Suppression Of Bone Remodeling Research Articles

Comparison of bone turnover suppression in atypical femoral fractures and osteoporotic hip fractures

We aimed to compare the extent of bone turnover suppression between patients with atypical femoral fractures (AFFs) and osteoporotic hip fractures (typical femur fractures, TFFs) using a one-to-one matching strategy. A single-center retrospective comparison of females aged ≥ 60 years who underwent operative treatment for AFFs and TFFs between January 2010 and March 2021 was conducted. Demographic characteristics and clinical data including fracture site, past medical history, bone mineral density (BMD), bisphosphonate (BP) medication history, and serum bone turnover marker (BTM) levels were examined. Moreover, we performed a logistic regression analysis to determine the risk factors for AFFs and a one-to-one matched-pair analysis to compare various BTMs. Overall, 336 consecutive females were included: 113 with AFFs and 213 with TFFs. The mean age, BMI, and lowest BMD T-score were 78.6 years, 22.8 kg/m2, and −3.3, respectively. Patients with AFF were younger, had lower BMD, higher BMI, higher prevalence of rheumatoid arthritis, a greater proportion with previous steroid or BP use, and a longer history of BP use than patients with TFF. The 48:48 matched-pair analysis revealed higher serum 25(OH) vitamin-D (30.5 vs 18.2 ng/mL, P < 0.001) and calcium levels (8.8 vs 8.3 ng/dL, P = 0.009) and lower serum CTX levels (0.33 vs 0.54 ng/mL, P = 0.010) in the AFF group than in the TFF group, suggesting a more suppressed bone remodeling. No differences in the other BTM levels were found. Despite identical histories and durations of BP use, the AFF group exhibited lower CTX levels, suggesting more suppressed bone remodeling. This observation leads us to infer that more suppressed bone remodeling, indicated by lower CTX levels, could be linked to the occurrence of AFFs.

PTH treatment before cyclic joint loading improves cartilage health and attenuates load-induced osteoarthritis development in mice.

Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.

Position Statement: Atypical Femoral Fracture from the Korean Society for Bone and Mineral Research in 2023.

As the aging population increases, the number of patients with osteoporosis is gradually rising. Osteoporosis is a metabolic bone disease characterized by low bone mass and the microarchitectural deterioration of bone tissue, resulting in reduced bone strength and an increased risk of low-energy or fragility fractures. Thus, the use of anti-resorptive agents, such as bisphosphonates (BPs), to prevent osteoporotic fractures is growing annually. BPs are effective in reducing hip and other fractures. However, the longer a patient takes BPs, the higher the risk of an atypical femoral fracture (AFF). The exact mechanism by which long-term BP use affects the development of AFFs has not yet been clarified. However, several theories have been suggested to explain the pathogenesis of AFFs, such as suppressed bone remodeling, impaired bone healing, altered bone quality, and femoral morphology. The management of AFFs requires both medical and surgical approaches. BPs therapy should be discontinued immediately, and calcium and vitamin D levels should be evaluated and supplemented if insufficient. Teriparatide can be used for AFFs. Intramedullary nailing is the primary treatment for complete AFFs, and prophylactic femoral nailing is recommended if signs of an impending fracture are detected.

Bone remodeling in experimental diabetes mellitus and surgical menopause in Wistar rats

