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issn:0171-967
1.  Studying Variations in Bone Composition at Nano-Scale Resolutions: A Preliminary Report 
Calcified tissue international  2014;95(5):413-418.
Bone has a hierarchical structure extending from the micrometer to the nanometer scale. We report here the first analysis of non-human primate osteonal bone obtained using a spectrometer coupled to an AFM-microscope (AFM-IR), with a resolution of 50–100 nm. Average spectra correspond to those observed with conventional FTIR spectroscopy. The following validated FTIR parameters were calculated based on intensities observed in scans covering ~60 µm from the osteon center: mineral content (1030 cm−1/1660 cm−1); crystallinity (1030 cm−1)/1020 cm−1), collagen maturity (1660 cm−1/1690 cm−1) and acid phosphate content (1128 cm−1/1096 cm−1). A repeating pattern was found in most of these calculated IR parameters corresponding to the reported inter- and intra-lamellar spacing in human bone, indicating that AFM-IR measurements will be able to provide novel compositional information on the variation in bone at the nanometer level.
doi:10.1007/s00223-014-9909-9
PMCID: PMC4192085  PMID: 25155443
AFM-IR; nano-IR; bone composition; osteonal bone; bone nano-structure
2.  CCR2 Elimination in Mice Results in Larger and Stronger Tibial Bones but Bone Loss is not Attenuated following Ovariectomy or Muscle Denervation 
Calcified tissue international  2014;95(5):457-466.
Bone loss due to age and disuse contributes to osteoporosis and increases fracture risk. It has been hypothesized that such bone loss can be attenuated by modulation of the C-C chemokine receptor 2 (CCR2) and/or its ligands. The objectives of this study were to examine the effects of genetic elimination of CCR2 on cortical and trabecular bones in the mouse tibia and how bone loss was impacted following disuse and estrogen loss. Female CCR2 knockout (CCR2−/−) and wildtype mice underwent ovariectomy (OVX) or denervation of musculature adjacent to the tibia (DEN) to induce bone loss. Cortical and trabecular structural properties as well as mechanical properties (i.e., strength) of tibial bones were measured. Compared to wildtype mice, CCR2−/− mice had tibiae that were up to 9% larger and stronger; these differences could be explained mainly by the 17% greater body mass (p<0.001) of CCR2−/− mice. The majority of the tibia’s structural and functional responses to OVX and DEN were similar regardless of the lack or presence of CCR2, indicating that CCR2 is not protective against bone loss per se. These findings indicate that while CCR2−/− mice do have larger and stronger bones than do wildtype mice, there is minimal evidence that CCR2 elimination provides protection against bone loss during disuse and estrogen loss.
doi:10.1007/s00223-014-9914-z
PMCID: PMC4228687  PMID: 25234653
Chemokine receptor; estrogen; disuse; bone remodeling; Monocyte Chemoattractant Protein-1 (MCP-1)
3.  Impact of femoral neck and lumbar spine BMD discordances on FRAX probabilities in women; a meta-analysis of international cohorts 
Calcified tissue international  2014;95(5):428-435.
There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX.
We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS-FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS-FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort.
The absolute ΔLS-FN was greater than 2 SD for 2.5% of women and between 1 and 2 SD for 21%. ΔLS-FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95% CI = 1.04–1.15). In reclassification analyses, only 2.3–3.2% of the women moved to a higher or lower risk category when using FRAX with ΔLS-FN compared with FN-derived FRAX alone.
Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1-2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold.
doi:10.1007/s00223-014-9911-2
PMCID: PMC4361897  PMID: 25187239
FRAX; BMD; discordance; reclassification; fracture risk
4.  Effects of Dairy Products Consumption on Health: Benefits and Beliefs—A Commentary from the Belgian Bone Club and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases 
Dairy products provide a package of essential nutrients that is difficult to obtain in low-dairy or dairy-free diets, and for many people it is not possible to achieve recommended daily calcium intakes with a dairy-free diet. Despite the established benefits for bone health, some people avoid dairy in their diet due to beliefs that dairy may be detrimental to health, especially in those with weight management issues, lactose intolerance, osteoarthritis, rheumatoid arthritis, or trying to avoid cardiovascular disease. This review provides information for health professionals to enable them to help their patients make informed decisions about consuming dairy products as part of a balanced diet. There may be a weak association between dairy consumption and a possible small weight reduction, with decreases in fat mass and waist circumference and increases in lean body mass. Lactose intolerant individuals may not need to completely eliminate dairy products from their diet, as both yogurt and hard cheese are well tolerated. Among people with arthritis, there is no evidence for a benefit to avoid dairy consumption. Dairy products do not increase the risk of cardiovascular disease, particularly if low fat. Intake of up to three servings of dairy products per day appears to be safe and may confer a favourable benefit with regard to bone health.
doi:10.1007/s00223-015-0062-x
PMCID: PMC4703621  PMID: 26445771
Dairy products; Cardiovascular disease; Osteoporosis; Arthritis; Weight management; Lactose intolerance
6.  Relationship of Bone Mineralization Density Distribution (BMDD) in Cortical and Cancellous Bone Within the Iliac Crest of Healthy Premenopausal Women 
Calcified tissue international  2014;95(4):332-339.
