Search Results (170)

Background/Objectives: Intermittent parathyroid hormone (PTH) administration increases bone quantity. Existing animal studies have revealed improvements in tissue healing around implants after PTH administration. It is still unclear whether PTH has a beneficial short-term effect on the early healing of bone and soft tissue around implants in individuals with osteoporosis. The current study aims to examine whether short-term intermittent PTH administration accelerates and improves early tissue healing around implants in ovariectomized rats. Methods: Ovariectomized rats received implants at the healed sites of extracted maxillary first molar sockets 12 weeks after the ovariectomy surgery. A daily dose of PTH was subcutaneously administered in the test group, whereas saline was administered for the control group. Long bones and maxillae were harvested 1 week after PTH administration. The following criteria were assessed: quantity and quality of long bones and peri-implant bone, bone healing around the implants, and soft tissue healing. Results: PTH significantly increased the bone parameters of long bones. Moreover, the bone volume around the implant increased significantly compared to controls. Improved bone quality was indicated through PTH administration by increased numbers of osteoblasts and osteoclasts, as well as decreased quantities of sclerostin + osteocytes. Furthermore, PTH administration significantly improved soft tissue healing, promoted collagen production and angiogenesis, and increased the numbers of macrophages in the connective tissue around the implants. Conclusions: Short-term intermittent PTH administration significantly accelerates soft tissue healing, which could lead to enhanced early osseous healing and bone formation around implants. Thus, Intermittent PTH administration might be considered as an available treatment modality for dental implants in osteoporosis patients. Full article

Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS/MAPK pathway dysregulation on bone health remains poorly understood. Objectives: The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients. Methods: In this cross-sectional, case-control study, we analyzed 28 children (20 males) with a molecular diagnosis of NS and 35 healthy subjects (21 males), matched by age and sex. We assessed markers of bone metabolism and bone turnover (calcium, phosphate, PTH, 25(OH)-vitamin D, osteocalcin, procollagen I N-propeptide-P1NP, bone alkaline phosphatase-BALP, C-telopeptides of type I collagen-CTX) and bone remodeling (RANKL, OPG, and sclerostin). Bone mineralization was measured at the lumbar spine (L2–L4) using dual-energy X-ray absorptiometry (DEXA). Results: Serum CTX levels were significantly higher in NS patients compared to controls (1.8 ± 0.7 vs. 1.3 ± 0.5 ng/mL, p = 0.0004). RANKL levels were higher in NS patients, although the difference did not reach statistical significance. No significant differences were found for OPG, sclerostin, or other markers of bone metabolism between patients and controls. Conclusions: Children with NS exhibit increased bone resorption, as indicated by elevated CTX levels, suggesting a potential imbalance in bone remodeling processes. Further studies are warranted to better define the impact of RAS/MAPK pathway dysregulation on bone health in this population. Full article

Background/Objective: Palm tocotrienol has bone-protective properties in animal models, yet its underlying mechanism remains unclear. Given osteocytes’ role in bone homeostasis, this research aimed to investigate the effects of palm tocotrienol on the quantity of osteocytes and the expression of osteocyte-specific markers in ovariectomized rats. Methods: Adult female rats (Sprague Dawley; three-month-old; n = 6/group) were randomly divided into baseline, sham control, ovariectomized control, unemulsified palm tocotrienol (UPT), emulsified palm tocotrienol (EPT), and positive control. The baseline group was euthanized without intervention, whereas the sham group underwent a laparotomy procedure in which the ovaries were not excised. The other groups underwent bilateral removal of the ovaries and subsequently received UPT (100 mg/kg/day, 50% vitamin E), EPT (100 mg/kg/day, 25% vitamin E), or a combination of glucosamine sulfate (250 mg/kg/day) and calcium carbonate (1% in drinking water). Control groups were induced with similar gavage stress with olive oil. After 10 weeks, all rats were sacrificed for bone and serum analysis. Results: UPT and EPT significantly increased trabecular osteocyte and total lacunae numbers (p < 0.05 versus ovariectomized control). Both treatments significantly reduced mRNA expression levels of dentin matrix protein-1 (p < 0.05 versus ovariectomized control), whereas sclerostin mRNA expression was unchanged (p > 0.05 versus ovariectomized control). However, neither UPT nor EPT improved circulating or skeletal redox status (p > 0.05 versus ovariectomized control). Conclusions: Palm tocotrienol may support bone health by preserving the quantity of trabecular osteocytes and modulating osteocyte-mediated bone remodeling. Further research is required to elucidate its precise mechanisms. Full article

