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1.  Incident symptomatic hip osteoarthritis is associated with differences in hip shape by active shape modeling 
Arthritis care & research  2014;66(1):74-81.
To investigate hip shape by active shape modeling (ASM) as a potential predictor of incident radiographic and symptomatic hip OA (rHOA and srHOA).
All hips developing rHOA from baseline (Kellgren-Lawrence [KL] grade 0/1) to mean 6 year follow up (KL ≥2, 190 hips), and 1:1 control hips (KLG 0/1 at both times, 192 hips) were included. Proximal femur shape was defined on baseline AP pelvis radiographs and submitted to ASM, producing a mean shape and continuous variables representing independent modes of shape variation. Mode scores (n=14, explaining 95% of shape variance) were simultaneously included in logistic regression models, with incident rHOA and srHOA as dependent variables, adjusted for intra-person correlations, sex, race, body mass index (BMI), baseline KL and/or symptoms.
We evaluated 382 hips from 342 individuals: 61% women, 83% white, with mean age 62 years and BMI 29 kg/m2. Several modes differed by sex and race, but no modes were associated with incident rHOA overall. Among men only, modes 1 and 2 were significantly associated (for a 1-SD decrease in mode 1 score, OR 1.7 [95% CI 1.1, 2.5], and for a 1-SD increase in mode 2 score, OR 1.5 [95% CI 1.0, 2.2]) with incident rHOA. A 1-SD decrease in mode 2 or 3 score increased the odds of srHOA by 50%.
This study confirms other reports that variations in proximal femur shape have a modest association with incident hip OA. The observation of proximal femur shape associations with hip symptoms requires further investigation.
PMCID: PMC3959908  PMID: 23926053
2.  Glucocorticoids and Osteocyte Autophagy 
Bone  2013;54(2):279-284.
Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk is high. While previous studies have found GC effects on both osteoclasts and oteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis. This paper will review the data to support the role of GCs in osteocyte autophagy.
PMCID: PMC3784314  PMID: 23356984
Glucocorticoids; autophagy; bone fragility
3.  The association of parity with osteoarthritis and knee replacement in the Multicenter Osteoarthritis Study 
We evaluated the association of parity to both risk of knee replacement (KR) and knee osteoarthritis (OA).
The NIH-funded Multicenter Osteoarthritis Study (MOST) is a longitudinal observational study of persons age 50 to 79 years with either symptomatic knee OA or at elevated risk of disease. Baseline and 30-month knee radiographic OA (ROA) was defined as Kellgren/Lawrence (K/L) grade≥2 or KR. Women were grouped based by number of births: 0; 1 (reference group); 2; 3; 4; and 5 or more. We examined the relation of parity to the incidence over 30 months of ROA and KR using a Poisson regression model. Generalized estimating equations were used to control for correlation between two knees within a subject. We adjusted for age, BMI, race, education, occupation, baseline estrogen use, clinical site, injury, and for KR analyses WOMAC pain and use of pain medication.
Among 1618 women who reported parity information, mean age was 62.6 years, mean BMI 30.7 kg/m2, mean WOMAC pain subscale score 3.7 at baseline. There were 115 KRs and 134 cases of incident knee ROA over 30 months. The relative risk of incident KR was 2.7 times as high (95% CI: 1.0, 7.3) and relative risk of incident knee ROA was 2.6 times as high (95% CI: 1.2, 5.3) among women with 5–12 children compared with those with one birth.
Parity in women at risk for OA is associated with both incident ROA and KR, particularly for those with more than 4 children.
PMCID: PMC3855897  PMID: 24029601
parity; knee; osteoarthritis; joint replacement
4.  Targeting the Wnt Signaling Pathway to Augment Bone Formation 
Current osteoporosis reports  2008;6(4):142-148.
Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and post-natal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists.
PMCID: PMC3891875  PMID: 19032924
5.  Glucocorticoid Excess in Mice Results in Early Activation of Osteoclastogenesis and Adipogenesis and Prolonged Suppression of Osteogenesis 
Arthritis and rheumatism  2008;58(6):1674-1686.
Glucocorticoid (GC) excess induces alterations in bone metabolism that weaken bone structure and increase fracture risk. The aim of this study was to identify genes associated with bone metabolism in GC-treated mice, by performing a microarray analysis.
Long bones from mice exposed to GC excess were collected after 0, 7, 28, and 56 days of treatment, to measure bone microarchitecture and extract RNA for microarray analyses.
