Decreased Bone Resorption Research Articles

Drug-induced hypocalcemia

Hypocalcemia (HCa) is one of the main water-electrolyte disturbances in clinical practice. An acute decrease in serum calcium levels can lead to seizures, ventricular arrhythmias, bronchospasm and laryngospasm. Chronic HCa can result in disorientation and confusion. To prevent these complications, the risk factors for low calcium levels must be carefully evaluated. One of these factors is drugs, in which case we are talking about drug-induced (DI) HCa. The list of drugs-inducers of DI HCa is quite extensive, but the leading role in this disorder is played by drugs for the treatment of osteoporosis, antineoplastic and antiepileptic drugs, as well as drugs for anti-tuberculosis therapy. When taking zoledronic acid, DI HCa is observed with a frequency of up to 39%. When taking imatinib, a targeted anticancer drug, a decrease in calcium levels was observed in 40% of cases. The pathophysiological mechanisms of DI HCa can be a decrease in bone resorption, a decrease in the concentration of vitamin D, inhibition of the action of parathyroid hormone and impaired calcium absorption. Risk factors in most cases of DI HCa are vitamin D deficiency and hypomagnesemia. An acute decrease in calcium levels leads to symptoms of neuromuscular excitability, abnormalities on the electrocardiogram (ECG) and electroencephalogram (EEG). The basis for the treatment of DI HCa is the drug withdrawal and the appointment of calcium. It is also necessary to prescribe vitamin D. The main methods of prevention of DI HCa are to determine the level of calcium and vitamin D before starting therapy with culprit medication, and to correct its level. It is also important to prescribe additional amounts of calcium and vitamin D during therapy with such drugs. Awareness of the attending physicians about the problem of DI HCa, a thorough assessment of its risk factors and the prophylactic administration of calcium and vitamin D preparations will help to effectively prevent those serious complications resulting from a decrease in calcium levels in clinical practice.

Enhancement of Bone Regeneration Through the Converse Piezoelectric Effect, A Novel Approach for Applying Mechanical Stimulation.

Serious bone injuries have devastating effects on the lives of patients including limiting working ability and high cost. Orthopedic implants can aid in healing injuries to an extent that exceeds the natural regenerative capabilities of bone to repair fractures or large bone defects. Autografts and allografts are the standard implants used, but disadvantages such as donor site complications, a limited quantity of transplantable bone, and high costs have led to an increased demand for synthetic bone graft substitutes. However, replicating the complex physiological properties of biological bone, much less recapitulating its complex tissue functions, is challenging. Extensive efforts to design biocompatible implants that mimic the natural healing processes in bone have led to the investigation of piezoelectric smart materials because the bone has natural piezoelectric properties. Piezoelectric materials facilitate bone regeneration either by accumulating electric charge in response to mechanical stress, which mimics bioelectric signals through the direct piezoelectric effect or by providing mechanical stimulation in response to electrical stimulation through the converse piezoelectric effect. Although both effects are beneficial, the converse piezoelectric effect can address bone atrophy from stress shielding and immobility by improving the mechanical response of a healing defect. Mechanical stimulation has a positive impact on bone regeneration by activating cellular pathways that increase bone formation and decrease bone resorption. This review will highlight the potential of the converse piezoelectric effect to enhance bone regeneration by discussing the activation of beneficial cellular pathways, the properties of piezoelectric biomaterials, and the potential for the more effective administration of the converse piezoelectric effect using wireless control.

Effects of sclerostin antibody on bone healing.

Promoting bone healing after a fracture has been a frequent subject of research. Recently, sclerostin antibody (Scl-Ab) has been introduced as a new anabolic agent for the treatment of osteoporosis. Scl-Ab activates the canonical Wnt (cWnt)-β-catenin pathway, leading to an increase in bone formation and decrease in bone resorption. Because of its rich osteogenic effects, preclinically, Scl-Ab has shown positive effects on bone healing in rodent models; researchers have reported an increase in bone mass, mechanical strength, histological bone formation, total mineralized callus volume, bone mineral density, neovascularization, proliferating cell nuclear antigen score, and bone morphogenic protein expression at the fracture site after Scl-Ab administration. In addition, in a rat critical-size femoral-defect model, the Scl-Ab-treated group demonstrated a higher bone healing rate. On the other hand, two clinical reports have researched Scl-Ab in bone healing and failed to show positive effects in the femur and tibia. This review discusses why Scl-Ab appears to be effective in animal models of fracture healing and not in clinical cases.

