregnancy and lactation associated osteoporosis (PLO) is a rare presentation of early-onset osteoporosis characterized by low trauma, spontaneous fractures during late pregnancy/lactation. Herein, we report areal BMD (aBMD) by DXA and volumetric BMD (vBMD), microarchitecture and strength at the distal radius and tibia by HR-pQCT in 59 women with PLO - in comparison to both healthy premenopausal Controls (n= 28) and premenopausal women with idiopathic osteoporotic fractures not associated with pregnancy/lactation (Non-PLO IOP;n= 50). Women with PLO (aged 34 ± 6yrs) had a more severe clinical presentation than Non-PLO IOP: 80% had vertebral and 92% had multiple fractures (P<.001). They had lower DXA aBMD at all sites vs Controls (all P<.001) and non-PLO IOP (all P<.05). By HR-pQCT, PLO had deficits in all radial/tibial density and most microarchitecture parameters, and lower bone strength than Controls (all P<.001). Compared to non-PLO IOP, PLO had lower total and trabecular density at radius and tibia (all P≤.01) and significant deficits in trabecular microstructure and cortical thickness at the radius only. We studied PLO subgroups with clinical factors potentially related to bone physiology: Within PLO, women with vertebral fractures had lower spine aBMD and higher tibial cortical porosity but were otherwise structurally similar to the nonvertebral group. Those with prior heparin exposure had larger bone size and trabecular area, and those with renal stones had smaller bone size and lower 1/3radius aBMD. We also compared groups based on postpartum timing: Recent PLO (n= 25) evaluated ≤12M postpartum, before expected recovery of pregnancy/lactation bone loss, had significantly lower aBMD than Distant PLO (n= 34) evaluated >12M postpartum. However, radial/tibial HR-pQCT measures did not differ, suggesting pre-existing and/or persistent structural deficits. This structural study increases our mechanistic understanding of the severe bone fragility presentation that characterizes PLO and also highlights areas of potential mechanistic heterogeneity that require additional investigation.

Low bone mineral density and its influencing factors in spinal muscular atrophy without disease-modifying treatment: a single-centre cross-sectional study

BackgroundChildren with spinal muscular atrophy (SMA) are at risk of low bone mineral density (BMD) and bone fragility. This study aims to assess lumbar spine BMD measured by quantitative computed tomography (QCT) and investigate influencing factors of low BMD in children with SMA without disease-modifying treatment.MethodsDemographic data, laboratory parameters, QCT data, and data on spinal radiographs were collected. A linear regression model was carried out to explore the correlations between BMD and its related factors.ResultsSixty-six patients with SMA who had complete records between July 2017 and July 2023 were analyzed, with SMA with a mean age of 5.4 years (range, 2.4–9.7 years), including type 1 in 14, type 2 in 37, and type 3 in 15. 28.8% of patients (19/66) were diagnosed with low BMD (Z-scores ≤ − 2), and the mean BMD Z-scores on QCT was − 1.5 ± 1.0. In our model, BMD Z-scores was associated with age (β=-0.153, p = 0.001). SMA phenotype and serum bone metabolism markers, such as serum phosphorus (P), alkaline phosphatase (ALP) and 25-Hydroxyvitamin D (25-OH-D) levels did not independently predict low BMD. ROC analysis showed that the age ≥ 6.3 years predicts a Z-scores ≤ -2.0 with a sensitivity of 68.4% and a specificity of 68.1%.ConclusionsLow BMD were highly prevalent in children with SMA without disease-modifying treatment in our centre. Regular monitoring of BMD is necessary for all types of SMA children, especially those aged ≥ 6.3 years.

Patella Fractures are Associated with Bone Fragility - A Retrospective Study.

Patella fractures are not typically considered osteoporotic fractures. We compared bone mineral density (BMD) and microstructure in elderly women from a multiethnic population-based study in New York City with any history of a patella fracture (n = 27) to those without historical fracture (n = 384) and those with an adult fragility forearm fracture (n = 28) using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT). Compared to those without fracture, women with patella fracture had 6.5% lower areal BMD (aBMD) by DXA only at the total hip (P=.007), while women with forearm fracture had lower aBMD at multiple sites and lower trabecular bone score (TBS), adjusted for age, body mass index (BMI), race and ethnicity (all P<.05). By HR-pQCT, adjusted radial total and trabecular (Tb) volumetric BMD (vBMD) and Tb number were 10-24% lower while Tb spacing was 12-23% higher (all P<.05) in the fracture groups versus women without fracture. Women with a forearm, but not a patella, fracture also had lower adjusted radial cortical (Ct) area and vBMD and 21.8% (P<.0001) lower stiffness vs. women without fracture. At the tibia, the fracture groups had 9.3-15.7% lower total and Tb vBMD (all P<.05) compared to the non-fracture group. Women with a forearm fracture also had 10.9, and 14.7% lower tibial Ct area and thickness versus those without fracture. Compared to women without fracture, tibial stiffness was 9.9 and 12% lower in the patella and forearm fracture groups, respectively (all P<.05). By HR-pQCT, the patella vs. forearm fracture group had 36% higher radial Tb heterogeneity (P<.05). In summary, women with patella fracture had Tb deterioration by HR-pQCT associated with lower tibial mechanical competence that was similar to those with fragility forearm fracture, a more universally accepted "osteoporotic" fracture. These data suggest patella fractures are associated with skeletal fragility and warrant skeletal evaluation.