Bone loss in this animal model was confirmed by changes in bone turnover markers as well as bone architecture, as measured by microfocal computed tomography. GC excess induced an early up-regulation of genes involved in osteoclast activation, function, and adipogenesis, which peaked on day 7. The expression of genes associated with osteoclast cytoskeletal reorganization and genes associated with matrix degradation peaked on day 28. On day 28 and day 56, the expression of genes associated with osteoblast activation and maturation was decreased from baseline, while the expression of Wnt antagonists was increased. In addition, the expression of genes expressed in osteocytes associated with bone mineralization was significantly higher at the later time points, day 28 and day 56. Reverse transcription–polymerase chain reaction confirmed the results of microarray analysis in selected genes.
GC excess is associated with early activation of genes associated with osteoclastogenesis and adipogenesis and a later suppression of genes associated with osteogenesis and mineralization. Novel interventions with agents that modulate either Wnt signaling or mineralization may be effective in GC-induced osteoporosis.
PMCID: PMC3892702  PMID: 18512788
6.  The Degree of Bone Mineralization is Maintained with Single Intravenous Bisphosphonates in Aged Estrogen Deficient Rats and is a Strong Predictor of Bone Strength 
Bone  2007;41(5):10.1016/j.bone.2007.06.021.
The treatment of osteoporotic women with bisphosphonates significantly reduces the incidence of bone fractures to a degree greater than can be explained by an increase in bone mineral density. In this Study, 18 month Fischer 344 rats were ovariectomized and treated with a single dose of risedronate (intravenous, iv, 500μg), zoledronic acid (iv, 100μg) or continuous raloxifene (2mg/kg, po., 3x/wk). High resolution microCT was used to measure lumbar vertebral bone microarchitecture, the degree of bone mineralization (DBM) and the distribution of mineral. Small angle x-ray scattering was used to investigate mineral crystallinity. We found prolonged estrogen deficiency, reduced trabecular bone volume, and increased micro architecture bone compression strength. lowered the degree of mineralization. Treatment with resorptive agents (bisphosphonates > raloxifene) prevented the loss of mineralization, trabecular bone volume and bone compression strength. Crystal size was not changed with OVX or with anti-resorptive treatments. In conclusion, in the aged estrogen deficient rat model, single intravenous doses of two bisphosphonates were effective in maintaining the compressive bone strength for 180 days by reducing bone turnover, and maintaining the DBM to a greater degree than with raloxifene.
PMCID: PMC3883569  PMID: 17825637
intravenous bisphosphonates; bone mineralization; compression strength; rat; OVX
7.  Prolonged Alendronate Treatment Prevents The Decline In Serum TGF-β1 Levels And Reduces Cortical Bone Strength In Long-Term Estrogen Deficiency Rat Model 
Bone  2012;52(1):424-432.
While the anti-resorptive effects of the bisphosphonates (BPs) are well documented, many questions remain about their mechanisms of action, particularly following long-term use. This study evaluated the effects of alendronate (Ale) treatment on TGF-β1 signaling in mesenchymal stem cells (MSCs) and osteocytes, and the relationship between prolonged alendronate treatment on systemic TGF-β1 levels and bone strength.
TGF-β1 expression and signaling were evaluated in MSCs and osteocytic MLO-Y4 cells following Ale treatment. Serum total TGF-β1 levels, a bone resorption marker (DPD/Cr), three-dimensional microCT scans and biomechanical tests from both the trabecular and cortical bone were measured in ovariectomized rats that either received continuous Ale treatment for 360 days or Ale treatment for 120 days followed by 240 days of vehicle. Linear regression tests were performed to determine the association of serum total TGF-β1 levels and both the trabecular (vertebrae) and cortical (tibiae) bone strength.
Ale increased TGF- β1 signaling in the MSCs but not in the MLO-Y4 cells. Ale treatment increased serum TGF-β1 levels and the numbers of TGF-β1-positive osteocytes and periosteal cells in cortical bone. Serum TGF-β1 levels were not associated with vertebral maximum load and strength but was negatively associated with cortical bone maximum load and ultimate strength.
The increase of serum TGF-β1 levels during acute phase of estrogen deficiency is likely due to increased osteoclast-mediated release of matrix-derived latent TGF- β1. Long-term estrogen-deficiency generally results in a decline in serum TGF-β1 levels that are maintained by Ale treatment. Measuring serum total TGF-β1 levels may help to determine cortical bone quality following alendronate treatment.