Role of the Myokine Irisin on Bone Homeostasis: Review of the Current Evidence.

Bone is a highly dynamic tissue that is constantly adapting to micro-changes to facilitate movement. When the balance between bone building and resorption shifts more towards bone resorption, the result is reduced bone density and mineralization, as seen in osteoporosis or osteopenia. Current treatment strategies aimed to improve bone homeostasis and turnover are lacking in efficacy, resulting in the search for new preventative and nutraceutical treatment options. The myokine irisin, since its discovery in 2012, has been shown to play an important role in many tissues including muscle, adipose, and bone. Evidence indicate that irisin is associated with increased bone formation and decreased bone resorption, leading to reduced risk of osteoporosis in post-menopausal women. In addition, low serum irisin levels have been found in individuals with osteoporosis and osteopenia. Irisin targets key signaling proteins, promoting osteoblastogenesis and reducing osteoclastogenesis. The present review summarizes the existing evidence regarding the effects of irisin on bone homeostasis.

Increased Potential of Bone Formation with the Intravenous Injection of a Parathyroid Hormone-Related Protein Minicircle DNA Vector.

Osteoporosis is commonly treated via the long-term usage of anti-osteoporotic agents; however, poor drug compliance and undesirable side effects limit their treatment efficacy. The parathyroid hormone-related protein (PTHrP) is essential for normal bone formation and remodeling; thus, may be used as an anti-osteoporotic agent. Here, we developed a platform for the delivery of a single peptide composed of two regions of the PTHrP protein (1–34 and 107–139); mcPTHrP 1–34+107–139 using a minicircle vector. We also transfected mcPTHrP 1–34+107–139 into human mesenchymal stem cells (MSCs) and generated Thru 1–34+107–139-producing engineered MSCs (eMSCs) as an alternative delivery system. Osteoporosis was induced in 12-week-old C57BL/6 female mice via ovariectomy. The ovariectomized (OVX) mice were then treated with the two systems; (1) mcPTHrP 1–34+107–139 was intravenously administered three times (once per week); (2) eMSCs were intraperitoneally administered twice (on weeks four and six). Compared with the control OVX mice, the mcPTHrP 1–34+107–139-treated group showed better trabecular bone structure quality, increased bone formation, and decreased bone resorption. Similar results were observed in the eMSCs-treated OVX mice. Altogether, these results provide experimental evidence to support the potential of delivering PTHrP 1–34+107–139 using the minicircle technology for the treatment of osteoporosis.

Tetraspanin 7 regulates osteoclast function through association with the RANK/αvβ3 integrin complex.

Actin rings are unique structures that facilitate the attachment of osteoclasts to the bone matrix during bone resorption. Previous studies have shown that tetraspanin7 (TSPAN7) plays an important role in the reorganization of the cytoskeleton necessary for the bone-resorbing activity of osteoclasts. However, questions remain as to the mechanisms by which TSPAN7 regulates this cytoskeletal rearrangement. In this study, we investigated the roles of TSPAN7 in osteoclasts by deleting the Tm4sf2 gene in mice, which encodes TSPAN7. The Tm4sf2 global knockout model showed protective effects on pathological bone loss, but no discernible changes in bone phenotypes under physiological conditions. In vitro study revealed that ablation of Tm4sf2 caused significant defects in integrin-mediated actin ring formation, thereby leading to significantly decreased bone resorption. Additionally, we demonstrated an association between TSPAN7 and the receptor activator of nuclear factor-кB/αvβ3 integrin. Overall, our findings suggest that TSPAN7 acts as a novel modulator regulating the bone-resorbing function of osteoclasts.

Native Collagen II Relieves Bone Impairment through Improving Inflammation and Oxidative Stress in Ageing db/db Mice.

