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Objective: A test-retest cohort study was conducted to assess the use of a novel computer-aided, combined movement examination (CME) to measure change in low back movement after pain management intervention in 17 cases of lumbar spondylosis. Additionally we desired to use a CME normal reference range (NRR) to compare and contrast movement patterns identified from 3 specific structural pathologic conditions: intervertebral disc, facet joint, and nerve root compression., Methods: Computer-aided CME was used before and after intervention, in a cohort study design, to record lumbar range of movement along with pain, disability, and health self-report questionnaires in 17 participants who received image-guided facet, epidural, and/or rhizotomy intervention. In the majority of cases, CME was reassessed after injection together with 2 serial self-reports after an average of 2 and 14 weeks. A minimal clinically important difference of 30% was used to interpret meaningful change in self-reports. A CME NRR (n = 159) was used for comparison with the 17 cases. Post hoc observation included subgrouping cases into 3 discrete pathologic conditions, intervertebral disc, facet dysfunction, and nerve root compression, in order to report intergroup differences in CME movement., Results: Seven of the 17 participants stated that a "combined" movement was their most painful CME direction. Self-report outcome data indicated that 4 participants experienced significant improvement in health survey, 5 improved by ≥30% on low back function, and 8 reported that low back pain was more bothersome than stiffness, 6 of whom achieved the minimal clinically important difference for self-reported pain. Subgrouping of cases into structure-specific groups provided insight to different CME movement patterns., Conclusion: The use of CME assists in identifying atypical lumbar movement relative to an age and sex NRR. Data from this study, exemplified by representative case studies, provide preliminary evidence for distinct intervertebral disc, facet joint, and nerve root compression CME movement patterns in cases of chronic lumbar spondylosis., (Copyright © 2017. Published by Elsevier Inc.)

Background: Interspinous spacer/implants like the Device for Intervertebral Assisted Motion (DIAM™) are controversially yet commonly used in the surgical treatment of lumbar degenerative pathologies. Criticism is based on ill-defined indications, lack of superiority over decompression, and a poorly understood mechanical effect. Yet, continued use by surgeons implies their perceived clinical merit. We examined radiographic spinal alignment for 12 months, and pain and function for 24 months, after DIAM-augmented surgery to improve the understanding of the mechanical effect relating to clinical outcomes in patients., Methods: We undertook a single-surgeon prospective, longitudinal study of 40 patients (20 F, 20 M) who received DIAM-augmented surgery in treatment of their symptomatic lumbar degenerative condition. Outcomes measured included sagittal spinal alignment (lumbar lordosis, sacral inclination, primary (PDA), supradjacent (SDA) disc angles, and regional sagittal balance (RSB; standing lateral radiographs), and back and leg pain (visual analogue scale; VAS) and function (Oswestry Disability Index; ODI). Responders were identified as those with clinically meaningful improvement to pain (>20%) and function (>15%) at 24 months postoperatively; features of sagittal spinal alignment between responders and non-responders were examined., Results: Sagittal alignment was unchanged at 12 months. At 6 weeks postoperatively, PDA (mean (SD)) reduced by 2.2° (4.0°; p  < 0.01) and more-so in back pain non-responders (3.8° (3.2°)) than responders (0.7° (4.4°); p  < 0.05). Positive preoperative RSB in responders (26.7Rmm (42.3Rmm); Rmm is a system-relative measure) decreased at 6 weeks (by 3.1Rmm (9.1Rmm)). Non-responders had a negative RSB preoperatively (-1.0Rmm (32.0Rmm)) and increased at 6 weeks (11.2Rmm (15.5Rmm); p  < 0.05). Clinically meaningful improvement for the whole cohort for back pain and function were observed to 24 months (back pain: 25.0% (28.0); function: 15.4% (17.6); both p  < 0.0001)., Conclusions: Unaltered sagittal alignment at 12 months was not related to symptoms after DIAM-augmented lumbar surgery. Subtle early flattening at the index disc angle was not maintained. Preoperative and early post-operative sagittal alignment may indicate response after DIAM-augmented surgery for mixed lumbar pathologies. Further investigation toward defining indications and patient suitability is warranted.

Combined movement examination (CME) of the lumbar spine has been recommended for clinical examination as it confers information about mechanical pain patterns. However, little quantitative study has been undertaken to validate its use in manual therapy practice. This study used computer aided CME to develop a normal reference range, and to guide provisional diagnosis and management. Two cases were assessed, before and after manual therapy using CME, a pain Visual Analogue Scale, the Roland Morris Low Back Pain and Disability Questionnaire and the Short Form (SF-12) Health Survey. Diagnosis and management were guided by comparing each CME pattern with the age and gender matched reference range. Self-reports data and CME total change scores were markedly improved for both cases, particularly for the most painful and restricted CME directions. This report describes how computer-aided CME and a normal reference range may be used objectively to inform a diagnosis and as an outcome measure in cases of mechanical LBP. Future investigations of cases with specific lumbar pathologies are required to validate this concept., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Abstract: The communication involved in the foraging behaviour of social insects is integral to their success. Many ant species use trail pheromones to make decisions about where to forage. The strong positive feedback caused by the trail pheromone is thought to create a decision between two or more options. When the two options are of identical quality, this is known as symmetry breaking, and is important because it helps colonies to monopolise food sources in a competitive environment. Symmetry breaking is thought to increase with the quantity of pheromone deposited by ants, but empirical studies exploring the factors affecting symmetry breaking are limited. Here, we tested if (i) greater disparity between two food sources increased the degree to which a higher quality food source is favoured and (ii) if the quality of identical food sources would affect the degree of symmetry breaking that occurs. Using the mass-recruiting Pharaoh ant, Monomorium pharaonis , we carried out binary choice tests to investigate how food quality affects the choice and distribution of colony foraging decisions. We found that colonies could coordinate foraging to exploit food sources of greater quality, and a greater contrast in quality between the food sources created a stronger collective decision. Contrary to prediction, we found that symmetry breaking decreased as the quality of two identical food sources increased. We discuss how stochastic effects might lead to relatively strong differences in the amount of pheromone on alternative routes when food source quality is low., Significance Statement: Pheromones used by social insects should guide a colony via positive feedback to distribute colony members at resources in the most adaptive way given the current environment. This study shows that when food resources are of equal quality, Pharaoh ant foragers distribute themselves more evenly if the two food sources are both of high quality compared to if both are of low quality. The results highlight the way in which individual ants can modulate their response to pheromone trails which may lead colonies to exploiting resources more evenly when in a resource rich environment.

Background: In 2010, the Australian Institute of Health and Welfare published a report examining the characteristics of Australian women diagnosed with ductal carcinoma in situ (DCIS). This study identified the characteristics of women who were diagnosed with DCIS in Western Australia (WA) 1996-2005, and built on a national study by determining the rate of second operation and breast cancer events (BCE) in WA., Methods: A retrospective analysis of data from the WA Cancer Registry and the Hospital Morbidity Database was undertaken. The main outcome measures were histological characteristics, second operation rate, breast cancer events., Results: A total of 1356 cases of DCIS were diagnosed in WA between 1996 and 2005, with a minimum 5-year follow-up. The age-standardised incidence rate in 2005 was 15.4 per 100,000 women. 72 % of patients received breast-conserving therapy for primary treatment, 18 % of patients requiring a second operation to obtain adequate margins and 35 % of patients received postoperative radiotherapy. 17.3 % of cases had a subsequent BCE, with the 5- and 10-year probabilities being 4.36 and 8.27 %, respectively. A BCE was significantly associated with age (p < 0.001), no second operation (p < 0.001) and no radiotherapy (p = 0.049 recurrence, p = 0.043 invasion)., Conclusion: This study supports the need to ensure adequate margins during primary surgery for DCIS is obtained to reduce the need for a second operation or the risk of a subsequent BCE. The consideration of mastectomy versus radiotherapy should be made in conjunction with the identified risk factors, specifically age and whether a second operation was performed.

