This review aims to synthesize current knowledge regarding the use of bisphosphonates (BPs) in the treatment of bone complications in patients with neurofibromatosis type 1 (NF1). NF1 is a genetic disorder marked by multiple benign tumors of the nervous system and various skeletal abnormalities, such as osteoporosis and an increased risk of fractures. BPs are drugs that inhibit bone resorption, commonly used to treat osteoporosis and other bone diseases. The review identified multiple studies examining the effects of BP therapy in NF1 patients. Most studies reported improvements in bone mineral density and reduced fracture occurrence. The most commonly reported side effects were mild gastrointestinal symptoms and transient musculoskeletal pain. However, the evidence is limited by the small number of studies and the heterogeneity of patient populations and treatment protocols. In conclusion, BPs show improvements in managing NF1 complications such as osteoporosis and a reduction of fracture risk in NF1 patients. While the existing studies suggest positive outcomes, there is a need for more rigorous, large-scale studies to establish standardized treatment protocols and long-term safety profiles. Healthcare providers should consider BP therapy as a potential option for NF1 patients with significant bone complications, while also monitoring for possible adverse effects.

Background: Bone-target agents (BTAs), including denosumab (DMAb), are one of the bone metastasis treatments that should continue indefinitely. However, BTAs may be interrupted in some cases. In osteoporosis, DMAb withdrawal causes a rebound effect characterized by an increased bone turnover with spine fractures and hypercalcemia; evidence of the DMAb withdrawal effect in oncology is lacking. Methods: This study aimed to identify the DMAb withdrawal effect amongst lung cancer patients treated with DMAb for bone metastases between January 2020 and December 2021. Patients who discontinued DMAb were included. Encounter notes, radiological and laboratory findings were comprehensively reviewed. Results: Thirty patients were included with a median follow-up of 21 months (interquartile range [IQR], 10-30) after DMAb discontinuation. Bisphosphonates were administered before starting DMAb in 7 patients (23.3%) and after DMAb withdrawal in 4 cases (13.3%). Three cases of DMAb withdrawal-related hypercalcemia and 3 cases of spine fractures following DMAb cessation were identified in 5 patients (16.7%), all of them were females and the median age was 65 years old (IQR, 65-70). No statistical difference in DMAb duration or number of injections was found in patients developing DMAb withdrawal-related spine fractures or hypercalcemia compared with others (binary logistic regression, p=0.688 and p=0.938, respectively). Conclusions Patients with bony-metastatic lung cancer, especially post-menopausal women, are at risk of fractures and calcium abnormalities after DMAb discontinuation, suggesting that DMAb withdrawal effect may also be present in the oncological setting. A close follow-up and careful monitoring during and after discontinuation of DMAb is necessary.

Background: Due to the contradictory and temporally variable effects of transforming growth factor-β (TGF-β) and the Wnt/β-catenin pathways on osteogenic differentiation in different stem cell types, we sought to examine the activity of these pathways as well as their interaction during the osteogenic differentiation of the osteo-induced adiposederived mesenchymal stem cells (AD-MSCs). Methods: The osteo-induced AD-MSCs were treated with TGF-β1 (1 ng/mL) either alone or together with its antagonist SB- 431542 (10 μM) or that of the Wnt antagonist, inhibitor of Wnt production 2 (IWP2) (3 μM), every 3 days for 21 days. Cells were then analyzed for calcium deposit, bone matrix production, and the osteogenic markers gene expression. Results: Our results showed firstly that, either of the pathways is active since the mRNA expressions of their respective target genes, PAI-1 and Cyclin D1 were detectable although the latter was at a very low level. Secondly that, treatment with TGF-β1 decreased levels of calcium deposit, bone matrix production and the osteogenic markers gene expression. Accordingly, osteogenesis was induced in those treated with SB either alone or together with the TGF-β1, pointing to inhibitory effect of TGF-β pathway on osteogenic differentiation. Thirdly that following treatment with IWP2 and TGF-β1, the inhibitory effect of TGF-β1 on bone matrix production was reversed. Fourthly, there was constantly low expression of Wnt3amRNA but progressively increasing that of its endogenous antagonist Dkk-1mRNA throughout. Conclusions Together these results suggest that TGF-β1 requires the active Wnt/β-catenin signaling pathway to exert its inhibitory effects on osteogenic differentiation of AD-MSCs.