PMCID: PMC3804116  PMID: 23088940
Alendronate; TGF- β1; cortical bone; bone quality
8.  Subchondral Bone Trabecular Integrity Predicts and Changes Concurrently with Radiographic and MRI Determined Knee Osteoarthritis Progression 
Arthritis and rheumatism  2013;65(7):1812-1821.
To evaluate subchondral bone trabecular integrity (BTI) from a radiograph as a predictor of knee osteoarthritis (OA) progression.
Longitudinal (baseline, 12- and 24-month) knee radiographs were available from 60 female subjects with knee OA. OA progression was defined by 12- and 24-month change in radiographic medial compartment minimal joint space width (JSW) and medial joint space area (JSA), and medial tibial and femoral cartilage volume from magnetic resonance imaging. Bone Trabecular Integrity (BTI) of the medial tibial plateau was analyzed by fractal signature analysis with a commercially available software. Receiver Operating Characteristic curves of BTI were used to predict 5% change in OA progression parameters.
Individual terms (linear and quadratic) of baseline BTI of vertical trabeculae predicted knee OA progression based on 12- and 24-month change in JSA (p<0.01 for 24 months), 24-month change in tibial (p<0.05) but not femoral cartilage volume, and 24-month change in JSW (p=0.05). ROC utilizing both terms of baseline BTI predicted 5% change in the OA progression parameters over 24 months with high accuracy as reflected by the area under the curve (AUC) measures: JSW 81%, JSA 85%, tibial 75% and femoral 85% cartilage volume. Change in BTI was also significantly associated (p<0.05) with concurrent change in JSA over 12 and 24 months and change in tibial cartilage volume over 24 months.
BTI predicts structural OA progression as determined by radiographic and MRI outcomes. BTI may therefore be worthy of study as an outcome measure for OA studies and clinical trials.
PMCID: PMC4152231  PMID: 23576116
9.  Kyphosis and Decline in Physical Function Over 15 Years in Older Community-Dwelling Women: The Study of Osteoporotic Fractures 
Maintaining physical function is an important prerequisite for preserving independence in later life. Greater degrees of kyphosis in the thoracic spine are prevalent in older persons and accompanied by reduced physical function in multiple cross-sectional studies. It is unknown whether kyphosis predicts worse physical function over time.
We retrospectively assessed whether greater magnitude of kyphosis is associated with decline in self-reported and objectively measured physical function over 15 years. Digitized Cobb angle kyphosis (T4–T12) was derived from supine lateral thoracic spine radiographs in a cohort of 1,196 women aged 65 and older (mean = 69.3 years [SD = 4.0]). Using regression models, we evaluated associations of baseline kyphosis with both self-reported functional status and objectively measured gait speed, grip strength, and timed chair stands cross-sectionally and as change assessed over 15 years.
In cross-sectional multivariate analyses, with each 10-degree increment of kyphosis, grip strength was 0.24kg lower (p = .02), but there were no significant associations between kyphosis and functional status, gait speed, or timed chair stand, likely reflecting the high functioning study participants. In multivariate longitudinal analysis, with each 10-degree increment in baseline kyphosis, there was 0.07 point additional decline in functional status (p = .09), 0.01 m/s more decline in gait speed (p = .07), and 0.32 s greater decline in time to complete five chair stands (p = .004), but no association with decline in grip strength.
Greater magnitude of kyphosis may predict worsening lower extremity function over time in older women. Early recognition and preventative measures against kyphosis progression may help preserve physical function over the long term.
PMCID: PMC3712361  PMID: 23633167
Normative aging; Physical function; Imaging
10.  Variant Alleles of the WNT Antagonist FRZB Are Determinants of Hip Shape and Modify the Relationship between Hip Shape and Osteoarthritis 
Arthritis and Rheumatism  2012;64(5):1457-1465.
(1) To test whether single nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape. (2) To determine whether FRZB variant alleles affect the relationship between hip shape and radiographic hip osteoarthritis (RHOA).
A nested case-control study of Caucasian women aged ≥ 65 years in the Study of Osteoporotic Fractures (SOF) was performed. Cases (n = 451) demonstrated incident RHOA during follow-up (mean 8.0 ± 0.4 years). Controls (n = 601) had no RHOA at baseline or follow-up. Statistical shape modeling (SSM) of digitized hip radiographs was used to assess proximal femur shape, and center-edge angle and acetabular depth were used to assess acetabular shape. The association of the rs288326 and rs7775 FRZB variant alleles with hip shape was analyzed using linear regression. The effect of these alleles on the relationship between hip shape and RHOA was analyzed using logistic regression with and without interaction terms.