Bone mineralization density distribution (BMDD) is an important determinant of bone mechanical properties. The most available skeletal site for access to the BMDD is the iliac crest. Compared to cancellous bone much less information on BMDD is available for cortical bone. Hence, we analyzed complete transiliac crest bone biopsy samples from premenopausal women (n = 73) aged 25–48 years, clinically classified as healthy, by quantitative backscattered electron imaging for cortical (Ct.) and cancellous (Cn.) BMDD. The Ct.BMDD was characterized by the arithmetic mean of the BMDD of the cortical plates. We found correlations between Ct. and Cn. BMDD variables with correlation coefficients r between 0.42 and 0.73 (all p < 0.001). Additionally to this synchronous behavior of cortical and cancellous compartments, we found that the heterogeneity of mineralization densities (Ct.CaWidth), as well as the cortical porosity (Ct.Po) was larger for a lower average degree of mineralization (Ct.CaMean). Moreover, Ct.Po correlated negatively with the percentage of highly mineralized bone areas (Ct.CaHigh) and positively with the percentage of lowly mineralized bone areas (Ct.CaLow). In conclusion, the correlation of cortical with cancellous BMDD in the iliac crest of the study cohort suggests coordinated regulation of bone turnover between both bone compartments. Only in a few cases, there was a difference in the degree of mineralization of >1wt % between both cortices suggesting a possible modeling situation. This normative dataset of healthy premenopausal women will provide a reference standard by which disease- and treatment-specific effects can be assessed at the level of cortical bone BMDD.
doi:10.1007/s00223-014-9901-4
PMCID: PMC4464772  PMID: 25134800
Bone mineralization density distribution (BMDD); Cortical bone; Iliac crest biopsy; Quantitative backscattered electron imaging (qBEI); Premenopausal women
7.  A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study 
Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12–50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0–12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95 % CI 0.9–1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95 % CI 1.1–1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies.
doi:10.1007/s00223-015-0059-5
PMCID: PMC4703626  PMID: 26412463
Homocysteine; Aging; Falling; Physical function; Vitamin B12; Folic acid
8.  Characteristics Associated with Bone Mineral Density Responses to Alendronate in Men 
Calcified tissue international  2013;92(6):548-556.
Background
Some patients experience reduced bone mineral density (BMD) despite bisphosphonate therapy. We performed a retrospective chart review study to detect factors associated with decreased BMD in men prescribed alendronate.
Methods
Two investigators reviewed eligible medical records and used a standardized form to record potential characteristics predicting men’s response to alendronate. We analyzed patient characteristics associated with annualized change in hip and spine BMD (D-BMD).
Results
Among 115 eligible men, 19 (17%) experienced significantly decreased BMD at the hip or spine, defined as a change exceeding precision error. Eleven men (10%) fractured during therapy. Spine D-BMD was positively associated with adherence to alendronate (R = 0.23, p=0.02) and inversely associated with baseline body weight (R = −0.21, p=0.03). Hip D-BMD was positively associated with annualized weight change (R = 0.19, p=0.0498) and negatively associated with patient age and number of concomitant medications (R = −0.21, p=0.03; R = −0.20, p = 0.03, respectively). In stepwise linear models, spine D-BMD was positively associated with alendronate adherence and multivitamin use, and negatively with baseline body weight. Hip D-BMD was negatively associated with age. Fracture during treatment was associated with fracture prior to therapy (p=0.03)
Conclusions
In this small study of men prescribed alendronate, BMD response showed a positive association with adherence to therapy, weight gain, and use of a multivitamin. By contrast, older age, higher baseline body weight, and higher number of medications were each associated with a decrease in BMD. Larger studies are needed to confirm and extend these findings.
doi:10.1007/s00223-013-9715-9
PMCID: PMC4560467  PMID: 23494407
adherence; efficacy; men; osteoporosis; treatment
9.  Downregulation of Notch Modulators, Tetraspanin 5 and 10, Inhibits Osteoclastogenesis in vitro 
Calcified tissue international  2014;95(3):209-217.