The proton beam energy of an isochronous 18MeV cyclotron was determined using a novel version of the stacked copper-foils technique. This simple method used stacked foils of natural copper forming 'thick' targets to produce Zn radioisotopes by the well-documented (p,x) monitor-reactions. Primary beam energy was calculated using the (65)Zn activity vs. depth profile in the target, with the results obtained using (62)Zn and (63)Zn (as comparators) in close agreement. Results from separate measurements using foil thicknesses of 100, 75, 50 or 25µm to form the stacks also concurred closely. Energy was determined by iterative least-squares comparison of the normalized measured activity profile in a target-stack with the equivalent calculated normalized profile, using 'energy' as the regression variable. The technique exploits the uniqueness of the shape of the activity vs. depth profile of the monitor isotope in the target stack for a specified incident energy. The energy using (65)Zn activity profiles and 50-μm foils alone was 18.03±0.02 [SD] MeV (95%CI=17.98-18.08), and 18.06±0.12MeV (95%CI=18.02-18.10; NS) when combining results from all isotopes and foil thicknesses. When the beam energy was re-measured using (65)Zn and 50-μm foils only, following a major upgrade of the ion sources and nonmagnetic beam controls the results were 18.11±0.05MeV (95%CI=18.00-18.23; NS compared with 'before'). Since measurement of only one Zn monitor isotope is required to determine the normalized activity profile this indirect yet precise technique does not require a direct beam-current measurement or a gamma-spectroscopy efficiency calibrated with standard sources, though a characteristic photopeak must be identified. It has some advantages over published methods using the ratio of cross sections of monitor reactions, including the ability to determine energies across a broader range and without need for customized beam degraders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study is to report the development and validation of a low back computer-aided combined movement examination protocol in normal individuals and record treatment outcomes of cases with symptomatic degenerative lumbar spondylosis., Design: Test-retest, following intervention., Background: Self-report assessments and combined movement examination were used to record composite spinal motion, before and following neurosurgical and pain medicine interventions., Methods: 151 normal individuals aged from 20 years to 69 years were assessed using combined movement examination between L1 and S1 spinal levels to establish a reference range. Cases with degenerative low back pain and sciatica were assessed before and after therapeutic interventions with combined movement examination and a battery of self-report pain and disability questionnaires. Change scores for combined movement examination and all outcome measures were derived., Findings: Computer-aided combined movement examination validation and intraclass correlation coefficient with 95% confidence interval and least significant change scores indicated acceptable reliability of combined movement examination when recording lumbar movement in normal subjects. In both clinical cases lumbar spine movement restrictions corresponded with self-report scores for pain and disability. Post-intervention outcomes all showed significant improvement, particularly in the most restricted combined movement examination direction., Interpretation: This study provides normative reference data for combined movement examination that may inform future clinical studies of the technique as a convenient objective surrogate for important clinical outcomes in lumbar degenerative spondylosis. It can be used with good reliability, may be well tolerated by individuals in pain and appears to change in concert with validated measures of lumbar spinal pain, functional limitation and quality of life., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

New macrobicyclic cage amine or "sarcophagine" (sar) bifunctional chelators have been synthesised that form copper complexes of exceptional in vivo stability and incorporate isothiocyanate (-NCS) functional groups for conjugation to an antibody. The chelators were synthesised from the methyl-capped complex [Mg(II)(CH3)(NH2)sar](2+). Coordination of Mg(II) within the cavity of the cage amine ligand protects the secondary amine atoms from reacting with the -NCS functional groups. Two different [Mg(II)(NCS-sar)](2+) derivatives were conjugated to the HER2/neu-targeting antibody trastuzumab and the progress of the reaction monitored by electrospray mass spectrometry. The Mg(II) ion was removed from the immunoconjugates under mild conditions (0.1 M citrate buffer, pH 6). Labelling of the (CH3)(p-NCS-Ph)sar-trastuzumab conjugate with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (∼5 min) and easily performed at room temperature with high radiochemical purity (>95%). Biodistribution and PET imaging studies in vivo showed that (64)Cu-labelled (CH3)(p-NCS-Ph)sar-trastuzumab maintained high stability under physiological conditions with high and selective uptake in a HER2-positive cancer cell line. The stability of the copper complex and the 12.7 h half-life of the radioisotope allows clear visualisation of tumours out to 48 h.

We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell-line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent). Increasing the PEG molecular weight (from 10 to 40 kDa) or decreasing the PEG particle size (from 1400 to 150 nm) reduces phagocytic blood cell association of the PEG particles. Mice biodistribution studies show that the PEG particles exhibit extended circulation times (>12 h) compared with the MS@PEG particles and that the retention of smaller PEG particles (150 nm) in blood, when compared with larger PEG particles (>400 nm), is increased at least 4-fold at 12 h after injection. Our findings highlight the influence of unique aspects of polymer hydrogel particles on biological interactions. The reported PEG hydrogel particles represent a new class of polymer carriers with potential biomedical applications.

We measured the excitation functions of (nat)Zn (p,x) reactions up to 17.6MeV, using the stacked-foils activation technique. High-purity natural zinc (and copper) foils were irradiated with proton beams generated by an 18MeV isochronous cyclotron. Activated foils were measured using high-purity Ge gamma spectroscopy to quantify the radionuclides (61)Cu, (66)Ga, (67)Ga, and (65)Zn produced from the reactions. Thick-target integral yields were also deduced from the measured excitation functions of the produced radioisotopes. These results were compared with the published literature and were found to be in good agreement with most reports, particularly those most recently compiled., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The enzyme-mediated site-specific bioconjugation of a radioactive metal complex to a single-chain antibody using the transpeptidase sortase A is reported. Cage amine sarcophagine ligands that were designed to function as substrates for the sortase A mediated bioconjugation to antibodies were synthesized and enzymatically conjugated to a single-chain variable fragment. The antibody fragment scFv(anti-LIBS) targets ligand-induced binding sites (LIBS) on the glycoprotein receptor GPIIb/IIIa, which is present on activated platelets. The immunoconjugates were radiolabeled with the positron-emitting isotope (64)Cu. The new radiolabeled conjugates were shown to bind selectively to activated platelets. The diagnostic potential of the most promising conjugate was demonstrated in an in vivo model of carotid artery thrombosis using positron emission tomography. This approach gives homogeneous products through site-specific enzyme-mediated conjugation and should be broadly applicable to other metal complexes and proteins., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Approximately one quarter of patients undergoing breast conserving therapy for breast cancer will require a second operation to achieve adequate clearance of the margins. A number of techniques to assess margins intraoperatively have been reported. This systematic review examines current intraoperative methods for assessing margin status. The final pathology status, statistical measures including accuracy of tumour margin assessment, average time impact on the procedure and second operation rate, were used as criteria for comparison between studies. Although pathological methods, such as frozen section and imprint cytology performed well, they added on average 20-30 min to operation times. An ultrasound probe allows accurate examination of the margins and delivers results in a timely manner, yet it has a limited role with DCIS where calcification is present and in multifocal cancer. Further research is required in other intraoperative margin assessment techniques, such as mammography, radiofrequency spectroscopy and optical coherence tomography., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu(II) with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr(3)-octreotate. Radiolabeling of SarTATE with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (~20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of (64)CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between (64)CuSarTATE and (64)Cu-labeled DOTA-Tyr(3)-octreotate ((64)CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of (64)CuDOTATATE decreased significantly at 24 h, (64)CuSarTATE activity was retained, improving contrast at later time points. (64)CuSarTATE accumulated less than (64)CuDOTATATE in the non-target organs, liver and lungs. The uptake of (64)CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr(3)-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of (64)Cu- and (67)CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to (64)CuDOTATATE at longer time points.

Previously we reported that the corresponding 2-dimensional (2D) structural geometry measures derived from quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) of femoral neck were different. Now, we test the hypothesis that the following 4 measures: areal bone mineral density, W, and 2 new measures, standard deviation (σ) of a normalized mineral mass projection profile distribution and the displacement between centre of mineral mass and geometric centre of mineral mass (δ) of the projection profile allow transformation from one measurement modality to the other with high precision. QCT and DXA scans and hip structural analysis (HSA) performed on 237 women were randomly allocated into cohorts of 118 (cohort A) and 119 (cohort B). Intercepts and gradients from linear regression of the 4 QCT- and DXA-derived measures were obtained from cohort A and used to convert cohort B QCT-derived structural geometry measurements into their DXA equivalent. Corresponding cohort B QCT- and DXA-derived structural geometrical measurements were compared using Bland-Altman plots and regression analysis. Apart from W, comparisons of the 7 nontransformed QCT- and DXA-derived variables were significantly different using paired t-tests. Cross-calibration with the set of 4 base measures resolved the differences in all original variables. These data provide a mechanism for cross-calibrating HSA outcomes acquired using QCT and DXA and demonstrate that a complex 2D digitized structure can be described by 4 variables., (Copyright © 2014 The International Society for Clinical Densitometry. All rights reserved.)

One of the pathological hallmarks of Alzheimer's disease is the presence of amyloid-β plaques in the brain and the major constituent of these plaques is aggregated amyloid-β peptide. New thiosemicarbazone-pyridylhydrazine based ligands that incorporate functional groups designed to bind amyloid-β plaques have been synthesized. The new ligands form stable four coordinate complexes with a positron-emitting radioactive isotope of copper, (64)Cu. Two of the new Cu(II) complexes include a functionalized styrylpyridine group and these complexes bind to amyloid-β plaques in samples of post-mortem human brain tissue. Strategies to increase brain uptake by functional group manipulation have led to a (64)Cu complex that effectively crosses the blood-brain barrier in wild-type mice. The new complexes described in this manuscript provide insight into strategies to deliver metal complexes to amyloid-β plaques.

