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Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab.

(18)F-fluoride positron emission tomography ((18)F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an (18)F-PET scan, and bone plasma clearance, K i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K i between the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 μm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K i corrected for BMAD (K i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of (18)F-PET as a diagnostic tool for identifying CKD patients with ABD.

Abnormalities of bone metabolism and increased vascular calcification are common in chronic kidney disease (CKD) and important causes of morbidity and mortality. The Wnt signaling pathway may play a role in the bone and vascular disturbances seen in CKD, termed collectively "CKD-MBD." The aim of the study was to investigate the possible association of circulating concentrations of the secreted Wnt signaling inhibitors DKK1 and sclerostin with BMD and arterial stiffness in predialysis CKD. Seventy-seven patients (48 M, 29 F), mean age 57 (SD = 14) years with CKD stages 3B (n = 32) and 4 (n = 45) were studied. Sclerostin, DKK1, PTH, and 1,25(OH)(2)D were analyzed. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH), and forearm (FARM). Arterial stiffness index was determined by contour analysis of digital volume pulse (SI(DVP)). There was a positive correlation between sclerostin and age (r = 0.47, p < 0.000). Sclerostin was higher in men than women (p = 0.013). Following correction for age and gender, there was a negative association between GFR and sclerostin (p = 0.002). We observed a positive association between sclerostin and BMD at the LS (p = 0.0001), FN (p = 0.004), and TH (p = 0.002). In contrast, DKK1 was negatively associated with BMD at the FN (p = 0.038). A negative association was seen between DKK1 and SI(DVP) (p = 0.027). Our data suggest that the Wnt pathway may play a role in CKD-MBD. Prospective studies are required to establish the clinical relevance of sclerostin and DKK1 as serological markers in CKD.

Uncertainties exist regarding whether FGF-23 production is influenced by PTH and its involvement in bone formation. We evaluated FGF-23 response and its relation to changes in biomarkers of bone formation following intermittent PTH treatment. Twenty-seven women with a mean [SD] age of 75.8 [5.4] years with postmenopausal osteoporosis were treated with PTH(1-34) for 18 months. Bone mineral density (BMD) was measured at 6 and 18 months at the lumbar spine (LS) and total hip (TH). Blood samples were obtained at baseline, 1-3, 6-9, and 12-18 months. Serum calcium, phosphate, PTH, 25(OH)vitamin D, 1,25(OH)(2)vitamin D, markers of bone turnover, FGF-23, and sclerostin were measured. BMD increased at both the LS (11.6%, P < 0.001) and TH (2.5%, P < 0.01). The bone formation marker P1NP increased early (baseline mean [SD] 39.9 [24.4] μg/l, 1-3 months 88 [37.9] μg/l; P < 0.001) and remained higher than baseline throughout 18 months. FGF-23 also increased, with a peak response at 6-9 months (increase 65%, P = 0.002). Serum phosphate remained stable. A significant increase in 1.25(OH)(2)vitamin D (P = 0.02) was seen at 1-3 months only. A small but significant reduction in sclerostin was seen at 6-9 (P = 0.02) and 12-18 months (P = 0.06). There was a positive correlation between changes in P1NP and FGF-23 (6-9 months r = 0.78, P < 0.001). FGF-23 is increased by intermittent PTH(1-34). This is related to early changes in P1NP, suggesting that the skeletal effects of PTH may involve FGF-23. Further studies are required to elucidate this.

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (P = 0.04). There was a significant negative correlation between PWV and hip BMD (r = -0.35, P = 0.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (P = 0.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (r = 0.44, P = 0.001), which remained significant when adjusted for age (P = 0.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.

Treatment of postmenopausal osteoporosis (PMO) is based primarily on antiresorptive agents, including hormone replacement therapy (HT). To evaluate whether anabolic therapy together with HT provides additional benefits in the treatment of PMO, we evaluated the effects of parathyroid hormone (PTH) 1-84 in postmenopausal women with low bone mineral density (BMD) who were receiving chronic (> or =6 months) HT. Subjects were randomized to receive 100 microg PTH(1-84) or placebo injections daily for 24 months (n = 90/group). The primary efficacy outcome was change from baseline in lumbar spine BMD. Secondary end points included changes in hip and distal radius BMD, bone turnover markers, and fracture incidence. The study was terminated early following recommendations regarding HT for PMO. At 18 months, the mean increase in lumbar spine BMD was 7.9% for PTH(1-84) subjects vs. 1.5% for those receiving HT alone; between-group differences were significant at 6 months and persisted throughout the study. Lumbar spine BMD increased in 94% of women receiving PTH(1-84) compared to 59% for HT alone. Femoral neck BMD and bone turnover markers were significantly higher in PTH(1-84)-treated subjects, but the changes in total hip and distal radius BMD were not significant. PTH(1-84) treatment was generally well-tolerated, with hypercalciuria, hypercalcemia, nausea, vomiting, and dizziness reported more frequently in the HT + PTH(1-84) group. In conclusion, addition of PTH(1-84) to stable HT produced marked increases in lumbar spine BMD and may represent an additional approach to the treatment of PMO women receiving HT.