Ageing-related bone impairment due to exposure to hyperglycemic environment is scarcely researched. The aim was to confirm the improvement effects of Native Collagen II on bone impairment in ageing db/db mice, and the ageing model was established by normal feeding for 48-week-old. Then, the ageing db/db mice were randomly assigned to Native Collagen II intervention, the ageing model, and the chondroitin sulfate + glucosamine hydrochloride control groups. After 12 weeks of treatment, femoral microarchitecture and biomechanical parameters were observed, biomarkers including bone metabolism, inflammatory cytokines, and oxidative stress were measured, and the gastrocnemius function and expressions of interleukin (IL) 1β, receptor activator of nuclear factor (NF)-κB ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) were analyzed. The results showed that the mice in the Native Collagen II intervention group showed significantly superior bone and gastrocnemius properties than those in the ageing model group, including bone mineral density (287.65 ± 72.77 vs. 186.97 ± 32.2 mg/cm3), gastrocnemius index (0.46 ± 0.07 vs. 0.18 ± 0.01%), muscle fiber diameter (0.0415 ± 0.005 vs. 0.0330 ± 0.002 mm), and cross-sectional area (0.0011 ± 0.00007 vs. 0.00038 ± 0.00004 mm2). The Native Collagen II intervention elevated bone mineralization and formation and decreased bone resorption, inflammatory cytokines, and the oxidative stress. In addition, lower protein expression of IL-1β, RANKL, and TRAP in the Native Collagen II intervention group was observed. These findings suggested that Native Collagen II improved bones impaired by T2DM during ageing, and the likely mechanism was partly due to inhibition of inflammation and oxidative stress.

Effects of phytase and 25-hydroxyvitamin D3 supplementation on growth performance and bone development in weaned piglets in Ca- and P-deficient dietary.

The beneficial function of phytase and 25-hydroxyvitamin D3 (HyD) on the feed utilization rate has been widely investigated. However, studies concerning its influence on weaned piglets largely lag behind. The aim of this study was to investigate the effects of phytase and HyD supplementation on the growth performance and bone development in weaned piglets under dietary Ca and P deficiency. The results showed that dietary Ca and P deficiency decreased (P < 0.05) the content of serum P in 6-10 kg piglets, as well as reducing (P < 0.05) the contents of serum Ca and P, average daily gain (ADG), bone mineral density (BMD), breaking force (BF), bone ash and femur Ca in 10-20 kg piglets. Compared with the control group, the feed-to-gain ratio (F/G) of 6-10 kg piglets in the Phy group was decreased (P< 0.05), whereas the ADG, blood Ca and P, BMD, BF, bone ash, P apparent digestibility, Ca and P retention rate of 10-20 kg piglets were increased (P < 0.05). The contents of serum osteocalcin and HyD in 6-10 kg piglets and ADG were higher than in the control group (P < 0.05), as well as the contents of serum Ca and HyD in 10-20 kg piglets in the HyD treatment group. Supplementation with both Phy and HyD decreased the F/D (P < 0.05) and increased the contents of serum Ca, P and HyD in 6-10 kg piglets as well as enhancing the ADG, BMD, BF, bone ash, femur Ca and P, serum Ca and P, HyD, and the apparent digestibility and retention of Ca and P (P < 0.05) in 10-20 kg piglets. Supplementation with Phy and HyD in Ca- and P-deficient dietary decreased bone resorption, and improved tight arrangement of collagen fibers and oblique fibers in weaned piglets. These data indicated that supplementation with both 1500 U kg-1 Phy and 50 μg kg-1 HyD could enhance dietary Ca and P utilization and promote bone development in low Ca and P dietary, and supplementation with both Phy and HyD had a significant synergy effect compared to single supplement. © 2021 Society of Chemical Industry.

Serum Osteoprotegerin Level Is Negatively Associated with Bone Mineral Density in Patients Undergoing Maintenance Hemodialysis.

Background and Objectives: Osteoprotegerin (OPG), a potent osteoclast activation inhibitor, decreases bone resorption and plays a role in mediating bone mineral density (BMD). Our aim was to evaluate the relationship between BMD and serum OPG in maintenance hemodialysis (MHD) patients. Materials and Methods: Fasting blood samples were obtained from 75 MHD patients. BMD was measured by dual-energy X-ray absorptiometry in lumbar vertebrae (L2–L4). The WHO classification criteria were applied to define osteopenia and osteoporosis. A commercial enzyme-linked immunosorbent assay was used to measure serum OPG values. Results: Among all MHD patients, seven (9.3%) and 20 patients (26.7%) were defined as osteoporosis and osteopenia, respectively. Female patients had lower lumbar BMD than males (p = 0.002). Older age (p = 0.023), increased serum OPG (p < 0.001) urea reduction rate (p = 0.021), Kt/V (p = 0.027), and decreased body mass index (p = 0.006) and triglycerides (p = 0.020) were significantly different between the normal, osteopenia, and osteoporosis groups. Lumbar spine BMD was positively correlated with body mass index (BMI) (p < 0.001) but negatively correlated with OPG (p < 0.001) and age (p = 0.003). After grouping patients into T scores < −1 and < −2.5, female sex and OPG (adjusted odds ratio [aOR] 1.022, 95% confidence interval [C.I.] 1.011–1.034, p < 0.001) were predictors of T scores < −1, whereas only OPG was predictive of T scores < −2.5 (aOR 1.015, 95% C.I. 1.005–1.026, p = 0.004) by multivariate stepwise logistic regression analysis. The areas under the curve for predicting T scores < −1 or < −2.5 were 0.920 (95% C.I. 0.834–0.970, p < 0.001) and 0.958 (95% C.I. 0.885–0.991, p < 0.001), respectively. Conclusions: Increased serum OPG negatively correlated with lumbar BMD and could be a potential biomarker predictive of osteoporosis in MHD patients.