Genetic studies in human and mice have pinpointed an essential role of Notch signaling in osteoblast and osteoclast differentiation during skeletal development and bone remodeling. However, the factors and pathways regulating Notch activation in bone cells remain largely unknown. In this in vitro study, we have provided evidence that two of the TspanC8 subfamily members of tetraspanins, Tspan-5 and Tspan-10, are up-regulated during osteoclast differentiation and knockdown of their expression by shRNAs dramatically inhibits osteoclastogenesis. Loss of Tspan-5 and Tspan-10 in osteoclast lineage cells results in attenuation of ADAM10 maturation and Notch activation. Therefore, these two tetraspanins play a critical role in osteoclast formation, at least in part, by modulating Notch signaling pathway.
doi:10.1007/s00223-014-9883-2
PMCID: PMC4139439  PMID: 24935633
Tetraspanin; ADAM10; Notch; Osteoclast; Bone resorption
10.  Improved Trabecular Bone Structure of 20-Month-Old Male Spontaneously Hypertensive Rats 
Calcified tissue international  2014;95(3):282-291.
A few clinical studies have reported that elderly male participants with hypertensive disease frequently have higher BMD than the normotensive participants at several skeletal sites. The detailed mechanism is still unknown; therefore a study of bone structure and density using the hypertensive animal models could be informative. We used micro-computed tomography (μCT) to quantitatively evaluate the tibial and 3rd lumbar vertebral bones in the 20-month-old male spontaneous hypertensive rat (SHR). The BMD, volume fraction, and the microarchitecture changes of the SHR were compared to those of same-age normotensive controls (Wistar-Kyoto rat, WKY). We found that in the very old (20-month) male rats, the trabecular bone fraction and microstructure were higher than those in the same-age normotensive controls. The observation of the association of hypertension with BMD and bone strength in hypertensive rats warrants further investigations of bone mass and strength in elderly males with hypertension.
doi:10.1007/s00223-014-9893-0
PMCID: PMC4153466  PMID: 25106873
Trabecular Structure; Quantitative Micro-CT; Bone Strength; Hypertension; Spontaneous Hypertensive Rat; Aging
11.  Reduced tissue-level stiffness and mineralization in osteoporotic cancellous bone 
Calcified tissue international  2014;95(2):125-131.
Osteoporosis alters bone mass and composition ultimately increasing the fragility of primarily cancellous skeletal sites; however, effects of osteoporosis on tissue-level mechanical properties of cancellous bone are unknown. Dual-energy x-ray absorptiometry (DXA) scans are the clinical standard for diagnosing osteoporosis though changes in cancellous bone mass and mineralization are difficult to separate using this method. The goal of this study was to investigate possible difference in tissue-level properties with osteoporosis as defined by donor T-scores. Spine segments from Caucasian female cadavers (58–92 yrs) were used. A T-score for each donor was calculated from DXA scans to determine osteoporotic status. Tissue level composition and mechanical properties of vertebrae adjacent to the scan region were measured using nanoindentation and Raman spectroscopy. Based on T-scores, six samples were in the Osteoporotic group (58–74 yrs) and four samples were in the Not Osteoporotic group (65–92 yrs). The indentation modulus and mineral to matrix ratio (mineral:matrix) were lower in the Osteoporotic group than the Not Osteoporotic group. Mineral:matrix ratio decreased with age (r2 = 0.35, p = 0.05), and the indentation modulus increased with a real bone mineral density (aBMD) (r2 = 0.41, p = 0.04).
This study is the first to examine cancellous bone composition and mechanical properties from a fracture prone location with osteoporosis. We found differences in tissue composition and mechanical properties with osteoporosis that could contribute to increased fragility in addition to changes in trabecular architecture and bone volume.
doi:10.1007/s00223-014-9873-4
PMCID: PMC4104238  PMID: 24888692
Nanoindentation; Raman spectroscopy; Osteoporosis; Human trabecular bone
12.  A New Concept of Health Can Improve the Definition of Frailty 
Calcified Tissue International  2015;97(5):429-431.
Following a newly developed concept of health, this viewpoint suggests that the concept of frailty can usefully be defined as: the weakening of health, i.e. the resilience or capacity to cope, and to maintain and restore one’s integrity, equilibrium, and sense of wellbeing in three domains: physical, mental, and social.