DXA-derived bone structural geometry has been reported extensively but lacks an accuracy standard. In this study, we describe a novel anthropometric structural geometry phantom that simulates the proximal femur for use in assessing accuracy of geometry measurements by DXA or other X-ray methods. The phantom consists of seven different interchangeable neck modules with geometries that span the range of dimensions in an adult human proximal femur, including those representing osteoporosis. Ten repeated hip scans of each neck module using two current DXA scanner models were performed without repositioning. After scanner specific calibration, hip structure analysis was used to derive structural geometry. Scanner performance was similar for the two manufacturers. DXA-derived HSA geometric measurements were highly correlated with values derived directly from phantom geometry and position; R² between DXA and phantom measures were greater than 94% for all parameters, while precision error ranged between 0.3 and 3.9%. Despite high R² there were some systematic geometry errors for both scanners that were small for outer diameter, but increasing with complexity of geometrical parameter; e.g. buckling ratio. In summary, the anthropometric phantom and its fabrication concept were shown to be appropriate for evaluating proximal femoral structural geometry in two different DXA systems.

Background: Spinal rotation couples with lateral flexion as a composite movement. Few data report the in vivo mechanical deformation of the nucleus pulposus following sustained rotation. MRI provides a non-invasive method of examining nucleus pulposus deformation by mapping the hydration signal distribution within the intervertebral disc., Methods: T1 weighted coronal and sagittal lumbar images and T2 weighted axial images at L1-2 and L4-5 were obtained from 10 asymptomatic subjects (mean age 29, range: 24-34 years) in sustained flexed and extended positions plus combined positions of left rotation with flexion and extension. Nucleus pulposus deformation was tracked by mapping the change in hydration profiles from coronal and sagittal pixel measurements., Findings: An average sagittal change in position of 44° (SD 14.5°) from flexion to extension was recorded between L1 and S1 (range: 18°- 60°) resulting in a mean anterior nucleus pulposus deformation of 16% of disc hydration profile (range: 3.5%-19%) in 19/20 discs. When rotation was combined with either flexion or extension, mean coronal deformation was 4.8% (SD-5.1%; range: 0.4%-15%). Lateral nucleus pulposus deformation direction varied in rotation (44% deformed left and 56% deformed right). Intersegmental lateral flexion direction more strongly predicted nucleus pulposus deformation direction with 75% deforming contralaterally., Interpretation: Nucleus pulposus deformation direction in young subjects was more predictable following sagittal position change than in rotation combined with flexion or extension. Deformation magnitude was reduced in rotated positions. Intersegmental lateral flexion was a stronger predictor of nucleus pulposus deformation direction., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Unlabelled: Structural geometric parameters at neck of the proximal femur were obtained using DXA-derived hip structural analysis (APEX 3) and quantitative computed tomography-derived (BIT QCT) techniques in 237 elderly females. Linear correlations for parameters ranged from 0.45 to 0.90. The average value of the subperiosteal width, as determined by the two techniques, was the same; variables dependent on mass measurements were different., Introduction: There has been increasing interest in using bone structural geometry to assess bone fragility to complement bone mineral mass. The objective of this study is to compare structural geometrical differences between "2D" DXA-derived and "3D" QCT-derived techniques in unselected clinical cases., Methods: All 237 females had both DXA and QCT assessments of femoral neck structural geometry. Variables compared were areal bone mineral density, cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), averaged cortical thickness (Ct), endosteal width (ESW), subperiosteal width (W), and buckling ratio (BR)., Results: Correlation of femoral neck variables ranged from 0.45 for ESW to 0.90 for CSA. APEX 3 and BIT QCT-derived femoral neck W values were numerically similar. However CSA, CSMI, Z and Ct values measured by APEX 3 were higher and ESW and BR values were lower than corresponding BIT QCT., Conclusions: 2D DXA structural analysis of neck of femur is related to but different from same parameters calculated from true 3D images obtained by CT. Femoral neck size values are similar for DXA and QCT, but structural geometrical variables dependent on mass calibration standards, location of neck ROI and mathematical derivation techniques are different.

Some previously immunodeficient HIV patients responding to antiretroviral therapy display poor recovery of CD4⁺ T cells. Evaluation of the contribution of thymic function requires sensitive detection and quantitation of metabolically active thymic tissue. We describe patients with low but detectable thymopoiesis assessed as circulating CD4⁺ naive T cells expressing CD31. High-resolution computed tomography and PET scans found no residual thymic tissue even though metabolic activity was demonstrable by PET in lymph nodes.

Human lactation is associated with transient decreases in bone mineral density (BMD). Bone strength is related to both mass and structural geometry. This study investigated longitudinal changes of hip bone strength during lactation using hip structural analysis (HSA), which determines hip structural geometry (including areal BMD, BMDa) from dual-energy X-ray absorptiometry scans (DXA). Forty-eight lactating women were studied longitudinally at the proximal femur using DXA at approximately 2 weeks postpartum, peak-lactation and post-lactation. Nonpregnant, nonlactating women (NPNL, n=23) were studied concurrently at baseline and after 1 year. Hip scans were analysed using HSA at the narrow neck, intertrochanter and proximal shaft. No significant change (>0.05) was observed in NPNL women for any measurement. In contrast, for lactating women BMDa decreased significantly from 2 weeks postpartum to peak-lactation at narrow neck (-2.8%), intertrochanter (-3.2%) and shaft (-1.4%). Cross-sectional area (CSA) decreased at narrow neck (-3.4%) and intertrochanter (-2.7%). There were no significant changes in bone width. Section modulus decreased at intertrochanter (-2.1%). At shaft, cortical thickness decreased (-1.7%) and buckling ratio increased (2.3%). By post-lactation, measurements were not significantly different from 2 weeks postpartum except for decrements in BMDa (-1.1%) and CSA (-1.2%) at the shaft. During the study, lactating women lost 5% of their body weight. Adjusting for weight changes decreased the magnitude and significance of HSA changes at peak-lactation and by post-lactation there were no significant differences from 2 weeks postpartum. Calcium intake was not a significant predictor of changes in HSA variables. In conclusion, lactation is associated with significant but transient changes in hip BMD and structural geometry. Changes in body weight but not calcium intake were associated with these changes. These small changes at the hip during lactation occurred mainly at internal surfaces and had minimal impact on bending or compressive strength., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation., Competing Interests: The authors have declared that no competing interests exist.

Background: Osteoporosis research has focused on vertebral fractures and trabecular bone loss. However, non-vertebral fractures at predominantly cortical sites account for 80% of all fractures and most fracture-related morbidity and mortality in old age. We aimed to re-examine cortical bone as a source of bone loss in the appendicular skeleton., Methods: In this cross-sectional study, we used high-resolution peripheral CT to quantify and compare cortical and trabecular bone loss from the distal radius of adult women, and measured porosity using scanning electron microscopy. Exclusion criteria were diseases or prescribed drugs affecting bone metabolism. We also measured bone mineral density of post-mortem hip specimens from female cadavers using densitometry. Age-related differences in total, cortical, and trabecular bone mass, trabecular bone of cortical origin, and cortical and trabecular densities were calculated., Findings: We investigated 122 white women with a mean age of 62.8 (range 27-98) years. Between ages 50 and 80 years (n=89), 72.1 mg (95% CI 67.7-76.4) hydroxyapatite (68%) of 106.5 mg hydroxyapatite of bone lost at the distal radius was cortical and 34.3 mg (30.5-37.8) hydroxyapatite (32%) was trabecular; 17.1 mg (11.7-22.5) hydroxyapatite (16%) of total bone loss occurred between ages 50 and 64 years (n=34) and 89.4 mg (83.7-101.1) hydroxyapatite (84%) after age 65 years (n=55). Remodelling within cortex adjacent to the marrow accounted for 49.9 mg (45.4-53.7) hydroxyapatite (47%) of bone loss. Between ages 50-64 years (n=34) and 80 years and older (n=33), cortical density decreased by 127.8 mg (93.1-162.1) hydroxyapatite per cm(3) (15%, p<0.0001) before porosity trabecularising the cortex was included, but 374.3 mg (318.2-429.5) hydroxyapatite per cm(3) (43%, p<0.0001) after; trabecular density decreased by 18.2 mg (-1.4 to 38.2) hydroxyapatite per cm(3) (14%, p=0.06) before cortical remnants were excluded, but 68.7 mg (37.7-90.4) hydroxyapatite per cm(3) (52%, p<0.0001) after., Interpretation: Accurate assessment of bone structure, especially porosity producing cortical remnants, could improve identification of individuals at high and low risk of fracture and therefore assist targeting of treatment., Funding: Australia National Health and Medical Research Council., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Hip structural analysis (HSA) has been developed over 20 yr, applied extensively in research, and has demonstrated useful outcomes associating bone structural geometry with bone fragility (research-HSA or r-HSA). In 2007, Hologic Inc. (Bedford, MA) incorporated HSA with some modifications as an option for Hologic dual-energy X-ray absorptiometry (DXA) scanners (clinical HSA or c-HSA). This brought HSA from the research environment into the clinical environment. This article reports a comparison of r-HSA and c-HSA implementations using DXA scans from a group of 191 females. Bland-Altman plots at the narrow-neck (NN) HSA region indicated higher r-HSA areal bone mineral density (mean difference: 0.27 g/cm(2); 21.7% [of mean]); cross-sectional area (0.63 cm(2); 18.7%); cross-sectional moment of inertia (0.26 cm(4); 11.1%), and section modulus (0.22 cm(3); 14.5%) compared with c-HSA. The converse was observed for NN subperiosteal width (-0.09 cm; 3.1%). High linear correlations (r(2) > 0.81) were found between r-HSA and c-HSA NN structural geometric outcomes, with the exception of neck shaft angle (r(2) > 0.47). As differences were significant (p < 0.001), slopes and intercepts are provided to enable linear transformations from r-HSA to corresponding c-HSA structural geometric data.