A Case of Fluorosis: Fluoride-Induced Osteopetrosis

There are multiple etiologies of increased bone density, including osteopetrosis and fluorosis. Osteopetrosis can either be a malignant autosomal recessive condition found in children or a benign autosomal dominant adult variant; both of which are characterized by decreased bone resorption. In contrast, fluorosis is characterized by increased bone formation secondary to chronic fluoride intoxication, but with a similar clinical manifestations to osteopetrosis.A 70-year-old lady with generalized joint aches, stiffness as well as fatigue, was found to have high bone mineral density and alarmingly high fluoride levels. The patient was found to be drinking fluoride containing water from an untreated local well for many years.Fluorosis results in increased bone mineral density and disease progression correlates with length of exposure. Fluorosis can result in reversible musculocutaneous symptoms and radiological findings. However, severe chronic cases may develop irreversible neurologic manifestations. Urinary fluoride testing is the screening modality of choice, and the key component of management is avoidance of the source of fluoride intoxication as well as monitoring of urinary fluoride levels.

Bone mass protective potential mediated by bovine milk basic protein requires normal calcium homeostasis in mice

ObjectivesMilk provide protective effects against bone loss caused by an impaired calcium balance. Although the effects of some elements have previously been confirmed, the involvement of milk basic protein (MBP) in bone mineral metabolism remains poorly characterized. Moreover, the importance of mineral nutrition sufficiency to establish the effect of MBP must be evaluated. MethodsFirst, to evaluate the physiological conditions required for MBP activity, we examined the bone and mineral phenotypes of mice that suffer from insufficient calcium absorption due to a lack of intestinal vitamin D signaling. Second, to determine whether vitamin D signaling affects the effect of MBP on bone resorption, in vitro osteoclastogenesis were assessed using bone marrow cells. ResultsIn mice with systemic vitamin D receptor (Vdr) inactivation, dietary MBP supplementation was unable to normalize hypercalcemia and hyperparathyroidism and failed to rescue bone mineralization impairments. In contrast, calcium and bone homeostasis responded to MBP supplementation when Vdr inactivation was restricted to the intestines. Hyperparathyroidism in intestine-specific Vdr knockout mice was also improved by MBP supplementation, along with a decrease in bone resorption in response to the level of serum tartrate-resistant acid phosphatase 5b. These results corresponded with a reduction in tartrate-resistant acid phosphatase-stained osteoclast numbers and the eroded surface on the tibia. MBP treatment dose-dependently suppressed osteoclastogenesis in cultured bone marrow macrophages regardless of vitamin D activity. These effects of MBP were blunted when parathyroid hormone was added to the culture medium, which is in line with the in vivo phenotype observed with systemic Vdr inactivation and suggests that severe hyperparathyroidism limits MBP activity in the bone. ConclusionsTherefore, adaptive calcium homeostasis is an essential requirement when MBP exerts protective effects through the inhibition of bone resorption.