doi:10.1007/s00223-015-0038-x
PMCID: PMC4598346  PMID: 26215399
Health; Frailty; Sarcopenia; Opsteoporosis; Gerontolog
13.  Use of Glucagon-Like-Peptide 1 Receptor Agonists and Risk of Fracture as Compared to Use of Other Anti-hyperglycemic Drugs 
Calcified Tissue International  2015;97(5):506-515.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a new class of drugs that might have a potential beneficial effect on bone metabolism. Data on the effect of GLP-1 RAs and fracture risk are lacking. The aim of the present study was to investigate the association between the use of GLP-1 and the risk of fracture. A case–control study was performed using Danish National Health Service data. Cases were those who sustained a fracture and controls were those without a fracture during the study period (2007–2011), all aged 18 years and above. Conditional logistic regression estimated the odds ratios (OR) of fracture with current use of DPP4-I use. Analyses were adjusted for comorbidities and recent drug use. Among cases (n = 229,114), there were 6993 current non-insulin anti-diabetic drug (NIAD) users (excluding incretin users) and 255 GLP-1 RA users. Similarly, among controls (n = 229,114), 7209 were NIAD users (excluding incretin users) and 220 were GLP-1 RA users. Current GLP-1 RA use was not associated with a decreased risk of fracture [adjusted (adj.) OR 1.16; 95 % CI 0.83–1.63]. Osteoporotic fracture risk was also not associated with current GLP-1 RA use (adj. OR 0.78; 95 % CI 0.44–1.39). In our nation-wide case–control study, we identified that the use of GLP-1 RA was not associated with fracture risk as compared to the use of other anti-hyperglycemic drugs. Additionally, current GLP-1 RA use, stratified by cumulative or average daily dose, is not associated with fracture risk. Further research should focus on long-term use of GLP-1 RA and fracture risk.
doi:10.1007/s00223-015-0037-y
PMCID: PMC4598352  PMID: 26184119
GLP-1 RA; Fracture; Type 2 diabetes mellitus; Case–control
14.  Early Effects of Single and Low-Frequency Repeated Administration of Teriparatide, hPTH(1-34), on Bone Formation and Resorption in Ovariectomized Rats 
Calcified Tissue International  2015;97(4):412-420.
Intermittent repeated administration of teriparatide (TPTD) has potent anabolic effects on bones in vivo. However, TPTD has both anabolic and catabolic effects on osteoblasts in vitro, and the mechanisms underlying its promotion of bone formation are unclear. This study aimed to elucidate the time-dependent changes in bone formation and resorption by examining changes in bone turnover markers and bone tissue over time after TPTD administration with low frequency in ovariectomized rats. The amount of serum osteocalcin, a bone formation marker, was transiently reduced after single TPTD administration, but increased thereafter, remaining increased for several days. In contrast, the amount of excreted urinary C-telopeptide, a bone resorption marker, increased transiently after single TPTD administration, and subsequently returned to control levels on the day after administration. Tissue histomorphometric analyses conducted 8 h after administration showed no changes in bone formation or bone resorption parameters. However, at 48 h, the bone formation parameters OS/BS and Ob.S/BS were increased, while the bone resorption parameter ES/BS was decreased. After repeated TPTD administration for 4 weeks, OS/BS, Ob.S/BS, and MS/BS increased, while Oc.S/BS decreased. Serum osteocalcin at 4 weeks after repeated administration was significantly correlated with OS/BS and Ob.S/BS. These present findings indicate that TPTD has dual, time-dependent effects on bone resorption and bone formation. Immediately after single administration, there was transient promotion of bone resorption and suppression of bone formation. However, sustained stimulation of bone formation occurred thereafter. Furthermore, these data suggest that this sustained bone formation led to anabolic effects with repeated TPTD administration.
doi:10.1007/s00223-015-0026-1
PMCID: PMC4564449  PMID: 26141479
Teriparatide; Bone turnover marker; Bone formation; Bone resorption; Histomorphometry
15.  Deficiency in Perlecan/HSPG2 during Bone Development Enhances Osteogenesis and Decreases Quality of Adult Bone in Mice 
Calcified tissue international  2014;95(1):29-38.
Perlecan/Hspg2 (Pln) is a large heparan sulfate proteoglycan abundant in the extracellular matrix of cartilage and the lacuno-canalicular space of adult bones. While Pln function during cartilage development is critical, evidenced by deficiency disorders including Schwartz-Jampel Syndrome and dyssegmental dysplasia Silverman-Handmaker type, little is known about its function in development of bone shape and quality. The purpose of this study was to understand the contribution of Pln to bone geometric and mechanical properties. We used hypomorph mutant mice that secrete negligible amount of Pln into skeletal tissues and analyzed their adult bone properties using micro-computed tomography and three-point-bending tests. Bone shortening and widening in Pln mutants was observed and could be attributed to loss of growth plate organization and accelerated osteogenesis that was reflected by elevated cortical thickness at older ages. This effect was more pronounced in Pln mutant females indicating a gender-specific effect of Pln deficiency on bone geometry. Additionally, mutant females, and to a lesser extent mutant males, increased their elastic modulus and bone mineral densities to counteract changes in bone shape, but at the expense of increased brittleness. In summary, Pln deficiency alters cartilage matrix patterning and, as we now show, coordinately influences bone formation and calcification.
doi:10.1007/s00223-014-9859-2
PMCID: PMC4137566  PMID: 24798737
Perlecan; Heparan Sulfate; Proteoglycan; Bone Quality; Schwartz-Jampel Syndrome; dyssegmental dysplasia Silverman-Handmaker
16.  Physical Activity, Bone Health, and Obesity in Peri-/Pre- and Postmenopausal Women: Results from the EPIC-Potsdam Study 
Calcified Tissue International  2015;97(4):376-384.
