Biomedical subjects
Publications and source records attributed to E V McCloskey.
We report unusual clinical and radiological features of Paget's disease of bone in three family members. All three patients had satisfactory biochemical and symptomatic response to treatment with an intravenous bisphosphonate (clodronate).
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.
BACKGROUND: Myelomatosis is associated with considerable skeletal morbidity, particularly bone pain and fractures. Hypercalcaemia is a common presenting feature but less common after adequate chemotherapy. These complications are caused by progressive focal and generalized osteolysis due, in turn, to increased activation of osteoclasts by osteoclast activating factors. These include tumor necrosis factor-beta, interleukin-1, and interleukin-6. The knowledge that disturbed bone remodeling is due to the activation of authentic osteoclasts provides the rationale for the use of bisphosphonates in myelomatosis. METHODS: This article reviews the place of bisphosphonates in the management of myeloma. RESULTS: There is good evidence that hypercalcaemia can be corrected with intravenous or oral bisphosphonates, and they are now the specific treatment of choice. Several studies have shown that their intravenous administration is beneficial in the acute management of bone pain due to malignancy, but studies in myelomatosis are lacking. In contrast, a number of well designed controlled studies have shown significant effects of long term treatment with clodronate and pamidronate to decrease the incidence of skeletal complications in myelomatosis. Benefits reported are a decreased incidence of bone pain, hypercalcaemia, vertebral and long-bone fractures, and the extension of osteolytic lesions. There may be a beneficial effect on survival, but this is much less certain. CONCLUSIONS: These agents provide a valuable adjunct to the management of myelomatosis.
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.
The diagnosis of osteoporosis is based on bone mass measurement. To avoid the errors associated with the measurement of spinal bone density the total hip has been accepted as the standard measurement site. This information is not available for many early measurements. We have assessed whether it is possible to derive clinically useful information about total hip bone mineral density (BMD) from measurements at other hip sites. The bone mass measurements of 46 patients participating in a current trial of therapy for osteoporosis were reviewed. The total hip BMD as directly measured was compared with that obtained from the formula: Total hip BMD = 0.48 x Neck BMD + 0.62 x Trochanteric BMD + 0.03. In 30 patients with follow-up data the rate of change in hip BMD over a year was also determined by both methods. In the pretreatment state there was good agreement between the two measures (r2 = 0.96, SEE 0.012 g/cm2). If the formula was used to compute a change in total hip BMD, the agreement between both methods remained good. However, the standard error of the estimate of the change represented 59% of the observed change. This indicates that the error associated with this estimate is too great to allow clinically meaningful conclusions to be drawn from calculated total hip BMD. We conclude that, whilst it may be possible to obtain reasonable point estimates of total hip BMD from other measures in the hip, these estimates are too imprecise to allow conclusions about change in BMD to be made.
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.
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Because treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3-9.9], and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1-57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer.
The economic impact of using prophylactic clodronate as an adjunct to chemotherapy in the management of multiple myeloma for the first 4 years following diagnosis was established from the perspective of the National Health Service (NHS). A state-transition model of the course of multiple myeloma was constructed using the MRC VI myelomatosis trial results and information on patient management obtained retrospectively from clinical trialists. Data were collected on resource use and corresponding costs for standard management and managing severe hypercalcaemia, vertebral and non-vertebral fractures. Managing patients with prophylactic clodronate cost the NHS a mean 22 934 pound silver per patient; comprising 16 697 pounds silver for standard management, 4862 pound silver for clodronate therapy and 1376 pound silver for adverse events. Managing patients without prophylactic clodronate cost a mean 19 557 pound silver (16 697 pound silver and 2860 pound silver for standard management and adverse events respectively). Therefore prophylactic clodronate therapy increased the cost by 3377 pound silver, or 17% per patient. Hospitalization accounted for 32% of the total cost, whereas chemotherapy accounted for 5%. The results were robust to sensitivity analyses (range 2605 pound silver-4150 pound silver). Further studies are required to assess the impact of prophylactic clodronate on quality of life to enable the clinical benefits and additional cost of this treatment to be compared with other healthcare interventions.
We examined the incidence of vertebral and non-vertebral fractures in published randomised clinical trials using calcitonin by parenteral injection or intranasal spray. Trials were reviewed that compared calcitonin with placebo, no therapy, or calcium with or without vitamin D, and that mentioned fracture as an outcome. Studies that compared the effect of calcitonin with other active treatments were excluded. Fourteen trials with 1309 men and women were identified. In the calcitonin and the control groups, vertebral and non-vertebral fractures were summed and divided by the number of individuals originally allocated to the treatment groups. The relative risk of any fracture for individuals taking calcitonin versus those not taking calcitonin was 0.43 (95% CI 0.38-0.50). The effect was apparent for both vertebral fracture (RR 0.45; 95% CI 0.39-0.53) and non-vertebral fractures (RR 0.34; 95% CI 0.17-0.68). When studies identifying patients with fracture, rather than numbers of fractures were pooled, the magnitude of effect was less (RR 0.74; 95% CI 0.60-0.93), and the separate effects on vertebral and non-vertebral fractures was of borderline significance. We conclude that, within the limitations of this study, treatment with calcitonin is associated with a significant decrease in the number of vertebral and non-vertebral fractures.
