Modified calcaneal index: a new screening tool for osteoporosis based on plain radiographs of the calcaneum.

PURPOSES: To assess osteoporosis using plain radiography of the calcaneum by studying the performance characteristics of the modified calcaneal index through inter- and intra-observer agreement. To study the correlation of the modified calcaneal index to quantitative ultrasound of the calcaneus and bone mineral density (BMD) of the femoral neck and distal radius. METHODS: Lateral calcaneal radiographs of 252 women who participated in a clinical trial for osteoporosis were reviewed. The BMD of the hip and distal radius was measured and the calcanea were assessed using ultrasound. The calcaneal radiographs were graded by 3 clinicians according to a previously described 5-grade calcaneal index. A modified 3-grade calcaneal index was then developed. RESULTS: The highest scores of intra- and inter-observer reliability of the modified calcaneal index were 0.45 and 0.40, respectively, which were higher than those of the 5-grade calcaneal index. The correlation of the modified calcaneal index with other measures was significant (hip BMD, r=0.31; distal radius BMD, r=0.28; calcaneal speed of sound, r=0.20; broadband ultrasound attenuation, r=0.36) [p<0.005]. There were significant differences in hip BMD, distal radial BMD, calcaneal speed of sound, and broadband ultrasound attenuation between the 3 grades of the modified calcaneal index (Kruskal-Wallis 1-way ANOVA; p<0.0001). CONCLUSION: The modified calcaneal index can be used to measure bone structure and skeletal strength and is a suitable screening tool for osteoporosis in places where advanced approaches to bone-status assessment are not available.

Performance of clinical referral criteria for bone densitometry in patients under 65 years of age assessed by spine bone mineral density.

BACKGROUND: A case finding strategy based on a number of established risk factors has been suggested by Royal College of Physicians' (RCP) guidelines to optimise bone densitometry referrals for assessment of osteoporosis. OBJECTIVE: The performance of clinical referral criteria was examined in women and men aged <65 years referred for bone mineral density (BMD) assessment. STUDY DESIGN: Cross sectional observational study over six months. RESULTS: Though BMD tended to be lower in patients with multiple criteria for referral, differences from those referred with a single criterion were not statistically significant. The overall prevalence of osteoporosis was higher than expected in both sexes, 11.6% in women and 27.5% in men (expected prevalences were 8% and <1% respectively). BMD was significantly lower in patients referred with a single criterion compatible with the RCP guidelines than in age matched controls or in those patients referred with non-RCP criteria (mean (SD) Z score -0.47(1.38) v 0.35(1.41), p<0.001). Low body mass index was also significantly associated with a lower than expected BMD. In contrast, spine BMD was higher than expected in those with self reported back pain, loss of height, or spinal curvature (p = NS). CONCLUSION: Most of the criteria recommended by the RCP performed well in identifying relatively younger patients with low BMD and osteoporosis. However, prior fractures and corticosteroid use did not reach statistical significance probably due to inclusion of all energy fractures, and current or past steroid use of unspecified dose or duration. Criteria like loss of height and/or spine curvature perform relatively poorly, reflecting the need for further investigation to better identify those needing BMD assessment.

Early human renal allograft fibrosis: cellular mediators.

