Uncoupling Of Bone Resorption Research Articles

Roles of Altered Macrophages and Cytokines: Implications for Pathological Mechanisms of Postmenopausal Osteoporosis, Rheumatoid Arthritis, and Alzheimer's Disease.

Postmenopausal osteoporosis (PMOP) is characterized by the uncoupling of bone resorption and bone formation induced by estrogen deficiency, which is a complex outcome related to estrogen and the immune system. The interaction between bone and immune cells is regarded as the context of PMOP. Macrophages act differently on bone cells, depending on their polarization profile and secreted paracrine factors, which may have implications for the development of PMOP. PMOP, rheumatoid arthritis (RA), and Alzheimer’s disease (AD) might have pathophysiological links, and the similarity of their pathological mechanisms is partially visible in altered macrophages and cytokines in the immune system. This review focuses on exploring the pathological mechanisms of PMOP, RA, and AD through the roles of altered macrophages and cytokines secretion. First, the multiple effects on cytokines secretion by bone-bone marrow (BM) macrophages in the pathological mechanism of PMOP are reviewed. Then, based on the thought of “different tissue-same cell type-common pathological molecules-disease pathological links-drug targets” and the methodologies of “molecular network” in bioinformatics, highlight that multiple cytokines overlap in the pathological molecules associated with PMOP vs. RA and PMOP vs. AD, and propose that these overlaps may lead to a pathological synergy in PMOP, RA, and AD. It provides a novel strategy for understanding the pathogenesis of PMOP and potential drug targets for the treatment of PMOP.

MON-180 EVEROLIMUS ASSOCIATED OSTEONECROSIS OF THE JAW IN KIDNEY TRANSPLANT RECIPIENT

Mammalian target of rapamycin (mTOR) inhibitors, used in kidney transplant recipients, inhibit T-cell activation and vascular endothelial growth factor (VEGF) pathways, thereby exerting antiproliferative and antiangiogenic effects. Osteonecrosis of the jaw (ONJ) is a serious side-effect of antiresorptive and anti-angiogenic therapies. We report a unique case of osteonecrosis of the jaw associated with use of everolimus in a kidney transplant recipient. A 65-year-old man with polycystic kidney disease and subtotal parathyroidectomy for tertiary hyperparathyroidism, received a deceased donor kidney transplant in 2015 with basiliximab, tacrolimus, mycophenolate and prednisolone immunosuppression. He suffered non-immune delayed graft function and recovered with a 12-month serum creatinine of 230umol/L (eGFR 25ml/min/1.73sq.m). Tacrolimus was changed to everolimus to optimise renal function and retard interstitial fibrosis secondary to CNI use. In November 2017, he presented with swollen gums and left maxillary tenderness with gingival inflammation, exposed maxilla and purulent discharge, indicating infective periodontal disease. He was managed conservatively with antibiotics and dental extractions. His renal function was stable on everolimus 1mg BD with a trough level (C0) at 3.0-4.0 ng/ml. Six months later, he had progressive severe pain limiting oral intake, with 10kg weight loss. A CT head showed progressive bony destruction of maxilla, erosion of the maxillary sinus floor and an oro-antral fistula, consistent with ONJ. Bone biopsy ruled out malignancy, showing necrotic bony trabeculae filled with bacteria. He had never received bisphosphonate, denosumab or radiotherapy. He was on everolimus 0.75mg BD (C0= 3.0ng/ml). Tests revealed relatively low bone turnover markers in the context of active osteonecrosis: parathyroid hormone (PTH) <1.1pmol/L (1.6-6.0pmol/L), procollagen type 1 N propeptide (P1NP) 17ug/L(15-80ug/L), alkaline phosphatase (ALP) 69 U/L (30-110U/L), and C-telopeptide (CTX) 432ng/L (100-600ng/L). In view of its anti-proliferative and possible inhibitory effects on bone turnover, everolimus was ceased. He underwent surgical exploration of the sinuses, debridement of the palate with full upper dental clearance. He was treated with teriparatide 20ug monthly to stimulate bone turnover. Four-months later, the osteonecrotic process had abated, the exposed bone was stable and there were signs of healing. His nutrition status improved and he gained back his lost weight. This is the first case of everolimus associated ONJ in a kidney transplant recipient, despite being on relatively low dose therapy. The suppression of bone resorption via parathyroidectomy and additional inhibitory effect of everolimus resulted in the uncoupling of bone resorption and formation processes. This case not only underlies the importance of considering the potential of ONJ with everolimus in transplant recipients, particularly in those with poor dentition, malignancy, hypoparathyroidism or previous parathyroidectomy, and renal bone disease but also indicates possible therapeutic role of teriparatide in this situation.

GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men

Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR). Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH2. The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 μg), GLP-2 (800 μg), GIP(3-30)NH2 (800 pmol/kg/min) + GLP-2 (800 μg), and placebo. The main outcomes were bone resorption measured as collagen type 1 C-terminal telopeptide (CTX) and bone formation measured as procollagen type 1 N-terminal propeptide (P1NP). CTX (mean ± SEM) significantly decreased after both GIP (to 55.3 ± 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 ± 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30)NH2 + GLP-2 (to 63.2 ± 3.1% of baseline) did not differ from GLP-2 alone (p = 0.95) nor did net AUC0-240 (-6801 ± 879%*min vs -6027 ± 648%*min, p = 0.56). At t = 30 min, GIP significantly (p < 0.0001) increased P1NP to 115.1 ± 2.2% of baseline compared with 103.1 ± 1.5% after placebo. Both GLP-2 and GIP(3-30)NH2 + GLP-2 significantly (p < 0.0001) decreased P1NP to 91.3 ± 1.1% and 88.1 ± 3.0% of baseline, respectively (at t = 45 min) compared with placebo. GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans. ClinicalTrials.gov (NCT03159741).

Cytokines Behavior in Multiple Myeloma Patients during Zoledronic Acid Treatment

Objective: Multiple Myeloma (MM) is characterized by uncoupling of bone resorption from bone formation which leads to the predominance of resorption. Bisphosphonates are chemical compounds that selectively concentrate at the interface of the active osteoclasts and the bone resorption surface where they inhibit osteoclast activity. Aim of this study was to describe cytokines behaviour in MM and to evaluate whether zoledronic acid could have an in vivo anti-angiogenic property in MM as observed in solid tumours.Methods: Serum samples from 29 (16 males and 13 females) consecutive MM patients with lytic bone lesions treated with 4 mg of zoledronic acid were tested for platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumor necrosis factor (TNF α) and insulin growth factor (IGF-I). Basal cytokine levels were compared with the values observed after 1, 2, 7 and 21 days of treatment, using the Wilcoxon’s test for nonparametric-dependent continuous variables.Results: A significant increase in IL-6 and TNF α was observed on days 1 and 2. As for VEGF, the levels of this cytokine did not change significantly from basal values during the entire period of observation except for a significant increase day 7 (P=0.0005). Moreover, PDGF significantly decreased (P=0.005) after 2 days from zoledronic acid infusion.Conclusions: From this study appears that in MM, treatment with zoledronic acid induces a transient reduction in PDGF according with previous studies in solid cancer, while the increase of IL-6 and VEGF could be related through a paracrine mechanism. The anti-myeloma effect of this drug could be driven through this mechanism.