Sclerostin, encoded by the SOST gene, is a novel bone anabolic target for bone diseases. Humanized anti-sclerostin antibody, romosozumab, was approved for treatment of postmenopausal osteoporosis by the US Food and Drug Administration (FDA), but with a black-box warning on cardiovascular risk. The clinical data regarding cardiovascular events from various pre-marketing and post-marketing studies of romosozumab were inconsistent. Overall, the cardiovascular risk of sclerostin inhibition could not be excluded. The restriction of romosozumab in patients with cardiovascular disease history would be necessary. Moreover, genome-wide association study (GWAS) analyses of SOST variants revealed inconsistent results of the association between SOST variations and cardiovascular diseases. Further research incorporating larger sample sizes and functional analyses are necessary. In analyses of serum/tissue sclerostin levels in patients with cardiovascular diseases, the results were controversial but indicated an association between sclerostin and the presence/severity/outcomes of cardiovascular diseases. Nonclinical studies in rodents indicated the inhibitory effect of sclerostin on inflammation, aortic aneurysm, atherosclerosis, and vascular calcification. Sclerostin loop3 participated in the inhibitory effect of sclerostin on bone formation, while the cardiovascular protective effect of sclerostin was independent of sclerostin loop3. Macrophagic sclerostin loop2–apolipoprotein E receptor 2 (ApoER2) interaction participated in the inhibitory effect of sclerostin on inflammation in vitro. Sclerostin in human aortic smooth muscle cells participated in the reduction in calcium deposition. The role of sclerostin in cardiovascular system deserves further investigation. Full article

Childhood leukemia survivors are at risk of long-term complications. Data on bone remodeling in childhood acute lymphoblastic leukemia (ALL) are limited. This 2-year prospective longitudinal study investigated bone remodeling and bone turnover markers at diagnosis, during treatment, and until stopping treatment, in ALL patients < 18 years, to clarify the influence of leukemia itself and/or chemotherapy on bone. Methods: A total of 22 ALL children (12 males, age 5.5 ± 3.6 years) underwent blood sampling at the 5 time point (T0−T4). Osteoprotegerin (OPG), receptor-activator-NF-B-ligand (RANKL), osteocalcin (OC), C-terminal-telopeptide-type-I-collagen (CTX), bone-alkaline-phosphatase (bALP), tartrate-resistant acid-phosphatase-5b (TRACP5b), procollagen-type-I-N-terminal-propeptide (P1NP), Dickkopf-1 (DKK-1), and sclerostin were assessed. Data from patients at T0 were compared to a control group of healthy children. We used the principal component analysis (PCA) for statistics. Results: Levels of CTX, OC, P1NP, and bALP resulted lower in ALL children than controls (p = 0.009 for CTX and p < 0.001 for the others), also DKK1 and sclerostin (p < 0.0001 and p = 0.023). RANKL ed OPG were higher in patients. During T0−T4, CTX, OC, P1NP, TRACP5b, and bALP showed a significant increase, in particular at T0−T1 (end-of-induction). Less evident changes were detected onwards. Conclusions: The onset of leukemia has been revealed as a key point in determining a slowing of bone remodeling in ALL children. Full article