Measurement of skin thickness has been proposed as a method of predicting low bone mineral density (BMD) and the consequent risk of osteoporotic fracture in postmenopausal women. The Episcan I-100 device is a new type of ultrasound device that uses high-frequency (20 MHz) ultrasound to measure skin thickness using a small probe placed on the skin. The aims of this study were to investigate whether there is any correlation between skin thickness as measured by ultrasound and BMD as measured by dual-energy X-ray absorptiometry, to establish whether patients with osteoporotic fractures have reduced skin thickness, and to investigate the relationship between skin thickness and clinical risk factors for osteoporosis. Short-term precision based on duplicate measurements on 132 patients gave a coefficient of variation of 3.2%. Small but statistically significant correlations between skin thickness measurements and BMD measurements at axial and peripheral sites were observed (r = 0.21-0.29, P < 0.0001). An odds ratio of 1.42 was found for identifying patients with a prevalent fracture at any skeletal site, suggesting that skin thickness measurements can discriminate patients with fractures. ROC analyses also demonstrated the ability of skin thickness measurements to discriminate fracture patients from controls. When measured by the decrease in Z-score, clinical risk factors for low BMD were found to affect skin thickness measurements to a similar extent as spine and hip BMD measurements. Skin thickness measurements have limited utility in identifying patients with low bone mass.

The aim of this study was to determine whether forearm bone mineral density (BMD) measurements are affected by clinical risk factors for osteoporosis to the same extent as spine and hip BMD. The study population consisted of 1,009 female patients and volunteers, of whom 238 were premenopausal. Women were placed into seven groups according to which clinical risk factor they had (women could be placed in more than one group): (1) atraumatic fracture since the age of 25 years, (2) report of X-ray osteopenia, (3) predisposing medical condition or use of therapy known to affect bone metabolism, (4) premature menopause before the age of 45 years or a history of amenorrhea of longer than 6 months' duration, (5) family history of osteoporosis, (6) body mass index (BMI) <20 kg/m(2), and (7) current smoking habit. Forearm BMD was measured using an Osteometer DTX-200 peripheral dual-energy X-ray absorptiometry scanner, and spine and hip BMD measurements were obtained on a Hologic QDR-4500 scanner. Manufacturers' reference ranges were used to calculate Z scores for the spine and forearm, and the NHANES III reference range was used to calculate Z scores for the hip. Multivariate regression analysis was used to estimate the mean decrease in Z score associated with each clinical risk factor. The Z-score reductions associated with the seven risk factors were similar for forearm and central BMD measurements. For forearm measurements, Z-score decreases associated with a history of atraumatic fracture (-0.25), a medical condition or therapy known to affect bone metabolism (-0.26), premature menopause or history of amenorrhea (-0.30), and BMI <20 kg/m(2) (-0.82) were all statistically significantly different from zero (P < 0.05). With an increasing number of risk factors in each individual, the mean Z score at each measurement site became progressively more negative. In conclusion, clinical risk factors for low BMD affect forearm BMD measurements to a similar extent as central BMD.

The ability to assess a patient's risk of fracture is fundamental to the clinical role of bone densitometry. Fracture discrimination is quantified by the relative risk (RR), defined as the increased risk of fracture for a 1 standard deviation decrease in bone mineral density (BMD). The larger the value of RR, the more effective measurements are at identifying patients at risk of fracture. Epidemiological studies show that RR values for predicting the risk of any fracture are approximately the same for all BMD measurement sites. In this study, we show theoretically that this interesting observation is predictable and a consequence of two related observations: (1) that fracture prediction by BMD measurement sites distant from the fracture site is quantitatively explained by the correlation of BMD measurements and (2) that all correlation coefficients between distant BMD sites are comparable, with values in the range r = 0.55-0.65. The first of these conditions (referred to as the correlation hypothesis) is important because it sets a lower limit on the RR values at distant BMD sites on the assumption that measurements at these sites contain no independent information about fracture risk over and above that provided by their correlation with the fracture site BMD. If the correlation hypothesis is true, the present study points to the importance of the correlation coefficient between BMD sites as a key index that is indicative of the ability of different types of measurement to predict fracture risk. If, on the contrary, the correlation hypothesis is not valid, there is scope to improve bone densitometry by further studies to better identify those measurements that do provide independent information about fracture risk and how best to integrate this information with existing techniques to improve decision making.

It is widely believed that the most reliable BMD measurement for predicting fracture risk at any given skeletal site is one made at the fracture site itself. This study examines the hypothesis that the ability of BMD measurements at other distant sites in the skeleton remote from the fracture site to predict fracture risk is due to their correlation with the BMD measurements at the fracture site. We refer to this assumption as the correlation hypothesis. We show that the correlation hypothesis predicts the relationship betadist = rbetafrac, where beta is the gradient of the exponential relationship between fracture risk and Z-score, betafrac is the beta-value for the fracture site, betadist the beta-value for the distant BMD site, and r is the correlation coefficient between the Z-scores at the two sites. In practice it is important to consider the effect of BMD measurement errors on the (r, beta) relationship. We show that the effect of errors at the distant site is to reduce betadist and r in a way that preserves their original relationship. When errors at the fracture site are taken into account the effect on the (r, beta) plot is for the point representing the fracture site to fall below the extrapolation of the straight-line relationship predicted for the points representing the distant BMD sites. We tested the correlation hypothesis by using data from the Study of Osteoporotic Fractures to examine the (r, beta) plots for hip, spine and forearm fractures. For the hip the data are consistent with a straight-line relationship and suggest that measurements made at other sites provide no additional information about fracture risk over and above that provided by hip BMD itself. For spine and forearm fractures the data show that distant sites do provide additional information about fracture risk in a way that is quantitatively consistent with the BMD measurement errors reported in cadaver studies. It is clear that random BMD errors at the fracture site cause loss of information about fracture risk and that some of this lost information is recoverable from measurements made at other sites in the skeleton. Overall, this study points to BMD correlation as an important factor in explaining the ability of measurements made at distant sites to predict fracture risk.