The rs288326 and rs7775 alleles were associated with shape of the proximal femur (SSM Mode 2). There was a significant interaction between the rs288326 SNP and proximal femur shape (Mode 2) in predicting RHOA (p for interaction = 0.022). Among subjects with the rs288326 variant allele, there were increasing odds of RHOA with increasing quartiles of proximal femur shape Mode 2 (OR for 4th quartile of Mode 2 = 2.5, 95% confidence interval 1.2–5.3; p for linear trend = 0.02).
The rs288326 and rs7775 FRZB SNPs are associated with the shape of the proximal femur. The presence of the rs288326 SNP alters the relationship between proximal femur shape and incident RHOA. Together, these findings suggest that FRZB may serve an important role in determining hip shape and may modify the relationship between hip shape and OA.
PMCID: PMC3340442  PMID: 22544526
FRZB; WNT pathway; osteoarthritis; joint shape; active shape modeling; bone
11.  Global point signature for shape analysis of carpal bones 
Physics in medicine and biology  2014;59(4):961-973.
We present a method based on spectral theory for the shape analysis of carpal bones of the human wrist. We represent the cortical surface of the carpal bone in a coordinate system based on the eigensystem of the two-dimensional Helmholtz equation. We employ a metric—global point signature (GPS)—that exploits the scale and isometric invariance of eigenfunctions to quantify overall bone shape. We use a fast finite-element-method to compute the GPS metric. We capitalize upon the properties of GPS representation—such as stability, a standard Euclidean (ℓ2) metric definition, and invariance to scaling, translation and rotation—to perform shape analysis of the carpal bones of ten women and ten men from a publicly-available database. We demonstrate the utility of the proposed GPS representation to provide a means for comparing shapes of the carpal bones across populations.
PMCID: PMC3966902  PMID: 24503490
carpal bone; shape comparison; global point signature; morphometry; eigenfunctions; wrist
12.  Osteoporosis: yesterday, today and tomorrow 
Rheumatology (Oxford, England)  2011;50(7):1181-1183.
PMCID: PMC3116213  PMID: 21680613
13.  Differential Maintenance of Cortical and Cancellous Bone Strength Following Discontinuation of Bone-Active Agents 
Osteoporotic patients treated with antiresorptive or anabolic agents experience an increase in bone mass and a reduction in incident fractures. However, the effects of these medications on bone quality and strength after a prolonged discontinuation of treatment are not known. We evaluated these effects in an osteoporotic rat model. Six-month-old ovariectomized (OVX) rats were treated with placebo, alendronate (ALN, 2 µg/kg), parathyroid hormone [PTH(1–34); 20 µg/kg], or raloxifene (RAL, 2 mg/kg) three times a week for 4 months and withdrawn from the treatments for 8 months. Treatment with ALN, PTH, and RAL increased the vertebral trabecular bone volume (BV/TV) by 47%, 53%, and 31%, with corresponding increases in vertebral compression load by 27%, 51%, and 31%, respectively (p < .001). The resulting bone strength was similar to that of the sham-OVX control group with ALN and RAL and higher (p < .001) with PTH treatment. After 4 months of withdrawal, bone turnover (BFR/BS) remained suppressed in the ALN group versus the OVX controls (p < .001). The vertebral strength was higher than in the OVX group only in ALN-treated group (p < .05), whereas only the PTH-treated animals showed a higher maximum load in tibial bending versus the OVX controls (p < .05). The vertebral BV/TV returned to the OVX group level in both the PTH and RAL groups 4 months after withdrawal but remained 25% higher than the OVX controls up to 8 months after withdrawal of ALN (p < .05). Interestingly, cortical bone mineral density increased only with PTH treatment (p < .05) but was not different among the experimental groups after withdrawal. At 8 months after treatment withdrawal, none of the treatment groups was different from the OVX control group for cortical or cancellous bone strength. In summary, both ALN and PTH maintained bone strength (maximum load) 4 months after discontinuation of treatment despite changes in bone mass and bone turnover; however, PTH maintained cortical bone strength, whereas ALN maintained cancellous bone strength. Additional studies on the long-term effects on bone strength after discontinuation and with combination of osteoporosis medications are needed to improve our treatment of osteoporosis. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179292  PMID: 20839286
14.  Active Shape Modeling of the Hip in the Prediction of Incident Hip Fracture 