BACKGROUND: Osteoporosis is metabolic skeletal disease characterized with low bone mass, bone microarchitecture disturbance that together lead to high prevalence of fragility fractures. Postmenopausal osteoporosis accounts for about 80% of the osteoporosis structure in women over 50 years. Diabetes mellitus (DM) is an independent risk factor for low-traumatic fractures. The incidence of both type 2 DM and osteoporosis increases during menopause. Therefore, the study of bone metabolism in experimental diabetes and surgical menopause seems important.THE AIM of the study was to investigate bone metabolism parameters during menopause and experimental type 2 DM.MATERIALS AND METHODS: The half of female Wistar rats had been subjected to bilateral ovariectomy at the beginning of the experiment. Diabetes mellitus (DM) was modelled using a high-fat diet and streptozotocin+nicotinamide. Four weeks after the following groups were formed: «Сontrol» (females without any interventions receiving standard chew, n=5) «OE» (females after ovariectomy n=5), «DM» (females with DM, n=4), «OE+DM» (females after ovariectomy with DM, n=4). The observation period lasted 8 weeks. Bone turnover and calcium-phosphorus metabolism markers (osteocalcin, osteoprotegerin (OPG), nuclear factor-kappa-beta receptor activator ligand (RANKL), sclerostin, fibroblast growth factor-23 (FGF-23), calcium, phosphorus) were measured in the end of experiment. Bone histomorphometry was performed after euthanasia.RESULTS: Phosphorus level was significantly lower both in the «OE» group (1.63 [1.58; 1.65] mmol/L) and in the «DM» group (2.81 [2.57; 2.83] mmol /l) compared to the «Control» group (3.12 [2.55; 3.24] mmol/l) (p&lt;0.001). This marker was significantly higher in the «OE+DM» group (2.79 [2.46; 2.81] mmol/l) in comparison to the «OE» group (2.79 [2.46; 2.81] mmol /l), p=0.025. Osteocalcin level was significantly lower in the «DM» group (8.1 [7.8; 9.2] ng/ml) compared to the «Control» group (16.97 [14.07; 17.07] ng/ml ), p=0.005. A weak negative correlation (r= -0.5, p&lt;0,05) was found between glucose and osteocalcin levels (p=0.03). RANKL level was significantly lower in the «OE+DM» group (278,1 [273.1; 289.7] pg/mL) compared to the «OE» group (400.6 [394.5; 415.1] pg/mL), besides the OPG/RANKL ratio was higher in this group (0.03 [0.02; 0.035] and 0.01 [0.004; 0.014], respectively), p=0.05. In the «OE» group lower OPG level (5.1 [1.5; 5.6] pmol/L) and OPG/RANKL ratio (0.01 [0.003; 0.014]) were obtained in comparison to the «Control» group (12.3 [8.8; 14.2] pmol/l and (0.34[0.33; 0.4], p=0.025 and p=0.07, respectively. The area of bone trabeculae in the epiphyseal zone was the largest in the «Control» group (42 [39; 45]) %; the difference was significant compared to the «OE» group (29 [25; 33] %, p=0.011) and the «OE+DM» group (30 [23; 25] %, p=0.016). The area of bone trabeculae in the metaepiphyseal zone was also the largest in the «Control» group (49 [46; 52] %) compared to the «OE» (35 [25; 39] %), «DM» (31 [26; 34] %), «OE+DM» (35 [33; 38] %), p&lt;0.001. There was no difference in the thickness of the bone trabeculae among the groups.CONCLUSION: DM induction can significantly inhibit bone remodeling in animals without menopause, which is reflected in a lower osteocalcin level. Bone turnover during DM and surgical menopause is characterized by lower RANKL levels and higher OPG/RANKL ratio. The effect of ovariectomy on bone metabolism was manifested in more extensive decrease in bone trabeculae area than in DM.

Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker.

The chronic kidney disease-mineral bone disorder (CKD-MBD) is a complex multi-component syndrome occurring during kidney disease and its progression. Here, we update progress in the components of the syndrome, and synthesize recent investigations, which suggest a potential mechanism of the bone-vascular paradox. The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox. Among the factors produced by calcifying arteries, sclerostin secretion is especially enlightening. Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. Subsequent studies showing that inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu. Thus, the target of therapy in the chronic kidney disease-mineral bone disorder is not inhibition of sclerostin function, which would intensify vascular calcification. Rather, decreasing sclerostin production by decreasing the vascular osteoblastic/osteocytic transdifferentiation is the goal. This might decrease vascular calcification, decrease vascular stiffness, decrease cardiac hypertrophy, decrease sclerostin production, reduce serum sclerostin and improve skeletal remodeling. Thus, the therapeutic target of the chronic kidney disease-mineral bone disorder may be vascular osteoblastic transdifferentiation, and sclerostin levels may be a useful biomarker for the diagnosis of the chronic kidney disease-mineral bone disorder and the progress of its therapy.