Unlabelled: Two-dimensional areal bone mineral density (aBMD) of the proximal femur measured by three-dimensional quantitative computed tomography (QCT) in 91 elderly women was compared to dual-energy X-ray absorptiometry (DXA) aBMD results measured in the same patients. The measurements were highly correlated, though QCT aBMD values were marginally lower in absolute units. Transformation of the QCT aBMD values to T score values using National Health and Nutrition Examination Survey (NHANES) DXA-derived reference data improved agreement and clinical utility., Introduction: World Health Organization guidelines promulgate aBMD (g cm(-2)) measurement of the proximal femur for the diagnosis of bone fragility. In recent years, there has been increasing interest in QCT to facilitate understanding of three-dimensional bone structure and strength., Objective: To assist in comparison of QCT-derived data with DXA aBMD results, a technique for deriving aBMD from QCT measurements has been developed., Methods: To test the validity of the QCT method, 91 elderly females were scanned on both DXA and CT scanners. QCT-derived DXA equivalent aBMD (QCT(DXA) aBMD) was calculated using CTXA Hip software (Mindways Software Inc., Austin, TX, USA) and compared to DXA-derived aBMD results., Results: Test retest analysis indicated lower root mean square (RMS) errors for CTXA; F test between CTXA and DXA was significantly different at femoral neck (FN) and trochanter (TR) (p < 0.05). QCT underestimates DXA values by 0.02 +/- 0.05 g cm(-2) (total hip, TH), 0.01 +/- 0.04 g cm(-2) (FN), 0.03 +/- 0.07 g cm(-2) (inter-trochanter, IT), and 0.02 +/- 0.05 g cm(-2) (TR). The RMS errors (standard error of estimate) between QCT and DXA T scores for TH, FN, IT, and TR were 0.36, 0.40, 0.39, and 0.49, respectively., Conclusions: This study shows that results from QCT aBMD appropriately adjusted can be evaluated against NHANES reference data to diagnose osteoporosis.

Background: Interspinous process implants, used to augment lumbar spine surgery, putatively induce a local segmental lumbar kyphosis yet few investigations outline the effect in vivo on thoracolumbar sagittal curvature. Changes in lumbar skeletal alignment and posture have traditionally relied upon radiographic and back surface spinal curvature measurements, respectively., Methods: Lumbar lordosis curvature in 10 healthy subjects (6F, 4M; mean age 36 years) and 10 interspinous implant lumbar surgery patients (5F, 5M; mean age 51 years) was assessed with rasterstereography at baseline and at 6 weeks. Skeletal lumbar lordosis in standing was measured from lateral erect radiography pre- and 6 weeks post-operatively in the surgical cohort, and compared to angulation obtained for surface lordosis curvature derived from rasterstereography., Findings: Repeatable measurement of standing lumbar lordosis from rasterstereographic back shape imaging in healthy volunteers and lumbar surgery cases was demonstrated. Reductions of 0.6 (NS) in healthy and 3.1 (significant, P<0.001) in surgical subjects were recorded for surface lumbar lordosis angle between the 6 week time-points. Slight flattening of the segmental angle and regional lordosis after DIAM surgery was revealed by radiography. Skeletal and surface lumbar lordosis changes were uncorrelated preoperatively (rho=0.28) and postoperatively (rho=0.26)., Interpretation: Rasterstereography is sensitive in assessing lumbar lordosis changes in healthy and lumbar surgical individuals over time. Surgery with DIAM for lumbar pathology may result in an initial mild flattening of lordosis. Serial investigations of spinal curvature after surgery with DIAM interspinous implant are warranted in order to better understand the time-course of spinal posture changes of such cases.

The healthcare cost of managing osteoporotic fractures is projected to rise because of the change in population demographics. To reduce the fracture epidemic, strategies are needed to identify those at risk early to allow preventative intervention to be implemented. The aim of this study was to investigate if low-cost community-based assessments, such as calcaneal ultrasound and falls risk assessments, can discriminate a group of elderly women at risk of osteoporotic fracture from those at lower risk. Over the period of 2002-2003, 104 community-dwelling women (mean age 71.3, standard deviation 5.8) were recruited via various modes including advertisements in community newspaper and community centres. These women underwent dual-energy X-ray absorptiometry bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) measurements; spinal radiography; and performance-based assessment of strength, mobility and balance. The women were classified into a 'high risk' (osteoporotic) group, based on low BMD (T-score of

Areal bone mineral density (aBMD), derived from dual-energy X-ray absorptiometry (DXA) scanners is used routinely to infer bone strength. With DXA hip scans there is growing acceptance of the advantages of also measuring bone structural geometric variables, that complement conventional aBMD to improve understanding of bone modelling, remodelling and processes of metabolic bone disease. However, phantoms for assessing structural geometric variables from DXA scans are not widely available, unlike those for aBMD. This study describes the development of such a phantom, simulating the cortical shell of the human femoral neck, using dental plaster as a material radiologically similar to cortical bone. The mass attenuation coefficient of the dental plaster differed by < 1% from cortical bone, over the relevant energy range. Performance testing was carried out with DXA, to determine accuracy and precision of the phantom structural geometry, using its dimensions and composition as 'gold standards'. Accuracy and precision of cortical structural geometry were poor when measured in a simulated 1 mm-thick osteoporotic cortex (5.5% precision and 50% accuracy errors), but improved with increasing cortical thickness. This study demonstrates the limitations of DXA-based Hip Structure Analysis when applied to femora with thin cortices, and indicates improvements in the design of a phantom to better simulate such cortical structures.

Unlabelled: A population-based study on 1008 postmenopausal women identified that the 24% of women achieving high levels of PA and CI had 3.4-4.4% higher femoral bone strength in axial compression and 1.7-5.2% in bending than those achieving low levels, indicating that lifestyle factors influence bone strength in the proximal femur., Introduction: Extensive research has shown that increased physical activity (PA) and calcium intake (CI) decrease the rate of bone loss; however, there is little research on how these lifestyle variables affect bone geometry. This study was designed to investigate the effects of modifiable lifestyle variables, habitual PA and dietary CI, on femoral geometry in older women., Materials and Methods: Femoral geometry, habitual PA, and dietary CI were measured in a population-based sample of 1008 women (median age+/-interquartile range, 75+/-4years) enrolled in a randomized controlled trial (RCT) of calcium supplementation. Baseline PA and CI were assessed by validated questionnaires, and 1-year DXA scans (Hologic 4500A) were analyzed using the hip structural analysis technique. Section modulus (Z), an index of bending strength, cross-sectional area (CSA), an index of axial compression strength, subperiosteal width (SPW), and centroid position, the position of the center of mass, were measured at the femoral neck (NN), intertrochanter (IT), and femoral shaft (FS) sites. These data were divided into tertiles of PA and CI, and the results were compared using analysis of covariance (ANCOVA), with corrections for age, height, weight, and treatment (calcium/placebo)., Results and Conclusions: PA showed a significant dose-response effect on CSA all hip sites (p<0.03) and Z at the narrow neck and intertrochanter sites (p<0.02). For CI, there was a dose-response effect for centroid position at the intertrochanter (p=0.03). These effects were additive, such that the women (n=240) with PA in excess of 65.5 kcal/day and CI in excess of 1039 mg/day had significantly greater CSA (NN, 4.4%; IT, 4.3%; FS, 3.4%) and Z (NN, 3.9%; IT, 5.2%). These data show a favorable association between PA and aspects of bone structural geometry consistent with better bone strength. Association between CI and bone structure was only evident in 1 of 15 variables tested. However, there was evidence that there may be additive effects, whereby women with high levels of PA and CI in excess of 1039 mg/day had significantly greater CSA (NN, 0.4%; FS, 2.1%) and Z (IT, 3.0%) than women with high PA but low CI. These data show that current public health guidelines for PA and dietary CI are not inappropriate where bone structure is the health component of interest.

