Denosumab Research Articles

Influence of antiresorptive/antiangiogenic therapy on the surgical treatment outcomes of experimentally induced peri-implantitis lesions

ObjectiveTo investigate the influence of various antiresorptive and antiangiogenic medications on the resolution of experimentally induced peri-implantitis lesions after different surgical treatment approaches.Materials and methodsForty-eight albino rats randomly received a dual application of the following medications: (1) amino-bisphosphonate (zoledronate (Zo)) (n = 8), (2) RANKL inhibitor (denosumab (De)) (n = 8), (3) antiangiogenic (bevacizumab (Be)) (n = 8), (4) Zo + Be (n = 8), (5) De + Be (n = 8), or (6) no medication (control (Co)) (n = 8). Ligature-induced peri-implantitis lesions were established at 2 maxillary implants over 16 weeks. Afterward, animals were randomly treated either with open flap debridement (OFD) or reconstructive therapy (RT). Treatment procedures were followed by a 12-week healing period. The histological outcomes included residual defect length (DL); defect width (DW) at the bone crest (BC-DW); 25%, 50%, and 75% of the DL; and areas of inflammatory cell infiltrate (ICT). When present, areas of bone sequester (BS) were assessed considering the animal as a statistical unit.ResultsA total of 21 animals were analyzed (Zo: RT = 3, OFD = 1; De: RT = 3, OFD = 2; Be: OFD = 1; Zo + Be: RT = 2, OFD = 2; Co: RT = 3, OFD = 2). Implant loss rates were comparable among the experimental groups. Except for the 25% and 75% DW values that were significantly higher in the Zo + Be group compared to the Co group (p = 0.04 and p = 0.03, respectively), no significant differences were found among the experimental groups for the DL (lowest—Be: 0.56 mm; highest—Co: 1.05 mm), BC-DW (lowest—De: 0.86 mm, highest—Co: 1.07 mm), 50% DW (lowest—De: 0.86 mm; highest—Be + Zo: 1.29 mm), and ICT (lowest—Be: 0.56 mm2; highest—Be + Zo: 1.65 mm2). All groups, except for the Zo and Be following RT, showed presence of BS.ConclusionsThe present findings did not reveal a marked effect of various antiresorptive/antiangiogenic medications on the resolution of experimentally induced peri-implantitis lesions, regardless of the surgical approach employed (OFD and RT).Clinical relevanceResolution of peri-implantitis lesions may not be affected by the investigated antiresorptive/antiangiogenic medications.

Electroacupuncture stimulating Zusanli (ST36), Sanyinjiao (SP6) in mice with collagen-induced arthritis leads to adenosine A2A receptor-mediated alteration of p38α mitogen-activated protein kinase signaling and inhibition of osteoclastogenesis.

To observe the effect of electroacupuncture (EA) stimulating Zusanli (ST36), Sanyinjiao (SP6) on inhibition of osteoclastogenesis and the role of the adenosine A2A receptor (A2AR) and the p38α Mitogen-Activated Protein Kinase (MAPK) signaling pathway in mediating this effect. Mice with collagen induced arthritis (CIA) received different treatments. Immunohistochemistry and western blotting were used to determine the levels of multiple signaling molecules in these joints [receptor activator of nuclear transcription factor-κB (NF-κB) ligand (RANKL), receptor activator of NF-κB (RANK), tumor necrosis factor receptor associated factor 6 (TRAF6), p38α, NF-κB, and nuclear factor of activated T cells C1 (NFATc1)]. Osteoclasts were identified using tartrate-resistant acid phosphatase (TRAP) staining. The immunohistochemistry results indicated upregulation of p38α, NF-κB, and NFATc1 in the CIA-control and CIA-EA-SCH58261 groups, but reduced levels in the CIA-EA group. Western blotting indicated upregulation of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1 in the CIA-control and CIA-EA-SCH58261 groups, but reduced expression in the CIA-EA group. Osteoclasts were more abundant in the CIA-control and CIA-EA-SCH58261 groups than in the CIA-EA group. EA treatment enhanced the A2AR activity and inhibited osteoclast formation by inhibition of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1. SCH58261 reversed the effect of EA. These results suggest that EA regulated p38α-MAPK signaling by increasing A2AR activity, which inhibited osteoclastogenesis.

Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats.

Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 is expressed on the cell surface of mature osteoclasts. Anti-Siglec-15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec-15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4-month-old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, -18.7%), trabecular bone volume (-43.1%), trabecular connectivity (-59.7%), and bone stiffness (-76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec-15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Clinical Studies On Romosozumab: An Alternative For Individuals With A High Risk Of Osteoporotic Fractures: A Current Concepts Review (Part II)

Romosumab (ROMO) should be used to treat postmenopausal women with osteoporosis at high fracture risk after carefully considering the cardiovascular status and the risk/benefit balance. Clinicians should avoid ROMO for patients with a history of myocardial infarction or stroke in the past 12 months. Although ROMO offers an alternative for patients with a high risk of osteoporotic fractures, it is affected by previous osteoporosis treatment: using denosumab (DENO) and oral bisphosphonates for over one year attenuates its effect. An additional 12 months of DENO appears to be more effective than ibandronate for the enhancement of bone mineral density (BMD) as a sequential agent after 12 months of ROMO, with few severe adverse events. However, it is important to emphasize that ROMO is not a first-choice medication. It is only indicated when bisphosphonates cannot help, and its clinical use has demonstrated cardiovascular risks. The cost and availability could also make its use problematic in clinical practice. Therefore, although ROMO represents an important advance in the treatment of osteoporosis, it is by no means a solution for osteoporosis.

Abstract PO-099: Short-term outcomes of an extended endoscopic endonasal resection of a clival giant cell tumor with adjuvant RANK-L inhibitor therapy: Case report

Abstract Background Clival giant cell tumors (GiCT) are rare neoplasms that commonly target the epiphysis. Recently, skull base GiCTs have been reported, predominantly in the sphenoid and temporal bones. Although typically benign, GiCTs of the skull-base can cause neurologic deficits due to compression of cranial nerves or intracranial contents. The efficacy of adjuvant chemotherapy in treating GiCTs is not known. One potential treatment option neoplastic mononuclear stromal cells in GiCTs express NF-κB ligands (RANK-L), which can be therapeutically targeted with Denosumab, a monoclonal antibody against RANK-L. Here, we describe the case of a GiCT invasive to the clivus, an extended endoscopic endonasal resection of the tumor, and management of the lesion with Denosumab. Methods A retrospective chart review was performed on the patient of interest. Magnetic resonance imaging (MRI) and computed tomography (CT) scans were used to assess disease growth and response to surgical and therapeutic intervention. Case presentation A previously healthy seventeen-year-old female presented with headaches and numbness of the left V2 and V3. A diagnosis of a clival giant cell tumor was confirmed with strict pathologic, radiographic, and clinical correlation. She was found to have a clival mass extending into the sphenoid sinus. Surgical excision was performed by both the otolaryngology and neurosurgery departments at a single institution. She underwent an extended endoscopic endonasal resection of the clival mass. Following surgery, the numbness on the left V2 and V3 distribution improved. She occasionally reported bilateral V3 distribution symptoms without definite anatomic correlates for right sided complaints. Due to the presence of residual tumor, we recommended adjunctive medical therapy. We performed adjunctive medical therapy with Denosumab, a RANKL inhibitor. Discussion When complete surgical excision with negative margins is not feasible in lesions of the skull base, adjuvant treatment is commonly required to achieve local disease control. Our case demonstrates the efficacy of a combined approach where surgery is used to achieve a histologic diagnosis, decompression and evaluate for respectability. Adjuvant medical therapy using RANKL inhibitors is a promising approach that may be effective to achieve lifelong disease control but requires continued maintenance on therapy. Citation Format: Myra A. Zaheer, Abhisri Ramesh, Aadit P. Mehta, Adriana S. Fonseca, Daniel A. Donoho. Short-term outcomes of an extended endoscopic endonasal resection of a clival giant cell tumor with adjuvant RANK-L inhibitor therapy: Case report [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-099.