The objective of this study was to evaluate right proximal femur shape as a risk factor for incident hip fracture using active shape modeling (ASM). A nested case-control study of white women 65 years of age and older enrolled in the Study of Osteoporotic Fractures (SOF) was performed. Subjects (n = 168) were randomly selected from study participants who experienced hip fracture during the follow-up period (mean 8.3 years). Controls (n = 231) had no fracture during follow-up. Subjects with baseline radiographic hip osteoarthritis were excluded. ASM of digitized right hip radiographs generated 10 independent modes of variation in proximal femur shape that together accounted for 95% of the variance in proximal femur shape. The association of ASM modes with incident hip fracture was analyzed by logistic regression. Together, the 10 ASM modes demonstrated good discrimination of incident hip fracture. In models controlling for age and body mass index (BMI), the area under receiver operating characteristic (AUROC) curve for hip shape was 0.813, 95% confidence interval (CI) 0.771–0.854 compared with models containing femoral neck bone mineral density (AUROC = 0.675, 95% CI 0.620–0.730), intertrochanteric bone mineral density (AUROC = 0.645, 95% CI 0.589–0.701), femoral neck length (AUROC = 0.631, 95% CI 0.573–0.690), or femoral neck width (AUROC = 0.633, 95% CI 0.574–0.691). The accuracy of fracture discrimination was improved by combining ASM modes with femoral neck bone mineral density (AUROC = 0.835, 95% CI 0.795–0.875) or with intertrochanteric bone mineral density (AUROC = 0.834, 95% CI 0.794–0.875). Hips with positive standard deviations of ASM mode 4 had the highest risk of incident hip fracture (odds ratio = 2.48, 95% CI 1.68–3.31, p < .001). We conclude that variations in the relative size of the femoral head and neck are important determinants of incident hip fracture. The addition of hip shape to fracture-prediction tools may improve the risk assessment for osteoporotic hip fractures. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179295  PMID: 20878772
15.  IL-23 Is Critical for Induction of Arthritis, Osteoclast Formation, and Maintenance of Bone Mass 
The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4+ T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23–induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19−/− mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19−/− mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides. The Journal of Immunology, 2011, 187: 951–959.
PMCID: PMC3896980  PMID: 21670317
16.  Kyphosis and paraspinal muscle composition in older men: a cross-sectional study for the osteoporotic fractures in men (MrOS) research group 
The prevalence of hyperkyphosis is increased in older men; however, risk factors other than age and vertebral fractures are not well established. We previously reported that poor paraspinal muscle composition contributes to more severe kyphosis in a cohort of both older men and women.
To specifically evaluate this association in older men, we conducted a cross-sectional study to evaluate the association of paraspinal muscle composition and degree of thoracic kyphosis in an analytic cohort of 475 randomly selected participants from the Osteoporotic Fractures in Men (MrOS) study with baseline abdominal quantitative computed tomography (QCT) scans and plain thoracic radiographs. Baseline abdominal QCT scans were used to obtain abdominal body composition measurements of paraspinal muscle and adipose tissue distribution. Supine lateral spine radiographs were used to measure Cobb angle of kyphosis. We examined the linear association of muscle volume, fat volume and kyphosis using loess plots. Multivariate linear models were used to investigate the association between muscle and kyphosis using total muscle volume, as well as individual components of the total muscle volume, including adipose and muscle compartments alone, controlling for age, height, vertebral fractures, and total hip bone mineral density (BMD). We examined these associations among those with no prevalent vertebral fracture and those with BMI < 30 kg/m2.
Among men in the analytic cohort, means (SD) were 74 (SD = 5.9) years for age, and 37.5 (SD = 11.9) degrees for Cobb angle of kyphosis. Men in the lowest tertile of total paraspinal muscle volume had greater mean Cobb angle than men in the highest tertile, although test of linear trend across tertiles did not reach statistical significance. Neither lower paraspinal skeletal muscle volume (p-trend = 0.08), or IMAT (p-trend = 0.96) was associated with greater kyphosis. Results were similar among those with no prevalent vertebral fractures. However, among men with BMI < 30 kg/m2, those in the lowest tertile of paraspinal muscle volume had greater adjusted mean kyphosis (40.0, 95% CI: 37.8 – 42.1) compared to the highest tertile (36.3, 95% CI: 34.2 – 38.4).
These results suggest that differences in body composition may potentially influence kyphosis.