Background: The nucleus pulposus deforms towards an area of least compression in response to offset loading, however, there is a lack of data reporting the deformation patterns of nuclear material in rotated positions of the lumbar spine. Our purpose was to assess a novel methodology using MRI to track nuclear deformation in response to flexion and extension positions, and the combined positions of flexion with left rotation and extension with left rotation, at L1-2 and L4-5., Methods: Three asymptomatic female subjects, mean age 27 years, underwent T2 weighted MRI sequences in flexed, extended, and left rotated positions combined with flexion and extension. A pixel profile technique was employed to determine direction and magnitude of nuclear deformation., Results: In 5 of 6 discs examined, deformation of the nucleus occurred anteriorly in extension and posteriorly in flexion. Left rotation resulted in migration of nuclear material to the right in 9 of 12 discs. Of the three discs that demonstrated a right nuclear migration, two occurred at L4-5 and one at L1-2., Interpretation: This methodology demonstrated that nucleus pulposus deformation can be measured reliably in various positions achieved within the confines of the MRI. The consistent migration of nuclear material following sagittal plane movement and the less consistent response to rotation positions suggest other asymmetrical loading on the intervertebral disc may accompany rotation.

Hip structural analysis (HSA) is a technique for extracting strength-related structural dimensions of bone cross-sections from two-dimensional hip scan images acquired by dual energy X-ray absorptiometry (DXA) scanners. Heretofore the precision of the method has not been thoroughly tested in the clinical setting. Using paired scans from two large clinical trials involving a range of different DXA machines, this study reports the first precision analysis of HSA variables, in comparison with that of conventional bone mineral density (BMD) on the same scans. A key HSA variable, section modulus (Z), biomechanically indicative of bone strength during bending, had a short-term precision percentage coefficient of variation (CV%) in the femoral neck of 3.4-10.1%, depending on the manufacturer or model of the DXA equipment. Cross-sectional area (CSA), a determinant of bone strength during axial loading and closely aligned with conventional DXA bone mineral content, had a range of CV% from 2.8% to 7.9%. Poorer precision was associated with inadequate inclusion of the femoral shaft or femoral head in the DXA-scanned hip region. Precision of HSA-derived BMD varied between 2.4% and 6.4%. Precision of DXA manufacturer-derived BMD varied between 1.9% and 3.4%, arising from the larger analysis region of interest (ROI). The precision of HSA variables was not generally dependent on magnitude, subject height, weight, or conventional femoral neck densitometric variables. The generally poorer precision of key HSA variables in comparison with conventional DXA-derived BMD highlights the critical roles played by correct limb repositioning and choice of an adequate and appropriately positioned ROI.

Unlabelled: The effects of dietary calcium intake and physical activity on longitudinal changes in BMD over a mean of 9.4 years were examined in 62 healthy young women. Proximal femur BMD declined, lumbar spine BMD increased, and physical activity was associated with BMD change at intertrochanter and total hip sites., Introduction: Maximizing premenopausal BMD is an important strategy for the prevention of osteoporosis and resultant fractures later in life., Materials and Methods: Young women who previously participated in a placebo-controlled 2-year calcium intervention study at a mean age of 18.5 +/- 0.3 years were remeasured at 27.8 +/- 1.0 years of age. DXA (Hologic QDR 1000W) was used to measure changes in BMD, and lifestyle factors were ascertained by questionnaire., Results and Conclusions: Early decline in BMD at the neck of femur (-3.3%/decade) and the converse gain in BMD at the lumbar spine (+4.3%/decade) and intertrochanter (+1.9%/decade) suggest site-specific changes in BMD in young premenopausal women. No effect of previous calcium supplementation was seen on current BMD or changes in BMD (p > 0.10). Lifestyle predictors of change in BMD were determined using hierarchical regression analysis after forced correction for the covariates baseline BMD and previous calcium supplementation. Physical activity was positively associated with change in BMD at total hip and intertrochanter sites (beta-coefficients, beta = 0.26 and 0.26 respectively; p < 0.05). Calcium intake was negatively associated with change in BMD at the lumbar spine (beta = -0.27, p < 0.05). Parity was negatively associated with change in BMD at all sites (beta = -0.40 to -0.26, p < 0.05). These data show that BMD is already declining at the proximal femur in these healthy young women. Physical activity assists in maintenance of BMD at some sites and thus may contribute to lifelong fracture prevention. There was no positive association between calcium intake and change in BMD.

Patients attending a routine bone densitometry clinic were scanned on two different densitometers on the same day using a pencil-beam (Hologic QDR1000W) and fan-beam (Hologic QDR4500W) machine. Subjects were scanned at the lumbar spine site and or the proximal femur. The differences in bone mineral density (BMD) between the fan-beam and pencil-beam (QDR4500W-QDR1000W) were determined for all pairs of scans. The mean difference in BMD was also calculated to see if there was a systematic bias between the machines. The mean difference in BMD was -8 mg/cm2 and 25 mg/cm2 at the spine and total hip, respectively. The individual differences in BMD between the two machines were examined to assess if they were significantly greater than measurement error. The percentage of scans classified as significantly different was calculated for the difference in BMD before and after adjusting for the mean difference in BMD. The percentage of individuals classified as significantly different ranged from 17.1-45.0% before adjustment, at the spine and total hip, respectively, and 16.1-22.6% after adjustment. From a clinical perspective, this degree of misclassification is probably unacceptable. These results suggest that scans obtained from a QDR4500W fan-beam system and QDR1000W pencil-beam system should not be compared, with or without adjustment for systematic bias.

We report a prospective, randomized, multicenter, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below - 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d; group HRT/D received HRT plus calcitriol 0.25 microg bd. All with a baseline dietary calcium (Ca) of < 1 g/ d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P < 0.001) BMD increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, intertrochanter and femoral shaft (% group mean delta 4.2, 6.1, 9.3, 3.7, 3.3 and 3.3%, respectively). On HRT, at these 6 sites, significant deltaS were restricted to the trochanter and Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BMD at the hip, the major site of osteoporotic fracture.

There are uncertainties concerning the optimal threshold value of bone mineral density (BMD) for the diagnosis of osteoporosis using dual-energy X-ray absorptiometry (DXA). The most widely accepted clinical criteria are based on T- and Z-scores, derived statistically from an age-dependent BMD reference range that includes healthy young adults. This study has compared different analyses of BMD data of healthy, nonfractured, adult white females aged 18-90 years, consisting of 953 studied with DXA in the L1-L4 spine and 1018 measured at the hip. Four regression curves were applied to each reference data set; mean peak BMD (PBMD(R)) and the age-independent standard deviation (SD(R)) were calculated. These data, plus derived T-score thresholds, were compared with equivalent values (PBMD(YN), SD(YN)) determined from BMDs of a subgroup of young normals. Choice of regression curve caused a variation of 0.044 g/cm(2) in spinal PBMD(R) and 0.015-0.022 g/cm(2) in the hip. The variation in calculated SD(R) between the regressions was minimal (maximum variation, 0.03 SD unit in the spine). A split-linear model was chosen as the best overall fit for both the spine and the hip on the basis of goodness-of-fit and biological plausibility. PBMD(R) and PBMD(YN) varied by less than 1% at the spine or hip. Although the difference between SD(R) and SD(YN) was < or =7% for the hip sites, SD(R) was 0.022 g/cm(2) > SD(YN) for the spine (17% difference). At each hip site, BMD T-score thresholds, derived from regression analysis of the entire reference range (T(R)) or from young normals only (T(YN)), were not significantly different; however, equivalent spinal values differed by 0.062 g/cm(2) for T = -2.5. The percentage of the Australian female population (AFP) aged 50 yr or older and classified as osteoporotic, using population census data and the split-line-based T-score threshold of T(R) = -2.5, was 23% for spinal BMD and 17% for the total hip. For T(YN) = -2.5, the values were 36% (spine) and 17% (total hip). The hip BMDs of this study were greater than those of NHANES III in the third, seventh and eighth decades by as much as 0.6 SD. This produced a difference of 0.049-0.077 g/cm(2) for T(YN) = -2.5 between the two reference ranges.

Bone mineral density (BMD) was measured at three sites (forearm, spine, and hip) using dual X-ray and single-photon absorptiometry in 68 patients with Paget's disease before and after treatment with iv pamidronate. Patients were treated according to the severity of their disease; the mild category (Group I, hydroxyproline excretion (Hyp(E)) <5.0 micromol/L GF) received 120 mg, the moderate category (Group II, Hyp(E) 5.0-9.99 micromol/GF) 180 mg, and the severe category (Group III, > or = 10.0 micromol/GF) 240 mg. Group I was followed for 1 year, and both Groups II and III for 2 years. At the lumbar spine in pagetic bone there were no differences between groups in early responses, with a profound increase 6 months after treatment 20.5 +/- 2.0% above baseline values to 1.403 +/- 0.063 g/cm(2) (mean +/- SEM)(P < 0.001). This increase in BMD was sustained to 2 years (1.355 +/- 0.078 g/cm(2), P < 0.001) and was 15.0 +/- 2.2% above baseline values. The pagetic total hip BMD increased after treatment in all groups, with a mean rise of 10.4 +/- 1.4% at 1 year to 1.505 +/- 0.083 g/cm(2) (P < 0.01). At the pagetic femoral neck the response was similar, with a peak significant rise at 1 year of 10.7 +/- 1.7% to 1.403 +/- 0.097 g/cm(2) (P < 0.01). In nonpagetic spinal bone there were no differences between the group responses, with a combined mean increase of 4.3 +/- 0.7% at 1 year to 0.999 +/- 0.027 g/cm(2) (P < 0.01). In both Groups II and III the increase in BMD was significantly higher than baseline values at 1 and 2 years (P < 0.01). In the nonpagetic total hip BMD remained unchanged over the 2-year period and likewise, there were no significant changes from baseline at the nonpagetic femoral neck site. In the nonpagetic forearm we found a significant loss in BMD at the ultradistal (mainly trabecular), midregion (80% cortical), and proximal shaft (95% cortical) sites in Group III, persisting to 2 years at the latter two sites. The increase in bone density in pagetic bone, persisting at least 2 years, provides a new modality of assessment of the response of pagetic bone to treatment and suggests a mechanism for the reduction in fracture risk in such bone after effective bisphosphonate treatment. Severity-dependent nonpagetic forearm bone loss, persisting to 2 years at cortical sites, suggests a potential drug-induced fracture risk at the forearm and possibly elsewhere in the absence of appropriate preventive cotreatment.

