[Show abstract][Hide abstract] ABSTRACT: Periostin is a highly conserved matricellular protein that shares close homology with the insect cell adhesion molecule fasciclin 1. Periostin is expressed in a broad range of tissues including the skeleton, where it serves both as a structural molecule of the bone matrix and a signaling molecule through integrin receptors and Wnt-beta-catenin pathways whereby it stimulates osteoblast functions and bone formation. The development of periostin null mice has allowed to elucidate the crucial role of periostin on dentinogenesis and osteogenesis, as well as on the skeletal response to mechanical loading and parathyroid hormone. The use of circulating periostin as a potential clinical biomarker has been explored in different non skeletal conditions. These include cancers and more specifically in the metastasis process, respiratory diseases such as asthma, kidney failure, renal injury and cardiac infarction. In postmenopausal osteoporosis, serum levels have been shown to predict the risk of fracture-more specifically non-vertebral- independently of bone mineral density. Because of its preferential localization in cortical bone and periosteal tissue, it can be speculated that serum periostin may be a marker of cortical bone metabolism, although additional studies are clearly needed.
Full-text · Article · Dec 2015 · Molecular and Cellular Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Subjects with Type 1 diabetes mellitus have decreased bone mineral density and an up to 6 fold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with type 1 diabetes (T1DM) have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF-1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn increasing physical activity in children with diabetes as well as good glycaemic control appear to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.
Preview · Article · Nov 2015 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Periostin (a product of Postn gene) is a matricellular protein which is increased in periosteal osteoblasts and osteocytes upon mechanical stimulation. We previously reported that periostin-deficient mice (Postn(-/-)) have low bone mass and a diminished response to physical activity due to a lack of sclerostin (a product of Sost gene) inhibition by mechanical loading. Here we hypothesized that periostin could play a central role in the control of bone loss during unloading induced by hindlimb suspension (HU). In Postn(+/+) mice (wildtype littermate), HU significantly decreased femur BMD, as well as trabecular BV/TV and thickness (Tb.Th). Cortical bone volume and thickness at the femoral midshaft, also significantly decreased. These changes were explained by an inhibition of endocortical and periosteal bone formation activity and correlated with a decrease of Postn expression and a consecutive increase in Sost early after HU. Whereas trabecular bone loss in Postn-/- mice was comparable to Postn(+/+) mice, HU did not significantly alter cortical bone microstructure and strength in Postn-/- mice. Bone formation remained unchanged in these mice, as Sost did not increase in the absence of periostin. In contrast, changes in Dkk1, Rankl and Opg expression in response to HU were similar to Postn(+/+) mice, indicating that changes in periostin expression were quite specifically related to changes in Sost. In conclusion, HU inhibits periostin expression, which in turn plays an important role in cortical bone loss through an increase in Sost. These results further indicate that periostin is an essential mediator of cortical bone response to mechanical forces (loading and unloading).
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is a complex disease, with both environmental and genetic components. Moreover, there are clear suggestions that nutritional and genetic factors interact to influence bone modeling and mineral homeostasis during the years of peak bone mass acquisition, as well as influence bone remodeling and the maintenance of bone mass. Here we review the bases for candidate gene and genome-wide association studies with bone mineral density and fractures, as well as the candidate gene studies that investigated gene-dietary interactions in osteoporosis. These include the VDR, ESR1, and Il-6 gene with vitamin D and/or calcium intake, and Ppar and lipids intake. Notably, few genome-wide association studies (GWAS) to date have incorporated G*E interactions into the analysis design and this is primarily due to the challenges associated with such an approach. Also, more refined phenotypes than areal bone mineral density (aBMD) are required, with a focus on cellular and molecular processes in bones in response to nutrition. If successful, such genome-wide interaction studies (GWIS) can contribute to better bone health by proposing individualized Recommended Dietary Allowances (RDA) for various nutrients.
[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: High protein (> median:Hprot) vs. moderate (< median:MProt) intake was shown to enhance the positive impact of high physical activity (HPA) on proximal femur BMC/aBMD/Area in healthy prepubertal boys. We tested the hypothesis that this synergistic effect would track and influence bone structure and strength until mid-adolescence. BMC/aBMD/Area was measured at femoral neck (FN) and total hip (TotHip) by DXA in 176 boys at 7.4 ± 0.4 and 15.2 ± 0.5 years (± SD). Distal tibia (DistTib) microstructure and strength were also assessed at 15.2 years by high?resolution peripheral computerized tomography (HR-pQCT) and micro-finite element analysis (μFEA). The positive impact of HProt vs. MProt on FN and TotHip BMC/aBMD/Area, recorded at 7.4 years remained unabated at 15.2 years. At this age, at DistTib, HProt-HPA vs. MProt-HPA was associated (p < 0.001) with larger cross-sectional area (CSA, mm2), trabecular number (Tb.N, mm-1) and lower trabecular separation (Tb.Sp, μm). The interaction between physical activity and protein intake was signi ficant for CSA (p = 0.012) and Tb.N (p = 0.043). Under MProt (38.0 ± 6.9 g.d-1), a difference in PA from 168 ± 40 to 303 ± 54 kcal.d-1was associated with greater stiffness (kN/mm) and failure load (N) of +0.16 and +0.14 Z-score, respectively. In contrast, under HProt (56.2 ± 9.5 g.d-1), a difference in PA of similar magnitude, from 167 ± 33 to 324 ± 80 kcal.d-1, was associated with a larger difference in stiffness and failure load of +0.50 and +0.57 Z-score, respectively. In conclusion, the positive influence of relatively HProt on the impact of HPA on proximal femur macrostructure tracks from prepuberty to mid-late puberty. At this stage, the impact of HProt on HPA is also associated with microstructural changes that should confer greater mechanical resistance to weight-bearing bones. These results underscore the importance of protein intake and exercise synergistic interaction in the early prevention of adult osteoporosis.