Physical activity (PA) is suggested to increase the peak bone mass and to minimize age-related bone loss, and thereby to reduce the risk of osteoporosis. However, the relation between PA and bone health considering the obesity status is unclear so far. The present study examines the association between PA levels and calcaneal broadband ultrasound attenuation (BUA), particularly under consideration of obesity. Data from a population-based sample of 6776 German women from the EPIC-Potsdam cohort were analyzed. Calibrated PA data were used. Statistical analyses were stratified by menopausal and obesity status. Multiple linear regression was used to model the relationship between PA and BUA levels after adjustment for age, body mass index (BMI), smoking status, education, alcohol and calcium intake, and hormone use. Peri-/premenopausal had higher BUA levels (112.39 ± 10.05 dB/MHz) compared to postmenopausal women (106.44 ± 9.95 dB/MHz). In both groups, BUA levels were higher in the fourth compared to the lowest quartile of PA (p for trend < 0.05). In women with BMI < 30, but not BMI ≥ 30 kg/m2, PA remained positively associated with BUA levels (p for interaction = 0.03). However, when waist circumference higher than 88 cm or body fat percentage (BF %) measures above the median were used to define obesity, a significant positive relationship was also observed in women with BMI < 30 kg/m2 but with higher waist circumference or BF %. In conclusion, our results strengthen the hypothesis that PA has a positive influence on BUA levels, though dependent on weight.
Electronic supplementary material
The online version of this article (doi:10.1007/s00223-015-0027-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00223-015-0027-0
PMCID: PMC4564447  PMID: 26108649
Bone mineral density; Physical activity; Broadband ultrasound attenuation; Bone loss; Obesity
17.  Measuring Differences in Compositional Properties of Bone Tissue by Confocal Raman Spectroscopy 
Calcified tissue international  2011;89(2):111-122.
The full range of fracture risk determinants arise from each hierarchical level comprising the organization of bone. Raman spectroscopy is one tool capable of characterizing the collagen and mineral phases at a near sub-micron length scale, but the ability of Raman spectra to distinguish compositional differences of bone is not well defined. Therefore, we analyzed multiple Raman peak intensities and peak ratios to characterize their ability to distinguish between the typically less mineralized osteonal tissue and the more mineralized interstitial tissue in intra-cortical human bone. To further assess origins of variance, we collected Raman spectra from embedded specimens and for 2 orientations of cut. Per specimen, Raman peak intensities or ratios were averaged among multiple sites within 5 osteons and 5 neighboring interstitial tissue. The peak ratios of ν1 phosphate (PO4) to Proline or Amide III detected the highest increases of 15.4% or 12.5%, respectively, in composition from osteonal to interstitial tissue. The coefficient of variance (COV) was less than 5% for each as opposed to a COV of ∼8% for the traditional ν1PO4/Amide I, a peak ratio that varied the most between transverse and longitudinal cuts for each tissue type. Although embedding affected Raman peaks, it did not obscure differences in most peak ratios related to mineralization between the 2 tissue types. In studies with limited sample size but sufficient number of Raman spectra per specimen for spatial averaging, ν1PO4/Amide III or ν1PO4/Proline is the Raman property that is most likely to detect a compositional difference between experimental groups.
doi:10.1007/s00223-011-9497-x
PMCID: PMC4471954  PMID: 21597909
Raman; Embedding; Cortical Bone; Collagen; Mineral
18.  Osteoporosis screening and treatment among Veterans with recent fracture after implementation of an electronic consult service 
Calcified tissue international  2014;94(6):659-664.
Purpose
Less than 24 percent of Veterans received appropriate evaluation and/or treatment for osteoporosis within 6 months of an index fracture. An electronic consult (E-consult) service was implemented at 3 Veterans Affairs Medical Centers to facilitate identification of and to recommend management for patients with recent fracture.
Method
The E-consult service used clinical encounter data based on ICD9 diagnosis codes to prospectively identify patients with potential osteoporotic fractures. Eligible patients' medical records were reviewed by a metabolic bone specialist and an E-consult note was sent to the patient's primary provider with specific recommendations for further management. Recommendations were initiated at the provider's discretion.
Results
Between 2011 and 2013, the E-consult service identified 444 eligible patients with a low-trauma fracture who were not already on treatment. One hundred twenty-nine (29.1%) consults recommended immediate bisphosphonate treatment and 258 (58.1%) recommended bone density assessments. Primary providers responded by prescribing bisphosphonates in 74 patients (57.4%) and by ordering bone density testing in 183 (70.9%) patients. At the facility level, prior to implementation of the E-consult service, the rate of osteoporosis treatment following a fracture was 4.8% for bisphosphonates and 21.3% for calcium/vitamin D. After implementation, the treatment rate increased to 7.3% for bisphosphonates (P = 0.02) and 35.2% for calcium/vitamin D (P < 0.01).