An Electron Gamma Shower version 4 (EGS4) based user code was developed to simulate the absorbed dose in humans during routine diagnostic radiological procedures. Measurements of absorbed dose using thermoluminescent dosimeters (TLDs) were compared directly with EGS4 simulations of absorbed dose in homogeneous, heterogeneous and anthropomorphic phantoms. Realistic voxel-based models characterizing the geometry of the phantoms were used as input to the EGS4 code. The voxel geometry of the anthropomorphic Rando phantom was derived from a CT scan of Rando. The 100 kVp diagnostic energy x-ray spectra of the apparatus used to irradiate the phantoms were measured, and provided as input to the EGS4 code. The TLDs were placed at evenly spaced points symmetrically about the central beam axis, which was perpendicular to the cathode-anode x-ray axis at a number of depths. The TLD measurements in the homogeneous and heterogenous phantoms were on average within 7% of the values calculated by EGS4. Estimates of effective dose with errors less than 10% required fewer numbers of photon histories (1 x 10(7)) than required for the calculation of dose profiles (1 x 10(9)). The EGS4 code was able to satisfactorily predict and thereby provide an instrument for reducing patient and staff effective dose imparted during radiological investigations.

The internal architecture of the vertebral bodies spanning the levels T1 to L5 in seven male columns was studied using mammographic-resolution radiographs of 2.5-mm-thick planar parasagittal slices. The overlapping radiographic shadows of vertebral trabeculae combined in the image to form a series of 'elements', broadly representative of the cancellous structure. The orientations and sizes of these elements were analysed by applying the Fast Fourier transform (FFT) to the digitized radiographic images. Elements aligned in the 'vertical' orientation, along the long axis of the column, were the most prominent for all vertebral levels. The relative prominence of horizontal to vertical elements was generally constant along the column below T5. In contrast, the relative prominence of oblique to vertical elements declined in the cranio-caudal direction, particularly in individuals aged > or = 60 years. The ratio of 'large' (x > 0.3 mm) to 'small' (0.15 mm < or = x < or = 0.3 mm) elements was unchanged cranio-caudally in specimens < 60 years. However, in individuals > or = 60 years, large elements increased in relative prominence in the caudal direction. These results suggest that a basic orthogonal pattern of trabeculae is found along the male human spine, regardless of differences in vertebral body size. Power-spectral analysis is shown to yield information summarizing the predominant orientations and sizes of radiographically rendered architectural elements of vertebral cancellous bone, to define the effects of ageing on architecture, and to identify broad structural differences between vertebral levels in the adult male spine.

Postmenopausal Caucasian women aged less than 80 years (n = 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (-E study), age 70.8 +/- 0.8 years (mean +/- SEM) were all treated with calcium (Ca) 1.0-1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on, 3 months off, initial dose 60 mg/day; group F CaD, n = 34) or no NaF (group CaD, n = 31). In the second study 34 patients, age 65.5 +/- 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n = 17; E CaD, n = 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to +/- NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p = 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft -7.3% (p = 0.005); femoral shaft -7.1% (p = 0.004); distal forearm -4.0% (p=0.004); total hip -4.1% (p = 0.003); and femoral neck -3.5% (p = 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p < 0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox's proportional hazards model, in the -E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p = 0.008, 95% CI 2.3-255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: -23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups; there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts, if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor.

There are limited data detailing the pattern of age and gender-related changes to the thoracic vertebral bodies and intervertebral discs. A retrospective MR investigation, involving T1-weighted midsagittal images from 169 cases, was undertaken to examine age influences on the anterior wedge (anteroposterior height ratio or Ha/Hp), biconcavity (midposterior height ratio or Hm/Hp), and compression indices (posterior height/anteroposterior diameter or Hp/D) of the thoracic vertebral bodies. Disc degenerative changes in the annulus, nucleus, end-plate and disc margin were noted on T2-weighted sagittal images for the 169 cases, based on a 3-level grading system. A linear age-related decline in the Ha/Hp and Hm/Hp indices was noted. The Hp/D index increased during the first few decades of life, then decreased gradually thereafter. The prevalence of abnormal findings in the annuli, nuclei and disc margins increased with increasing age, particularly in the mid and lower thoracic discs. Greater disc degenerative changes were observed in males. These findings provide further insight into the nature of thoracic vertebral shape changes across the lifespan, and the typical patterns of degeneration of the thoracic intervertebral discs.

Objective: The aim of this study was to examine age, gender, and segmental trends in thoracic vertebral body shape, utilising thoracic spine magnetic resonance images involving an age range spanning the life span., Design: A quantitative, cross-sectional, retrospective study design involving a sample of convenience., Background: Thoracic vertebral shape data are commonly derived from radiographic resources. The non-ionising properties of magnetic resonance imaging and availability of digital data for image analysis suggest potential for MR-based morphometric studies. For the thoracic spine, there is limited vertebral shape data on males, while few studies have examined the pattern of age-related changes across the life span., Methods: Morphometry was performed on 220 mid sagittal T1-weighted MR images using image analysis software. Three indices of vertebral shape were utilised: the antero-posterior height ratio or anterior wedge index, mid-posterior height ratio or biconcavity index, and ratio of posterior vertebral height to mid antero-posterior diameter or compression index., Results: Different segmental patterns were noted for the vertebral shape indices. Significantly lower mean values were noted in males for the compression index. Age trends were significant, with a linear age-related decline demonstrated for the anterior wedge and biconcavity indices, and a quadratic trend noted for the compression index., Conclusions: Thoracic vertebral body shape may be uniquely described using specific shape indices, for examining various segmental, gender and age-associated changes., Relevance: These results suggest the importance of defining specific reference criteria for thoracic vertebral body shape indices, particularly age-related data encompassing a wide age range. Magnetic resonance studies enable interpretation of vertebral shape data in relation to the wide spectrum of pathologies afflicting the thoracic spine, without the concerns of ionising radiation.

Objectives: To compare the Cobb technique for measuring kyphosis with an alternative Cobb method and a computer-assisted curve assessment technique, and to examine the influence of vertebral body and disc shape on kyphosis., Methods: Kyphosis measurements were derived from 93 lateral spinal radiographs or sagittal computed tomography images of cadaveric spines, using: (i) a computer-assisted method for estimating radius of curvature; (ii) the traditional Cobb method; and (iii) an alternative Cobb method. Regression models were applied for agreement analyses, and to examine the relative contribution of vertebral body and disc shape on the extent of curvature. Results and conclusions. Strong associations existed between curvature and angle data derived from the three methods, confirming the clinical utility of these techniques for the quantification of thoracic kyphosis. However, the traditional Cobb method tended to overestimate kyphosis in the presence of vertebral body end-plate deformation. The degree of kyphosis was strongly reflective of the extent of deformity of the vertebral bodies, and to a lesser extent the shape of the thoracic discs.