Background/Objectives: Osteoporosis is a major public health concern, due to its high risk of fractures and disability and associated medical costs. Romosozumab, an anabolic agent, has been approved for the treatment of osteoporosis in postmenopausal women at high risk of fractures. However, limited data exist on its long-term effects in the Korean population, particularly regarding its impact on bone mineral density (BMD), bone turnover markers, and body composition. This study aimed to evaluate the 12-month effects of romosozumab treatment on BMD, bone turnover markers, and body composition in postmenopausal Korean women with high-fracture-risk osteoporosis (T-scores ≤ −3.0). Additionally, the impact of concomitant postmenopausal hormone therapy (MHT) on BMD changes was assessed. Methods: This multicenter, retrospective observational study included 50 postmenopausal women diagnosed with osteoporosis (T-scores ≤ −3.0) who received 12 monthly doses of romosozumab (210 mg) at two hospitals in Korea. Changes in BMD in the lumbar spine, femoral neck, and total hip were assessed using dual-energy X-ray absorptiometry (DXA). Bone turnover markers, including procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX), were measured at baseline and at 3, 6, and 12 months. Changes in body composition, including the skeletal muscle index (SMI), body mass index (BMI), and visceral adipose tissue (VAT), were also analyzed. Results: After 12 months of romosozumab treatment, BMD significantly increased at the lumbar spine (14.65%), femoral neck (6.58%), and total hip (4.19%) (p < 0.05). P1NP levels increased significantly at 3 months (+37.9%), but returned to baseline at 6 months, while CTX levels continuously decreased (−27.8%) over 12 months. No significant changes were observed in SMI or BMI, but the VAT showed a slight decreasing trend (p < 0.05). Additionally, patients receiving concomitant MHT demonstrated a significantly greater increase in lumbar spine BMD compared to those receiving romosozumab alone (p < 0.05), while no significant differences were observed in femoral neck and total hip BMD. Conclusions: This study demonstrated that 12 months of romosozumab treatment significantly improved BMD and bone turnover markers in postmenopausal Korean women with severe osteoporosis. The combination of romosozumab and MHT further enhanced lumbar spine BMD gains. These findings support the use of romosozumab as an effective treatment for high-risk osteoporotic fractures in postmenopausal Korean women, and suggest potential benefits of a combined therapeutic approach. Full article

(1) Background: The challenges in Implantology involve the development of alternative methods to enhance bone repair in patients with systemic conditions, such as osteoporosis. This study aimed to evaluate the effect of a local anti-sclerostin monoclonal antibody (Scl-Ab) on the functionalization of titanium implant surfaces through a dip-coating technique in peri-implant bone repair. (2) Methods: A total of 32 female rats were separated into four groups (n = 8): SHAM NT (Sham surgery), OVX NT (ovariectomy), SHAM Scl-Ab (SHAM; implants functionalized with Scl-Ab), and OVX Scl-Ab (OVX; implants functionalized with Scl-Ab). Implant surgery was executed 30 days after ovariectomy, and the rats were euthanized 28 days postoperatively. The right tibia was used for removal torque and RT-PCR, while the left tibia was collected for micro-CT and laser confocal microscopy. (3) Results: Functionalization with Scl-Ab significantly increased the gene expression of bone markers, especially ALP, in the SHAM Scl-Ab group compared to the other groups (p < 0.05). (4) Conclusions: Some parameters of this study indicate that implants functionalized with anti-sclerostin bone anabolic drug enhance peri-implant bone repair, especially in healthy rats. However, more studies must be carried out to confirm the therapeutic benefits of this approach. Full article

Twin pregnancies, with higher incidences of preterm birth, are becoming more prevalent. Progesterone has shown effectiveness in the prevention of preterm labour, though other factors related to pregnancy and neonatal health may be affected by this hormone and have not been previously addressed. This study aims to evaluate the impact of progesterone administration on oxidative stress and bone turnover during twin gestation and investigate associations with some maternal/neonatal variables of interest. Women pregnant with twins were recruited in the “Virgen de la Arrixaca” University Hospital and randomly assigned to two groups: control (n = 49) and progesterone (n = 50). A total of 600 mg/day of progesterone was vaginally administered from 11 to 14 to 34 weeks of gestation. Blood samples were taken in the first (T1) and third trimester (T3), analyzing biomarkers related to oxidative stress and bone turnover. Most bone turnover and oxidative markers experiment with significant changes during gestation. Progesterone administration significantly increased (p < 0.05) the levels of osteocalcin in T3 and decreased (p < 0.05) the levels of sclerostin. Regarding oxidative stress, the progesterone group, unlike the control group, showed no significant increase in oxidative stress between T1 and T3. In conclusion, results show that progesterone administration could increase maternal bone formation and modulate oxidative stress. Full article

