[Show abstract][Hide abstract] ABSTRACT: Hindlimb suspension reduced BMD, trabecular and cortical microarchitecture.•In Postn+/+, unloading decreases bone formation and increases bone resorption.•Unloading is associated with a decrease in Postn and an increase in Sost mRNA expression.•In Postn−/− mice, Sost increase in response to unloading is lower than in Postn+/+.•In Postn−/− mice, unloading did not alter cortical bone formation, bone structure and strength.
[Show abstract][Hide abstract] ABSTRACT: Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes where the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARß(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARß(-/-) mice and investigate both the mechanism behind those changes with age as well as their response to exercise. Compared to their wildtype, PPARß(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation and increased resorption. In addition, mesenchymal cells from PPARß(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARγ, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARß(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARß controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARß deficiency leads to glucose intolerance, decreased muscle function and reduced bone strength. On a molecular level, PPARß appears to regulate myostatin and PPARγ expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances.
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.
Swiss medical weekly: official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology 01/2014; 144:w13952. · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn (-/-) and Postn (+/+) mice after fatigue stimulus by axial compression of their tibia. In Postn (+/+) mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn (+/+) mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn (-/-) mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn (+/+) . Fatigue significantly increased CsNb and CsS in Postn (-/-) , but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn (-/-) , and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn (-/-) mice. Contrary to Postn (+/+) , which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures.
PLoS ONE 10/2013; 8(10):e78347. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context:Sclerostin inhibits bone formation and is involved in the bone response to mechanical loading, but the role and significance of circulating sclerostin is poorly understood.Objective:We assessed the association between serum sclerostin and calcitropic hormones, bone turnover marker levels, bone mineral content/density (BMC/BMD), and microstructure using three different immunoassays.Design, Setting, and Participants:In a cross-sectional study, serum sclerostin was measured in a cohort of 187 healthy subjects (98 women; 89 men) aged 65±1 (x±SD) years.Results:Overall, mean sclerostin (95% CI) was 37.3 (18.0-69.2) ng/l, 1165.8 (464.0-2296.4) ng/l, and 513.5 (250.7-950.9) ng/l with assays I, II and III, respectively. Serum sclerostin was higher in men with assays II and III. In all three assays, sclerostin and PTH were inversely correlated, only after adjustment for whole-body BMC (WB-BMC). After adjustment for sex and WB-BMC, the bone turnover markers P1NP and CTX negatively correlated, only with assay II. In all three assays, sclerostin positively correlated to WB-BMC, distal radius and distal tibia cortical area, cancellous bone volume (BV/TV) and trabecular number, and lumbar spine and proximal femur areal BMD following adjustment for sex.Conclusion:Sclerostin levels are markedly different according to the immunoassay used. Detection of an association with calcitropic hormones or turnover markers relies on the epitope recognized by the immunoassay and adjustment for bone mass.
The Journal of Clinical Endocrinology and Metabolism 07/2013; · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetes alters bone mass and/or quality and increases fracture risk. However, in type 2 diabetes, bone mineral density (BMD) is usually not diminished, pertaining to increased weight and fat mass, which complicates the diagnosis of osteoporosis by DXA (T-score <-2.5). Similarly, estimates of fracture probability by FRAX may underestimate fracture risk in type 2 diabetes. Adequate glycemic control with insulin and/or oral antidiabetics decreases fracture risk, whereas thiazolidinediones increase it. Eventually, osteoporosis drugs such as bisphosphonates and SERMs seem to have similar efficacy in diabetic and non-diabetic patients.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.
American Journal Of Pathology 04/2013; · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn(+/+) and Postn(-/-) (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn(-/-). Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn(-/-) and Postn(+/+), both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn(-/-) vs Postn(+/+) confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn(-/-) and Postn(+/+) mandible, and Zol 1W increased the number of empty lacunae in Postn(-/-), however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn(-/-) mice, zoledronate is not sufficient to induce bone necrosis.
PLoS ONE 03/2013; 8(3):e58726. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonates are the major treatment of choice for osteoporosis, given that they are attached preferentially by bone and significantly reduce the risk of fractures. Oral bisphosphonates are poorly absorbed (usually less than 1% for nitrogen-containing bisphosphonates) and when taken with food or beverages create complexes that cannot be absorbed. For this reason, they must be taken on an empty stomach, and a period of up to 2 hours must elapse before the consumption of any food or drink other than plain water. This routine is not only inconvenient but can lead to discontinuation of treatment, and when mistakenly taken with food, may result in misdiagnosis of resistance to or failure of treatment. The development of an enteric-coated delayed-release formulation of risedronate with the addition of the calcium chelator, ethylenediaminetetraacetic acid (EDTA), a widely used food stabilizer, eliminates the need for fasting without affecting the bioavailability of risedronate or its efficacy.