Conclusion
While feasible and relatively low cost, an E-consult service modestly improved the rate of osteoporosis treatment among patients with a recent fracture. These results suggest that a program with direct patient interaction is probably required to substantially improve treatment rates.
doi:10.1007/s00223-014-9849-4
PMCID: PMC4058771  PMID: 24699797
Osteoporosis; fracture; electronic medical record; bone density; health services research
19.  Type III collagen regulates osteoblastogenesis and the quantity of trabecular bone 
Calcified tissue international  2014;94(6):621-631.
Type III Collagen (Col3), a fibril-forming collagen, is a major extracellular matrix component in a variety of internal organs and skin. It is also expressed at high levels during embryonic skeletal development and is expressed by osteoblasts in mature bone. Loss of function mutations in the gene encoding Col3 (Col3a1) are associated with vascular Ehlers Danlos Syndrome (EDS). Although the most significant clinical consequences of this syndrome are associated with catastrophic failure and impaired healing of soft tissue structures, several studies have documented skeletal abnormalities in vascular EDS patients. However, there are no reports of the role of Col3 deficiency on the murine skeleton. We compared craniofacial and skeletal phenotypes in young (6-8 weeks) and middle-aged (>1 year) control (Col3+/+) and haploinsufficient (Col3+/−) mice, as well as young null (Col3−/−) mice using microcomputed tomography (μCT). Although Col3+/− mice did not have significant craniofacial abnormalities based upon cranial morphometrics, microCT analysis of distal femur trabecular bone demonstrated significant reductions in bone volume (BV), bone fraction volume (BV/TV), connectivity density (ConnD), structure model index (SMI) and trabecular thickness (TbTh) in young adult, female Col3+/− mice relative to wild-type littermates. The reduction in BV/TV persisted in female mice at one year of age. Next we evaluated the role of Col3 in vitro. Osteogenesis assays revealed that cultures of mesenchymal progenitors harvested from Col3−/− embryos display decreased alkaline phosphatase activity and reduced capacity to undergo mineralization. Consistent with this data, a reduction in osteogenic markers (type I collagen, osteocalcin and bone sialoprotein) correlates with reduced bone Col3 expression in Col+/− mice and with age in vivo. A small but significant reduction in osteoclast numbers was found in Col3+/− compared to Col3+/+ bones. Taken together, these findings indicate that Col3 plays a role in development of trabecular bone through its effects on osteoblast differentiation.
doi:10.1007/s00223-014-9843-x
PMCID: PMC4335719  PMID: 24626604
Type III collagen; Extracellular matrix; Bone formation; Osteogenesis; Osteoporosis; Mineralization
20.  Effects of 1,25-Dihydroxyvitamin D3 and Vitamin D3 on the Expression of the Vitamin D Receptor in Human Skeletal Muscle Cells 
Calcified tissue international  2014;96(3):256-263.
Vitamin D receptor (VDR) expression and action in non-human skeletal muscle have recently been reported in several studies, yet data on the activity and expression of VDR in human muscle cells are scarce. We conducted a series of studies to examine the (1) effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on VDR gene expression in human primary myoblasts, (2) effect of 16-week supplementation with vitamin D3 on intramuscular VDR gene expression in older women, and (3) association between serum 25-hydroxyvitamin D (25OHD) and intramuscular VDR protein concentration in older adults. Human primary myoblasts were treated with increasing concentrations of 1,25(OH)2D3 for 18 h. A dose-dependent treatment effect was noted with 1 nmol/L of 1,25OH2D3 increasing intramuscular VDR mRNA expression (mean fold change ± SD 1.36 ± 0.33; P = 0.05). Muscle biopsies were obtained at baseline and 16 weeks after vitamin D3 supplementation (4,000 IU/day) in older adults. Intramuscular VDR mRNA was significantly different from placebo after 16 weeks of vitamin D3 (1.2 ± 0.99; −3.2 ± 1.7, respectively; P = 0.04). Serum 25OHD and intramuscular VDR protein expression were examined by immunoblot. 25OHD was associated with intramuscular VDR protein concentration (R = 0.67; P = 0.0028). In summary, our study found VDR gene expression increases following treatment with 1,25OH2D3 in human myoblasts. 25OHD is associated with VDR protein and 16 weeks of supplementation with vitamin D3 resulted in a persistent increase in VDR gene expression of vitamin D3 in muscle tissue biopsies. These findings suggest treatment with vitamin D compounds results in sustained increases in VDR in human skeletal muscle.
doi:10.1007/s00223-014-9932-x
PMCID: PMC4429607  PMID: 25479835
Vitamin D; Skeletal muscle; Vitamin D receptor; Human; Primary myoblasts; Aging
21.  Mechanical Loading Reduces Inflammation-Induced Human Osteocyte-to-Osteoclast Communication 
Calcified Tissue International  2015;97(2):169-178.