Resolvin D1 shows osseous-protection via RANK reduction on monocytes during orthodontic tooth movement.

The study aimed to investigate the role of RvD1 in acute and prolonged sterile inflammation and bone remodeling. A mouse model of sterile inflammation that involves bone resorption was used to examine endogenous RvD1 kinetics during inflammation. Application of exogenous RvD1 significantly inhibited bone remodeling via osteoclast reduction, alongside an anti-inflammatory secretome shift, increased macrophages recruitment and reduction of T-cytotoxic cells. In vitro and in vivo, RvD1 led to significant reduction in RANK expression which reduce osteoclastogenesis in a dose-dependent manner. Taken together, the data shows a dual role for RvD1, as a potent immunoresolvent agent alongside an osteoresolvent role, showing a potential therapeutic agent in bone resorption associated inflammatory conditions.

Medication Related Osteonecrosis of the Jaw: A Conservative Approach

Medication-related osteonecrosis of the jaw is a well-known condition to the oral and maxillofacial surgeon despite being considered rare. In recent epidemiologic studies, the incidence of MRONJ was found to be between < 0.05% among patient taking antiresorptive medications for osteoporosis and ∼1.5% for cancer therapy. The pathophysiology is believed to be multifactorial involving bone remodeling inhibition, inflammation/infection, angiogenesis inhibition, dysfunctional immunity and genetics. Most recently, the American Association of Oral and Maxillofacial surgeons (AAOMS) released an updated position paper (2022) for guidelines regarding diagnosis and management of this condition.

The effect of zoledronic acid and denosumab on the mandible and other bones: a 18F-NaF-PET study.

The primary purpose of this study was to determine whether both zoledronic acid (ZA) and denosumab (Dmab) equally suppress bone remodeling of the normal mandible, and the secondary purpose was to determine the influence of ZA and Dmab on other normal bones. 18F-sodium fluoride-positron-emission-tomography (18F-NaF-PET) was used to perform quantitative analysis of the bone metabolism in various parts. The end points of the study were the mean standardized uptake value (SUV) of each member of the ZA group (n = 9), the Dmab group (n = 16), and the Control group (n = 23). The SUV at the thoracic vertebrae in the ZA group were significantly lower than those of the Dmab and Control group (p < 0.05) In addition, the mean SUVs of the cervical vertebrae in the ZA group were significantly lower than those in the Control group (p < 0.05). There was no significant difference among ZA, Dmab and Control group in the other sites. There was no significant difference between the Dmab and Control groups at all sites. The remodeling of mandible was not suppressed due to the treatment with anti-resorptive agents. Differences in the mechanisms of action between the BP and Dmab caused the specificity of the effect on the metabolism of normal bone.

Comparison of Denosumab and Zoledronic Acid in Postmenopausal Women With Osteoporosis: Bone Mineral Density (BMD) and Trabecular Bone Score (TBS).

BackgroundDenosumab (DEN) and zoledronic acid (ZOL) currently represent the most potent antiresorptive agents for the treatment of osteoporosis. Despite similar effects on bone resorption, these agents have distinct mechanisms of action. The objective of this study was to compare the effect of DEN and ZOL after two-year administration on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers, and persistence.MethodsA total of 585 postmenopausal women with osteoporosis who did not use osteoporosis medications were retrospectively reviewed. 290 patients were administered 60 mg DEN subcutaneously every 6 months from 2017 to 2018, and 295 patients were treated with 5 mg ZOL intravenously yearly from 2015 to 2017. BMD, TBS, and C-terminal cross-linking telopeptide of type 1 collagen (CTX) measurements were obtained at baseline and two-year after DEN injection or ZOL infusion.ResultsAfter two-year follow-up, 188 patients in the DEN group and 183 patients in the ZOL group were compared. BMD change from baseline at two years was significantly greater in the DEN group compared with the ZOL group (P < 0.001). The changes of TBS in the DEN group were statistically significant compared with baseline (P < 0.001) and the ZOL group (P < 0.001). The DEN group led to significantly greater reduction of CTX compared with ZOL group (P = 0.041).ConclusionIn postmenopausal women with osteoporosis, DEN was associated with greater BMD increase at all measured skeletal sites, greater increase of TBS, and greater inhibition of bone remodeling compared with ZOL.