The DMS Lexxos is the first cone-beam dual X-ray absorptiometry (DXA) system capable of performing bone mineral density (BMD) measurements of the spine and hip. By using a two-dimensional (2-D) detector array rather than the linear array used with conventional fan-beam DXA systems, image acquisition time on Lexxos is only 1.5 s. However, the need to correct for the large signal from scattered radiation reaching the detector is a potential source of error in cone-beam DXA. The aim of this clinical evaluation of the Lexxos bone densitometer was to investigate the relative accuracy of cone-beam BMD measurements compared with conventional DXA by performing an in vivo cross-calibration study with an established fan-beam system, the Hologic QDR-4500. Spine (L1-L4) and hip BMD measurements were performed in 135 patients (111 women, 24 men) referred for a bone densitometry examination. Duplicate Lexxos measurements were performed in 27 female patients to evaluate precision. On average, Lexxos spine and femoral neck BMD measurements were 2% lower than those on the QDR-4500, whereas total hip BMD was 5% higher. Larger differences were found for the trochanter and Ward's triangle regions. For all sites, Lexxos BMD measurements showed a strong linear relationship with those measured on the QDR-4500 with correlation coefficients in the range r = 0.95 to 0.97 for the clinically important spine, femoral neck, and total hip regions. The root mean standard error (RMSE) between Lexxos and QDR-4500 BMDs ranged from 0.037 g/cm(2) for the femoral neck to 0.060 g/cm(2) for the spine, whereas Lexxos precision was 1.3% for total hip, 2.0% for femoral neck, and 2.3% for spine BMD. Although for the hip BMD sites the RMSE and precision of Lexxos measurements were similar to studies of pencil-beam and fan-beam DXA systems, the results for the spine were poorer than expected. The findings of this study suggest that Lexxos corrects accurately for the effects of scattered radiation at the detector, but that the precision of spine BMD measurements may be limited by involuntary patient movement between the high and low energy X-ray exposures.

The aim of this study was to determine whether calcaneal quantitative ultrasound can discriminate between women with and those without fragility fracture at (1) the wrist or (2) at sites other than the spine, hip, or forearm, as well as axial DXA measurements of BMD can. The study population consisted of 342 postmenopausal Caucasian women who were placed into one of three groups: (1) healthy women with no clinical risk factors for osteoporosis (n = 240); (2) women with a history of atraumatic fracture at the wrist (n = 50); (3) women with a history of atraumatic fracture at a skeletal site other than the spine, hip, or wrist (n = 52). Subjects had DXA measurements of the lumbar spine (LS), femoral neck (FN), and total hip (THIP), and calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements on the Hologic Sahara (s) and Osteometer DTUone (d). Z-scores were calculated using the mean and SD obtained from the healthy postmenopausal group. All the BMD and QUS variables were significantly reduced in women reporting a fracture of the wrist or at a site other than the spine, hip, or forearm. When the group of women with a history of wrist fracture were compared with the postmenopausal controls, age-adjusted logistic regression yielded odds ratios associated with a 1 SD decrease, that were significant for both BMD and QUS, averaging 2.2. The AUC values ranged from 0.65 for FN BMD to 0.75 for BUAd. BMD and QUS measurements were also significantly reduced in women reporting a skeletal fracture at a site other than the spine, hip, or wrist, and odds ratios for BMD and QUS were significant, averaging 1.7. BMD and QUS showed similar fracture discriminatory abilities that were not significantly different from one another. In conclusion, calcaneal QUS can discriminate between women with and those without fracture at the wrist or at sites other than the spine, hip, or forearm as well as axial DXA measurements of BMD can.

Genetic factors are important in the pathogenesis of osteoporosis but less is known about their possible role in predicting response to anti-osteoporotic therapy. Previous studies have shown that a polymorphic Sp1 binding site in the collagen type 1 alpha 1 gene (COLIA1) is associated with bone mineral density (BMD) and osteoporotic vertebral fracture. In this study we sought to determine if the COLIA1 Sp1 polymorphism might also act as a predictor of the response to treatment of osteoporosis with bisphosphonate therapy. The study group comprised 108 perimenopausal women with osteopenia who had been randomized to receive cyclical etidronate therapy for 2 years with a 1-year treatment-free follow-up as part of a randomized placebo controlled trial. Bone mineral density was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry and genotyping performed on DNA extracted from peripheral blood leukocytes using standard techniques. The distribution of COLIA1 genotypes was similar to that previously reported in Caucasians with 69 (63.9%) "SS" homozygotes, 38 (35.2%) "Ss" heterozygotes, and 1 (0.9%) "ss" homozygote. There was no association between COLIA1 genotype and response of lumbar spine BMD during etidronate treatment or the follow-up phase. The response of femoral neck (FN) BMD, however, differed significantly between the genotype groups throughout the study period, such that FN BMD increased by 0.56%, 2.36%, 1.82%, and 1.32 % after 1, 2, 2.5, and 3 years, respectively in the "SS" genotype group, compared with -1.56%, -0.62%, -0.37%, and -0.66% in the "Ss/ss" genotype groups (P = 0.002). The data presented here show that site-specific heterogeneity exists in the response of BMD to cyclical etidronate therapy, which is related to COLIA1 genotype. Our data raise the possibility that COLIA1 genotyping could be used to target etidronate therapy to those most likely to respond in terms of FN BMD, with potential benefits in terms of economic cost and clinical outcome.