BACKGROUND: The development of early renal interstitial fibrosis (IF) in renal allografts is likely to depend on multiple factors. We studied retrospectively renal biopsies from cadaveric human renal allografts, transplanted from 1996 to 1998, with the intention of detecting early fibrotic changes and determining the underlying cellular mediators. We studied 23 transplant patients whose 46 renal biopsies were analysed, including a donor biopsy taken routinely at implantation from each patient and 23 follow-up biopsies, taken as clinically indicated over a period of 3 months following transplantation. METHODS: Histological evaluation of induction and progression of fibrosis relied on point count analysis of conventional (Masson's trichrome/MT) and immunohistochemical staining for collagen III and IV, and alpha-smooth muscle actin (alpha-SMA) as a marker of myofibroblast differentiation. Mast cells (MC) were counted in sections stained with an anti-human mast cells tryptase monoclonal antibody. Activated macrophages as well as total, helper and cytotoxic T-lymphocytes were identified on frozen sections by direct immunofluorescence using mouse anti-CD71, CD3, CD4 and CD8 antibodies respectively. Eosinophils (E) were counted in hematoxylin and eosin (HE)-stained sections. Changes in interstitial fibrosis (IF) scores were evaluated and correlated with myofibroblasts, MC, E and lympho-monocytic cells. RESULTS: We noted a significant increase in IF over a 3 months period following transplantation. There was also a significant increase in alpha-SMA+ cells, MC and E counts from implantation to follow-up biopsies. Similarly, there was a significant increase in interstitial infiltration by T-lymphocytes (modal category = 2 versus 0, p = 0.012) but not by macrophages. MC at implantation and follow-up were found to be predictive of IF (immunostainable collagen III) at follow-up (R(2) = 0.510, p = 0.023 and p = 0.030). Further, the predictive value for total T-lymphocyte infiltration at follow-up was also significant (R(2) = 0.617, p = 0.036). A strong correlation was found between alpha-SMA+ cells and MC counts at implantation (r = 0.7259, p < 0.001) and in follow-up biopsies (r = 0.5183, p < 0.01). However, there was no correlation between E counts and either alpha-SMA+ cells or MC either at implantation or in follow-up biopsies. Based on changes in interstitial immunostainable alpha-SMA, our patients were divided arbitrarily into 2 groups; group 1 (n = 12) with >100% increase in alpha-SMA and group 2 (n = 11) with <100% increase. Group 1 patients differed significantly from group 2 regarding the degree of MC infiltration at follow-up (t = 0.4519, p < 0.05) with the mean increase in MC count from implantation to follow-up biopsies being +5.1 cells/high power field (HPF) in group 1 and +0.8 cell/HPF in group 2 (p = 0.0237). MC counts in group 1 were associated with a higher modal category (greater than one) of cytotoxic: helper T-lymphocytes ratio compared to group 2 (2:1 versus 1:1 respectively). CONCLUSION: Multiple cells may contribute to early interstitial fibrosis in a subgroup of human renal allograft recipients with MC playing a major role.

Early progressive interstitial fibrosis in human renal allografts.