In a randomized trial involving 71 postmenopausal osteoporotic women with vertebral compression fractures, radiocalcium absorption studies using the (45)Ca single isotope method (alpha) were performed at baseline and after 8 months of treatment with either continuous combined hormone replacement therapy (HRT, as piperazine estrone sulfate 0.625-0.937 mg daily +/- medroxyprogesterone acetate 2.5 mg daily depending on uterine status) or HRT plus calcitriol 0. 25 microg twice daily. A calcium supplement of 600 mg nocte was given to only those women who had a daily calcium intake of less than 1 g per day at baseline, as assessed by recalled dietary intake. There was a significant decrease [0.74 (+/- 0.35 SD) to 0.58 (+/- 0. 22), Dalpha = -0.17 (+/- 0.26), p<0.0005] in alpha at 8 months compared with baseline in the HRT-treated group, but a significant increase [0.68 (+/- 0.31) to 0.84 (+/- 0.27), Dalpha = +0.16 (+/- 0. 30), p<0.003] in the HRT-plus-calcitriol treated patients, resulting in alpha being significantly higher after 8 months in the latter group than in the HRT-only group. Although 72% of the patients had been supplemented with calcium between the first and second studies, separate analyses revealed that the change in calcium intake had not affected the result. Further breakdown of the groups into baseline 'normal' absorbers (alpha >/=0.55) and 'malabsorbers' (alpha <0.55) revealed that alpha decreased with HRT treatment only in the normal absorbers, and remained stable in the malabsorbers. Conversely, following HRT plus calcitriol treatment, alpha increased only in the malabsorbers, the normal absorbers in this group remaining unchanged. In conclusion, our data show that HRT, of the type and dose used in this study, did not produce an increase in absorption efficiency; it was in fact associated with a fall. Increased absorption efficiency cannot be achieved unless calcitriol is used concurrently, and then only in patients with malabsorption. Calcitriol also had a significant effect in normal absorbers in that it prevented the decline in alpha seen with HRT alone, and thus should be considered in all patients with postmenopausal osteoporosis treated with HRT.

Twenty-five years after the first paper on etidronate in Paget's disease, there are few published papers that address bisphosphonate resistance as a specific clinical phenomenon. We report our data from two studies. Study 1 is a retrospective study of 20 patients with moderate to severe disease who were treated with intravenous (iv) pamidronate (221 +/- 18 mg [SEM]; range 60-360 mg), and after biochemical remission and relapse were retreated with generally larger iv dosage (293 +/- 28 mg; range 180-600 mg). The nadir bone turnover values were similar: plasma alkaline phosphatase (pAP) in 20 patients was 243 +/- 40 IU/l (mean +/- SEM) after the first course, and 267 +/- 44 IU/l after the second (reference range [RR] 35-135 IU/l). Likewise, fasting urinary hydroxyproline excretion (HypE) in 14 of the 20 patients was 4.5 +/- 1.1 micromol/LGF and 4.1 +/- 0.9 micromol/LGF, respectively (RR 0.40-1.92 micromol/LGF). However the minimum duration of biochemical remission was significantly shorter after the second course-10.9 +/- 1.7 months (first) and 5.6 +/- 0.9 months (second) (p < 0.03; Friedman's ANOVA n = 17). A subgroup of 10 patients who were followed for three courses showed a significantly higher pAP nadir in the third course. Study 2 is a prospective study of 40 patients, 23 previously untreated (NILPREV) and 17 previously treated with iv pamidronate (PAMPREV) and in biochemical relapse, who were randomly allocated to either oral alendronate 40 mg daily in 3 month units, or iv pamidronate 60 mg every 3 months. Treatment was continued until pAP and fasting urinary deoxypyridinoline/creatinine (Dpy/Cr) ratios (RR 5-27 micromol/mol) were both in the reference range, or a clear plateau in each marker developed. At baseline, there were no significant differences in either marker between the two NILPREV groups and between the two PAMPREV groups. Using log-transformed data, in NILPREV the pAP reductions were significant and similar over the first 6 months. However, although each Dpy/Cr reduction was also significant, the difference in responses favored alendronate (p < 0.015). In PAMPREV both markers showed no significant response to pamidronate; comparison showed a significantly greater response to alendronate (pAP p < 0.02; Dpy/Cr p < 0.002). Using two-way ANOVA, the pAP responses to alendronate in NILPREV and PAMPREV were similar and those to pamidronate were different (p = 0.034). The percentage of patients with both markers in the RR at 6 months or earlier were identical in NILPREV patients: alendronate 87% and pamidronate 87%. However in PAMPREV they were different: alendronate 83% and pamidronate 0% (p = 0.003). These data indicate: 1) patients treated with the same aminobisphosphonates for two courses show similar nadir values of bone turnover markers but a shorter remission time after the second course. In a third course the nadirs are significantly higher; and 2) in the alendronate/pamidronate comparison, NILPREV and PAMPREV patients showed similar pAP responses to alendronate, but significantly different responses to pamidronate. Thus, patients showing acquired partial resistance to one aminobisphosphonate (usually after two or more previous courses) are still capable of remission after exposure to another compound of the same class.

Objective: The aim of this study was to quantify the morphology or shape of thoracic vertebral bodies and intervertebral discs, and to examine the ex vivo association of thoracic kyphosis with these shape parameters., Design: A quantitative, retrospective study design was applied to define vertebral body and disc influences on thoracic kyphosis., Background: Age-related progression of thoracic kyphosis is a well-defined process that is influenced by the morphology of vertebral bodies. However, little is known about the contribution of intervertebral disc shape to the thoracic curvature., Methods: Vertebral and disc morphology, as represented by antero-posterior height ratios, were quantified in 93 lateral spine radiographs and midsagittal computed tomography films of ex vivo spines. Kyphosis was indicated by the Cobb angle. Linear and stepwise regression were applied to examine relationships for cumulative (T1-T12) and regional (T4-T9) analyses., Results: Vertebral morphology was highly predictive of thoracic curvature, while a poorer association was noted for disc morphology. The combined influence of both accounted for >85% of the variability in kyphosis. There was a trend for a more pronounced anterior wedge configuration of the midthoracic vertebral bodies and discs. Higher associations between variables were also noted in this region., Conclusions: The normal kyphosis of the thoracic spine reflects the morphological adaptation of both the vertebral bodies and intervertebral discs., Relevance: This study contributes new data on the thoracic spine, particularly the characteristics of thoracic discs and their contribution to kyphosis genesis. Future directions for morphology studies should encompass more detailed examination of the thoracic discs and greater emphasis on the midthoracic segments, considering the prevalence of osteoporosis related fractures and subsequent deformity at these levels.

It has been shown previously that intravenous pamidronate treatment for severe Paget's disease is associated with appendicular bone loss. This 2 year study was designed to determine whether cotreatment with calcitriol and a calcium supplement would prevent this. Intravenous pamidronate was used to treat 49 patients with symptomatic Paget's disease. Patients were stratified into two groups of differing biochemical severity based on hydroxyproline excretion (HypE) expressed as micromoles per liter of glomerular filtrate (GF): (1) a severe group with HypE > 10 micromol/L GF; and (2) a moderate group with HypE 5-10 micromol/L GF. Within each group, patients were randomly allocated to receive supplements of calcium and calcitriol (supplemented) or no supplements (unsupplemented) after initiation of pamidronate therapy. The severe group received 360 mg of pamidronate as six doses of 60 mg once weekly and the moderate group received 240 mg as four weekly doses of 60 mg. Patients were followed for 24 months following treatment and had serial bone densitometry of the forearm measured as well as urine and plasma biochemistry. When the groups were combined, the unsupplemented patients showed a decrease in bone mineral density (BMD) at the ultradistal forearm site, which persisted to 24 months. Those supplemented with calcium and calcitriol showed an increase in BMD and the difference between the two groups was significant at all times posttreatment (p < 0.03). When the groups were analyzed separately, those with moderate disease again showed significant differences in BMD between supplemented and unsupplemented patients at all timepoints. In the severe group, the differences did not reach statistical significance due to smaller patient numbers. Similar changes in BMD were also observed at the forearm shaft site. When serial parathyroid hormone (PTH) levels (with the moderate and severe groups combined) were plotted against time since treatment the rise in PTH in the supplemented patients was less than the rise in the unsupplemented patients (p < 0.04). These results suggest that forearm bone loss after intravenous pamidronate treatment for moderate-to-severe Paget's disease can largely be prevented by administration of calcium and calcitriol. The mechanism may be a blunting of the secondary hyperparathyroidism that occurs after intravenous pamidronate. These findings may have wider application in moderate-to-severe Paget's disease treated with other bisphosphonates.

Morphometric X-ray absorptiometry (MXA) offers some potential advantages over spinal radiography for the quantitative evaluation of vertebral fractures in individuals with spinal osteoporosis. This ex vivo study examined the accuracy of MXA and quantitative morphometry (QM) for the evaluation of vertebral height, in relation to direct measurements from cadaveric vertebral columns. Spinal radiographs and MXA scans were obtained from nine cadaveric vertebral columns (mean age at death 64 years). Anterior, middle and posterior vertebral body heights of all segments from T4 to L4 were measured interactively using MXA software and QM (from the spinal radiographs), and compared with direct measurements derived using digital callipers following cadaveric dissection. Coefficients of variation for repeat QM and MXA scan analysis were less than 2%. The QM and MXA measurements were both strongly correlated (r(2) = 0.99) with the direct measurements, with accuracy errors of between 2.6% and 4.3%, and 4.5% and 4.8%, for QM and MXA respectively. At the three measurement sites, analysis of measurement differences showed that QM tended to overestimate the true height and MXA tended towards under-estimation. The mean difference between the direct measurements and QM measurements ranged from 2.7% to 8.7%, and the mean difference between direct and MXA measurements ranged from -2. 9% to 4.1%. There was strong linear association between the MXA and QM measurements (r(2) = 0.99) with mean differences at the three measurement sites ranging from -4.1% to -5.9%. Under the optimal (ex vivo) scanning conditions used in this study, MXA is comparable to spinal radiography for the assessment of vertebral height. Further studies are required to determine the conditions under which satisfactory MXA image resolution and measurement accuracy can be achieved in a clinical population.