Association between radius axial low-frequency ultrasound velocity and bone fragility in primary hyperparathyroidism.

Radius quantitative ultrasound measurement, that utilized a portable low-frequency (VLF) axial transmission ultrasound for assessing the properties of radius cortical bone in a non PHPT population revealed a possible role as a screening tool prior to DXA to evaluate fragility fracture. To evaluate this portable ultrasound device as a screening tool of skeletal fragility in PHPT patients. We enrolled 117 postmenopausal women with PHPT. Every subject had a DXA of femur, lumbar spine, non-dominant distal 1/3 radius, TBS measurement, VLF with a portable device and spine x- ray. The mean age of the patients was 68 ± 10 years. The measurement of agreement between radius DXA and VLF was: K = 0.43, p < 0.001. A lower radius US T-score, also adjusted for years since menopause and BMI, was associated with osteoporosis identified with DXA at lumbar and/or femoral neck sites: OR = 1.852 (CI 1.08, 3.18). All fractures were associated with femoral neck T-score: OR = 1.89 (95% CI 1.24, 2.89), as well as with total hip T-score: OR = 1.65 (95% CI 1.09, 2.50), and years since menopause: OR = 1.25 (95% CI 1.02, 1.54).Morphometric vertebral fractures were associated with years since menopause: OR = 1.28 (95% CI 1.02,1.61), femoral neck T-score OR = 1.96 (95% CI 1.227, 3.135), total hip T-score OR = 1.64 (95% CI 1.04, 2.60), TBS OR = 0.779 (95% CI 0.60-0.99), both ultra-distal radius T-score: OR = 1.50 (95% CI 1.05, 2.156), and radius US T-score: OR = 1.67 (95% CI 1.09, 2.56). VLF could be used for screening purposes prior to DXA to evaluate PHPT fracture risk, only in conditions in which DXA measurement cannot be performed.

7635 Severe Osteoporosis in a Patient with Heterotopic Calcification: A Case Report

Abstract Disclosure: D. Salih Bacha: None. L.Z. Khan: None. Background: While osteoporosis and heterotopic ossification (HO) are distinct conditions affecting bone health, their coexistence poses intriguing clinical challenges. Osteoporosis, characterized by increased bone fragility, typically results from various factors such as aging, steroid use, or malabsorption. HO is a condition where bone forms abnormally in soft tissues. Risk factors that predispose to HO include male sex, spinal cord injury, trauma, surgery, and genetic factors. Treatment of HO is typically surgical resection and NSAIDs. Initial evidence supported the use of bisphosphonates for preventing ectopic bone formation post-trauma, but recent data failed to show significant benefit in HO prevention. This case presents a patient with unique challenges of both HO and bone fragility with multiple severe vertebral fractures. Case: A 44-year-old male patient had a major motor vehicle accident necessitating multiple recurrent abdominal surgeries. During one exploratory laparotomy, diffuse mesenteric calcifications were noted, indicative of HO. A baseline Dual X-ray Absorptiometry (DXA) scan revealed bone density of 1.003 g/cm2 and 0.788 g/cm2 at the spine and femoral neck, respectively, concerning for osteopenia. He was started on zoledronic acid in preparation for upcoming intestinal transplant. Few months after the transplant, he was started on daily tacrolimus and hydrocortisone for immunosuppression. Within months, he experienced sudden back pain while riding an elevator, and was found to have acute fractures in T8 and T9 vertebrae. A repeat DXA scan showed a further decline in bone density to 0.909 g/cm2 and 0.748 g/cm2 at the spine and femoral neck, respectively. Within a year, additional fractures occurred in the thoracic and lumbar spine (T10, T11, T12, L1, L2, L3, and L4), requiring multiple kyphoplasty interventions. Over time, worsening kyphosis, back pain, and height loss occurred, significantly affecting the patient's quality of life. He continued receiving yearly zoledronic acid infusions and underwent regular DXA scans, which revealed mild improvement in his bone density. Currently, there are no established guidelines specifying the optimal duration for bisphosphonate treatment in such cases. Therefore, our individualized treatment plan involves a tentative 10-year course of bisphosphonate treatment with yearly assessment of bone mineral density. Conclusion: Although the patient had some risk factors for osteoporosis, including daily steroid and tacrolimus use, the severity and frequency of his fractures suggested a potential synergy between osteoporosis and HO, where the formation of heterotopic calcifications may have been exacerbating his bone loss. The coexistence of osteoporosis and HO in this patient underscores the need for individualized care and establishment of treatment guidelines in patients with multiple bone disorders. Presentation: 6/3/2024