OBJECTIVE: Vertebral osteophytes are a characteristic feature of intervertebral disc degeneration. There are, however, few population data concerning the occurrence of and clinico-biological correlates of vertebral osteophytes in both the dorsal and lumbar spine. Our purpose was to determine the frequency and distribution of anterior osteophytes in the thoracic and lumbar spine, and their relationship with both various putative risk factors, including physical activity and obesity, and self-reported back pain. METHODS: Men and women aged 50 years and over were recruited from primary care based registers in 5 UK centers. They were invited to attend for an interviewer administered lifestyle questionnaire, assessment of height and weight, and lateral spinal radiographs. Lateral spinal radiographs were evaluated by a single observer for the presence of osteophytes from T4 to L5 using a semiquantitative score (grade): 0 = none, 1 = doubtful, 2 = mild, 3 = moderate, 4 = severe. Based on these data 2 summary statistics were derived: the maximum osteophyte grade at any vertebral level (MAX), and the sum of the osteophyte grades at the individual vertebral levels (TOT). RESULTS: In total, 681 women, mean age 63.3 years, and 499 men, mean age 63.7 years, were studied; 84% of men and 74% of women had at least one vertebral level with a grade 1 or higher osteophyte. Both the sum of the individual grades (TOT) and the proportion of subjects with MAX > or =2 were greater in men than in women in both the dorsal and lumbar spine, and both increased with age. The pattern of spinal involvement was similar in the sexes, with osteophytes occurring most frequently at T9-10 and L3. Increasing body mass index was associated with more frequent osteophytes at both dorsal and lumbar spine, although the relationship was stronger at the dorsal spine. Heavy physical activity, particularly in young adult life, was associated with osteophytosis in men. Self-reported back pain, both ever and in the past year, was linked with lumbar osteophytes in men. CONCLUSION: The distribution within the spine in our study and the relationship with heavy physical activity points to mechanical factors being important in pathogenesis of vertebral osteophytosis. Prospective studies are needed to explore the types of physical activity that increase susceptibility to vertebral osteophytosis. In men, osteophytes affecting the lumbar spine are associated with back pain.
Osteoporosis is caused by a reduction in bone mass, but the cause of osteoporotic fractures is multifactorial because fractures arise following various degrees of trauma. There are therefore several different categories of risk factors for osteoporotic fracture. They may be related to the determinants of bone mineral density, capture the risk of falls, be related to skeletal fragility independently of bone mineral density or a combination of these. The identification of strong risk factors permits the identification of patients in whom further assessment and treatment can be offered in case finding strategies.
Densitometric measurements are prone to imprecision in elderly subjects and the present study was primarily designed to dissect out the effects of age and bone mineral density on proximal femur dual energy x-ray absorptiometry (DXA) reproducibility. The study comprised 17 elderly women (mean age 74.6 years, range 65-84 years), 13 early postmenopausal women with osteopenia (mean age 56.2 years, range 50-63 years), and 17 elderly men (mean age 73.8 years, range 65-86 years). Each subject was given triplicate proximal femur scans by a QDR 2000 Densitometer (Hologic Inc., Waltham, MA) with repositioning between scans. Because of subject selection in the early postmenopausal women there were no significant differences in bone mineral density (BMD) at any site among the three groups. Despite this, reproducibility errors expressed as either coefficient of variation (CV) % or mean standard deviation (SD) were greater in the elderly subjects, regardless of gender, when compared with the younger female subjects. The variability in measurement errors with age were least marked for the total hip and trochanteric sites. Within the elderly subjects, BMD appeared to exert little influence on measurement errors. We conclude that short-term proximal femur reproducibility is dependent on age-related factors other than BMD. There is no influence of gender on the measurement errors. It is likely that local factors (e.g., hip osteoarthritis) or general frailty may influence repositioning but this needs further exploration. In the meantime, the total hip and trochanteric sites should be used as they provide the most reproducible measurements in the elderly.