Multiple factors contribute to bone loss in inflammatory diseases such as rheumatoid arthritis (RA), but circulating inflammatory factors and immobilization play a crucial role. Mechanical loading prevents bone loss in the general population, but the effects of mechanical loading in patients with RA are less clear. Therefore, we aimed to investigate whether mechanical stimuli reverse the stimulatory effect of RA serum on osteocyte-to-osteoclast communication. Human primary osteocytes were pretreated with 10 % RA serum or healthy control serum for 7 days, followed by 1 h ± mechanical loading by pulsating fluid flow (PFF). Nitric oxide (NO) and prostaglandin E2 were measured in the medium. Receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), interleukin-6 (IL-6), cyclooxygenase-2 (COX2), matrix-extracellular phosphoglycoprotein (MEPE), cysteine-rich protein 61 (CYR61), and SOST gene expression was quantified by qPCR. Osteoclast precursors were cultured with PFF-conditioned medium (PFF-CM) or static-conditioned medium (stat-CM), and osteoclast formation was assessed. RA serum alone did not affect IL-6, CYR61, COX2, MEPE, or SOST gene expression in osteocytes. However, RA serum enhanced the RANKL/OPG expression ratio by 3.4-fold, while PFF nullified this effect. PFF enhanced NO production to the same extent in control serum (2.6–3.5-fold) and RA serum-pretreated (2.7–3.6-fold) osteocytes. Stat-CM from RA serum-pretreated osteocytes enhanced osteoclastogenesis compared with stat-CM from control serum-pretreated osteocytes, while PFF nullified this effect. In conclusion, RA serum, containing inflammatory factors, did not alter the intrinsic capacity of osteocytes to sense mechanical stimuli, but upregulated osteocyte-to-osteoclast communication. Mechanical loading nullified this upregulation, suggesting that mechanical stimuli could contribute to the prevention of osteoporosis in inflammatory disease.
doi:10.1007/s00223-015-9999-z
PMCID: PMC4491366  PMID: 25967362
Rheumatoid arthritis; Generalized osteoporosis; Inflammatory cytokines; Pulsating fluid flow; Osteoclastogenesis
22.  A Dual Isotope Hybrid Whole Body Micro-PET/CT System Reveals Functional Heterogeneity and Early Local and Systemic Changes Following Targeted Radiation to the Murine Caudal Skeleton 
Calcified tissue international  2014;94(5):544-552.
The purpose of this study is to develop a longitudinal non-invasive functional imaging method using a dual isotope hybrid micro-PET/CT scanner in order to assess both the skeletal metabolic heterogeneity and the effect of localized radiation that models therapeutic cancer treatment on marrow and bone metabolism. Skeletally mature BALB/c female mice were given clinically relevant local radiation (16 Gy) to the hind limbs on day 0. Micro-PET/CT acquisition was performed serially for the same mice on days -5 and +2 with FDG and days -4 and +3 with NaF. Serum levels of pro-inflammatory cytokines were measured. Significant differences (p<0.0001) in marrow metabolism (measured by FDG) and bone metabolism (measured by NaF) were observed among bones before radiation which demonstrates functional heterogeneity in the marrow and mineralized bone throughout the skeleton. Radiation significantly (p<0.0001) decreased FDG uptake but increased NaF uptake (p=0.0314) in both irradiated and non-irradiated bones at early time points. An increase in IL-6 was observed with a significant abscopal (distant) effect on marrow and bone metabolic function. Radiation significantly decreased circulating IGF-1 (p<0.01). Non-invasive longitudinal imaging with dual isotope micro-PET/CT is feasible to investigate simultaneous changes in marrow and bone metabolic function in local and distant skeletal sites in response to focused radiation injury. Distinct local and remote changes may be affected by several cytokines activated early after local radiation exposure. This approach has the potential for longer term studies to clarify the effects of radiation on marrow and bone.
doi:10.1007/s00223-014-9839-6
PMCID: PMC3987955  PMID: 24562595
translational research; radiotherapy; micro-PET/CT; bone
23.  Three-Times-Weekly Administration of Teriparatide Improves Vertebral and Peripheral Bone Density, Microarchitecture, and Mechanical Properties Without Accelerating Bone Resorption in Ovariectomized Rats 
Calcified Tissue International  2015;97(2):156-168.