Both diabetes and osteoporosis are serious chronic conditions. Evidence is mounting that several bone-derived hormones play a role in glucose metabolism in patients with diabetes. Notably, novel biotargeted anti-osteoporotic agents have been recently found to reduce the risk of diabetes. This review explores the correlation of osteokines, including the receptor activator of nuclear factor-κB ligand (RANKL), sclerostin, and Dickkopf-1 (DKK1) with glycemic indicators in patients with diabetes, as well as the effects of their respective monoclonal antibodies on glucose metabolism and their possible mechanisms. Denosumab, the monoclonal antibody against RANKL, has been shown to reduce glycated hemoglobin (HbA1c) and the risk of diabetes, possibly by enhancing pancreatic β-cell survival and glucagon-like peptide-1 secretion. Sclerostin was positively correlated with HbA1c and may induce insulin resistance via endoplasmic reticulum stress. The association of DKK1 with fasting plasma glucose and HbA1c is still unclear, though decreasing DKK1 levels may correlate with β-cell survival. However, few studies have investigated the effects of antibodies against sclerostin or DKK1 on glucose metabolism. Further research is required to elucidate the influence of novel anti-osteoporotic biotargeted agents on glucose homeostasis in patients with diabetes and their underlying mechanisms. Full article

In this review paper, we will evaluate LRP4, a low-density lipoprotein receptor-related protein, and its many roles involving myasthenia gravis (MG), Wnt signaling, bone formation and craniofacial development. In MG, LRP4 is critical to the formation of the neuromuscular junction (NMJ) and the key function is to allow for controlled muscle contraction. LRP4 works in combination with agrin and MuSK to form the functional complex. In Wnt signaling, LRP4 was recently identified as a critical player in the pathway for both bone and tooth development and function. Its ability to act as an inhibitor sheds new light on bone formation and resorption. LRP4 binds sclerostin to LRP5 and LRP6, facilitating inhibitory effects important for bone homeostasis and remodeling. In this review paper, we will summarize the known roles of LRP4 as well as explore future directions for research surrounding LRP4 functionality. Full article

Background/Objectives: Osteoporosis and cardiovascular disease (CVD) share common risk factors and pathophysiological mechanisms, raising concerns about the cardiovascular implications of sclerostin inhibition. Romosozumab, a monoclonal antibody that targets sclerostin, is effective in increasing bone mineral density (BMD) and reducing fracture risk. However, evidence suggests that sclerostin inhibition may adversely affect vascular calcification, potentially increasing the risk of myocardial infarction (MI) and stroke. Methods: This review synthesizes data from clinical trials, such as ARCH, BRIDGE, and FRAME, alongside genetic studies and observational analyses, to evaluate the cardiovascular safety of romosozumab. PubMed was searched for relevant studies published within the last five years. Studies addressing the relationship between romosozumab and cardiovascular outcomes were included, emphasizing both its efficacy in osteoporosis management and potential cardiovascular risks. Results: Romosozumab significantly improves BMD and reduces fracture risk in postmenopausal women and men with osteoporosis. However, clinical trials report an increased incidence of major adverse cardiovascular events (MACE), particularly in patients with pre-existing cardiovascular conditions such as chronic kidney disease (CKD), diabetes, or prior CVD. Genetic studies indicate that SOST gene variants may also influence cardiovascular outcomes. Conclusions: While romosozumab is an effective treatment for osteoporosis, careful cardiovascular risk assessment is crucial before initiating therapy, especially for high-risk populations. Long-term studies are needed to evaluate chronic safety. Future therapeutic strategies should aim to maintain bone health while minimizing cardiovascular risks, ensuring a balance between efficacy and safety in osteoporosis treatment. Full article