Decreased bone mineral density and periodontal management

The definition of osteoporosis has evolved beyond low bone mineral density to include impaired bone morphology and matrix properties. As such, the subsequent bone density insufficiencies extend beyond the skeletal risks of fracture and have implications for oral health management patients. As our population ages there is a worldwide increase in the risk of decreased bone mineral density and its subsequent morbidity. This makes age an independent risk factor for fracture and decreased bone mineral density. Multiple examinations and diagnostic tests are currently used in combination to develop an algorithm to assess osteoporotic risk. Oral health care professionals should follow these principles and caution should be used in applying a single independent assessment to determine a patient's osteoporotic or bone metabolism risk. Therapeutic approaches for osteoporosis are often divided into nonpharmacological interventions and pharmacological therapies. The periodontist and other oral health care professionals should have a full understanding of the therapeutic options, benefits and implementation of preventive therapies. Bone turnover is a coupled event of bone formation and bone resorption and it is the imbalance of this homeostasis that results in osteoporosis. Based on this uncoupling of bone resorption and formation, osteoporosis or decreased bone mineral density and osteopenia, may be a risk factor for alveolar bone loss in periodontitis. The role of prevention and maintenance with a history of periodontitis and oesteopenia extends beyond biofilm control and should include management of bone mineral density. The chronic periodontal infection in a patient with osteopenia may place the patient at greatly increased risk for alveolar bone loss, gingival recession and root caries. A key component in the management is the oral health professional's knowledge of the interrelationship between skeletal health and periodontal health.

Rosiglitazone Decreases Bone Mass and Bone Marrow Fat

Activation of peroxisome proliferator-activated receptor-γ is believed to promote adipocyte development from mesenchymal stem cells in the bone marrow at the expense of osteoblasts, leading to decreased bone mineral density (BMD) and increased marrow fat. The objective of the study was to examine the effect of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, on BMD assessed by dual-energy x-ray absorptiometry in 53 healthy postmenopausal women and spine bone marrow fat assessed by magnetic resonance imaging proton spectroscopy. This was a 14-wk prospective, double-blind, randomized, placebo-controlled trial. The study was conducted in the general community. Fifty-three healthy postmenopausal women participated in the study. Intervention included rosiglitazone tablets of 8 mg/d. The primary end point was a change in BMD. At the femoral neck, BMD decreased by 1.34 ± 0.60% (mean ± sem) in the rosiglitazone group, whereas BMD increased by 0.28 ± 0.56% in the placebo group (P = 0.055). At the lumbar spine, BMD decreased by 1.03 ± 0.34% in the rosiglitazone group and 0.42 ± 0.35% in the placebo group (P = 0.22). The bone resorption marker carboxy-terminal telopeptide increased by 20.4 ± 7.7% (mean ± sem) in the rosiglitazone group and decreased by 7.1 ± 4.7% in the placebo group (P = 0.003). Spine fat decreased by 13.5 ± 5.5% (mean ± sem) in the rosiglitazone group and increased by 6.8 ± 7.4% in the placebo group (P = 0.056). Contrary to what was expected, spine fat decreased during rosiglitazone treatment. Furthermore, rosiglitazone treatment resulted in uncoupling of bone resorption and formation leading to bone loss. Our data suggest that the bone marrow osteoblast-adipocyte relationship is more complex than was assumed and that the two cell types can be independently affected.

Cannabinoids and Bone: Friend or Foe?

The endocannabinoid system is recognized to play an important role in regulating a variety of physiological processes, including appetite control and energy balance, pain perception, and immune responses. The endocannabinoid system has also recently been implicated in the regulation of bone metabolism. Endogenously produced cannabinoids are hydrophobic molecules derived from hydrolysis of membrane phospholipids. These substances, along with plant-derived and synthetic cannabinoids, interact with the type 1 (CB(1)) and 2 (CB(2)) cannabinoid receptors and the GPR55 receptor to regulate cellular function through a variety of signaling pathways. Endocannabinoids are produced in bone, but the mechanisms that regulate their production are unclear. Skeletal phenotyping of mice with targeted inactivation of cannabinoid receptors and pharmacological studies have shown that cannabinoids play a key role in the regulation of bone metabolism. Mice with CB(1) deficiency have high peak bone mass as a result of an osteoclast defect but develop age-related osteoporosis as a result of impaired bone formation and accumulation of bone marrow fat. Mice with CB(2) deficiency have relatively normal peak bone mass but develop age-related osteoporosis as a result of increased bone turnover with uncoupling of bone resorption from bone formation. Mice with GPR55 deficiency have increased bone mass as a result of a defect in the resorptive activity of osteoclasts, but bone formation is unaffected. Cannabinoids are also produced within synovial tissues, and preclinical studies have shown that cannabinoid receptor ligands are effective in the treatment of inflammatory arthritis. These data indicate that cannabinoid receptors and the enzymes responsible for ligand synthesis and breakdown play important roles in bone remodeling and in the pathogenesis of joint disease.