Investigation of Giant Cell Tumor of Bone and Tissue Engineering Approaches for the Treatment of Giant Cell Tumor of Bone.

Primary bone tumors such as Ewing sarcoma, osteosarcoma, and chondrosarcoma, secondary bone tumors developed from progressive malignancies, and metastasized bone tumors are more prevalent and studied descriptively through biology and medical research. Less than 0.2% of cancer diagnoses are caused by rare bone-originating tumors, which despite being rare are particularly difficult due to their high death rates and substantial disease burden. A giant cell tumor of bone (GCTB) is an intramurally invasive but rare and benign type of bone tumor, which seldom metastasizes. The most often prescribed medication for GCTB is Denosumab, a RANKL (receptor activator of nuclear factor κB ligand) inhibitor. Because pharmaceutical drug companies rely on two-dimensional and animal models, current approaches for investigating the diverse nature of tumors are insufficient. Cell line based medication effectiveness and toxicity studies cannot predict tumor response to antitumor medicines. It has already been investigated in detail why molecular pathways do not reproduce in vitro, a phenomenon known as flat biology. Due to physiological differences between human beings and animals, animal models do not succeed in identifying side effects of the treatment, emulating metastatic growth, and establishing the link between cancer and the immune system. This review summarizes and discusses GCTB, the disease, its cellular composition, various bone tumor models, and their properties and utilization in research. As a result, this study delves deep into in vitro testing, which is vital for scientists and physicians in various fields, including pharmacology, preclinical investigations, tissue engineering, and regenerative medicine.

Denosumab Improves Glycaemic Parameters in Postmenopausal Osteoporosis Patients with Combined Type 2 Diabetes Mellitus.

This study aimed to determine whether RANKL inhibitors in postmenopausal osteoporosis patients with combined type 2 diabetes mellitus (T2DM) could improve their glucose metabolism index. First of all, 84 patients affected with postmenopausal osteoporosis with combined T2DM attending the Department of Endocrinology at the Third Hospital of Hebei Medical University were selected and randomized into two groups of 42 patients each. One group was given Denosumab 60 mg once every six months (denosumab group, D.G.), and the other group was given 2 mg ibandronate once every three months (ibandronate group, I.G.). Blood glucose parameters were compared before and after treatment in both groups and serum active GLP-1 levels and DPP-4 levels were also assessed. After treatment, there was no significant difference in fasting glucose between the two groups, but there was a significant decrease in fasting glucose in the Denosumab Group (D.G.) compared to before treatment. There was a significant difference in 2-hour postprandial glucose (2hPG) between the two groups after treatment, with the D.G. being lower than the ibandronate group (I.G.). Glycosylated haemoglobin (HbA1c) was lower in the D.G. than in the I.G. after treatment, but the difference between them was insignificant. In the D.G., serum active GLP-1 levels increased after treatment, and serum DPP-4 levels decreased. Serum GLP-1 and DPP-4 levels in the I.G. did not change compared with those before treatment. In conclusion, In the clinical management of postmenopausal osteoporosis patients with combined T2DM, the choice of RANKL inhibitors as anti-osteoporosis therapy may benefit their glycaemic parameters by elevating serum active GLP-1 levels and decreasing serum DPP-4 levels.

Medication-related osteonecrosis of the jaw without osteolysis on computed tomography: a retrospective and observational study

Medication-related osteonecrosis of the jaw (MRONJ) is a refractory osteonecrosis caused by antiresorptive agents such as bisphosphonate and denosumab (DMB). In MRONJ surgery, computed tomography (CT) is generally used to determine the extent of bone resection. However, in some recent MRONJ cases, no abnormal findings were detected on CT. Therefore, we aimed to clarify the characteristics of MRONJ without osteolysis. This retrospective and observational study included 18 patients diagnosed with MRONJ between October 2020 and October 2022 at Department of Dentistry and Oral Surgery, Kansai Medical University Medical Center. In four of 18 patients with MRONJ, no abnormal findings such as osteolysis, separation of sequestrum, and periosteal reaction were observed on CT images at the first visit. All four patients with non-osteolytic MRONJ had malignant tumors and received high-dose DMB, and in the four patients there were no preceding dental infections such as apical lesions or periodontal disease and the trigger of MRONJ was unknown. Surgery was performed in three of the four patients. The extent of bone resection was determined using magnetic resonance imaging and intraoperative gross findings. In the future, it is necessary to establish a method for diagnosing non osteolytic MRONJ and determining the extent of bone resection.

Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway.

Background and Objectives: Damage to normal bone tissue following therapeutic irradiation (IR) represents a significant concern, as IR-induced bone microenvironment disruption can cause bone loss and create a more favorable environment for tumor metastases. The aim of the present study was to explore the cellular regulatory mechanism of IR-induced bone microenvironment disruption to effectively prevent radiotherapy-associated adverse effects in the future. Materials and Methods: In this study, a mouse model of local IR was established via local irradiation of the left hind limb of BALB/c mice with 12 Gy X-rays, and an in vitro osteocyte (OCY) model was established by exposing osteocyte-like MLO-Y4 cells to 2, 4, and 8 Gy irradiation to analyze multicellular biological injuries and cellular senescence. Small interfering RNA (siRNA) transfection at the cellular level and a selective antagonist intervention C-176 at the animal level were used to explore the potential role of the stimulator of interferon genes (STING) on IR-induced bone microenvironment disruption. Results: The results showed that 12 Gy local IR induces multicellular dysfunction, manifested as ascension of OCYs exfoliation, activation of osteoclastogenesis, degeneration of osteogenesis and fate conversion of adipogenesis, as well as cellular senescence and altered senescence-associated secretory phenotype (SASP) secretion. Furthermore, the expression of STING was significantly elevated, both in the primary OCYs harvested from locally irradiated mice and in vitro irradiated MLO-Y4 cells, accompanied by the markedly upregulated levels of phosphorylated TANK-binding kinase 1 (P-TBK1), RANKL and sclerostin (SOST). STING-siRNA transfection in vitro restored IR-induced upregulated protein expression of P-TBK1 and RANKL, as well as the mRNA expression levels of inflammatory cytokines, such as IL-1α, IL-6 and NF-κB, accompanied by the alleviation of excessive osteoclastogenesis. Finally, administration of the STING inhibitor C-176 mitigated IR-induced activation of osteoclastogenesis and restraint of osteogenesis, ameliorating the IR-induced biological damage of OCYs, consistent with the inhibition of P-TBK1, RANKL and SOST. Conclusions: The STING-P-TBK1 signaling pathway plays a crucial role in the regulation of the secretion of inflammatory cytokines and osteoclastogenesis potential in IR-induced bone microenvironment disruption. The selective STING antagonist can be used to intervene to block the STING pathway and, thereby, repair IR-induced multicellular biological damage and mitigate the imbalance between osteoclastogenesis and osteoblastgenesis.

Do Bisphosphonates and RANKL Inhibitors Alter the Progression of Coronary Artery Calcification? A Systematic Review

Do Bisphosphonates and RANKL Inhibitors Alter the Progression of Coronary Artery Calcification? A Systematic Review

P-102 Inhibition of RANKL increases the number of motile sperm in a subgroup of infertile men

