Long-term therapy in COPD: any evidence of adverse effect on bone?

Patients with COPD have high risk for osteoporosis and fractures. Hip and vertebral fractures might impair mobility, and vertebral fractures further reduce lung function. This review discusses the evidence of bone loss due to medical treatment opposed to disease severity and risk factors for COPD, and therapeutic options for the prevention and treatment of osteoporosis in these patients. A review of the English-language literature was conducted using the MEDLINE database until June 2009. Currently used bronchodilators probably lack adverse effect on bone. Oral corticosteroids (OCS) increase bone resorption and decrease bone formation in a dose response relationship, but the fracture risk is increased more than reflected by bone densitometry. Inhaled corticosteroids (ICS) have been associated with both increased bone loss and fracture risk. This might be a result of confounding by disease severity, but high doses of ICS have similar effects as equipotent doses of OCS. The life-style factors should be modified, use of regular OCS avoided and use of ICS restricted to those with evidenced effect and probably kept at moderate doses. The health care should actively reveal risk factors, include bone densitometry in fracture risk evaluation, and give adequate prevention and treatment for osteoporosis

Effects of vitamin D supplementation on bone turnover markers and other bone-related substances in subjects with vitamin D deficiency

In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0 nmol/L completed a four months intervention with vitamin D3 20,000 IU per week versus placebo. Mean serum 25(OH)D increased to 89.0 nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2 pg/mL and 1.5 ng/mL, respectively, P  6.5 pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects

Vitamin D and stress urinary incontinence in pregnancy: a cross-sectional study

Objective To assess the association between levels of vitamin D and urinary incontinence (UI) in pregnancy. Design A cross‐sectional study. Secondary analysis of a randomised controlled trial. Setting Two university hospitals in Norway. Population A total of 851 healthy, pregnant women >18 years in gestational weeks 18–22 with a singleton live fetus. Methods Data on UI were collected from a questionnaire at inclusion and serum analysis of 25‐hydroxy vitamin D (25(OH)D) was performed. Univariable and multivariable logistic regression analyses were applied to study associations between exposure and outcomes. Main outcome measures Prevalence of self‐reported UI, stress (SUI) and urge (UUI) or mixed UI. Results In total, 230/851 (27%) of the participants were vitamin D insufficient (25(OH)D <50 nmol/l) and 42% reported to have any UI. Women with 25(OH)D <50 nmol/l were more likely to report any UI (P = 0.03) and SUI (P < 0.01) compared with women with 25(OH)D ≥50 nmol/l. In a univariable logistic regression analysis, serum levels of 25(OH)D <50 nmol/l was associated with increased risk of any UI (odds ratio [OR] 1.5 with 95% CI 1.0–2.1), SUI only (OR 1.7, 95% CI 1.2–2.4), but not mixed UI or UUI only (OR 0.8, 95% CI 0.5–1.5). In a multivariable logistic regression model, serum levels of 25(OH)D <50 nmol/l were associated with a higher risk of experiencing SUI only (OR 1.5, 95% CI 1.1–2.2). Conclusions Serum 25(OH)D <50 nmol/l was associated with increased risk of any UI, and SUI in particular.publishedVersio

Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone

<p>Abstract</p> <p>Background</p> <p>All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.</p> <p>Methods</p> <p>Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.</p> <p>Results</p> <p>The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.</p> <p>Conclusion</p> <p>We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.</p

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.</p> <p>Methods</p> <p>Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.</p> <p>Results</p> <p>Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.</p> <p>Conclusions</p> <p>The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.</p

Lipocalin 2 is expressed in MLO-Y4 osteocytes and regulated by the peroxisome proliferator activated receptor α agonist fenofibrate.