Role of tissue factor in delayed bone repair induced by diabetic state in mice.

BackgroundTissue factor (TF) is the primary activator of the extrinsic coagulation protease cascade. Although TF plays roles in various pathological states, such as thrombosis, inflammatory diseases, cancer, and atherosclerosis, its involvement in bone metabolism remains unknown.Materials and methodsThe present study examined the roles of TF in delayed bone repair induced by a diabetic state in mice using wild-type (WT) and low TF-expressing (LTF) male mice. A diabetic state was induced by intraperitoneal injections of streptozotocin (STZ).ResultsA prolonged diabetic state significantly reduced total and trabecular bone mineral densities (BMD) as well as cortical bone thickness in WT and LTF mice; these BMD parameters were similar between WT and LTF mice treated with or without STZ. The diabetic state induced in WT mice delayed the repair of the femur following injury. The diabetic state induced in LTF mice was associated with further delays in bone repair. In in vitro experiments, TF significantly decreased receptor activator of nuclear factor-κB ligand-induced osteoclast formation and osteoclastogenic gene expression in RAW264.7 cells. However, it did not affect the gene expression levels of runt-related transcription factor 2 and osterix as well as alkaline phosphatase activity in mouse primary osteoblasts.ConclusionLow TF state was associated with enhanced bone repair delay induced by diabetic state in mice. The TF-induced suppression of bone remodeling may be a contributing factor to the protective effects of TF against delayed bone repair in a diabetic state.

Human semicircular canal form: Ontogenetic changes and variation of shape and size.

The semicircular canals (SCCs) transduce angular acceleration of the head into neuronal signals, and their morphology has been used to infer function. Once formed, the bony labyrinth, that surrounds the canals, is tightly regulated and has a very low bone turnover. However, relaxed postnatal inhibition of bone remodelling later in ontogeny may allow for some organised adjustments of shape and size or for greater stochastic variation. In the present study, we test the hypotheses that after birth, the shape and size of the bony canal changes or becomes more variable, or both. We study microCT scans of human perinatal and adult temporal bones using a combination of geometric morphometric analysis and cross-sectional measures. Results revealed marginal differences of size (<5%), of cross-sectional shape and of measurement variability. Geometry of the three canals together and their cross-sectional areas were, however, indistinguishable between perinates and adults. These mixed findings are indicative of diminutive levels of relaxed inhibition superimposed over a constrained template of SCC morphology.

Characteristics of patients with osteonecrosis of the jaw with oral versus intravenous bisphosphonate treatment

PurposeThis retrospective study was aimed to evaluate the clinical characteristics and treatment outcomes in patients with osteonecrosis of the jaw who were receiving oral versus intravenous (IV) bisphosphonate (BP).Materials and methodsThis retrospective study enrolled subjects who had been diagnosed with medication-related osteonecrosis of the jaw (MRONJ) during the period from July 2010 to June 2014. Information regarding the following demographic and clinical characteristics was collected: demographic data, administration route and type of BP, duration of BP medication, primary disease, number of involved sites, location of the lesion, number of surgeries, outcome of treatments, and laboratory test. All the patients were divided into oral and IV BP groups; and the between-group differences were compared.ResultsTotal 278 patients were divided into two groups as per the route of BP administration. The proportion of oral BP-related MRONJ group were more dominant over IV BP group (oral BP, n = 251; IV BP, n = 27). In the IV BP group, the average dosing duration (31.4 months) was significantly shorter than that in the oral BP group (53.1 months) (P < 0.001). The average number of involved sites in the oral BP group (1.21 ± 0.48) was smaller than that in the IV BP group (1.63 ± 0.84) (P < 0.001). The average number of surgeries was higher in the IV BP group (1.65 ± 0.95) as compared to that in the oral BP group (0.98 ± 0.73) (P < 0.001). Outcome after the surgery for MRONJ after IV BP was poor than oral BP group.ConclusionIV administration of BP causes greater inhibition of bone remodeling and could lead more severe inflammation. Therefore, even if the duration of IV administration of BP is shorter than that of oral BP, the extent of the lesion could be more extensive. Therefore, the result suggests that the MRONJ after IV BP for cancer patients needs to be considered as different characteristics to oral BP group for osteoporosis patents.