BACKGROUND: Early fibrosis has been described in renal allografts and implicated in the progression of chronic allograft nephropathy (CAN). The precise factors implicated in the initiation and progression of early allograft fibrosis remain uncertain. PATIENTS AND METHODS: We studied retrospectively 23 cadaveric renal allograft recipients over a 3-year period, who had paired renal biopsies (Bx) (at implantation and as clinically indicated) within 3 months of transplantation (Tx). Eight of them have progressed over an average period of 3.16 +/- 0.83 years to CAN. Histological evaluation of interstitial fibrosis (IF) relied on point count analysis of Masson's trichrome (MT) staining as well as immunostainable collagens III (iCol III) and IV (iCol IV). The severity of the IF scores was correlated with the clinical, biochemical and histological parameters. The nature and severity of the interstitial inflammatory infiltrate were also evaluated by immunofluorescence. In addition, patients were subdivided into those whose fibrosis progressed (> 50% increase in IF/iCol IlI; Group 1) and non-progressors (< 50% increase in fibrosis score; Group 2) in an attempt to determine discriminatory features. RESULTS: In the whole group, there was a significant increase in the IF score, as estimated by MT staining and iCol III, from implantation to follow-up Bx (p = 0.0027 and p = 0.0088, respectively). The changes in iCol IV were not significant. Further, the increase in interstitial inflammatory infiltrate of total T lymphocytes, and not of macrophages, from implantation (modal category = 2) to follow-up (modal category = 0) was significant (p = 0.0121). The predictive value of such increase was significant (R2 = 0.617, p = 0.03). The donor's age (R2 = 0.892, p = < 0.0001), death from cerebrovascular accident (CVA) (R2 = 0.822, p = 0.047), as well as recipient's body weight (R2 = 0.892, p = 0.001), male gender (R2 = 0.687, p = 0.041) and elevated mean arterial pressure (MAP) (R2 = 0.892, p = < 0.0001) were all significant risk factors for early IF. Delayed graft function (DGF) proved to be a significant predictor of early IF (R2 = 0.822, p = 0.003) and became more significant in the presence of superimposed acute rejection (AR) (p = 0.0001). Proteinuria > 1 g/day (R2 = 0.882, p = 0.004) and hypertriglyceridemia > 2.25 mmol/l (R2 = 0.808, p = < 0.0001) were also associated with early IF. Of the implantation histological parameters, iCol III proved to be a highly significant predictor of early IF (R2 = 0.892, p = < 0.0001). Interestingly, the predictive value of iCol III for graft survival in terms of CAN was significant (Cox p = 0.088). Group 1 progressor patients (n = 10) were all males (p = 0.038) and received their kidneys from donors who died from CVAs in 90% of cases (p = 0.011). They had, compared to non-progressors, a lower cyclosporin A level (p = 0.047), a higher incidence of AR episodes (80% versus 54%), a higher serum creatinine at 10 days post-Tx (p = 0.005), a higher proteinuria (2.07 +/- 3.89 g/l vs 0.96 +/- 0.97 g/l, p = 0.041) and a higher serum triglyceride (2.48 +/- 1.37 mmol/l vs 1.69 +/- 0.81 mmol/l, p = 0.039) level. 8% of Group 1 patients had DGF compared to 30% in Group 2 (p = 0.023). Of note, the modal category of cytotoxic: helper T lymphocytes ratio was greater than 1 in Group 1 (2:1) patients and not in Group 2 (1:1). CONCLUSION: Implantation histology, and in particular iCol III, is a predictor of early IF in a subgroup of patients with DGF and AR. Additional risk factors include hypertension, proteinuria and hypertriglyceridemia especially in patients receiving kidneys from older donors who died of CVAs.

Effects of clodronate on vertebral fracture risk in osteoporosis: a 1-year interim analysis.

The aim of this study was to determine whether clodronate reduced the incidence of vertebral fractures in patients with osteoporosis. We report here the interim analysis after 1 year of a 3-year double-blind placebo-controlled study. The objectives of the interim analysis were to determine whether there was a trend in fracture frequency and to examine the effects of clodronate on bone mineral density (BMD). Patients with densitometrically proven osteoporosis (T-score <-2.5 and <-3 for women and men, respectively) or with at least one prevalent vertebral fracture were recruited to a 3-year double-blind, controlled study. Patients were randomized to three strata, namely women with postmenopausal osteoporosis (stratum I, n = 483), women with secondary osteoporosis (II, n = 110), and men with osteoporosis of any causation (III, n = 84). They received either clodronate 800 mg daily by mouth or an identical placebo, and all patients received a calcium supplement of 500 mg daily. BMD was measured at six monthly intervals, and lateral spine radiographs for vertebral morphometry were obtained at baseline and 1 year. Treatment with clodronate was associated with a significant increase in BMD at the spine of 3.2 +/- 0.3% (p < 0.0001 vs. baseline) compared with a nonsignificant change of 0.5 +/- 0.3% in the placebo group (p < 0.0001 between treatments). At the hip, clodronate was associated with a significant increase in total hip BMD of 1.3 +/- 0.3% (p = 0.018 vs. baseline) compared with a small decrease of 0.4 +/- 0.3% in the placebo group (p = 0.027 for the difference between treatment groups). The mean changes at the spine and hip were similar in all three strata. Incident vertebral fractures were observed in 27 patients at 1 year in the placebo group (9.0%) and in 14 patients receiving clodronate (4.9%) (relative risk 0.54; 95% CI 0.29-1.02; p = 0.07). A trend was observed in all treatment strata. Treatment was well tolerated, with no significant adverse events attributable to clodronate treatment. We conclude that clodronate 800 mg daily is effective in preventing bone loss, and at 1 year, there is a trend consistent with antifracture efficacy in patients with established osteoporosis regardless of causation.