Paget Disease of the Temporal Bone

Paget disease of bone is a disorder of remodeling characterized by uncoupling of bone resorption and bone formation (1). It is thought to be caused by a slow virus infection. Paget disease can affect one or multiple bones in the systemic skeleton, including the temporal bone (1,2). Typically, there are three phases of activity in Paget disease affecting the systemic skeleton (1,2). The first or osteolytic phase demonstrates the prominent resorption of bone by numerous large osteoclasts. The second or mixed phase involves both osteoclastic and osteoblastic activities, creating a mosaic appearance typical of Paget disease. The third or osteoblastic phase is characterized by abundant osteoblastic activity and a prominent mosaic pattern. In the temporal bone, a fourth or remodeled phase, where areas of inactive osteoblastic pagetic bone are remodeled into healthier lamellar bone with distinct haversian canal systems, has been described (2).

Osteoporosis following solid organ transplantation

Damaris Vega & Khashayar Sakhaee† †Author for correspondence University of Texas Southwestern Medical Center, Department of Internal Medicine and, Charles & Jane Pak Center for Mineral Metabolism & Clinical Research, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885, USA Tel.: +1 214 590 7783; Fax: +1 214 590 4091; khashayar.sakhaee@utsouth western.edu ‘Despite the introduction of new immunosuppressive regimens designed for renal allograft recipients ... post-transplantation bone disease remains a major complication in this population.’ Since the introduction of new immunomodulatory agents, the number of organ transplants has increased significantly worldwide. Approximately 28,000 subjects received solid organ transplants in the USA from 2005 to 2006 [101] – approximately double the number of solid organ transplants performed in 1988. Despite the introduction of new immunosuppressive regimens designed for renal allograft recipients, including cyclosporine and tacrolimus, post-transplantation bone disease remains a major complication in this population. It was once thought that the introduction of these new immunomodulatory agents and the limited use of glucocorticoids would ameliorate this complication. However, the sustained loss of bone mineral density and spontaneous bone fractures remain a major cause of morbidity in these subjects [1–5]. The pathophysiologic mechanisms responsible for osteoporosis following organ transplantation are diverse and multifactorial [6]. The most common responsible factors include the underlying conditions leading to transplantation, lifestyle and nutritional changes, hormonal dysregulations, including abnormalities in calcitropic and gonadal hormones, and the skeletal effects of immunomodulatory agents [7–9]. Most commonly, medical immunosuppression has been implicated as the leading catalyst in the development of post-transplantation bone disease [10–13]. However, various renal, hepatic, cardiac and pulmonary diseases also have specific pathophysiologies that may contribute to the outcome of bone disease in this population [14–33]. Careful consideration should be given to the unique clinical picture of each individual patient before and after transplantation. Such a characterization will facilitate optimal management of this diverse group of patients to decrease the incidence of bone fractures and ultimately improve their quality of life. Bone disease is commonly encountered in chronic renal failure patients who experience a continual decline in renal function. Secondary hyperparathyroidism may persist following successful renal transplantation and potentially accentuate the adverse effects of immunosuppressive drugs on the development of bone disease [34]. In addition, the synergistic effect of parathyroid hormone and elevated serum concentrations of phosphatonins, including FGF-23, which has been demonstrated to be elevated after renal transplantation, result in renal phosphorus wasting by reducing renal tubular reabsorption [35–38]. Persistent phosphorus depletion will potentially contribute to defective bone mineralization and progression to osteomalacia and low bone turnover. However, these complications have been largely unnoticed. Therefore, the magnitude of skeletal abnormalities following renal transplantation are much broader than in other solid organ transplantations [39]. These factors may be partly responsible for the continued loss of bone mineral density and increased cumulative risk of new fractures following renal transplantation [3]. Moreover, glucocorticoid treatment, by uncoupling of bone resorption and bone formation, may attenuate the recovery of an impaired bone turnover caused by adynamic bone disease − the most predominant skeletal lesion encountered in patients during dialysis treatment [11,31,40–42].