Histomorphometric analysis of bone formation after using simvastatin chitosan nanoparticles as a local delivery system in periodontal bony defects in rabbits

Background: simvastatin (SV) has a characteristic effect on the regeneration of bony tissues and the decrease of bone resorption. Accordingly, this study aimed to explore the effect of locally applied simvastatin loaded in a chitosan nanoparticles as a delivery system for regeneration of bone in intrabony defects in a rabbit model. Materials and methods: This trial was carried out on 20 male albino New Zealand rabbits. The rabbits were randomly distributed into 4 groups where each group contained 5 rabbits (n=5) as follows: Group 1 (NC group) designed as the negative control, while, interventional groups where an intrabony defect was created designed as: Group 2 (PC) the positive control where the intrabony defects were covered with gingival flaps only. Group 3 (NP) and group 4 (SP) were received chitosan tripolyphosphate nanoparticles (CS-TPP NPs) and medicated SV -CS-TPP NPs respectively. All the animals were euthanized after 6 weeks. Descriptive histological and histomorphometric analysis of specimens stained with hematoxylin-eosin (H & E) and Masson’s trichrome stain (M T) was done. Results: The histomorphometric analysis of area percent of newly bone formation in mm2 showed statistically significant differences between interventional study groups. SV -CS-TPP NPs treated group showed the highest mean of area percent of newly formed bone 37.33 ± 3.82, Group 3 (NP) 18.57 ± 3.42 , while group 2 (PC) showed the lowest one 6.21 ± 2.30. Conclusion: Chitosan nanoparticles as a carrier for local application of simvastatin optimizing the new bone formation in intabony periodontal defects.

Inhibition of miR-29 Activity in the Myeloid Lineage Increases Response to Calcitonin and Trabecular Bone Volume in Mice.

The miR-29-3p family (miR-29a, miR-29b, miR-29c) of microRNAs is increased during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis. In vivo, activation of a miR-29-3p tough decoy inhibitor in Cre recombinase under the control of the lysozyme 2 promoter-expressing cells (myeloid lineage) resulted in mice displaying enhanced trabecular and cortical bone volume because of decreased bone resorption. Calcitonin receptor (Calcr) is a miR-29 target that negatively regulates bone resorption. CALCR was significantly increased in RANKL-treated miR-29-decoy osteoclasts, and these cells were more responsive to the inhibitory effect of calcitonin on osteoclast formation. Further, cathepsin K (Ctsk), which is critical for resorption, was decreased in miR-29-decoy cells. CALCR is a Gs-coupled receptor and its activation raises cAMP levels. In turn, cAMP suppresses cathepsin K, and cAMP levels were increased in miR-29-decoy cells. siRNA-mediated knock-down of Calcr in miR-29 decoy osteoclasts allowed recovery of cathepsin K levels in these cells. Overall, using a novel knockin tough decoy mouse model, we identified a new role for miR-29-3p in bone homeostasis. In RANKL-driven osteoclastogenesis, as seen in normal bone remodeling, miR-29-3p promotes resorption. Consequently, inhibition of miR-29-3p activity in the myeloid lineage leads to increased trabecular and cortical bone. Further, this study documents an interrelationship between CALCR and CTSK in osteoclastic bone resorption, which is modulated by miR-29-3p.

Targeted Remodeling of the Tumor Microenvironment Via Mechanical Stimulation Defines a Novel Therapeutic Strategy in Myeloma Bone Disease