Ultrasound velocity and dual-energy X-ray absorptiometry in normal and pagetic bone.

Bone affected by Paget's disease is known to be dense but more prone to fractures. It is proposed that dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) assess different aspects of the skeletal status. In this study, we used Paget's disease of the tibia as a model to explore this. Ten patients with Paget's disease affecting a single tibia were investigated with the normal side acting as the control within each individual. Tibial speed of sound (SOS) was measured at the midpoint of the affected and control tibiae using a Soundscan 2000 (Myriad Ultrasound System, Rehovot, Israel) device. Bone mineral density (BMD) of the tibia was measured at a level corresponding to the site of the tibial ultrasound using a QDR-2000+ (Hologic, Inc., Waltham, MA). The mean bone area and estimated volume in the pagetic tibia was greater than that in the normal tibia (bone area: 25.10 +/- 8.00 vs. 20.23 +/- 5.43 cm(2), p = 0.017; estimated bone volume: 68.79 +/- 41.99 vs. 43.62 +/- 22.56 cm(3), p = 0.02), reflecting the bone expansion characteristic of Paget's disease. The bone mineral content (BMC) was more markedly increased in the pagetic tibia (27.38 +/- 12.98 vs. 14.39 +/- 6.14 g, p = 0.003) and, consequently, areal bone mineral density (BMD) was also markedly increased in the pagetic bone (1.09 +/- 0.38 vs. 0.77 +/- 0.44 g/cm(2), p = 0.018). There was no significant difference in the estimated volumetric BMD between the pagetic and the normal tibia (0.48 +/- 0.24 vs. 0.47 +/- 0.51 g/cm(3), p = 0.96). In contrast, the mean tibial SOS in the leg affected by Paget's disease was significantly lower than in the unaffected leg (3228 +/- 234 vs. 3840 +/- 164 m/sec, p < 0.001). When expressed as a z score using the normal limb as reference, areal BMD was 0.72 SD higher in the affected limb, whereas tibial SOS was 3.72 SD lower. We conclude that tibial SOS detects important changes in bone quality in Paget's disease of bone, which are unrelated to calcium content.

Metacarpal morphometry using a semi-automated technique in the assessment of osteoporosis and vertebral fracture risk.

Metacarpal morphometry represents a potentially cheap and widely available non-invasive assessment of skeletal status. In two cross-sectional studies, we compared the performance characteristics of a semiautomated technique (the Teijin Bonalyzer) with an in-house manual measurement, and with measures of skeletal strength at other sites. The metacarpal cortical index (mCI) was measured on hand radiographs of 178 osteoporotic women using both the Teijin Bonalyzer and a digitizing tablet. Measurements on the latter were consistently lower than with the Bonalyzer except for mCI (0.443+/-0.080 vs 0.364+/-0.060, p<0.001), although correlation coefficients between these two methods were highly significant (r = 0.62-0.83, p<0.001). The reproducibility errors of metacarpal bone mineral density (mBMD) were constant (1.1-1.2%) whilst those for mCI showed a marked operator-dependency (2.0-7.9%). In 379 elderly community-dwelling women, Bonalyzer mCI and mBMD showed a significant decline with age (r = -0.30 and -0.27 respectively, p<0.05). Both mCI and mBMD correlated significantly with forearm BMD (r = 0.50 and 0.57 respectively, p<0.001) and hip BMD (r = 0.48 and 0.53 respectively, p<0.001). After adjustment for age and weight, hip BMD demonstrated the best discrimination for prevalent vertebral fractures as judged by the gradient of risk for a 1 SD decrease in measurement (odds ratio (OR) 2.17, 95% CI 1.56-3.01). Similar but smaller gradients of risk were shown by Bonalyzer mCI (OR 1.32, 95% CI 1.00-1.75), mBMD (OR 1.35, 95% CI 1.02-1.78) and forearm BMD (OR 1.39, 95% CI 1.08-1.80). MCI, and in particular mBMD, may be useful assessments of bone mass and fracture risk. In our study, it is comparable to peripheral assessment of skeletal status by forearm densitometry.