Mechanism, prevention, and treatment for medication-related osteonecrosis of the jaws.

The morbidity rate of medication-related osteonecrosis of the jaws (MRONJ) increased rapidly in recent years. Thusfar, the mechanism of MRONJ has no consensus. The possible mechanisms may include bone remodeling inhibition theory, angiogenesis inhibition theory, oral microorganism infection theory, immunosuppression theory, cytotoxicity-targeted oral epithelial cells, microcrack formation of maxillary or mandibular bone, and single nucleotide polymorphism. However, the efficacy of prevention and treatment based on a single mechanism is not ideal. Routine oral examination before MRONJ-related drug treatment, treatment of related dental diseases, and regular oral follow-up during drug treatment are of great significance for the prevention of MRONJ. During the treatment of MRONJ, the stage of MRONJ must be determined accurately, treatment must be standardized in accordance with the guidelines, and personalized adjustments must be made considering the specific conditions of patients. This review aimed to combine the latest research and guidelines for MRONJ and the experiences on the treatment of MRONJ in the Maxillofacial Surgery Department of West China Hospital of Stomatology, Sichuan University, and discuss the strategies to improve the clinical process.

Loss of miR-23a cluster in skeletal muscle can suppress bone remodeling.

Muscle-bone interaction might regulate bone remodeling in an endocrine manner, but the exact mediators have not been identified. Previous in vitro studies suggest that exosomal miRNAs are a candidate for this interaction. Here we present an in vivo study to show that targeted knockout of a muscle-specific miR-23a cluster including miR-23a, miR-27, and miR-24-2 in skeletal muscle tissues can suppress bone remodeling in mice. The effect of miR-23a cluster seem to not be related to aging, but can worsen the pathological extent of osteoporosis in mice. Our findings suggest that muscle-derived miRNAs may contribute to bone metabolism regulation through exosomes in muscle-bone interaction.

Effect of zoledronic acid on bone nanocomposites organization and prevention of bone mineral density loss in ovariectomized rats.

Osteoporosis often occurs in individuals of different age groups, frequently during menopause and after ovariectomy. It increases the risk of pathological fractures almost twice. The aim of our research was to assess bone metabolism, nanocomposite structure of the tibia under conditions of ovariectomy and zoledronic acid treatment. X-ray diffraction has been performed for nanostructure analysis of mineral crystallites and crystal lattice of hydroxyapatite in the tibia samples of ovariectomized rats with additional application of bisphosphonate zoledronic acid (0.025mg/kg). Markers of remodeling- osteocalcin, alkaline phosphatase, tartrate resistant acid phosphatase 5b- were determined. Quantitative amount of calcium in the bones was detected by atomic absorption method. Zoledronic acid prevented loss of mineral mass after ovariectomy. Rats after ovariectomy, treated with zoledronic acid, showed statistically higher (р<0.05) values of crystalline phase and calcium content compared with the SHAM-surgery and ovariectomy groups (р<0.05). Zoledronic acid inhibited bone remodeling, which is proved by tartrate resistant acid phosphatase 5b reduction and inhibition of osteoclasts during the experiment. These results enable to suggest that zoledronic acid can improve mineral mass of the bone during menopause in individuals of different age groups.

Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model.