Preview · Article · Oct 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
[Show abstract][Hide abstract] ABSTRACT: Odanacatib, a selective cathepsin K inhibitor, decreases bone resorption, whereas osteoclast number increases and bone formation is maintained, perhaps even increased on some cortical surfaces. In a phase 2 clinical trial, post-menopausal women receiving odanacatib presented a sustained reduction of bone resorption markers, whereas procollagen type 1 N-terminal propeptide returned to normal. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. Blosozumab and romosozumab are sclerostin neutralizing antibodies that exert potent anabolic effects on both trabecular and cortical compartments. A phase 2 clinical trial has reported areal bone mineral density gains at spine and hip that were greater with romosozumab compared with placebo, but also with teriparatide. It also showed that antagonizing sclerostin results in a transient stimulation of bone formation but progressive inhibition of bone resorption. Other new medical entities that are promising for the treatment of osteoporosis include abaloparatide, a parathyroid hormone-related analogue with improved bone formation–resorption ratio.
No preview · Article · Aug 2014 · Best Practice & Research: Clinical Endocrinology & Metabolism
[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.
Full-text · Article · Jun 2014 · Swiss medical weekly: official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology
[Show abstract][Hide abstract] ABSTRACT: Background
Osteoporosis is a highly heritable trait. Among the genes associated with bone mineral density (BMD), the low-density lipoprotein receptor-related protein 5 gene (LRP5) has been consistently identified in Caucasians. However LRP5 contribution to osteoporosis in populations of other ethnicities remains poorly known.
To determine whether LRP5 polymorphisms Ala1330Val and Val667Met are associated with BMD in North Africans, these genotypes were analyzed in 566 post-menopausal Tunisian women with mean age of 59.5 ± 7.7 years, of which 59.1% have low bone mass (T-score < −1 at spine or hip).
In post-menopausal Tunisian women, 1330Val was weakly associated with reduced BMD T-score at lumbar spine (p = 0.047) but not femur neck. Moreover, the TT/TC genotypes tended to be more frequent in women with osteopenia and osteoporosis than in women with normal BMD (p = 0.066). Adjusting for body size and other potential confounders, LRP5 genotypes were no longer significantly associated with aBMD at any site.
The less common Val667Met polymorphism showed no association with osteoporosis. The Ala1330Val polymorphism is weakly associated with lower lumbar spine bone density and osteopenia/osteoporosis in postmenopausal Tunisian women. These observations expand our knowledge about the contribution of LRP5 genetic variation to osteoporosis risk in populations of diverse ethnic origin.
[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.
[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.
Full-text · Article · Oct 2013 · Therapeutics and Clinical Risk Management
[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.
No preview · Article · Jul 2013 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The objective of this study is to determine in healthy premenopausal women with a history of fracture which bone structural components of the distal radius are the most closely associated with a risk of fracture.
Methods and participants:
The method was as follows: measurement of radial areal bone mineral density (aBMD) by DXA, microstructural components by high-resolution quantitative peripheral computerized tomography (HR-pQCT) and strength variables by micro Finite Element Analysis (μFEA) in 196 healthy premenopausal women aged 45.9 ± 3.7 (± SD) years with (FX, n = 96) and without (NO-FX, n = 100) a history of fracture. We evaluated differences in T-scores between FX and NO-FX and risk of fracture by Odds ratios (OR with 95% confidence intervals, CI) per one SD decrease, using logistic regression analysis after adjustment for age, height, weight, menarcheal age, calcium and protein intakes, and physical activity.
In the whole group the mean radial metaphysis aBMD T-score was not significantly different from zero. In the FX as compared to the NO-FX group, the differences in T-scores were as follows: for radial metaphysis: aBMD, -0.24 (P = 0.005); for distal radius microstructure components: cortical volumetric BMD, -0.38 (P = 0.0009); cortical thickness, -0.37 (P = 0.0001); cross-sectional area (CSA), +0.24 (P=0.034); and endosteal perimeter, +0.28 (P = 0.032); and for strength estimates: stiffness, -0.15 (P = 0.030); failure load, -0.14 (P = 0.044); and apparent modulus, -0.28 (P = 0.006). T-scores of trabecular volumetric BMD and thickness did not significantly differ between the FX and the NO-FX group. Accordingly, the risk of fracture (OR, 95% CI) for 1 SD decrease in radius bone parameters was as follows: radial metaphysis aBMD: 1.70 (1.18-2.44), P = 0.004; cortical volumetric BMD: 1.86 (1.28-2.71), P = 0.001; and cortical thickness: 2.36 (1.53-3.63), P = 0.0001. The corresponding fracture risk for the strength estimates was as follows: stiffness: 1.66 (1.06-2.61), P = 0.028; failure load: 1.59 (1.02-2.47), P = 0.041; and apparent modulus: 1.76 (1.17-2.64), P = 0.006.
In healthy premenopausal women, a history of fracture is associated with reduced T-scores in the distal radius, with the cortical components showing the greatest deficit. A reduction of one SD in cortical thickness is associated with a nearly three-fold increased risk of fracture. This finding strengthens the notion that, in healthy women, a certain degree of bone structural fragility contributes to fractures before the menopause and therefore should be taken into consideration in the individual prevention strategy of postmenopausal osteoporosis.