Development of a questionnaire (OPQ) to assess patient's knowledge about osteoporosis.

OBJECTIVE: to develop a self-administered questionnaire (OPQ) to assess the patient's knowledge about osteoporosis. METHODS: An initial item pool of 71 questions was developed with input from clinicians involved in the management of patients with osteoporosis. It was piloted in ten patients for face validity and comprehension. The questionnaire was then administered to 50 first-time attendees at a specialist osteoporosis unit. After item analysis using index of difficulty and index of discrimination, 20 items were selected for the final questionnaire (OPQ). These were in the areas of general information (5), risk factors (7), consequences and treatment (four each). RESULTS: the average index of difficulty and index of discrimination (D) of the 20 items was 0.56 (>0.75 is suggestive of a poor discriminator) and 54.8% (D value of 50% is associated with highest level of item discrimination) respectively. This means that all the items actively discriminated between high and low scorers. The Flesch readability index was 74.3 (a score between 70 and 100 means a document is easily understood) and the reliability coefficient was 0.84 (acceptable range 0.8-0.9). Criterion validity (verification that the scale measures what it claims to measure) was confirmed by the method of contrasted groups where members of an osteoporosis awareness charity had a significantly higher score than the first time attendees (13.6 +/- 4.3 vs. 8.5 +/- 5.4; P=0.003). CONCLUSIONS: we have developed a self-report, 20-item questionnaire (OPQ) to assess the patient's knowledge about osteoporosis. Psychometric analysis has shown that the items have a satisfactory index of difficulty and discrimination. The OPQ is internally reliable, valid and easily understandable. It can be used to identify individuals in need of educational interventions as well as assess the effectiveness of education efforts as a part of management of osteoporosis.

Lipid profiles in patients with atherosclerotic renal artery stenosis.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is an important cause of renal disease in the elderly, and these patients have a high morbidity and mortality. There are no data on their blood lipid profiles. METHODS: The lipoprotein profiles were examined in patients with proven ARAS and compared with patients matched for age, gender, renal function and presence of diabetes. RESULTS: The profiles did not show any significant difference for apolipoprotein B (control 1.31 +/- 0.39 vs. ARAS 1.24 +/- 0.28; mean +/- SD), cholesterol (control 5.65 +/- 1.28 vs. ARAS 6.12 +/- 1.29), LDL cholesterol (control 3.72 +/- 1.03 vs. ARAS 4.06 +/- 1.18), fibrinogen (control 2.48 +/- 1.39 vs. ARAS 3.29 +/- 1.49), HDL cholesterol (control 1.16 +/- 0.38 vs. ARAS 1.00 +/- 0.26) and triglyceride (control 1.68 +/- 0.80 vs. ARAS 2.32 +/- 1.73) levels between the groups. Surprisingly lipoprotein(a) levels were higher in the control group (0.58 +/- 0.45) vs. ARAS (0.31 +/- 0.21). The most striking abnormality was the markedly lower apolipoprotein A1 levels in the ARAS group (control 2.09 +/- 0.55 vs. ARAS 0.95 +/- 0. 30) and apolipoprotein A1/B ratio (control 1.74 +/- 0.71 vs. ARAS 0. 78 +/- 0.24). CONCLUSION: The lipoprotein abnormality in ARAS mirrors that in other severe vascular diseases. Potential therapeutic interventions in patients with ARAS should consider treatments to modify the apolipoprotein A1 concentration rather than cholesterol alone.

Symptomatic cardiomyopathy as a presentation in Whipple's disease.

A patient presenting with congestive cardiac failure and anaemia underwent investigation which led to the diagnosis of Whipple's disease, associated with dilated cardiomyopathy. Conventional antibiotic therapy for Whipple's disease resulted in resolution of the traditional features of Whipple's disease and a marked improvement in the patient's heart failure.