Background: Quantitative computed tomography (QCT) is essential for assessing osteoporosis and monitoring spinal deformities. “Clari-QCT,” a software that uses artificial intelligence to analyze conventional computed tomography (CT) scans and produce QCTequivalent reports. This study aims to evaluate the effectiveness of Clari-QCT by comparing its results with traditional QCT, with the goal of validating new diagnostic tools for spinal deformities. Methods: The study analyzed dual energy X-ray absorptiometry, CT, and QCT data from 18 patients at Inha University Hospital. Clari-QCT software was evaluated for its ability to generate QCT-equivalent reports from CT images. The software processes abdomen CT images, calculates bone density in designated slices, and provides bone mineral density (BMD), T-score, and Z-score values. Patients were classified into normal, mild, and severe spinal deformity groups. Intraclass correlation coefficient (ICC) analysis was used to measure the agreement between actual and predicted BMD values. Results: The study included participants with an average age of 64 and a mean body mass index of 24.88. The average BMD was 94.7 g/cm³ by QCT and 122.5 g/cm³ by Clari- QCT, with individual differences ranging from 4.9 to 61.8. T-score discrepancies ranged from 0.16 to 6.86. ICC analysis showed moderate to high agreement between methods, with ICC1 values of 0.597, ICC2 of 0.64, ICC3 of 0.81, and ICC1k, ICC2k, ICC3k values ranging from 0.748 to 0.895. Conclusions Clari-QCT demonstrates good agreement with actual QCT measurements in normal and severe spinal deformity groups but shows reduced accuracy in patients with mild deformities. If the limitations are addressed, it could become a useful tool for monitoring bone health in patients with spinal deformities.

Background: Patients with rheumatoid arthritis (RA) are at an increased risk of osteoporosis and vertebral fractures. This study aimed to investigate factors associated with vertebral fractures and treatment goals to prevent new vertebral fractures in patients with RA. Methods: The database used in this study included outpatient data of RA patients at the authors’ hospital of RA patients taken from 2018 to 2022. The patients underwent annual imaging evaluations to assess parameters, including bone mineral density of the lumbar spine (LS; L2-4), total hip, and femoral neck, as well as vertebral fractures. Vertebral fractures were evaluated using radiographic images of the T8 to L5 vertebrae. Results: The prevalence rates of new vertebral fractures in 2018–2019, 2019–2020, 2020– 2021, and 2021–2022 were 2.0%, 1.3%, 2.3%, and 2.0%, respectively. The presence of existing vertebral fractures was associated with new vertebral fractures (p=0.003; odds ratio, 0.241; 95% confidence interval, 0.093–0.624). The cut-off T-score values for the LS for new vertebral fractures in patients with or without pre-existing vertebral fractures were -0.7 (sensitivity, 40.9%; specificity, 100%) and -1.4 (sensitivity, 69.0%; specificity, 62.5%), respectively. Conclusions The presence of pre-existing vertebral fractures is an independent factor associated with new vertebral fractures. It is important to tailor treatment goals based on the presence or absence of vertebral fractures to effectively prevent new fractures.

Background: This study aims to investigate the effect of genetic polymorphisms of vitamin D receptor (VDR), estrogen receptor 1 (ER1), and Col1a1 on the response to bisphosphonate (BP) therapy in women with postmenopausal osteoporosis (OP). Methods: Twenty-one women with postmenopausal OP who received alendronate, ibandronate, or zoledronic acid for one year were enrolled in this study. Bone mineral density (BMD) at the lumbar spine and femoral neck were assessed by dual energy X-ray absorptiometry at baseline and after 12 months. Serum osteocalcin levels were measured at baseline and after 12 months. Polymorphic sites of the genes encoding ER1, VDR and Col1a1 proteins were amplified by polymerase chain reaction and examined using restriction fragment length polymorphism. Response to BP treatment and change in osteocalcin levels were compared among women with different gene polymorphisms. Results: Ratio of responders to treatment regarding improvements in the BMD of lumbar spine and femoral neck was adequate in 76% and 62%, respectively. There was no significant difference in treatment response regarding BMD in either region or change in serum osteocalcin levels among different gene polymorphisms. Conclusions These findings did not support the potential role of VDR BsmI, Col1a1 Sp1, ER1 PvuII, or XbaI polymorphisms in predicting the response to BP therapy in women with postmenopausal OP. Further investigation with larger prospective studies is required.