Cytokines Behaviour in Multiple Myeloma during Zoledronic Acid Treatment.

The main pathological feature underlying the bone disease in multiple myeloma is an uncoupling of bone resorption from bone formation so that resorption predominates. In the bone marrow (BM), MM plasmacells are in close contact with stromal elements and induce the release of several cytokines which modify the BM microenviroment, upregulating RANKL expression and secretion by both stroma and osteoblasts. Destruction of bone matrix induced by MM and its cellular interactions is accompanied by further release of cytokines. Bisphosphonates are chemical compounds which selectively concentrate at the interface of the active osteoclasts and the bone resorption surface where they inhibit osteoclast activity.Recently, in solid tumors, Santini et al have demostred that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels (Clin Cancer Res 2003; 9:2893–7). Taking into account that angiogenesis plays an important role in MM progression, we have investigated the behaviour of IL6, PDGF, IGF, TNFα and VEGF in a cohort of 28 (16 males and 13 females) consecutive MM pts with lytic bone lesions treated with 4 mg of zoledronic acid. Venous blood samples were drawn just before the beginning of drug infusion and at 1,2,7,21 (before the subsequent infusion) days after the zoledronic acid infusion. Serum samples were then tested for PDGF, VEGF, IL6, TNFα , and IGF with the R & D quantitative kits (R & D Systems, Minneapolis, USA), according to the manufacturer's instructions. Basal cytokine levels were compared with the values observed at 1, 2, 7 and 21 days using the Wilcoxon's test for nonparametric-dependent continuous variables. Differently from what observed by Santini et al in solid tumors, serum VEGF median levels did not decrease;on the contrary, it significantly increased at days 7 (P=0.0047). Moreover, IL 6 and TNFα levels significantly increased after 1 (P=0.0000 and 0.0001 respectively) and 2, ( P=0.0000 and 0.0021 respectively) days. Furthermore, PDGF significantly decreased (P=0.005) after 2 days following zoledronic acid infusion. Among these pts, 8 (28.5%) were receiving also Interferon; no statistically significant differences in the levels of VEGF, IL6, TNFa and IGF between the two groups were observed. Only the PDGF levels have shown a statistically significant decrease in the interferon group at 0, 1, 2, 7, 21 days (P<0.05). In conclusion, the cytokines' behaviour after the administration of zoledronic acid in MM is different from that observed in solid tumors; in particular, we did not observe a decrease in VEGF levels. This behaviour may partially explain why zoledronic acid has no effect on MM progression as originally postulated.

Nandrolone decanoate: pharmacological properties and therapeutic use in osteoporosis.

The therapeutic profile on bone of nandrolone decanoate is that of inhibitor of bone resorption with temporary increase in bone formation, followed by an absence of suppression of bone formation, indicating uncoupling of bone resorption and formation. This results is an increase in bone mineral content at the proximal and distal radius, and in some patients at the lumbar spine. Furthermore, nandrolone decanoate increases calcium balance and muscle mass, diminishes vertebral pain and increases the mobility of the spine. Virilization occurred in around 50% of the patients (mainly hoarseness and/or hirsutism), and 9% of the patients dropped out because of this reason. A dose of 50 mg every 3 to 4 weeks is indicated in the treatment of osteoporosis in women, especially when they have low muscle mass, associated debilitating disease, and in patients with corticosteroid induced osteoporosis. It should only be prescribed after the age of 65 to 75 years to minimize the occurrence of clinical adverse effects and to increase its tolerability, which is higher in this group. Although some effects are reported on fracture rate, insufficient prospective data are available.