A common problem encountered in clinical medicine is the classification of a lung lesion (nodule/opacity) on conventional imaging. Often attempts at biopsy are unsuccessful or are falsely reassuring, and the decision to send the patient for more invasive and potentially morbid procedures can be difficult. Our aim was to investigate the role of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in helping to identify more accurately those patients with malignant lesions. Sixty-three patients underwent FDG-PET scans following unsuccessful biopsy of a lung lesion or, in a lesser number of cases, when an attempt at biopsy was considered too dangerous. Follow-up was by histology or, if this was unavailable, by clinical progress to death or a minimum of 18 months post scan. Visual and quantitative analysis was performed. On visual analysis, positive and negative predictive values were 90% and 100%, respectively. On quantitative (SUV>2.5) analysis, positive and negative predictive values were 90% and 85%, respectively. We interpret these results as showing that the use of FDG-PET scans in patients in this circumstance is non-invasive and highly sensitive in diagnosing malignancy. The high positive predictive value suggests that those with a positive scan must undergo further investigation, while the 100% negative predictive value means those with no FDG uptake can safely be spared further invasive investigations

The objective of this study was to evaluate whether the pharmacological activity of cyclical etidronate therapy is sustained beyond the dosing period. A group of 121 postmenopausal women who had completed a 2-year, double-blind, placebo-controlled parallel study with etidronate or placebo (400 mg/day for 14 days every 3 months) and calcium agreed to participate in a 1-year open-label follow-up study to evaluate the effect of discontinuing etidronate treatment. Fifty-nine subjects in the former etidronate group and 62 in the placebo group received 500 mg/day of elemental calcium; 54/59 and 58/62 subjects, respectively, completed the study. Outcomes of the study were bone mineral density (BMD), measured by dual energy X-ray absorptiometry (DXA), and biochemical markers of bone turnover (urinary deoxypyridinoline/creatinine and serum osteocalcin). To determine whether there was a residual effect of previous therapy we compared mean percentage changes from baseline (year 0) to year 3 for both spinal and femoral neck BMD and markers of bone turnover in the former cyclical etidronate and placebo groups. To evaluate the carryover effect of treatment we compared the percent change from year 2 to year 3 for the same variables. Mean percentage change (SEM) from year 2 to year 3 for spinal BMD in the former cyclical etidronate group was -2.87% (0.48%) versus -0.99% (0.36%) in the placebo group (P = 0.0022). In the femoral neck, the BMD changes were -0.86% (0.42%) versus -1.01% (0.41%) (NS). Biochemical markers increased within 6 months toward baseline levels. Mean percentage changes from baseline (year 0) in both spinal and femoral neck BMD were significantly different between groups 1 year after treatment discontinuation. No differences between groups were maintained in deoxypyridinoline and osteocalcin. It is concluded that following withdrawal of cyclical etidronate therapy bone loss resumes at a normal and moderately accelerated rate in the proximal femur and lumbar spine, respectively. A positive effect on BMD at both cortical and trabecular sites is maintained for 1 year after treatment withdrawal.

To measure regional skeletal kinetics using fluorine-18 fluoride positron emission tomography (PET) it is necessary to know the concentration of radioactive tracer being delivered to bone by arterial plasma with relation to time, the arterial input function (IFa). Methods by which IFa can be derived without arterial sampling are attractive because of their relative technical simplicity and the reduction in possible morbidity to the subject. We have compared the use of a scaled population input function (IFp) and a corrected image-derived input function from the aorta (IFi) with an IFa directly measured from a radial artery line in ten normal postmenopausal women. Both of the aforementioned methods rely only on a small number of discrete venous samples. Each subject had a dynamic PET acquisition of the lumbar spine performed after the intravenous injection of 180 MBq (18)F-fluoride. Both the IFp and the IFi were compared with the IFa in terms of the accuracy of determination of six parameters. These were: plasma clearance of fluoride to bone mineral (K(i)), unidirectional plasma clearance to total bone tissue (K(1)) and individual rate constants k(2), k(3) and k(4), calculated using non-linear regression with a three-compartment model, and the plasma clearance to bone mineral calculated using the Patlak method (K(pat)). For both the IFp and the IFi method the root mean square errors for K(pat) and K(i) were similar and small (<8.2%). The errors in determining K(1) and the rate constants k(2) to k(4) are larger by either method, but with a small advantage using the IFp method. It is concluded that the use of either non-invasive method for determining the arterial plasma input function is suitable for the measurement of the most important parameters, K(i) and K(pat), in these subjects.

Interpretation of studies from all imaging modalities requires a knowledge of the possible pitfalls that may occur due to normal variation, artefacts and processes which may mimic pathology. The applications and use of not only 18-fluoro-2-deoxyglucose but also l-[methyl-(11)C] methionine positron emission tomography (PET) are widening and it is timely that the currently recognised interpretative pitfalls are reviewed as the number of dedicated PET scanners and coincidence gamma cameras increases.