PMCID: PMC4029749  PMID: 24428860
Kyphosis; Hyperkyphosis; Spinal muscle composition; Vertebral fractures; BMI
17.  Common mistakes in the clinical use of bone mineral density testing 
Bone mineral density (BMD) testing is used to diagnose osteoporosis, assess fracture risk and monitor changes in BMD over time. A variety of devices and technologies are used to measure BMD or other surrogate markers of bone strength. Measurements obtained with these devices are often reported according to different proprietary standards, and the comparability of values obtained with different instruments is often poor. In addition, there is a high degree of variability in the skills of the technologists performing the tests and the clinicians interpreting the results. Heterogeneity in the guidelines for using BMD measurements together with poor-quality BMD testing and reporting can result in inappropriate clinical decisions, causing unnecessary worry and expense for the patient and possible harm due to unnecessary treatment or treatment being withheld. This Review describes and discusses the mistakes commonly made in BMD testing, and emphasizes the importance of maintaining high-quality standards in order to optimize patient management.
PMCID: PMC3891842  PMID: 18936788
BMD; diagnosis; DXA; osteoporosis; pitfalls
18.  Higher Doses of Bisphosphonates Further Improve Bone Mass, Architecture, and Strength but Not the Tissue Material Properties in Aged Rats 
Bone  2009;46(5):1267-1274.
We report the results of a series of experiments designed to determine the effects of ibandronate (Ibn) and risedronate (Ris) on a number of bone quality parameters in aged osteopenic rats to explain how bone material and bone mass may be affected by the dose of bisphosphonates (BP) and contribute to their anti-fracture efficacy.
Eighteen-month old female rats underwent either ovariectomy or sham surgery. The ovariectomized (OVX) groups were left untreated for 2 months to develop osteopenia. Treatments started at 20 months of age as follows: sham and OVX control (treated with saline), OVX+risedronate 30 and 90 (30 or 90 μg/kg/dose), and OVX+ibandronate 30 and 90 (30 or 90 μg/kg/dose). The treatments were given monthly for four months by subcutaneous injection. At sacrifice at 24 months of age the 4th lumbar vertebra was used for μCT scans (bone mass, architecture, and degree of mineralization of bone, DMB) and histomorphometry, and the 6th lumbar vertebra, tibia, and femur were collected for biomechanical testing to determine bone structural and material strength, cortical fracture toughness, and tissue elastic modulus. The compression testing of the vertebral bodies (LVB6) was simulated using finite-element analysis (FEA) to also estimate the bone structural stiffness.
Both Ibn and Ris dose-dependently increased bone mass and improved vertebral bone microarchitecture and mechanical properties compared to OVX control. Estimates of vertebral maximum stress from FEA were correlated with vertebral maximum load (r=0.5, p<0.001) and maximum stress (r=0.4, p<0.005) measured experimentally. Tibial bone bending modulus and cortical strength increased compared to OVX with both BP but no dose-dependent effect was observed. DMB and elastic modulus of trabecular bone were improved with Ibn30 compared to OVX but were not affected in other BP-treated groups. DMB of tibial cortical bone showed no change with BP treatments. The fracture toughness examined in midshaft femurs did not change with BP even with the higher doses. In summary, the anti fracture efficacy of BP is largely due to their preservation of bone mass and while the higher doses further improve the bone structural properties do not improve the localized bone material characteristics such as tissue strength, elastic modulus, and cortical toughness.
PMCID: PMC3003226  PMID: 19931661
bisphosphonate; bisphosphonate dose; structural properties; material properties; bone mineralization
Stem cells (Dayton, Ohio)  2013;31(9):2003-2014.
Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs’ commitment, growth and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated α4β1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone. Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging.
PMCID: PMC3795809  PMID: 23818248
20.  Defining Incident Radiographic Hip Osteoarthritis for Epidemiologic Studies in Women 
Arthritis and rheumatism  2009;60(4):1052-1059.
To evaluate definitions of radiographic hip osteoarthritis (RHOA) for use in longitudinal epidemiologic studies of disease incidence in women.
We studied 5,839 women from the Study of Osteoporotic Fractures who had had serial pelvic radiographs obtained (mean of 8.3 years apart) and who were followed up (mean followup 7.1 years from the time of the second radiograph) for evaluation of clinical outcomes. Definitions of RHOA were assessed for construct validity (association with symptoms and signs at the time of the second radiograph) and predictive validity (association with total hip replacement [THR] and signs and symptoms a mean of 7.1 years later). Odds ratios (ORs) and 95% confidence intervals were calculated to assess the strength of association using logistic regression.