ABSTRACTPatients with type 1 diabetes mellitus (T1DM) exhibit reduced BMD and significant increases in fracture risk. Changes in BMD are attributed to blunted osteoblast activity and inhibited bone remodeling, but these cannot fully explain the impaired bone integrity in T1DM. The goal of this study was to determine the cellular mechanisms that contribute to impaired bone morphology and composition in T1DM. Nonobese diabetic (NOD) mice were used, along with μCT, histomorphometry, histology, Raman spectroscopy, and RNAseq analyses of several skeletal sites in response to naturally occurring hyperglycemia and insulin treatment. The bone volume in the axial skeleton was found to be severely reduced in diabetic NOD mice and was not completely resolved with insulin treatment. Decreased bone volume in diabetic mice was associated with increased sclerostin expression in osteocytes and attenuation of bone formation indices without changes in bone resorption. In the face of blunted bone remodeling, decreases in the mineral:matrix ratio were found in cortical bones of diabetic mice by Raman microspectroscopy, suggesting that T1DM did not affect the bone mineralization process per se, but rather resulted in microenvironmental alterations that favored mineral loss. Bone transcriptome analysis indicated metabolic shifts in response to T1DM. Dysregulation of genes involved in fatty acid oxidation, transport, and synthesis was found in diabetic NOD mice. Specifically, pyruvate dehydrogenase kinase isoenzyme 4 and glucose transporter 1 levels were increased, whereas phosphorylated‐AKT levels were significantly reduced in diabetic NOD mice. In conclusion, in addition to the blunted bone formation, osteoblasts and osteocytes undergo metabolic shifts in response to T1DM that may alter the microenvironment and contribute to mineral loss from the bone matrix. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Cyclosporine A Promotes Bone Remodeling in LPS-Related Inflammation via Inhibiting ROS/ERK Signaling: Studies In Vivo and In Vitro.

In some inflammatory diseases of bone, osteogenesis and osteoclasis are uncoupled and the balance is usually tipped resulting in bone destruction. The underlying mechanism of osteogenic dysfunction in inflammation still needs further study. This study is aimed at investigating the effects of cyclosporine A (CsA) on bone remodeling in lipopolysaccharide- (LPS-) related inflammation. In vivo, an alveolar bone defect model was established using 10-week-old C57BL/6J mice. The mice were divided into phosphate-buffered saline (PBS), LPS, and LPS+CsA groups. After 3 weeks, micro-CT analysis and histomorphometric evaluation were conducted. In vitro, murine osteoblasts were treated with vehicle medium, LPS, LPS+CsA, LPS+extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor (LPS+PD98059), and LPS+antioxidant (LPS+EUK134). Cell proliferation, osteogenic behaviors, oxidative stress, and ERK signaling were determined. By these approaches, LPS inhibited bone remodeling and promoted oxidative stress accumulation in alveolar bone defects. When animals were treated with CsA, all LPS-induced biochemical changes ameliorated with a marked protective effect. In vitro, the reactive oxygen species (ROS) levels in mitochondria increased in LPS-treated osteoblasts, with decreased expression of osteogenic differentiation genes. The CsA, PD98059, and EUK134 presented remarkable protective effects against LPS treatment. CsA effectively enhanced bone remodeling and attenuated oxidative stress caused by LPS via inhibiting ROS/ERK signaling. Taken together, the protective effect of CsA and the inhibitory effect of ERK signaling on the maintenance of mitochondrial function and reduction of ROS levels hold promise as a potential novel therapeutic strategy for inflammatory diseases in bones.

Early inhibition of subchondral bone remodeling slows load-induced posttraumatic osteoarthritis development in mice.

Posttraumatic osteoarthritis (PTOA) is associated with abnormal and increased subchondral bone remodeling. Inhibiting altered remodeling immediately following joint damage can slow PTOA progression. Clinically, however, inhibiting remodeling when significant joint damage is already present has minimal effects in slowing further disease progression. We sought to determine the treatment window following PTOA initiation in which inhibiting remodeling can attenuate progression of joint damage. We hypothesized that the most effective treatment would be to inhibit remodeling immediately after PTOA initiation. We used an animal model in which a single bout of mechanical loading was applied to the left tibia of 26-week-old male C57Bl/6 mice at a peak load of 9 N to initiate load-induced PTOA development. Following loading, we inhibited bone remodeling using daily alendronate (ALN) treatment administered either immediately or with 1 or 2 weeks' delay up to 3 or 6 weeks post-loading. A vehicle (VEH) treatment group controlled for daily injections. Cartilage and subchondral bone morphology and osteophyte development were analyzed and compared among treatment groups. Inhibiting remodeling using ALN immediately after load-induced PTOA initiation reduced cartilage degeneration, slowed osteophyte formation, and preserved subchondral bone volume compared to VEH treatment. Delaying the inhibition of bone remodeling at 1 or 2 weeks similarly attenuated cartilage degeneration at 6 weeks, but did not slow the development of osteoarthritis (OA)-related changes in the subchondral bone, including osteophyte formation and subchondral bone erosions. Immediate inhibition of subchondral bone remodeling was most effective in slowing PTOA progression across the entire joint, indicating that abnormal bone remodeling within the first week following PTOA initiation played a critical role in subsequent cartilage damage, subchondral bone changes, and overall joint degeneration. These results highlight the potential of anti-resorptive drugs as preemptive therapies for limiting PTOA development after joint injury, rather than as disease-modifying therapies after joint damage is established. © 2021 American Society for Bone and Mineral Research (ASBMR).