Variation in soft tissue composition is a potential cause of error in dual X-ray absorptiometry (DXA) measurements of bone mineral density (BMD). We investigated the effect of patients' change of weight on DXA scans in 152 women enrolled in a 2-year trial of cyclical etidronate therapy. Scans of the spine, hip, and total body were performed at baseline, 1 and 2 years on a Hologic QDR-2000. The study was completed by 135 subjects (64 on etidronate, 71 on placebo). Results were expressed as the percentage change in BMD (spine, femoral neck, total body) or bone mineral content (BMC)(total body only) at 2 years. Total body scans were analyzed using the manufacturer's 'standard' and 'enhanced' algorithms. Analysis was performed using multivariate regression with percentage change in BMD or BMC as the dependent variable, and treatment group and percentage change in weight as the independent variables. Weight change varied between -14.4% and +16.7%. All DXA variables showed a statistically significant treatment effect. Standard total body BMD and BMC and enhanced total body BMC all showed a significant dependence on weight change (P < 0.01, P < 0.001 and P < 0.01, respectively). No effect of weight change was seen on spine, femoral neck, or enhanced total body BMD. In order to investigate the effects of weight on long-term precision, patients were allocated to two groups according to baseline body mass index (BMI < 25 and > 25 kg/m2, respectively). For femoral neck BMD the root mean square (RMS) residual percentage change was statistically significantly larger in the high BMI group (P < 0.05) but all other bone density variables showed no significant difference. With patients allocated to two groups according to their absolute percentage change in weight (< 5% and > 5%, respectively) the RMS residual percentage changes in the bone density variables were statistically significantly larger in the large weight change group for femoral neck BMD (P < 0.05) and for standard and enhanced total body BMC (P < 0.01 and P < 0.05, respectively). With the exception of the standard total body algorithm, weight change in a longitudinal study of postmenopausal women was not found to cause systematic errors in the results of DXA studies but may adversely affect precision.

Recurrent hyperparathyroidism is rare following transcatheter ablation of mediastinal parathyroid adenomas. When it occurs it is usually early and resistant to further attempts at ablation. We present a patient with primary hyperparathyroidism in whom two surgical attempts at cure had been unsuccessful. Subsequently, a mediastinal adenoma was demonstrated angiographically and embolized with absolute alcohol. Hyperparathyroidism recurred 6 years later and the mediastinal adenoma was subsequently successfully ablated a second time by angiographic embolization with ionic contrast medium.

We report two cases, with magnetic resonance imaging correlation, of acute lateral collateral ligament tear of the knee following trauma with findings on bone scintigraphy with single-photon emission tomography (SPET). The typical bone scan features are presented. In addition, the advantages of the use of SPET in the detection of associated lesions are discussed.

Nineteen patients with angina were recruited in this study for comparison of two 1-day protocols (stress-4h rest and rest-4-h stress) and a 2-day protocol of technetium-99m tetrofosmin single-photon emission tomography (SPET). All of them underwent coronary angiography before or after the study. Exercise stress-rest study and rest-stress study were performed on two consecutive days. Delayed imaging was performed before the rest injection on the 2nd day. The stress study on the 1st day and rest study on the 2nd day were considered as a 2-day protocol. The 1-day stress-rest protocol had a sensitivity of 100% (18/18) and an accuracy of 100% (19/19) in diagnosing ischaemic heart disease. The 1-day rest-stress protocol had a sensitivity of 94.4% (17/18) and an accuracy of 94.7% (18/19). These differences were not statistically significant (P=0.5 for sensitivity and accuracy). There was also no statistically significant difference between the two protocols in the diagnosis of ischaemic heart disease in individual artery territories. For the left descending artery, sensitivity was 88.2% (15/17) vs 76.5% (13/17) (P=0.48) for the stress-rest and rest-stress studies respectively. For the left circumflex artery, sensitivity was 90% (9/10) vs 80% (8/10) (P=1) and specificity was 66.7% (6/9) vs 77.8% (7/9) (P=1) respectively. For the right coronary artery, the sensitivity was 100% (16/16) vs 94% (15/16) (P=1) respectively, while the specificity was 33.3% (1/3) in both studies. Three hundred and forty-two myocardial segments were analysed. The stress-rest and 2-day protocols showed no statistically significant difference in the overall identification of segments with reversible ischaemia (48/141 segments vs 48/141 segments) or in respect of individual artery territories. There was also no significant difference in the identification of reversible ischaemic segments between the rest-stress and 2-day protocols (48/141 segments vs 34/135 segments, P=0.14). Abdominal activity was seen in 36 studies and interpretation was affected in five of them. Five patients with 24-h delayed images were evaluated and 24 segments with washout were identified. It is concluded that 99mTc-tetrofosmin is a valuable new tracer in the investigation of ischaemic heart disease. The 1-day stress-rest protocol is as good as the 1-day rest-stress protocol in diagnosing coronary heart disease. The 1-day protocols and the 2-day protocol display no difference in identifying segments with reversible ischaemia.

New developments in dual x-ray absorptiometry (DXA) allow the performance of high precision anteroposterior (AP) and lateral scans of spinal bone mineral density (BMD, units: g/cm2) without the patient moving from the supine position. Data from both projections may be combined to give an estimate of the true volumetric bone mineral density (VBMD, units: g/cm3) of the lumbar vertebral bodies. This report presents a cadaver study designed to validate DXA measurements of volumetric bone density. Sections of whole lumbar spine were scanned in AP and lateral projections in a water tank to simulate soft tissue. Individual vertebrae were then divided to separate the vertebral body from the neural arch, and vertebral body volume was measured using the displacement of sand. The bone mineral content (BMC) of vertebral bodies and neural arches was measured by ashing at 250 degrees C for 60 hours followed by 500 degrees C for a further 24 hours. The results showed that DXA scanning systematically underestimated ashing data by 14% for AP BMC, 33% for vertebral body BMC, 23% for vertebral body volume, and 12% for VBMD. Despite these significant systematic errors, the DXA measurements and ashing values were highly correlated (r = 0.979-0.992). The results suggested that after allowing for the systematic errors, lateral DXA parameters related closely to true BMC, volume, and VBMD.