Abstract Study question Does inhibition of RANKL increase semen quality in infertile men? Summary answer Overall, inhibition of RANKL (Denosumab) did not affect semen quality. However, in a subgroup of men with high serum AMH sperm production was significantly increased. What is known already Currently, there is no treatment available for male infertility, but studies in animal and preclinical human data have suggested a role for RANKL in male reproduction. Study design, size, duration A single-center, double-blinded, randomized clinical trial in 100 infertile men randomly assigned (1:1) to s.c. injection with 60 mg/mL Denosumab or s.c. saline injection 1 mL (0.9%) (placebo). The primary endpoint was changes in semen production, though the study was designed as an explorative study, with the aim of investigating the profile of which infertile men who would have a beneficial treatment outcome of Denosumab. Participants/materials, setting, methods All participants were infertile men referred to our andrological clinic due to impaired semen quality. Blood and semen samples were collected at baseline and after one and two cycles of spermatogenesis on day 80 and day 160, respectively. Main results and the role of chance There were no differences in semen quality or reproductive hormones at day 80 or day 160 between men treated with Denosumab or placebo. However, men with a serum AMH ≥ 40 pmol/L had a significant increase in total motile sperm (143% (SD 116%); p = 0.011), progressive motile sperm (133% (SD 100%); p = 0.039) and a borderline increase in sperm concentration (64% (SD 95%); p = 0.056) at day 80 compared to baseline. Further stratifying men according to both serum AMH (≥ 40 pmol/L) and serum RANKL (highest 50%), showed a significantly higher increase in sperm concentration (107% (SD 111%) vs. -8% (SD 68%); p = 0.009), total motile sperm (256% (SD 270%) vs. 31% (SD 125%); p = 0.039) and progressive motile sperm (191% (SD 194%) vs. 18% (SD 134%) p = 0.013) at day 80 in men treated with Denosumab compared to placebo treated men. Furthermore, serum FSH (-28% (SD 33%) vs. 0%, (SD 22%); p = 0.041) and serum LH (-29% (SD 28%) vs. 20% (SD 51%), p = 0.048) were significantly lower and testosterone/LH ratio (50% (SD 51%) vs. -7% (SD 43%); p = 0.024) significantly higher at day 80 in men treated with Denosumab compared to placebo treatment. Limitations, reasons for caution This is a report from a randomized clinical trial, with an explorative design. Randomized clinical trials in a predefined group of infertile men with high serum AMH, are needed to explore if inhibition of RANKL improves semen quality and pregnancy rate in infertile couples with male factor infertility. Wider implications of the findings The increase in sperm production after Denosumab treatment in infertile men with preserved Sertoli cell function needs to be validated, in a trial selecting men based on serum AMH. Ultimately, Denosumab may be a potential breakthrough in treating male infertility at least in some infertile men with high serum AMH. Trial registration number NCT03030196

The vitamin D receptor in osteoblastic cells but not secreted parathyroid hormone is crucial for soft tissue calcification induced by the proresorptive activity of 1,25(OH)2D3

The vitamin D receptor (VDR) is expressed most abundantly in osteoblasts and osteocytes (osteoblastic cells) in bone tissues and regulates bone resorption and calcium (Ca) and phosphate (P) homeostasis in association with parathyroid hormone (PTH). We previously reported that near-physiological doses of vitamin D compounds suppressed bone resorption through VDR in osteoblastic cells. We also found that supra-physiological doses of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] induced bone resorption and hypercalcemia via VDR in osteoblastic cells. Here, we report that the latter, a proresorptive dose of 1,25(OH)2D3, causes soft tissue calcification through VDR in osteoblastic cells. High concentrations of vitamin D affect multiple organs and cause soft tissue calcification, with increases in bone resorption and serum Ca levels. Such a variety of symptoms is known as hypervitaminosis D, which is caused by not only high doses of vitamin D but also impaired vitamin D metabolism and diseases that produce 1,25(OH)2D3 ectopically. To clarify the biological process hierarchy in hypervitaminosis D, a proresorptive dose of 1,25(OH)2D3 was administered to wild-type mice in which bone resorption had been suppressed by neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody. 1,25(OH)2D3 upregulated the serum Ca x P product, concomitantly induced calcification of the aorta, lungs, and kidneys, and downregulated serum PTH levels in control IgG-pretreated wild-type mice. Pretreatment of wild-type mice with anti-RANKL antibody did not affect the down-regulation of PTH levels by 1,25(OH)2D3, but inhibited the increase of the serum Ca x P product and soft tissue calcification induced by 1,25(OH)2D3. Consistent with the effects of anti-RANKL antibody, VDR ablation in osteoblastic cells also did not affect the down-regulation of PTH levels by 1,25(OH)2D3, but suppressed the 1,25(OH)2D3-induced increase of the serum Ca x P product and calcification of soft tissues. Taken together with our previous results, these findings suggest that bone resorption induced by VDR signaling in osteoblastic cells is critical for the pathogenesis of hypervitaminosis D, but PTH is not involved in hypervitaminosis D.

Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals.

Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 107 β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells.

#5454 DESIGN AND OPTIMIZATION OF DRUG COMBINATION THERAPIES FOR OSTEOPOROSIS VIA SIMULATIONS OF BONE TURNOVER

Abstract Background and Aims Many chronic kidney disease (CKD) patients suffer from mineral and bone disorders like osteoporosis, which also affects a huge part of the general population, predominantly postmenopausal women. For the treatment of osteoporosis, several drug types with different mechanisms of action are available, such as bisphosphonates, PTH analogs, RANKL inhibitors and sclerostin inhibitors (some of which are contraindicated for CKD patients beyond CKD stage 3). Different drugs can be given individually or combined in various ways, simultaneously or sequentially, resulting in a huge number of theoretically possible drug combinations that are practically impossible to study in clinical studies. We aimed to study using simulations whether there are combination therapies that would work considerably better than those tested and employed in clinical practice. If so, this could be beneficial for the treatment of a large number of osteoporosis patients by leading to a higher increase in bone strength and a higher reduction in bone fracture risk than standard therapies. Method We developed a physiology-based mathematical model that simulates the process of bone renewal in the human body and can predict how different osteoporosis drugs (including bisphosphonates, PTH analogs, RANKL inhibitors, and sclerostin inhibitors) affect this process, alone and in combination [1]. Results The model was validated on over 30 clinical osteoporosis studies with about 90 study arms. It predicted the time courses of bone mineral density and bone turnover markers with a high degree of accuracy based on the knowledge of the used drugs and dosing schemes alone. We used the model to study how treatment results changed when merely reshuffling the order in which different drugs were given. For example, for 3-year drug therapies involving alendronate, denosumab and romosozumab (1 year each), our simulations showed that the order in which these drugs were given can have a considerable effect on short- and long-term therapy success [1]. This is due to different drugs favorably interacting when applied in the right sequence. Conclusion Our findings indicate that some osteoporosis drug administration schemes are superior to others while relying on the exact same types and amounts of drugs. Therefore, there is a large potential to improve pharmacologic therapies of osteoporosis using physiological simulations. For renal patients beyond CKD stage 3, a restricted set of drug types may be considered to account for contraindications related to impaired renal clearance. If translated into clinical practice, findings obtained using our model could give rise to novel treatments using combinations of existing drugs for osteoporosis that lead to a lower bone fracture risk than standard treatments. Moreover, our model could serve as a basis for personalizing osteoporosis therapy to individual patients.

Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study

IntroductionIncreased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. Materials and methodsWe have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). Results13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (−4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DiscussionThis study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. ConclusionDenosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.

Treatment options for postmenopausal osteoporosis

Osteoporosis is a systemic skeletal disease, characterized by a decrease of bone mass and bone quality, with a subsequent reduction of bone strenght and an increased risk of fracture. Hormone Therapy for menopausal women can significantly prevent osteopenia and osteoporosis, thus reducing the fracture risk. The use of HT, according to guidelines, is for postmenopausal women within 10 years since last menstruation or under the age of 60 years. Only HT at standard dose is able to reduce the fracture risk, while low-dose HT can prevent bone loss. Estrogens (with and without the addition of a progestin) and tibolone showed a fracture risk reduction effect. Also Tissue Selective Estrogen Complex (TSEC) can reduce the bone loss in postmenopause. For women without climacteric symptoms (as hot flushes and/or night sweats) the use of Selective Estrogen Receptor Modulators (SERMs) can be indicated, with a reduction of risk of vertebral fracture (for raloxifene and bazedoxifene), and non-vertebral fracture in high-risk women (for bazedoxifene). In more advence ages, antiresoptive agents as Bisphosphonates (Alendronate, Risedronate, Ibandronate and Zoledronate) can reduce the risk of vertebral, non-vertebral and hip fracture risk. Denosumab (DMAB), monoclonal antibobody against Rank-ligand (RANKL), providing an increased bone mass, significantly decreases risk of vertebral, non-vertebral and hip fracture. A drug holiday or treatment interruption is not recommended with DMAB, and DMAB dosing should not stopped without subsequent antiresorptive or other therapy to prevent a "rebound effect" with a possible increased risk of multiple vertebral fracture. Teriparatide (fraction 1-34 of recombinant PTH, administered daily 20 mcg sc) can stimulate osteoblast activity, with an important increase of bone mass and a significant reduction of risk of vertebral fracture, and of multiple vertebral fractures, but also of non-vertebral fragility fracture. Romosozumab (RMZ, adimnistered monlty 210 mg sc), is a bone-forming monoclonal antibody that binds to and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption. RMZ has showed to give marked increases in spine and hip bone density after 1 year of administration, also reducing fracture risk. The differences among the various treatments is the basis for the individualization of osteoporosis treatment, according to combination and/or sequential regimens of administration.