The cumulative incidence of RHOA ranged from 2.2% to 11.7%. All definitions displayed significant construct validity; the most consistent was found for composite definitions that required the concurrent presence of 2 or more individual radiographic features and definitions based on stringent criteria for joint space narrowing. All definitions except minimum joint space ≤2.5 mm displayed consistent predictive validity. Composite definitions had the strongest associations with THR (OR 10.5–18.5) and hip pain (OR 2.6–2.9). The hips identified as having OA by each definition varied, with especially small overlap between findings using definitions based on osteophytes and those using definitions based on joint space narrowing alone.
Most definitions of incident RHOA display good construct and predictive validity. Composite definitions have the best overall performance, and definitions requiring the presence of both osteophytes (in particular, femoral osteophytes) and joint space narrowing would be recommended for most epidemiologic and genetic studies.
PMCID: PMC3777428  PMID: 19333950
21.  Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass 
Nature medicine  2012;18(3):456-462.
Aging reduces the number of mesenchymal stem cells (MSCs) in the bone marrow which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct the MSCs to the bone surface by attaching a synthetic high affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface, to a bisphosphonate (alendronate, Ale) that has high affinity for bone. LLP2A-Ale increased MSCs migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation and immune competent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or following estrogen deficiency. These results provide a proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.
PMCID: PMC3755884  PMID: 22306732
22.  Prolonged Treatments With Antiresorptive Agents and PTH Have Different Effects on Bone Strength and the Degree of Mineralization in Old Estrogen-Deficient Osteoporotic Rats 
Current approved medical treatments for osteoporosis reduce fracture risk to a greater degree than predicted from change in BMD in women with postmenopausal osteoporosis. We hypothesize that bone active agents improve bone strength in osteoporotic bone by altering different material properties of the bone. Eighteen-month-old female Fischer rats were ovariectomized (OVX) or sham-operated and left untreated for 60 days to induce osteopenia before they were treated with single doses of either risedronate (500 μg/kg, IV), zoledronic acid (100 μg/kg, IV), raloxifene (2 mg/kg, PO, three times per week), hPTH(1-34) (25 μg/kg, SC, three times per week), or vehicle (NS; 1 ml/kg, three times per week). Groups of animals were killed after days 60 and 180 of treatment, and either the proximal tibial metaphysis or lumbar vertebral body were studied. Bone volume and architecture were assessed by μCT and histomorphometry. Measurements of bone quality included the degree of bone mineralization (DBM), localized elastic modulus, bone turnover by histomorphometry, compression testing of the LVB, and three-point bending testing of the femur. The trabecular bone volume, DBM, elastic modulus, and compressive bone strength were all significantly lower at day 60 post-OVX (pretreatment, day 0 study) than at baseline. After 60 days of all of the bone active treatments, bone mass and material measurements agent were restored. However, after 180 days of treatment, the OVX + PTH group further increased BV/TV (+30% from day 60, p < 0.05 within group and between groups). In addition, after 180 days of treatment, there was more highly mineralized cortical and trabecular bone and increased cortical bone size and whole bone strength in OVX + PTH compared with other OVX + antiresorptives. Treatment of estrogen-deficient aged rats with either antiresorptive agents or PTH rapidly improved many aspects of bone quality including microarchitecture, bone mineralization, turnover, and bone strength. However, prolonged treatment for 180 days with PTH resulted in additional gains in bone quality and bone strength, suggesting that the maximal gains in bone strength in cortical and trabecular bone sites may require a longer treatment period with PTH.
PMCID: PMC3276355  PMID: 18847326
PTH(1-34); intravenous bisphosphonates; bone mineralization; compression and bending strengths; bone mineral homogeneity
23.  Glucocorticoid-induced bone loss can be reversed by the actions of PTH and Risedronate on different pathways for bone formation and mineralization 
Arthritis and rheumatism  2008;58(11):3485-3497.
Glucocorticoid (GC) excess decreases bone mineralization and microarchitecture and lead to reduced bone strength. Both anabolic (PTH) and anti-resorptive agents are used to prevent and treat GC-induced bone loss, yet these bone active agents alter bone turnover by very different mechanisms. Our study objective was to determine how PTH and risedronate (Ris) alter bone quality following GC excess. Five-month-old Swiss-Webster male mice were treated with the glucocorticoid (GC) prednisolone (5 mg/kg 60-day slow-release pellet) or placebo (PL)]. At day 28−56, two groups of GC-treated animals had either PTH (5μg/kg, 5x/wk) or Ris (5μg/kg, 5x/wk) intervention. Bone quality and quantity measurements include x-ray tomography microscopy (XTM) for the degree of bone mineralization (DBM), microCT for bone microarchitecture, compression testing for trabecular bone strength, biochemistry and histomorphometry for bone turnover. In addition, real-time PCR and immunohistochemistry were performed to monitor the expression of several key genes regulating Wnt signaling (bone formation) and mineralization.