Background: Osteoporosis is a significant public health issue in aging populations. Despite advances in pharmacotherapy, underdiagnosis and undertreatment remain prevalent even in patients with recent fractures. This study examined 20-year trends (2002– 2022) in anti-osteoporotic medication (AOM) usage in South Korea. Methods: Data from the Korean National Health Information Database were retrospectively analyzed. The study included individuals aged ≥50 years and analyzed prescription trends, medication adherence, measured by the medication possession ratio (MPR), and treatment initiation rates post-fracture. The AOMs examined included bisphosphonates, selective estrogen receptor modulators, denosumab (DMAB), teriparatide (TPTD), and romosozumab (ROMO). Results: Over two decades, AOM use has shifted significantly from oral to injectable formulations, with injectables surpassing oral medications in 2020; from 397,440 prescriptions in 2016 to 1,162,779 in 2022. Prescriptions for DMAB surged following its approval as a first-line therapy in 2019, increasing 2.65 times from 217,606 in 2019 to 575,595 in 2022. The MPR improved from 35.4% in 2003 to 73.2% in 2021, with females demonstrating higher adherence than males. Post-fracture treatment rates increased from 31.1% in 2006 to 39.9% in 2021 but remained below 50%. Vertebral fractures had the highest treatment initiation rates, while anabolic agents, such as TPTD and ROMO were underprescribed despite their efficacy. Conclusions This 20-year analysis highlights significant progress in osteoporosis management in South Korea, including a shift towards injectable therapies and improved adherence. However, the persistent undertreatment of high-risk patients underscores the requirement for enhanced access to anabolic agents, clinician education, and policy reforms to optimize post-fracture care.

This review aims to synthesize current knowledge regarding the use of bisphosphonates (BPs) in the treatment of bone complications in patients with neurofibromatosis type 1 (NF1). NF1 is a genetic disorder marked by multiple benign tumors of the nervous system and various skeletal abnormalities, such as osteoporosis and an increased risk of fractures. BPs are drugs that inhibit bone resorption, commonly used to treat osteoporosis and other bone diseases. The review identified multiple studies examining the effects of BP therapy in NF1 patients. Most studies reported improvements in bone mineral density and reduced fracture occurrence. The most commonly reported side effects were mild gastrointestinal symptoms and transient musculoskeletal pain. However, the evidence is limited by the small number of studies and the heterogeneity of patient populations and treatment protocols. In conclusion, BPs show improvements in managing NF1 complications such as osteoporosis and a reduction of fracture risk in NF1 patients. While the existing studies suggest positive outcomes, there is a need for more rigorous, large-scale studies to establish standardized treatment protocols and long-term safety profiles. Healthcare providers should consider BP therapy as a potential option for NF1 patients with significant bone complications, while also monitoring for possible adverse effects.

Background: Bone-target agents (BTAs), including denosumab (DMAb), are one of the bone metastasis treatments that should continue indefinitely. However, BTAs may be interrupted in some cases. In osteoporosis, DMAb withdrawal causes a rebound effect characterized by an increased bone turnover with spine fractures and hypercalcemia; evidence of the DMAb withdrawal effect in oncology is lacking. Methods: This study aimed to identify the DMAb withdrawal effect amongst lung cancer patients treated with DMAb for bone metastases between January 2020 and December 2021. Patients who discontinued DMAb were included. Encounter notes, radiological and laboratory findings were comprehensively reviewed. Results: Thirty patients were included with a median follow-up of 21 months (interquartile range [IQR], 10-30) after DMAb discontinuation. Bisphosphonates were administered before starting DMAb in 7 patients (23.3%) and after DMAb withdrawal in 4 cases (13.3%). Three cases of DMAb withdrawal-related hypercalcemia and 3 cases of spine fractures following DMAb cessation were identified in 5 patients (16.7%), all of them were females and the median age was 65 years old (IQR, 65-70). No statistical difference in DMAb duration or number of injections was found in patients developing DMAb withdrawal-related spine fractures or hypercalcemia compared with others (binary logistic regression, p=0.688 and p=0.938, respectively). Conclusions Patients with bony-metastatic lung cancer, especially post-menopausal women, are at risk of fractures and calcium abnormalities after DMAb discontinuation, suggesting that DMAb withdrawal effect may also be present in the oncological setting. A close follow-up and careful monitoring during and after discontinuation of DMAb is necessary.