Background: Lipocalin 2 is highly expressed and secreted from osteoblasts in mice. Lately, bone-derived lipocalin 2 has been shown to suppress appetite by binding to the MC4R in hypothalamus. In the present study we wanted to examine whether the PPARα agonist fenofibrate exerts its weight-reducing effect through stimulation of lipocalin 2 secretion. Methods: The murine pre-osteoblast and osteocyte cell lines (MC3T3-E1 and MLO-Y4) were incubated with DMSO (control) and fenofibrate dissolved in DMSO for 24 and 72 hours. MC3T3-E1 cells were exposed to fenofibrate 10 µM, and MLO-Y4 cells to 1 and 10 µM. Lipocalin 2 in cell medium and lysate was measured by ELISA, and lipocalin 2 mRNA in MLO-Y4 cells by RTPCR. Lipocalin 2 was also analyzed in plasma from ovariectomized (OVX) rats exposed to fenofibrate (90 mg/kg/d) for eight weeks and in OVX controls. Results: Lipocalin 2 mRNA was significantly and highly expressed in MLO-Y4 cells after exposure to fenofibrate 1 and 10 µM for 24 hours. No significant differences in lipocalin levels were observed in cell medium or lysate from MC3T3-E1 and MLO-Y4 cells after incubation with fenofibrate. The highest levels of lipocalin 2 were seen after exposure of MLO-Y4 cells to fenofibrate 1 µM for 72 hours. The amount of lipocalin 2 appeared to be modest in MC3T3-E1 cells. Plasma levels of lipocalin 2 were higher in OVX rats exposed to fenofibrate than in controls, however, not significantly. Conclusion: We show for the first time that lipocalin 2 is expressed, translated and secreted from the osteocyte cell line MLO-Y4, and that lipocalin 2 mRNA expression is upregulated by fenofibrate

Cortical hand bone porosity and its association with distal radius Fracture in middle aged and elderly women

Objective: Reduced bone mineral density (BMD), assessed by Dual Energy X-ray absorptiometry (DXA), is a well-known risk factor for fragility fracture. A large proportion of patients with fracture have only slightly reduced BMD. Assessment of other bone structure features than BMD may improve identification of individuals at increased fracture risk. Digital X-ray radiogrammetry (DXR), which is a feasible tool for measurement of metacarpal cortical bone density, also gives an estimate of cortical bone porosity. Our primary aim was to explore the association between cortical porosity in the hand assessed by DXR and distal radius fracture. Methods: This case-control study included 123 women >50 years with distal radius fracture, and 170 controls. DXR was used to measure metacarpal BMD (DXR-BMD), cortical porosity (DXR-porosity), thickness (DXR-CT) and bone width (DXR-W) of the hand. Femoral neck BMD was measured by DXA. Results: The fracture group had a statistically significant lower DXR-BMD (0.492 vs. 0.524 g/cm2 p<0.001), higher cortical DXR-porosity (0.01256 vs. 0.01093, p<0.001), less DXR-CT (0.148 vs. 0.161cm, p<0.001) and lower femoral neck DXA-BMD (0.789 vs. 0.844 g/cm2, p = 0.001) than the controls. In logistic regression analysis adjusted for age, a significant association with distal radius fracture (OR, 95% CI) was found for body mass index (0.930, 0.880–0.983), DXA-BMD (0.996, 0.995–0.999), DXR-BMD (0.990, 0.985–0.998), DXR-porosity (1.468, 1.278–1.687) and DXR-CT (0.997, 0.996–0.999). In an adjusted model, DXR-porosity remained the only variable associated with distal radius fracture (1.415, 1.194–1.677). Conclusion: DXR derived porosity is associated with fracture at distal radius and might be a sensitive marker for skeletal fragility

Exploring the relationship between bone density and severity of distal radius fragility fracture in women

Background Bone mineral density (BMD) has been shown to be a consistent and independent risk factor for distal radius fracture. Inconsistent data have been reported on the association between BMD and severity of distal radius fracture. Our primary aim was to explore if there is an association between cortical BMD at the hand and the severity of fragility distal radius fracture. Methods Consecutively recruited females aged ≥50 years with fragility fracture at the distal radius (n = 110) from a county hospital were included. Cortical hand BMD was assessed by the digital X-ray radiogrammetry (DXR) method. X-rays of the fracture were scored by experienced orthopedic surgeons for fracture severity according to the Müller AO classification of long bones and radiographic parameters such as ulnar variance and dorsal angle. Results A weak association between lower DXR BMD and increased ulnar variance and dorsal angle was found but not with the AO scoring system for fracture type. A history of glucocorticoid (GC) use but not DXR-BMD was found to be significantly associated with the presence of having an intra- or extra-articular fracture. Conclusion Our data indicate that bone material properties which are impaired by GC use are more important for fracture severity than BMD