High definition macroradiography was used to provide an image of the detailed structural organization of the cancellous bone in human lumbar vertebrae. The fractal signature analysis (FSA) method was used to quantify the horizontal and vertical trabecular organization recorded within the image. Comparison of the FSA of the postero-anterior and lateral macroradiographs in postmortem lumbar vertebrae showed that neither the superimposition of the neural arch nor the radiographic angle affected the trabecular measurement within the vertebral body. FSA analysis of the trabecular structure measured from the macroradiographs of lumbar vertebrae in two groups of postmenopausal women, with high and low bone mineral density (BMD), showed that the large vertical trabecular structures correlated with the women's body weight (P < 0.01-0.03) and body mass index (P < 0.005-0.05), the fine horizontal structures correlated with the women's age (P < 0.005-0.05), and fine vertical trabecular structures were significantly greater (P < 0.005-0.05) in the low compared with the high BMD group.

Measurements of broadband ultrasonic attenuation (BUA) and velocity of ultrasound through the heel (heel velocity, HV) were performed with a Contact Ultrasonic Bone Analyzer (CUBA-Research model) in 229 women. The subjects consisted of 16 healthy young volunteers (Group 1, mean age 26 years), 170 healthy pre- and postmenopausal women (Group 2, mean age 53 years), and 43 osteoporotic women with radiographically defined vertebral crush fracture (Group 3, mean age 66 years). Subjects in Group 1 had 10 repeated measurements in a study of short-term precision. Women in Groups 2 and 3 also had dual X-ray absorptiometry (DXA) scans to measure lumbar spine and femoral neck bone mineral density (BMD). The BUA and HV measurements for all 229 women showed a significant correlation (r = 0.75, P < 0.001). The precision study on the subjects in Group 1 gave a root mean square coefficient of variation of 6.3% for BUA and 1.04% for HV. Linear regression analysis gave the following relationship between BUA and age for the 170 normal women in Group 2: BUA = 83.6-0.86 (age 40) dB/MHz (r = -0.31, P < 0.001, SEE = 16.3 dB/MHz). The relationship between HV and age was as follows: HV = 1614-2:3 (age 40) m/s (r = -0.33, P < 0.001, SEE = 42 m/s). Multivariate regression analysis showed that in addition to age, years since the menopause was also a significant factor in determining both BUA and HV.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone single-photon emission tomography (SPET) was performed in 40 patients within 6 months of acute knee injury where internal derangement of the knee was suspected, and the results related to the arthroscopy findings. Scan features with high sensitivity, specificity, and predictive accuracy for a meniscal tear could not be obtained on planar imaging. However, a half-crescent or more of increased tibial plateau activity on transaxial SPET gave a sensitivity of 89%, a specificity of 76%, a positive predictive accuracy of 77% and a negative predictive value of 89%. For longitudinal (bucket handle) tears alone the optimum scan pattern was a full crescent of increased tibial plateau activity with adjacent femoral activity and increased blood pool activity which gave corresponding values of 78%, 94%, 78% and 93%. It is concluded that the inclusion of tibial plateau activity of less than a full crescent and the presence of femoral condyle and blood pool activity in the diagnostic criteria improves the ability of bone SPET to detect meniscal tears. The value of bone SPET in the diagnosis of meniscal tears suggests that it could have a significant role to play in the management of knee injuries.

Bone mineral density (BMD) at the lumbar spine, femoral neck, trochanteric region, and Ward's triangle was measured using dual-energy X-ray absorptiometry (DXA) in 118 women with osteoporotic vertebral collapse (average age 65 years), divided into four groups according to numbers and SD of vertebral deformation below norms: group 1: -3SD deformations only; group 2: one -4SD deformation; group 3: two-four -4SD deformations; and group 4: 5 or more -4SD deformations. There were no significant differences between the groups. Results were compared with those from 80 premenopausal (average age 32 years, range 20-40 years) and 109 postmenopausal normal women (average age 64, range 60-70 years). Mean BMD in osteoporotic group 1 was lower than premenopausal normal women by 32% at the lumbar spine, 31% femoral neck, 30% trochanteric region, and 44% at Ward's triangle, and postmenopausal controls by 17% lumbar spine, 16% femoral neck, 17% trochanter, and 14% Ward's triangle. There was a clear trend to reduction in mean BMD between osteoporotic groups 1 and 4 at all four measured sites with significant differences at the spine of 0.102 g/cm2 (P < 0.01) and Ward's triangle 0.059 g/cm2 (P < 0.01). When compared with premenopausal controls, there was a reduction in mean BMD between osteoporotic groups 1 and 4 of 10% at the lumbar spine, 7% femoral neck, 8% trochanteric region, and 13% Ward's triangle. Receiver operating characteristic analysis showed no significant differences in diagnostic sensitivities among the four measured sites for vertebral fractures. We conclude from this cross-sectional data that the majority of bone loss in spinal osteoporosis occurs before the onset of fractures.