In patients with multiple myeloma, despite a major reduction of bone pain achieved with chemotherapy, skeletal disease continues to progress. The effects of clodronate, an inhibitor of osteoclastic bone resorption, are evaluated on the natural history of skeletal disease in patients with newly diagnosed multiple myeloma. Within the framework of the VIth MRC Multiple Myeloma Trial, 536 patients (218 women, 318 men) with recently diagnosed multiple myeloma were randomized to receive either clodronate 1600 mg daily (n=264) or an outwardly identical placebo (n=272) in addition to chemotherapy. Treatment with clodronate was associated with a 50% decrease in the proportion of patients with severe hypercalcaemia (5.1% v 10.1%, P=0.06) and a similar reduction in reported non-vertebral fractures (6.8% v 13.2%, P=0.04). Fewer patients receiving clodronate sustained vertebral fractures after entry to the trial (38% v 55%, P=0.01) and patients also lost less height over 3 years compared to those receiving placebo (2.0 v 3.4 cm, P=0.01). Biochemical indices of bone turnover were significantly lower in patients receiving concomitant clodronate, both at plateau and at disease relapse. The frequencies of back pain and poor performance status were significantly lower at 24 months in clodronate than in placebo-treated patients (10.9% v 19.9%, P=0.05, and 18.3% v 30.5% P=0.03 respectively.) There was no statistically significant difference in survival between the clodronate and placebo treated patients. The study indicates that long-term oral clodronate slows the progression of skeletal disease in multiple myeloma and decreases the associated morbidity. Patients without overt skeletal disease at diagnosis were also found to benefit from clodronate, indicating that this treatment should be initiated as early in the course of the disease as possible.
There are three principal disturbances in bone remodelling that occur in neoplasia affecting the skeleton. The first is an increase in bone turnover that in solid tumors may be confined to sites of metastases or be a generalized phenomenon, most likely related to the secretion of parathyroid hormone-related protein. In the bone remodelling sequence, bone resorption precedes formation, so that increases in turnover result in substantial skeletal deficits more marked at cancellous than cortical bone sites. The second abnormality in bone remodelling is an imbalance between the amount resorbed and that formed at each remodelling site. This is a conspicuous feature of myelomatosis with moderate grades of plasma cell infiltration. The third phenomenon is the process of uncoupling. In osteolytic disease this is associated with the creation of erosion cavities that are never subsequently repaired. Progressive waves of bone resorption result in the destruction of skeletal elements and focal osteolysis. Osteosclerotic metastases formed by uncoupled bone formation represent the deposition of new bone either on quiescent bone surfaces or arising from stromal condensations within the marrow cavity. In solid tumors biopsy evidence suggests that uncoupled bone resorption and formation occur within the same metastases and that the radiographic expression (osteosclerosis, osteolysis) depends on the predominant component. The understanding that abnormalities of skeletal metabolism are mediated by authentic bone cells raises the possibility that skeletal specific markers of bone turnover might be utilized for the diagnosis of metastases, to assess the skeletal prognosis, or to monitor treatment. A variety of skeletal markers have been assessed. The pyridinium crosslinks currently provide the markers of greatest predictive value. Although they have high specificity, their sensitivity is low (< 30%). This indicates that many individuals with skeletal metastases would be missed. In contrast, skeletal markers have proven invaluable in the assessment of the natural history of the disease and response to intervention. They have been particularly useful in assessing the pharmacodynamics of bisphosphonate treatment. However, their day-to-day precision is sufficiently low that they are of limited value in the monitoring of individuals.
Clodronate is a second-generation bisphosphonate of intermediate potency between etidronate and aminobisphosphonates. It is an effective inhibitor of bone resorption, but unlike etidronate does not impair the mineralization of bone. Unlike pamidronate, it can be given both intravenously and orally. There is wide experience in the use of clodronate in the management of patients of hypercalcemia. The most widely used therapeutic regimen is 300 mg intravenously repeated for 5 days or a single infusion of 1500 mg. Efficacy is nearly complete in patients with myelomatosis, less complete in solid tumors with hypercalcemia but without skeletal metastases, and intermediate in patients with solid tumors in the presence of skeletal metastases. Variations in effect appear to be due to differences in renal tubular reabsorption of calcium between the three disorders. Placebo-controlled studies examining the effects of clodronate on bone pain in the absence of hypercalcemia have shown significant decreases in the severity of bone pain. These findings, coupled with the knowledge that suppression of bone resorption persists for the duration of treatment, has led to the long term use of oral doses of clodronate to decrease the incidence of complications of osteolytic bone disease. The long term control of bone resorption with oral clodronate has been demonstrated by double blind histologic studies. The ultimate arbiter of the value of clodronate is whether it decreases the skeletal morbidity associated with osteolysis. Double blind prospective controlled studies suggest that the incidence of bone pain, fracture, and hypercalcemia can be decreased significantly in patients with breast carcinoma. In addition, the use of long term clodronate in patients with myelomatosis significantly decreases the progression of osteolytic bone lesions, the risk of fractures, and the incidence of hypercalcemia. These studies have raised the possibility that bone disease might be prevented in individuals at high risk. Double blind prospective studies in women with recurrent breast carcinoma but no evidence of skeletal metastases showed a small effect of clodronate in decreasing the proportion of women developing metastatic disease. However, there was a large and significant decrease in the number of skeletal metastases associated with a decrease in skeletal morbidity. These observations suggest that clodronate may modify the natural history of the expression of skeletal disease, and thereby significantly improve the quality of life of affected patients.
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