Response of Gli1+ Suture Stem Cells to Mechanical Force Upon Suture Expansion.

Normal development of craniofacial sutures is crucial for cranial and facial growth in all three dimensions. These sutures provide a unique niche for suture stem cells (SuSCs), which are indispensable for homeostasis, damage repair, as well as stress balance. Expansion appliances are now routinely used to treat underdevelopment of the skull and maxilla, stimulating the craniofacial sutures through distraction osteogenesis. However, various treatment challenges exist due to a lack of full understanding of the mechanism through which mechanical forces stimulate suture and bone remodeling. To address this issue, we first identified crucial steps in the cycle of suture and bone remodeling based on the established standard suture expansion model. Observed spatiotemporal morphological changes revealed that the remodeling cycle is approximately 3to4 weeks, with collagen restoration proceeding more rapidly. Next, we traced the fate of the Gli1+ SuSCs lineage upon application of tensile force in three dimensions. SuSCs were rapidly activated and greatly contributed to bone remodeling within 1 month. Furthermore, we confirmed the presence of Wnt activity within Gli1+ SuSCs based on the high co-expression ratio of Gli1+ cells and Axin2+ cells, which also indicated the homogeneity and heterogeneity of two cell groups. Because Wnt signaling in the sutures is highly upregulated upon tensile force loading, conditional knockout of β-catenin largely restricted the activation of Gli1+ SuSCs and suppressed bone remodeling under physiological and expansion conditions. Thus, we concluded that Gli1+ SuSCs play essential roles in suture and bone remodeling stimulated by mechanical force and that Wnt signaling is crucial to this process. © 2022 American Society for Bone and Mineral Research (ASBMR).

Effects of metformin on the prevention of bisphosphonate-related osteonecrosis of the jaw-like lesions in rats.

In this study, we aimed to investigate the effect of glucose metabolism on bone healing after tooth extraction in an osteoporosis rat model administered zoledronic acid (ZA) and dexamethasone (DX). In total, 24 male Wistar rats (4 weeks old) were randomly assigned to four groups: Control (subcutaneous physiological saline), ZD (subcutaneous ZA and DX twice a week), Ins+ZD (subcutaneous insulin followed by ZD treatment), and Met+ZD (oral metformin followed by ZD treatment). Blood was collected every two weeks . Two weeks after treatment initiation, the first molar tooth on the right maxilla was extracted from all rats. Four weeks later, the rats were sacrificed, and bone healing was assessed. Maxillae samples were fixed and scanned using micro-computed tomography for quantifying areas of bone defects. Hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP) staining were performed to evaluate bone apoptosis and osteoclast number. In all experimental groups, body weight was statistically lower than that in the Control group, with no changes observed in uncarboxylated osteocalcin concentrations. The radiological analysis revealed that insulin or metformin administration improved healing in the tooth extraction socket (p < 0.01). Histological examination revealed that the osteonecrosis area was reduced in the Ins+ZD and Met+ZD groups (p < 0.01). TRAP staining presented increased osteoclast numbers in the ZD group when compared with that observed in the Control. Tooth extraction with long-term ZA and DX administration inhibited bone remodeling and induced bisphosphonate-related osteonecrosis of the jaw-like lesions. Metformin exerted protective effects ag ainst osteonecrosis of the jaw.