This study explores how select microRNAs (miRNAs) influence bone structure in humans and in transgenic mice. In trabecular bone biopsies from 84 postmenopausal women (healthy, osteopenic, and osteoporotic), we demonstrate that DLEU2 (deleted in lymphocytic leukemia 2)-encoded miR-15a-5p is strongly positively associated with bone mineral density (BMD) at different skeletal sites. In bone transcriptome analyses, miR-15a-5p levels correlated positively with the osteocyte characteristic transcripts SOST (encoding sclerostin) and MEPE (Matrix Extracellular Phosphoglycoprotein), while the related miR-15b-5p showed a negative association with BMD and osteoblast markers. The data imply that these miRNAs have opposite roles in bone remodeling with distinct actions on bone cells. Expression quantitative trait loci (eQTL) variants confirmed earlier DLEU2 associations. Furthermore, a novel variant (rs12585295) showed high localization with transcriptionally active chromatin states in osteoblast primary cell cultures. The supposition that DLEU2-encoded miRNAs have an important regulatory role in bone remodeling was further confirmed in a transgenic mice model showing that miR-15a/16-1-deleted mice had significantly higher percentage bone volume and trabecular number than the wild type, possibly due to prenatal actions. However, the three-point mechanical break force test of mice femurs showed a positive correlation between strength and miR-15a-5p/miR-16-5p levels, indicating differential effects on cortical and trabecular bone. Moreover, these miRNAs appear to have distinct and complex actions in mice prenatally and in adult humans, impacting BMD and microstructure by regulating bone cell transcription. However, detailed interactions between these miRNAs and their downstream mechanisms in health and disease need further clarification. Full article

Renal osteodystrophy (ROD) represents histological bone changes in patients with chronic kidney disease and is classified according to turnover and mineralization. This cross-sectional study evaluates several bone biomarkers and their ability to discriminate turnover and mineralization defects in hemodialysis (HD) patients. Bone-specific [BSAP] and total [tAP] alkaline phosphatase, procollagen-1 N-terminal propeptide [P1NP], C-terminal cross-linking telopeptide [CTX], intact [iPTH] and whole [wPTH] parathyroid hormone, sclerostin [SOST], fibroblast growth factor 23 [FGF-23], vitamin D, osteoprotegerin [OPG], and receptor activator of nuclear factor κB ligand [RANKL] were collected before the bone biopsy. Thirty-two patients were evaluated by bone histomorphometry, which identified mineralization defects and low and high turnover in 47%, 50%, and 41% of patients, respectively. Bone biomarkers (tAP, BSAP, CTX, P1NP) and hormones (iPTH, wPTH, and SOST) were capable of identifying low and high turnover (AUC > 0.877 and >0.857, respectively, p < 0.001). PTH plus AP had the best accuracy for identifying high turnover. BSAP > 2x, iPTH > 8x, and wPTH > 6x upper limit of normal range identified high turnover. Lower calcium values (Ca < 8.7 mg/dL) were correlated with mineralization defects. On the other hand, FGF-23, OPG, and RANKL did not impact the turnover and mineralization. While bone histomorphometry is not widely available, bone biomarkers such as BSAP, P1NP, PTH, and calcium allow the assessment of turnover and mineralization defects in HD patients. Then, using bone biomarkers may help clinicians define treatments for ROD and osteoporosis and monitor therapeutic response. Full article

Background/Objectives: This study aims to investigate the association of movement behaviors with irisin, sclerostin, and bone turnover markers in young pediatric cancer survivors. Methods: A total of 116 young pediatric cancer survivors (12.1 ± 3.3 years; 42% female) were recruited. Time spent in movement behaviors over at least seven consecutive 24 h periods was measured by accelerometers (wGT3x-BT accelerometer, ActiGraph). Blood samples were collected at rest and serum was analyzed for irisin, sclerostin, cross-linked telopeptide of type I collagen (CTX), procollagen type I amino-terminal propeptide (P1NP), total osteocalcin (OC), alkaline phosphatase (ALP), 25-hydroxyvitamin D, parathyroid hormone (PTH), calcium, phosphorous, and magnesium. Results: Irisin and sclerostin were not significantly correlated with bone turnover markers. Sedentary time was negatively correlated with the P1NP (r = −0.411, p = 0.027) and total OC (r = −0.479, p = 0.015) Z-scores, whereas moderate-to-vigorous physical activity was positively correlated with the P1NP (r = 0.418, p = 0.024) and total OC (r = 0.478, p = 0.016) Z-scores. Moreover, total physical activity was positively correlated with the total OC Z-score (r = 0.448, p = 0.025). Finally, the uncoupling index [CTX/P1NP] was positively correlated with sedentary time (r = 0.424, p = 0.012) and negatively correlated with light physical activity (r = −0.352, 0.041). Conclusions: Reducing sedentary time and increasing physical activity may favor bone formation over resorption in young pediatric cancer survivors. Full article

Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation. Full article