Multiple myeloma (MM) patients develop devastating osteolytic bone disease causing non-healing bone fractures and pain. MM cells in the bone marrow microenvironment stimulate osteoclast activity and inhibit osteoblast and osteocyte function leading to massive bone resorption and therefore destruction. Bones have the capacity to locally adapt to changing loads and for self-repair and remodeling as dramatically seen in athletes during training. In this study we determined if mechanical loading can counterbalance osteolytic bone disease in the presence of established MM. We hypothesized that mechanical stimulation increases bone formation and decreases bone resorption by activating known bone (re)modeling pathways, which are deleteriously altered by MM cells in bone. We performed in vivo cyclic axial compressive tibial loading (Fig. 1) to MOPC315.BM BALB/c injected mice (n=19) with established MM bone disease (Fig. 2, bioluminescence imaging). The bone (re)modeling response to mechanical loading (5d/wk, over 3 wks) was investigated by longitudinal in vivo microCT imaging at days 14, 18, 23, 28 and 33 (Fig. 3, 4). Loading was administered to the left tibia starting 14 days after i.t. injection of left limbs of MOPC315.BM (n=10) and PBS (n=7) mice (left limb: εmax=2000µε determined by strain gauging, right limb was nonloaded). 15 mice served as nonloaded control mice (Fig. 3). We also analyzed a group of loaded, but not injected mice (n=10). MicroCT data (Fig. 3), such as cortical thickness (Ct.Th), cortical bone area (Ct.Ar) of loaded left limbs demonstrate that metaphyseal cortical bone formation was significantly greater and cortical porosity (Ct.Po) was lower compared to nonloaded control limbs. Our data provide for the first time an indication that mechanical loading counteracts MM induced bone loss over time. To further study mechanisms of mechanotransduction we used a small scale cell culture bioreactor system to analyze mechanical stimulation of human mesenchymal stem cells (hMSCs) and the translation of mechanical forces into biochemical signals. The bioreactor system allows for analysis of molecular mechanisms of mechanotransduction using a transcription factor activator protein (AP1) luciferase reporter gene construct. Cyclic stretching of telomerase immortalized hMSCs (hMSC-TERT cells) which were stably transfected by an AP1 construct resulted in stimulation of AP1 activity as measured by luciferase gene expression. We analyzed how MM cells interfere with mechanotransduction when co-cultured with hMSC-TERT cells. Our data show that in presence of MOPC315.BM cells and 2 (MM1S, INA-6) out of 4 human MM cell lines hMSCs can be mechanically stimulated and have osteogenic activity. In contrast the human MM cell lines Amo-1 and U266 inhibit the hMSC-TERT response to mechanical stimulation under these conditions. Biochemical and molecular genetic studies are underway to determine how MM cells in bone alter known bone (re)modeling pathways and which yet unanticipated factors regulate the anabolic response to mechanical loading in the MOPC315.BM model. Our study provides a first fundamental understanding of the mechano-biological mechanisms of anabolic bone adaption during MM bone disease in response to mechanical stimuli. We conclude that mechanical loading in the form of exercise has the potential to be a potent novel anabolic strategy for primary and secondary prevention of MM bone disease. Moreover dissection of the underlying molecular pathways will identify new targets for innovative antimyeloma strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Spinal Cord Injury Induced Osteoporosis: Case Report and Current Literature

Background: Among the various etiologies of osteoporosis, spinal cord injury has a drastic progression of the disease, causing weekly bone loss. There is no definitive treatment for the prevention of osteoporosis in these individuals. This review illustrates the recent findings on the pathophysiology, treatment, and management of spinal cord injury-induced osteoporosis. Furthermore, we cover a case of a male patient who experienced severe bone loss after a spinal cord injury at the age of 21 years.&#x0D; The Case: We have a 57-year-old man with a history of AIS grade A spinal cord injury, level T11 with rod fixation from a motorcycle collision at age 21. His fracture history following the injury includes tibia, femur, and vertebral fractures. Bone mineral density imaging revealed notable T-scores ranging from -3.1 to -3.4 at the hip and femurs. Treatment plan consisted of teriparatide, dietary supplements, and physical therapy. Biomarkers from baseline to post one month of treatment revealed the following: procollagen type 1 N-terminal propeptide from 38 mcg/L to 70 mcg/L and C-terminal telopeptide from 209 pg/mL to 88 pg/mL, representing an increased bone formation and decreased bone resorption, respectively. After two years, bone mineral density T-scores improved to -2.7 on the left and the patient was capable of standing for the first time with the assistance of a standing frame.&#x0D; Conclusion: Our case exemplified the progression of the disease and treatment options. A basis for the derivation of future innovative therapies has been covered. Favorable treatments and management are described in the review.

Skeletal responses to romosozumab after 12 months of denosumab.

ABSTRACTRomosozumab, a monoclonal anti‐sclerostin antibody that has the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. In a post hoc, exploratory analysis, we evaluated the effects of romosozumab after 12 months of denosumab in postmenopausal women with low bone mass who had not received previous osteoporosis therapy. This phase 2 trial (NCT00896532) enrolled postmenopausal women with a lumbar spine, total hip, or femoral neck T‐score ≤ −2.0 and ≥ −3.5. Individuals were randomized to placebo or various romosozumab dosing regimens from baseline to month 24, were re‐randomized to 12 months of denosumab or placebo (months 24–36), and then all received romosozumab 210 mg monthly for 12 months (months 36–48). Results for the overall population have been previously published. Here, we present results for changes in bone mineral density (BMD) and levels of procollagen type I N‐terminal propeptide (P1NP) and β‐isomer of the C‐terminal telopeptide of type I collagen (β‐CTX) from a subset of women who were randomized to placebo for 24 months, were re‐randomized to receive denosumab (n = 16) or placebo (n = 12) for 12 months, and then received romosozumab for 12 months. In women who were randomized to placebo followed by denosumab, romosozumab treatment for 12 months maintained BMD gained during denosumab treatment at the total hip (mean change from end of denosumab treatment of 0.9%) and further increased BMD gains at the lumbar spine (mean change from end of denosumab treatment of 5.3%). Upon transition to romosozumab (months 36–48), P1NP and β‐CTX levels gradually returned to baseline from their reduced values during denosumab administration. Transitioning to romosozumab after 12 months of denosumab appears to improve lumbar spine BMD and maintain total hip BMD while possibly preventing the rapid increase in levels of bone turnover markers above baseline expected upon denosumab discontinuation. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