RANKL Inhibition Reduces Cardiac Hypertrophy in mdx Mice and Possibly in Children with Duchenne Muscular Dystrophy.

Cardiomyopathy has become one of the leading causes of death in patients with Duchenne muscular dystrophy (DMD). We recently reported that the inhibition of the interaction between the receptor activator of nuclear factor κB ligand (RANKL) and receptor activator of nuclear factor κB (RANK) significantly improves muscle and bone functions in dystrophin-deficient mdx mice. RANKL and RANK are also expressed in cardiac muscle. Here, we investigate whether anti-RANKL treatment prevents cardiac hypertrophy and dysfunction in dystrophic mdx mice. Anti-RANKL treatment significantly reduced LV hypertrophy and heart mass, and maintained cardiac function in mdx mice. Anti-RANKL treatment also inhibited NFκB and PI3K, two mediators implicated in cardiac hypertrophy. Furthermore, anti-RANKL treatment increased SERCA activity and the expression of RyR, FKBP12, and SERCA2a, leading possibly to an improved Ca2+ homeostasis in dystrophic hearts. Interestingly, preliminary post hoc analyses suggest that denosumab, a human anti-RANKL, reduced left ventricular hypertrophy in two patients with DMD. Taken together, our results indicate that anti-RANKL treatment prevents the worsening of cardiac hypertrophy in mdx mice and could potentially maintain cardiac function in teenage or adult patients with DMD.

What's New in Musculoskeletal Infection.

What's New in Musculoskeletal Infection.

Inhibition of RANKL in the testis increased the number of motile sperm in a sub-group of infertile men with preserved Sertoli cell function

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Discovery of RANKL and the current and future impact of its research

Discovery of RANKL (receptor activator of NF-κB ligand) had an impact on identification of the mechanisms regulating osteoclast differentiation and function, resulting in establishment of research field bridging bone biology and immunology (osteoimmunology), and development of a human anti-RANKL monoclonal antibody (denosumab). Denosumab has been clinically available for treatment of osteoporosis and cancer-induced bone diseases in many countries. Denosumab is a so-called blockbuster of which sales amount was 5.3 billion US dollars in 2021. I will discuss the intense competition between Amgen Inc. and us regarding discovery of RANKL. One of the recent topics is the identification of RANKL reverse signaling with a RANKL-binding peptide, W9 known as a RANKL antagonist. The RANKL reverse signaling stimulates differentiation of osteoblasts and bone formation. The findings revealed the RANKL-RANK (a receptor of RANKL) dual signaling in coupling between bone resorption and bone formation. Interestingly, W9 also stimulates differentiation of chondrocytes and repairs defect of articular cartilage regardless of RANKL. Identification of the mechanisms will be useful for development of pharmaceuticals treating osteoarthritis. I also suggest possible applications of anti-RANKL antibody (anti-RANKL) to the treatment of cancer patients. RANKL has an important role in development of medullary thymic epithelial cells (mTECs) establishing self-tolerance. Anti-RANKL potentiates anticancer immune responses thorough regeneration of tumor-reactive T-cells by inhibiting mTEC development. I expect the synergy of anti-RANKL and immune checkpoint inhibitors such as anti-CTLA-4 antibody and anti-PD-1 antibody for immuno-oncology. Several clinical trials are currently in progress. It is likely that cancers will not be incurable diseases in the near future.