Daily and weekly administration of teriparatide (PTH1–34) reduces the risk of osteoporotic bone fractures. However, their effects on markers of bone formation and bone resorption differ. These results indicate that the dosing frequency of teriparatide may affect bone metabolism and bone structure, with different effects on bone strength. In the present study, to evaluate the dose-related effects of a low administration frequency of teriparatide on bone status, we investigated the effects of three-times-weekly administration of teriparatide (1.1, 5.6, or 28.2 µg/kg) for 12 months on bone parameters, including bone metabolism markers, bone mineral density (BMD), micro-computed tomography, and bone strength, using 6-month-old ovariectomized (OVX) rats. Three-times-weekly administration of teriparatide dose-dependently increased the BMD of the lumbar vertebra and femur in OVX rats, and increased serum osteocalcin (a marker of bone formation), but not type I collagen C-telopeptide (a marker of bone resorption). The trabecular number and thickness increased in the vertebrae and femur, as in prior reports of daily teriparatide administration in OVX rats. Cortical thickness increased only toward the endocortical side of the femur, unlike with daily administration. Bone strength of the vertebrae and proximal and shaft of the femur was correlated with the changes in BMD and bone structure. These results demonstrate the effects of low frequency, intermittent administration of teriparatide on the biomechanical, and microstructural properties of bone in OVX rats.
Electronic supplementary material
The online version of this article (doi:10.1007/s00223-015-9998-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00223-015-9998-0
PMCID: PMC4491365  PMID: 25911187
Teriparatide; Three-times-weekly; Bone metabolism; Mechanical strength; Micro-computed tomography
24.  Application of Structural Rigidity Analysis to Assess Fidelity of Healed Fractures in Rat Femurs with Critical Defects 
Calcified tissue international  2010;86(5):397-403.
Approximately 6 million fractures occur each year in the United States, with an estimated medical and loss of productivity cost of $99 billion. As our population ages, it can only be expected that these numbers will continue to rise. While there have been recent advances in available treatments for fractures, assessment of the healing process remains a subjective process. This study aims to demonstrate the use of micro-computed tomography (μCT)-based structural rigidity analysis to accurately and quantitatively assess the progression of fracture healing over time in a rat model. The femora of rats with simulated lytic defects were injected with human BMP-2 cDNA at various time points postinjury (t = 0, 1, 5, 10 days) to accelerate fracture healing, harvested 56 days from time of injury, and subjected to μCT imaging to obtain cross-sectional data that were used to compute torsional rigidity. The specimens then underwent torsional testing to failure using a previously described pure torsional testing system. Strong correlations were found between measured torsional rigidity and computed torsional rigidity as calculated from both average (R2 = 0.63) and minimum (R2 = 0.81) structural rigidity data. While both methods were well correlated across the entire data range, minimum torsional rigidity was a better descriptor of bone strength, as seen by a higher Pearson coefficient and smaller y-intercept. These findings suggest considerable promise in the use of structural rigidity analysis of μCT data to accurately and quantitatively measure fracture-healing progression.
doi:10.1007/s00223-010-9353-4
PMCID: PMC4405879  PMID: 20354683
Fracture healing; Healing strength; Structural rigidity analysis; Segmental defect; Rat model
25.  Bone Fracture Risk is Not Associated with the Use of Glucagon-Like Peptide-1 Receptor Agonists: A Population-Based Cohort Analysis 
Calcified Tissue International  2015;97(2):104-112.
Glucagon-like Peptide-1 receptor agonists (GLP1-ra) are a relatively new class of anti-hyperglycemic drugs which may positively affect bone metabolism and thereby decrease (osteoporotic) bone fracture risk. Data on the effect of GLP1-ra on fracture risk are scarce and limited to clinical trial data only. The aim of this study was to investigate, in a population-based cohort, the association between the use of GLP1-ra and bone fracture risk. We conducted a population-based cohort study, with the use of data from the Clinical Practice Research Datalink (CPRD) database (2007–2012). The study population (N = 216,816) consisted of all individuals with type 2 diabetes patients with at least one prescription for a non-insulin anti-diabetic drug and were over 18 years of age. Cox proportional hazards models were used to estimate the hazard ratio of fracture in GLP1-ra users versus never-GLP1-ra users. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and the use of other drugs. There was no decreased risk of fracture with current use of GLP1-ra compared to never-GLP1-ra use (adjusted HR 0.99, 95 % CI 0.82–1.19). Osteoporotic fracture risk was also not decreased by current GLP1-ra use (adjusted HR 0.97; 95 % CI 0.72–1.32). In addition, stratification according to cumulative dose did not show a decreased bone fracture risk with increasing cumulative GLP1-ra dose. We showed in a population-based cohort study that GLP1-ra use is not associated with a decreased bone fracture risk compared to users of other anti-hyperglycemic drugs. Future research is needed to elucidate the potential working mechanisms of GLP1-ra on bone.
doi:10.1007/s00223-015-9993-5
PMCID: PMC4491344  PMID: 25894068
GLP1-ra; Fracture; Diabetes mellitus type 2; Cohort study; CPRD

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