Forty-seven patients, 29 with chronic inflammatory bowel disease (IBD) and 18 with presumed irritable bowel syndrome, including one with uncomplicated diverticular disease, were studied with simultaneous technetium-99m hexamethylpropylene amine oxime and indium-111 oxine labelled leucocyte scans performed at 1, 3 and 24 h. Twenty-seven patients with IBD had active disease as judged by clinical and laboratory criteria and all of these had positive scans with both agents. No false positive studies were obtained. The 1-h 99mTc-HMPAO WBC scans showed the same distribution to disease as the 3-h 111-In WBC scans, with no difference in intensity (P < 0.92); they showed more extensive disease (P < 0.02) and more intense uptake (P < 0.001) than did the 1-h 111-In scans. The 3-h 99mTc-HMPAO WBC scans showed more extensive disease (P < 0.002), with greater intensity (P < 0.0005), than did the 3-h 111In WBC scans. Physiological bowel activity on 3-h 99mTc-HMPAO WBC scans was present in 12 patients but was faint and did not interfere with assessment of disease extent and activity. It is concluded that in terms of isotope availability, radiation dosimetry and image quality, 99mTc-HMPAO is the agent of choice in detecting active IBD, with localization of disease possible at 1-h after re-injection and optimal resolution and definition of disease extent at 3 h. A negative scan reliably excludes active disease.

In this prospective study, the radiological features characteristic of osteoarthritis of the hand were compared with the radionuclide bone scan images. A total of 32 patients was assessed at 6-monthly intervals for 18 months. Microfocal radiographs were taken at each visit. The high magnification and resolution of this technique permitted direct measurement of joint space width, subchondral sclerosis, osteophyte number and area and juxta-articular radiolucency area for each joint in the hand. Four-hour technetium 99m methylene diphosphonate bone scans were taken at 0 and 12 months and the activity of tracer uptake at each joint scored. The latter was compared with each X-radiographic feature at every visit and the changes between visits analysed. The scan scores did not correlate with any of the X-radiographic features other than osteophyte size. During the study the size of growing and remodelling osteophytes increased significantly at joints with raised or increased isotope uptake.

Dual photon absorptiometry enables measurement of bone mineral to be carried out at the clinically relevant sites of the spine and femur. Few would argue that it provides a powerful research tool, but defining its role in clinical practice has been somewhat more difficult. With the advent of X-ray based systems, studies can be rapidly carried out with improved precision, which has led to increased clinical interest. It is probable that this technology will be incorporated into routine use in the near future. In the present review we have addressed the role of dual photon absorptiometry in areas pertinent to osteoporosis and the direction in which recent developments are leading with regard to future research.

In two patients with metastatic disease more lesions were detected on scintigraphs obtained with the 'low uptake' bone-scanning agent dimethyl-amino-diphosphonate. The results in these two patients provide practical support for the suggestion that bone-scanning agents with low uptake in normal bone, but high tumour-to-normal bone ratios, will allow better delineation of focal bone abnormalities.

In 11 patients 99mTc-stannous H.E.D.P. bone scans showed absent renal images associated with symmetrical and uniformly increased uptake of radiopharmaceutical by the skeleton. These appearances are frequently seen in renal osteodystrophy but are uncommon in malignant disease. Their significance in hypervitaminosis D requires further evaluation.

Certain easily recognisable features are commonly seen in the bone scans of patients with metabolic bone disorders. Seven such features have been numerically graded by three independent observers in the scans of 100 patients with metabolic bone disease and of 50 control subjects. The total score for each patient is defined as the metabolic index. The mean metabolic index for each group of patients with metabolic bone disease is significantly greater than that for the control group (P less than 0.001).

Bone scans and X-rays from 23 subjects with symptomatic Paget's disease were evaluated. One-hundred and twenty-seven sites of Pagetoid involvement were found, of which 120 (94.5%) were recognised on the bone scan as compared to 94 (74%) on X-ray. The anatomical distribution and relationship of lesions on scan and X-ray to the patient's symptoms are also discussed. It is concluded that the bone scan is more sensitive than radiology in detecting Paget's disease and only rarely will a lesion that is seen on X-ray not be visualised by scanning.

Single or multiple transient photon deficient areas on 99mTc-DTPA scintigrams were found in 40% of a series of 34 patients who had undergone renal transplantion directly from CAPD maintenance. Ultrasound showed only loculated intraperitoneal CAPD fluid adjacent to the transplant with no evidence of local complications. We conclude that such collections are a common cause of photon deficient areas on 99mTc-DTPA transplantscintigrams and in the absence of ultrasound, these appearances should be interpreted with caution.

Radionuclide thyroid imaging was performed in 872 consecutive patients with hyperthyroidism. Of these, 84% were found to have diffuse toxic hyperplasia (Graves' disease), while 12% had autonomously functioning nodules (Plummer's disease), 3% had Graves' disease developing in a multinodular gland, and in the remaining 1%, either a clear diagnosis could not be established or the hyperthyroidism was due to thyroiditis or the Jod-Basedow phenomenon. It was found that a thyroid scan seldom provides additional diagnostic information in patients with Graves' disease when a diffuse goitre is present. However, if patients are to be treated with radioiodine (131I), thyroid imaging with tracer quantitation can replace a 24-h 131I uptake measurement, this having the advantages that the patients are required to attend only once, and that the gland size can be measured. In addition, visual confirmation of tracer uptake by the thyroid is obtained and patients with thyroiditis will not receive inappropriate therapy. When single or multiple thyroid nodules are palpated, a thyroid scan is crucial in establishing an accurate diagnosis, as it is not otherwise possible to differentiate between Plummer's disease and Graves' disease developing in a multinodular gland. Indeed, in 20 of our 63 patients (32%) with single autonomously functioning nodules, the initial clinical assessment had been incorrect.