Equatorial (d) and meridional (D) spacings of native rat tail tendon (RTT) and unmineralized native turkey leg tendon (UTLT) were measured at ambient and liquid-nitrogen temperatures, using X-ray diffraction. Cooling of air-dried RTT or UTLT caused little change in d, which was approximately equal (1.1 nm) in the two tissues before and after cooling. For fully hydrated RTT or UTLT, cooling caused the familiar broad equatorial diffraction pattern to increase in sharpness to more resemble the pattern seen in dehydrated tissue. The d-spacings of hydrated RTT and UTLT fell by 0.12 nm (8.5%) and 0.19 nm (13%), respectively to values seen (at ambient temperature) when the tissue water content is the maximum possible in the absence of unbound water (0.5 g water/g dry collagen). These results can be explained by the movement of water within the fibril. In tissue with a water content of greater than 0.5 g/g dry collagen the spacings reflecting the lateral packing of the axially-linked tropocollagen molecules comprising a collagen fibril are determined partly by the unbound component of intermolecular hydration. As the bulk water between the fibrils freezes, this mobile component remains initially unfrozen as the tissue is cooled below zero degree C. It diffuses from the intermolecular spaces into the interfibrillar spaces where it also rapidly freezes. This allows the d-spacing to decrease to the value appropriate for the presence of bound intermolecular water only. The mechanism is likely to be an energetically favourable relaxation of the lateral positions of the tropocollagen molecules from a quasi-hexagonal arrangement to hard-disk liquid-like packing. The results and methods of this study may be applicable in the elaboration of more complex collagenous systems.

The estimation of vertebral fracture risk in individuals with suspected osteopenia is commonly based on measurements of lumbar spine bone density. The efficacy of vertebral size and deformity, as assessed by vertebral morphometry, in the prediction of fractures has been less studied. In an ex vivo investigation the regional relationships between vertebral size, vertebral deformity, bone density and compressive strength throughout the thoracolumbar spine were examined. In 16 vertebral columns (T1-L5) the bone mineral content (BMC) and bone mineral density (BMD) of each segment were measured using lateral projection dual-energy X-ray absorptiometry, and the vertebral cancellous density (VCD) and mid-vertebral cross-sectional area (CSA) measured using quantitative computed tomography. Vertebral body heights were determined from mid-sagittal CT scans, and vertical height ratios calculated for each segment. The failure load and failure stress of the isolated vertebral bodies were determined using a material testing device. Separate analyses were performed for the upper (T1-4), middle (T5-8) and lower (T9-12) thoracic, and lumbar (L1-5) segments. In all regions, failure load was strongly correlated with BMD (r = 0.82-0.86), moderately correlated with VCD (r = 0.60-0.71) and vertebral height (r = 0.22-0.49), and poorly correlated with the height ratios (r = 0.04-0.33). Failure stress was best predicted by BMD (r = 0.73-0.78) and VCD (r = 0.70-0.78) but was poorly correlated with all morphometric variables (r = 0.01-0.33). The segmental correlations between BMD and VCD ranged form r = 0.49 to r = 0.79. For all regions, BMD and VCD were included in the stepwise regression models for predicting failure load and failure stress. Either the mid-vertebral height or CSA were included in all the failure load models, while mid-vertebral height was included in only one of the failure stress models. The results suggest that vertebral deformity and size (as assessed by vertebral morphometry) make only a minor contribution to the prediction of vertebral strength additional to that provided by bone densitometry alone. The consistent regional relationships between variables appear to support the practice of global fracture risk assessment based on lumbar spine densitometry.

An intravenous dosage schedule using pamidronate disodium, based on biochemical severity, was used to treat 71 patients with Paget's disease who had no previous bisphosphonate treatment. Disease severity was stratified by fasting hydroxyproline excretion (HypE): Group (Gp) I (mild disease; HypE < 5.0 mumol/LGF) received a total dose of 120 mg; Gp II (moderate; HypE 5.00-9.99) received 180 mg; and Gp III (severe; HypE > or = 10) received 240 mg. Within each group patients were randomly allocated to receive daily 30 mg or 60 mg infusions. Observations for 2 years included pain scores, indices of bone turnover, and radiology of lytic lesions. There was no difference in biochemical responses, or in the percentage of patients with early fever, between the 30 mg and 60 mg daily subgroups; for convenience, 60 mg infusions are recommended. Neutrophils and total white cell counts were both significantly below baseline 4 days after the first infusion; lymphocytes were significantly reduced by day 2; and all three measures had returned to within the reference range by day 6. Remission was assessed at 6 months, when both plasma alkaline phosphatase (ALP) and HypE had reached stable nadirs. Increasing severity was associated with increasing resistance to suppression of HypE at 6 months to within the reference range: Gp I, 87%; Gp II, 44%; and Gp III, 0% (p < 0.0001 by chi-square test). Biochemical relapse at 2 years (defined as ALP 50% above the 6 month level) was also dependent on initial disease severity (Gp I, 6%; GpII, 39%; Gp III, 62%; p < 0.0005 by chi-square test). There was no association between time to relapse and either initial dose or log dose. Radiologic lytic lesions (in 22 patients) were all in remission at 3 months; however, relapse rates at 2 years appeared to be severity-dependent: Gp I, 13%; Gp II, 43%; and Gp III, 57% (n.s. by chi-square test). Remission rates based on a fall to < 50% of pretreatment of either HypE or ALP were more in accord with lytic lesion remission rates than were rates based on HypE falling to within the reference range. Pamidronate produced a significant reduction from baseline in Pagetic bone, Pagetic joint, and unrelated musculoskeletal pain in the first 6 months (p < 0.0001). From 0 months to 2 years the maintenance of improvement in bone pain (p < 0.005) and joint pain (p < 0.05) was significantly better than in unrelated pain. Pamidronate is a safe, welltolerated, and effective treatment for Paget's disease. In spite of larger dosage in severe disease, increasing severity was associated with resistance to normalization of biochemistry and a higher incidence of biochemical and radiological relapse at 2 years. Our current dosage recommendation would be for two 60 mg infusions for mild disease (Gp I); and four 60 mg infusions for moderate disease (Gp II). Severe disease (Gp III) remains a challenge; regardless of dosage, the majority of patients will be in relapse 2 years after a single course of treatment.

We have compared the use of new markers of bone turnover in the assessment and treatment of Paget disease and made observations on the mechanisms of bone resorption. Urine hydroxyproline (Hyp) as a bone resorption marker and serum alkaline phosphatase (ALP) as a bone formation marker have traditionally been used to biochemically assess and monitor treatment of Paget disease. Hyp and total ALP were compared with total urine pyridinoline (Pyd) and deoxypyridinoline (Dpd), free urine Pyd and Dpd, urine type I collagen N-terminal cross-linked telopeptide (NTX), type I collagen C-terminal propeptide (PICP), serum osteocalcin, and bone ALP in Paget patients treated with pamidronate. Patients were divided into three biochemical severity-based treatment groups by their fasting urine hydroxyprolline excretion (HypE) levels (Le., group 1, HypE < 5.0 mumol/l of glomerular filtrate [GF]; group 2, HypE of 5.0-9.9 mumol/l of GF; group 3, HypE > 10 mumol/l of GF). Group 1 received one 60 mg intravenous infusion of pamidronate, and groups 2 and 3 received four and six 60 mg infusions at weekly intervals, respectively. Fasting serum and morning urine specimens were taken before and at 2, 6, 13, and 26 weeks after starting treatment. Baseline Z scores were used to compare separation of patient results from normal, and the difference in Z scores from baseline to 13 weeks was used to compare response to treatment. Baseline discrimination and response to treatment at all disease activity levels was greatest for NTX and was poor for osteocalcin, PICP, and C-terminal cross-linked telopeptide of type I collagen (ICTP). The other markers showed good discrimination and response at medium and high levels of disease activity. NTX, total Pyd and Dpd, free Pyd and Dpd, and ICTP are all pyridinoline cross-link-based markers, but discrimination and response by NTX was generally much greater than for the others. Determination of the mechanism of the difference between NTX and other cross-link measures is necessary for appropriate use of the markers and may also lead to a better understanding of the bone resorption process. It has been proposed that the greater sensitivity and discrimination of NTX is because it is more bone-specific than the other cross-link markers with significant amounts of free Pyd and Dpd coming from nonbone sources. We propose another model where the proportion of peptide-bound cross-links such as NTX may be increased in high bone turnover states partly due to a rate-limiting step in their degradation to free cross-links. Conditions with high bone resorption rates would have high levels of NTX that would decline rapidly when resorption rates fall to a level where the capacity to degrade NTX matches the rate of production.