Compared to the placebo treated mice, GC treatment decreased trabecular bone volume (BV/TV) and serum osteocalcin, but increased serum CTX and osteoclast surface with a peak at day 28. GC+PTH increased and GC+Ris restored BV/TV to the PL levels after a 28 day treatment period. Average DBM was lowered after GC treatment (−27%), and it was restored to PL level with GC+Ris and GC+PTH. At day 56, RT-PCR revealed that continuous exposure to GC and GC+PTH increased, while GC+Ris decreased the expression of genes that inhibit bone mineralization (Dmp1 and Phex), compared to the PL group. Wnt signaling antagonists Dkk1, Sost and Wif1 were up-regulated by GC treatment but were down-regulated after GC+PTH treatment. Immunohistochemistry of bone sections found GC increased N terminal dmp-1 while PTH treatment increased both N and C terminal dmp-1 staining around osteocytes.
GC excess reduced expression of genes that regulate mineralization and increased expression of genes that inhibit Wnt signaling which were associated with reduced bone formation and bone volume over a 60 day treatment period. The addition of both PTH and Ris improved bone mass, DBM and bone strength during concurrent GC treatment, with PTH lowering expression of Wnt inhibitors and increasing bone formation; while Ris lowered the expression of mineralization inhibitors and reversed the deterioration of bone mineralization induced by GC excess.
PMCID: PMC2597521  PMID: 18975341
Glucocorticoid; bone mineralization; risedronate; PTH; gene
24.  Role of Bone Architecture and Anatomy in Osteoarthritis 
Bone  2012;51(2):197-203.
When considering the pathogenesis of osteoarthritis (OA), it is important to review the contribution of bone in addition to the contribution of cartilage and synovium. Although bone clearly plays a role in determining the distribution of biomechanical forces across joints, which in turn plays a role in the initiation of OA, it has also more recently been appreciated that bone may contribute in a biological sense to the pathogenesis of OA. Far from being a static structure, bone is a dynamic tissue undergoing constant remodeling, and it is clear from a number of radiographic and biochemical studies that bone and cartilage degradation occur hand in hand. Whether the initial instigating event in OA occurs in cartilage or bone is not known, but it is clear that bony changes occur very early in the pathogenesis of OA and often predate radiographic appearance of the disease. This review focuses on the structural variants of both hip and knee that have been associated with OA and the ultrastructural bone changes in these sites occurring in early OA pathogenesis.
PMCID: PMC3372683  PMID: 22401752
25.  Hip Pain while using lower extremity joints is associated with sleep disturbances in elderly Caucasian women: the Study of Osteoporotic Fractures 
Arthritis care & research  2012;64(7):1070-1078.
To evaluate sleep quality in women with hip pain due to daily activities involving the lower extremity joints.
We evaluated the association of the the Western Ontario MacMaster Osteoarthritis Index (WOMAC) hip pain severity score, with objective sleep measures, obtained by wrist actigraphy, in 2225 Caucasian women ≥ 65 years from the Study of Osteoporotic fractures study.
Women had an increased odds of spending ≥1.5 hours awake after sleep onset (WASO) (OR: 1.28, 95% CI: 1.11–1.50) for every 5 units increase in hip pain score after adjustment for all covariates. Resting hip pain was the strongest predictor of sleep fragmentation (OR: 2.0, 95%CI 1.47–2.73), however standing pain was associated with higher WASO independent of pain while in bed (OR: 1.41, 95% CI: 1.07–2.01). Sleep disturbances increased significantly after the first two hours of sleep in women with severe hip pain compared to those without hip pain (1.4 ± 0.47 minutes per hour sleep p=<0.003). Similar associations were observed for long wake episodes greater than 5 minutes. There were no associations with daytime napping, sleep latency, sleep efficiency and total sleep minutes and WOMAC hip pain.
Fragmented sleep was greater in women with hip pain compared to those without hip pain. However, fragmented sleep in women with severe hip pain compared to those without hip pain was unchanged until after the first two hours of sleep. Further investigation, such as pain medications wearing off over time, or prolonged periods of inactivity decreasing the pain threshold are warranted.
PMCID: PMC3355201  PMID: 22298286

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