MO199DENOSUMAB: NOVEL APPROACH TO TREATMENT OF OSTEOPOROSIS IN RENAL DISEASE

Abstract Background and Aims Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast differentiating factor. It inhibits osteoclast formation, decrease bone resorption, increase bone mineral density (BMD), and reduce the risk of fracture. There is no restriction of its use in patients with renal disease, for whom biphosphonates are considered controindicated. The aim of our study was to evaluate the effectiveness in reducing facture risk and safety of Denosumab in patients with Osteoporosis and renal disease. Method This is a prospective analysis of 17 patients with Osteoporosis (average T-score below -2.5) admitted to our Nephrology Department for CKD in the last four years. in Vasculitis, Renal Allograft Recipients. Patients with severe Hyperparatiroidism were excluded. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. All patients were adequately supplemented with calcium and vitamin D before and while taking Denosumab 60 mg every 6 months. The primary endpoint is the change in bone mineral density (BMD) at one and two years. Secondary endpoints include changes in bone mineral metabolism parameters (Ca, P, PTHi, 25-OH VitD), incidence of fractures, and renal/allograft fuction at one and two years. Results The mean age was 52.5±4 years and 8/17 (47%) were females. N.13 patients (76.5%) were renal transplant recipients (RTR) on standard triple immunosoppression including steroids (prednisone 5 mg/day), CNI and MMF, with average eGFR 65.7±12.5 ml/min. N.2 patients (11.75%) were in hemodialysis. N.2 patients (11.75%) with Anca Vasculitis on steroid therapy and average eGFR 35.6±7.2 ml/min. All patients enrolled were with a BMD T-score of greater than -4.0 and less than -2.5. Only 2 patients had a history of fractures confirmed by a radiology report. Baseline parameters: calcium 9.8±0.32 mg/dl, phosphate 3.9±0.8 mg/dl, PTHi 137±91.0 ng/L, 25-OH VitD 18.3±8.9 ng/mL. From baseline at 1 month there were an increase in PTH and a decrease in calcemia in only 2 transplant recipients (CKD II and IV), that improved with an increased dose of Vit D. There were no significant difference in baseline bone mineral metabolism parameters to year 1 and 2 in all other patients. We found no difference in eGFR and proteinuria from baseline to 1 and 2 years in RTR and ANCA vasculitis. Significant improvement in T-score was observed at 1 year and 2 years (&amp;lt; -1) in all patients. No one discontinued therapy for adverse events. Conclusion Denosumab may have advantages in patients with kidney dysfunction, because not excreted by the kidney and there is no need for dose adjustment. This prospective study showed a significant improvement in osteoporosis (at Dexa mean T-score ≤ -1), but particular attention should be paid to ensuring that patients are calcium and Vitamin D replete.

Aromatase Inhibitor Induced Bone Loss: Do International Guidelines Accurately Stratify Fracture Risk and Selection of Anti-Osteoporosis Treatment?