[Show abstract][Hide abstract] ABSTRACT: Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.
Proceedings of the National Academy of Sciences 08/2012; 109(37):15048-53. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2-amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.
The Journal of clinical investigation 08/2012; 122(9):3295-306. · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Postmenopausal osteoporosis is mainly caused by increased bone remodeling resulting from estrogen deficiency. Indications for treatment are based on low areal bone mineral density (aBMD, T-score ≤ -2.5), typical fragility fractures (spine or hip), and more recently, an elevated 10-year fracture probability (by FRAX®). In contrast, there is no clear definition of osteoporosis nor intervention thresholds in younger individuals. Low aBMD in a young adult may reflect a physiologically low peak bone mass, such as in lean but otherwise healthy persons, whereas fractures commonly occur with high-impact trauma, i.e., without bone fragility. Furthermore, low aBMD associated with vitamin D deficiency may be highly prevalent in some regions of the world. Nevertheless, true osteoporosis in the young can occur, which we define as a T-score below -2.5 at spine or hip in association with a chronic disease known to affect bone metabolism. In the absence of secondary causes, the presence of fragility fractures, such as in vertebrae, may point towards genetic or idiopathic osteoporosis. In turn, treatment of the underlying condition may improve bone mass as well. In rare cases, a bone-specific treatment may be indicated, although evidence is scarce for a true benefit on fracture risk. The International Osteoporosis Foundation (IOF) convened a working group to review pathophysiology, diagnosis, and management of osteoporosis in the young, excluding children and adolescents, and provide a screening strategy including laboratory exams for a systematic approach of this condition.
Osteoporosis International 06/2012; · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE:NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo.DESIGN:Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice.RESULTS:Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid β-oxidation.CONCLUSION:These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.International Journal of Obesity advance online publication, 20 March 2012; doi:10.1038/ijo.2011.279.
International journal of obesity (2005) 03/2012; · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As they age, mice deficient for the β2-adrenergic receptor (Adrb2(-/-) ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of β1-adrenergic receptor signaling and its interaction with β2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for β1-adrenergic receptors and/or β2-adrenergic receptors. Upon axial compression loading of the tibia, bone density, cancellous and cortical microarchitecture, as well as histomorphometric bone forming indices, were increased in both Adrb2(-/-) and wild-type (WT) mice, but not in Adrb1(-/-) nor in Adrb1b2(-/-) mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2(-/-) mice, whereas in Adrb1(-/-) and Adrb1b2(-/-) double knockout mice, femur bone mineral density (BMD), cancellous bone volume/total volume (BV/TV), cortical size, and cortical thickness were lower compared to WT. Bone histomorphometry and biochemical markers showed markedly decreased bone formation in Adrb1b2(-/-) mice during growth, which paralleled a significant decline in circulating insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3). Finally, administration of the β-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-κB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2(-/-) mice. Altogether, these results demonstrate that β1- and β2-adrenergic signaling exert opposite effects on bone, with β1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas β2-adrenergic receptor signaling mainly regulates bone resorption during aging.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2012; 27(6):1252-62. · 6.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Denosumab is the first human monoclonal antibody for the treatment of osteoporosis. By inhibiting RANK Ligand, Denosumab prevents the development, activation and survival of osteoclasts. The FREEDOM study reported a 68 % reduction of vertebral fractures, 20 % of non-vertebral fractures and 40 % of hip fractures after 3 years in post-menopausal women with osteoporosis receiving denosumab 60 mg sc every six months vs. placebo. Five years extension of the denosumab group showed a further decrease in the rate of both vertebral and non-vertebral fractures, whereas BMD at spine and hip increased continuously. There was no increase in the rate of adverse events year after year, including of infections, cancer, atypical fractures, delayed fracture healing or ONJ. Clinical hypocalcemia was rare in the context of calcium and vitamin D supplementation. Pre-planned and post-hoc subgroup analyses have further shown the anti-fracture efficacy of denosumab in high-risk subgroups, such as older women and those with low T-scores and/or prevalent vertebral fractures. Denosumab withdrawal is accompanied by a transient rebound of bone turnover markers and a proportional BMD loss. Smaller randomized controlled studies have shown that denosumab further improves BMD after one year compared to alendronate.