A new method for the sequential monitoring of skeletal uptake of 99mTc-diphosphonate over a 5-day period, utilising both a gamma camera and whole-body monitor, is presented. It has been found that diphosphonate continues to be removed from bone over this period. Normal subjects appear to lose skeletal activity initially at a more rapid rate than those with altered skeletal metabolism and it is suggested that differences in binding characteristics may exist.

Accurate quantitation from the bone scan image of skeletal uptake of radiopharmaceutical would be of value in the assessment of patients with metabolic bone disease. Repeat measurements of bone to soft tissue (B/ST) ratios on the one set of images were made for 103 subjects, a) by the same observer using lumbar vertebra 2 for the area of bone; b) by the same observer using lumbar vertebra 2 then lumbar vertebra 4; c) by two observers both using lumbar vertebra 2. The median difference between repeat measurements by the same observer was well under 1% but the 5-95 percentile range was -13 to +14%. Between the two observers there was a median difference of 10.6% with a 5-95 percentile range of -11 to +44%. We also measured B/ST ratios in 150 control subjects and 139 patients with various metabolic bone disorders. While statistically significant differences for B/ST ratios were found between the osteomalacia, renal osteodystrophy, Paget's groups, and the control population (P less than 0.001 in all cases), there was appreciable overlap between individual patient results and the control range. It is concluded, therefore, that measurement of B/ST ratios for the individual is of limited value in clinical practice.

A comparison of 2 h and 4 h bone scan images obtained with technetium labelled H.E.D.P. in ten patients demonstrated no increase in lesion detection rate between the 2 h and 4 h scans. The 2 h bone scans were of sufficient quality to permit identification of tumours in all cases.

The diphosphonates are currently the skeletal imaging agents of choice and while extremely sensitive for bony abnormality their mechanism of action remains poorly understood. The current concepts in bone uptake mechanisms are reviewed and it is concluded that diphosphonate uptake is most likely related to sites of newly forming bone with diphosphonate adsorbed onto the surface of hydroxyapatite crystals. In situations where there is markedly increased skeletal uptake of tracer, increased vascularity alone cannot account for changes in tracer uptake and changes in skeletal extraction, related to newly forming bone are more important.

The bone scan is generally recognized to be an extremely powerful investigational tool in the evaluation of patients with skeletal disease. Currently 99mTc-methylene diphosphonate is the most widely used bone scanning agent, but recently several new diphosphonate compounds have been introduced which appear to have relatively higher skeletal affinity, leading to greater absolute uptake of tracer by bone. While the resulting improved contrast between bone and background soft-tissue may provide more pleasing scan images, it is not clear that increased bone uptake of tracer is equally desirable for identification of disease. Nevertheless, to date, no significant difference in lesion detection has been found in any comparative study of diphosphonate compounds. In this review the clinical studies evaluating diphosphonate bone scanning agents are summarized and the properties required of an ideal bone scanning agent in both benign and malignant disease discussed.

An improved method for parathyroid scanning using thallium-201 and technetium-99m subtraction imaging is described. The technique successfully localised ten of eleven parathyroid adenomas confirmed at neck exploration. Two false-positive studies were encountered in patients with no adenoma at operation, probably due to thyroid nodules. The technique was less successful in identifying diffusely hyperplastic parathyroid glands and was negative in a single patient with recurrent, functional parathyroid carcinoma.

A longitudinal study was performed to document the effect of surgical menopause and postmenopausal etidronate disodium therapy on several nonhistomorphometric indices of bone turnover. Twenty healthy, premenopausal women undergoing oophorectomy for nonmalignant conditions were studied preoperatively and at 3 monthly intervals postoperatively. Sequential measurements of serum calcium (Ca), alkaline phosphatase (AP), bone Gla protein (BGP), and urinary calcium and hydroxyproline excretion, expressed as a ratio of urinary creatinine (UCa/Cr and UOHp/Cr, respectively) were obtained. Twenty-four-hour whole body retention of diphosphonate (WBR) and radial bone density were also measured. When a postoperative increase in bone turnover was observed, patients were randomized to receive either 400 mg etidronate disodium daily or placebo for 3 months. Oophorectomy was associated with a significant increase in WBR, Ca, AP, and BGP and an insignificant rise in UCa/Cr. A variable pattern of UOHp/Cr was seen. Patients on placebo maintained these elevated levels of Ca, BGP, and UCa/Cr. WBR and AP continued to rise. Etidronate disodium therapy resulted in a fall towards premenopausal levels in WBR, Ca, and UCa/Cr. AP and BGP were unchanged. Three months after stopping etidronate, BGP fell significantly and the decrease in Ca was maintained; however, WBR and UCa/Cr had returned towards pretreatment values. Bone density measurements did not change significantly. An increase in several of the indices of bone turnover was seen following oophorectomy. Etidronate disodium suppressed this increase, affecting indices of both resorption and formation.(ABSTRACT TRUNCATED AT 250 WORDS)