Abstract Introduction: Aromatase inhibitors (AI) are used for adjunctive treatment of estrogen receptor-positive (ER+) breast cancer. Aromatase converts androgens to estrogens in the ovaries and peripheral tissues such as adipose, liver, muscle, and breast. In breast, estrogens increase cell proliferation in both normal and ER+ malignant tissue. AIs globally suppress estrogen production, and thereby can decrease tumor progression. However, in bone, estrogens suppress osteoclast activity and decrease bone resorption so AI use results in increased bone resorption and decreased bone mineral density (BMD). Several guidelines exist to direct management of AI-associated bone loss, but it is unclear whether adherence to these guidelines translates to decreased fracture risk. The International Osteoporosis Foundation (IOF) et al 2017 guidelines for the prevention of osteoporotic fractures in patients treated with AI recommended BMD measurement at the onset of AI use and use of anti-osteoporosis therapy (anti-OP) in those who met T-score and clinical risk factor (CRF) criteria. Hypothesis: We explored application of these guidelines and whether they were able to stratify patients according to risk, initiation of treatment, and fracture outcomes. Methods: 1517 charts were extracted from the electronic medical record (EMR) of a tertiary academic medical center based on history of breast cancer and use of AIs between 2008 and 2017. Charts were retrospectively analyzed to determine baseline BMD, osteoporosis risk factors, duration of AI use, duration of anti-OP therapy, and fractures. The IOF criteria were applied to each patient to determine applicability of anti-OP therapy. Fracture rates were compared using chi square test or Fisher’s exact test. Results: 1517 patients were included in the analysis. Regardless of whether criteria were met for treatment based on baseline BMD and CRF, the fracture rate was significantly higher in the treated versus the untreated group, 13.78% (CI: 9.56–18.99) versus 2.24% (p &amp;lt; 0.0001, CI: 1.51–3.21). Similarly, among those that met criteria, the fracture rate was significantly higher in the treated versus the untreated group, 10.24% (CI: 5.56–16.87) versus 2.61% (p = 0.0005, CI: 1.20–4.89). There was no significant difference in fractures between those who did versus did not meet treatment criteria, 4.66% (CI: 2.94–6.97) versus 3.64% (p = 0.34, CI 2.59–4.96). Conclusions: This retrospective EMR analysis of 1517 breast cancer patients on AIs between 2008 and 2017 observed a higher fracture incidence in patients who received anti-OP treatment compared to those who did not, regardless of meeting criteria for treatment per the IOF guidelines. It is possible that patients who initiated anti-OP therapy had additional CRFs not captured in the EMR and not factored into our analyses.

Experience With Anti-Sclerostin Antibody for Osteoporosis Patient With End-Stage Renal Disease on Hemodialysis

Background: Romosozumab is a sclerostin inhibitor indicated for treatment of postmenopausal osteoporosis. Sclerostin inhibits Wnt/Beta-catenin signaling pathway. When sclerostin is inhibited, stimulation of this pathway leads to increased bone formation and production of osteoprotegerin, which also decreases bone resorption. Patients with chronic kidney disease (CKD) demonstrate increased levels of sclerostin that negatively correlates with the rate of bone formation; however, data is lacking for use of romosozumab in this patient population. The report herein details the experience of use of romosozumab in a patient with end-stage renal disease (ESRD) on hemodialysis (HD). Clinical Case: A 37-year-old old African American male was referred after multiple rib fractures and severe non-traumatic T8 compression fracture with nerve compression. His past medical history includes lupus nephritis and cerebritis, ESRD on HD since age 22 status post (s/p) failed renal transplant, and tertiary hyperparathyroidism complicated with fracture in iliac brown tumor and mediastinal parathyromatosis s/p three parathyroid surgeries. Bone mineral density by DXA (g/cm2, Z-score) were as follows: lumbar spine (0.700, -4.0) femoral neck (0.676, -3.8), total hip (0.628,-4.0), 1/3 radius(0.443,-6.2). No prior exposure to antiresorptive or osteoanabolic agents. Pertinent labs included serum calcium 8.5 mg/dL (nl 8.9–10.3 mg/dl), albumin 4.2 g/dL, alkaline phosphatase 319 U/L (nl 38–126), Phosphorus 3.1 mg/dL (2.4–4.7), Creatinine 5.62 mg/dl, 25-OH Vitamin D 31 ng/mL (nl 25 - 80), intact parathyroid hormone 17.9 pmol/L (nl 1.6–6.9). Patient was in excruciating pain and not a surgical candidate due to poor bone quality. Osteoanabolic therapy was recommended given the severity of osteoporosis; however, teriparatide and abaloparaitde were contraindicated given comorbidities. The patient was offered off-label use of Romosozumab with clear understanding that the drug is not approved for this indication and safety/efficacy data in ESRD is not known. The boxed warning regarding increased risk of stroke, myocardial infarction and death were discussed and patient was willing to proceed. Repeat DXA after eleven monthly doses of Romosozumab resulted in a remarkable improvement in bone mineral density at all sites: lumbar spine (+47%), femoral neck (+41%), total hip (+28%), 1/3 radius (+20%). Patient tolerated medication with no side effects or fractures. Serum calcium was monitored prior to initiation and before every dose. No doses were held due to abnormal laboratory values or side effects. Conclusion: This case report summarizes successful experience with the use of Romosozumab in one patient with ESRD on HD with favorable outcomes.

Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity.

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.