Drug-Induced Metabolic Bone Disease

Drug-induced metabolic bone disease via modification of resorption, formation, and mineralization is responsible for a spectrum of disorders classified as osteoporosis, osteomalacia, and adynamic bone disease. Bone disease and the coincident risk of fracture and disability are well-documented with use of glucocorticoids, L-thyroxine, ethanol, tobacco, anticonvulsants, neuroleptics, and chemotherapeutic agents. Physician awareness of these risks highlights the need for close monitoring of dosages and drug interactions and allows for intervention with nutritional support, antiresorptive agents, and proformation agents.

Preventative treatment of involutional osteoporosis

The ultimate aim of prevention and treatment of osteoporosis is the prevention of bone fractures. Since 80% of fractures can be explained by reductions in bone mass, not only is inhibition of reduction in bone mass extremely important but it is also useful as an index for the evaluation of preventive therapeutic effects. Bone mass is reduced with aging, but the degree of reduction varies. Bone mass generally reaches its peak level in the 30s and 40s and decreases thereafter. There is a group, the fast loser group, in which loss of bone mass is rapid after menopause with a correspondingly increased risk for developing osteoporosis. There is also a group in which the maximum bone mass shows low peak levels and this group can be considered to be at increased risk for osteoporosis. Since there are fast losers and normal losers, it is very important that fast losers be identified at an early stage so that preventative measures can be taken, since treatment is difficult once bone mass has gone below the fracture threshold level. Once fast losers have been identified, the next step is determining the best method of treatment. It is well known that osteoporosis is caused by an imbalance in bone metabolism, i.e., an uncoupling of bone resorption and formation. From the standpoint of bone metabolism, the disease can be divided into two types: the high turnover type and the low turnover type. In the high turnover type, the rates of both bone resorption and formation are accelerated. However, since bone resorption exceeds bone formation, this leads to a reduction in bone mass. In the other group, even though the rates of bone resorption and formation are low, the rate of bone resorption exceeds formation so the bone mass is reduced. Most cases of postmenopausal osteoporosis are of the high turnover type. Many cases of senile osteoporosis are of the low turnover type, and this is considered to be caused by the decreased activity of osteoblasts associated with aging. It is not clear whether or not the high or low turnover types represent different forms of the disease with different etiologies or simply represent different stages of the same disease, as classification of the disease into these two types from the standpoint of bone turnover is very important when determining the appropriate method of treatment. In conclusion, in the high turnover type, the most effective means of treatment is to suppress bone resorption by giving antiresorbers. However, in the low metabolic turnover type, drugs that increase the rate of bone formation are recommended.

Microgravity and musculoskeletal system of mammals

This review surveys data in the literature and our own findings concerning the effects of weightlessness on bones and muscles of white rats flown on Cosmos biosatellites and Spacelab-3. It has been shown that the magnitude and sign of functional changes in muscles depend on their biomechanical profile. Structural and metabolic foundations of functional adaptation and its dynamics have been identified: in 5–7 day flights muscle contractility changes are mainly associated with a diminished activity of excitation-contraction coupling, in longer-term flights they are produced by changes in myosin populations specific for myofibers of different functional profile. At early flight stages (up to 1 week) osteoporosis and bone demineralization are very mild; therefore decrease in bone mechanical strength may be caused by changes in physico-chemical parameters of the collagen-crystal system. In flights of up to 3 weeks noticeable osteoporosis develops which is primarily produced by osteogenesis inhibition and which is responsible for a marked decrease of bone strength. These changes may result from uncoupling of bone resorption and remodelling processes. This uncoupling is characterized as incomplete osteogenesis and may be caused by changes in the collagen composition of the organic bone matrix. The above-mentioned adaptive changes in muscle functions of specific skeletal compartments may play a role in different responses of various bones to weightlessness.