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European semi-anthropomorphic phantom for the cross-calibration of peripheral bone densitometers: assessment of precision accuracy and stability.
A semi-anthropomorphic 'distal radius like' phantom, developed by Kalender and Ruegsegger for use in peripheral bone densitometry using single photon (DPA) dual X-ray (DXA) and quantitative computed tomography (QCT) machines, has been studied with a view to cross-calibrating different types and brands of densitometers in current use. In the context of an EU 'Concerted Action' (second Framework Programme) the phantom was repeatedly measured on six SPA machines, three DXA machines and nine QCT machines (545 measurements). Linear regression equations were derived, individual to each machine, which allowed the derivation of 'standardized densities'. In this way we converted measurements made by machines of the same modality to a common scale of measurements. Two machines (one DXA, one SPA) showed statistically significant instability over time emphasising the need for rigorous quality control in the application of densitometry. In other respects these results provide an encouraging basis for the derivation of standardized normative ranges and the more effective use of peripheral densitometry in future clinical and epidemiological studies.
Fluctuation of mineral apposition rate at individual bone-remodeling sites in human iliac cancellous bone: independent correlations with osteoid width and osteoblastic alkaline phosphatase activity.
We investigated the determinants of bone formation at individual remodeling sites (BMUs) in cancellous bone from 8 osteologically normal, sex hormone-replete women with endometriosis. All were tetracycline double-labeled (2, 12, 2, and 4 day regime) before iliac bone biopsy. At each BMU the mineral apposition rate (MAR) was determined conventionally from the distance between label midpoints (MAR 1) and also from the distance between the mineralization front and the trailing edge of the second label (MAR 2). MAR 1 and 2 were compared with within-BMU measurements of osteoid width (O.Wi) and the activities of osteoblastic alkaline phosphatase (AP) and succinic dehydrogenase (SDH, an enzyme in the Krebs cycle), both quantitated by microdensitometry. A total of 143 BMUs were evaluated, of which 88 were satisfactory for all measurements and 132 were satisfactory for all but SDH. There was a weak correlation (r = 0.34) between MAR 1 and 2 at individual sites, with a mean difference of 0.49 micron/day (mean MAR 0.82 micron/day). The mean MAR of individual subjects tended to be either increasing or decreasing (F = 16.1, p < 0.01). In linear regressions, MAR 2 was statistically dependent on O.Wi, AP, and SDH (73% of the variance accounted for). In contrast, MAR 1 was weakly correlated with O.Wi and only 30% of its variance was accounted for by AP, SDH, and O.Wi. The variance in the MAR 2 data was inversely increased (p < 0.01) compared with MAR 1 as the number of days of bone formation represented.(ABSTRACT TRUNCATED AT 250 WORDS)
Human parathyroid peptide treatment of vertebral osteoporosis.
Previous studies have shown that treatment with daily injections of human parathyroid peptide (hPTH) 1-34 increase axial cancellous bone mass partially at the expense of peripheral cortical bone. In the present work the same hPTH 1-34 regime given for 12 months has been combined with oestrogen or nandrolone therapy to control peripheral bone resorption. Spinal and iliac cancellous (but not cortical) bone increased by 40%-50% above initial values while no perceptible changes occurred in radial cortical or cancellous bone. The evidence of radiokinetic and histomorphometric studies performed before and in the last months of treatment suggested that bone remodeling had proceeded through a transient anabolic phase with increased activation, but that activation had become normal after 11-12 months in the cancellous bone of the ilium whereas it continued to be raised elsewhere in the skeleton. It is concluded that in combination with oestrogens, hPTH peptides given daily injections hold great promise for the treatment of patients with osteoporosis who have already lost substantial amounts of spinal cancellous bone.
Bone remodeling in hip fracture.
Hip fracture incidence has shown strong upward secular trends in many societies with wide differences in age adjusted incidence between nations. Falls and reduced physical activity have emerged as the strongest risk factors in epidemiological studies, while clinical investigations have pointed to secondary hyperparathyroidism as an important candidate cause of the loss of femoral cortical bone in old age. Until recently there have been few studies performed directly on the region of interest in the proximal femur. Non-invasive methodology using 85Sr has now been developed by our group for measuring bone formation and (with concurrent serial DXA densitometry) resorption in the femoral neck. Bone turnover averaged about 8% annually in controls. A group of younger cases of femoral fracture showed similar indices of total and regional bone formation to a control group; but their resorption was higher. To further investigate this, a femoral neck bone biopsy technique has been developed which can be applied to fracture cases treated by arthroplasty. Preliminary studies have established that the anatomical asymmetry of the neck in cross-section is considerable and imposes restraints on the interpretation of smaller or incomplete femur biopsies. Prospects are quite good that, in the absence of tetracycline pre-labeling, mineralization can be studied by assessment of alkaline phosphatase-positive surfaces in cryostat sections. Moreover, such sections will permit study of other anatomically localized metabolic activities as well as antigen expression and osteocyte viability. Candidate mechanisms for the regional decline in bone quality as well as bone mass in subjects suffering hip fracture can now be investigated more effectively.
Physical activity as a determinant of bone conservation in the radial diaphysis in rheumatoid arthritis.
OBJECTIVES: To determine if increasing physical activity is protective of diaphysial (cortical) bone mass METHODS: Fifteen patients attending two rheumatology clinics who had developed seropositive or classical rheumatoid arthritis up to 26 months previously were studied prospectively for two to three years. Rates of loss (or gain) in bone mass in the radial diaphysis and the trabecular bone of the distal radius were measured by quantitative computed tomography, and in the spine by dual photon absorptiometry. Physical activity was assessed by the Framingham physical activity index. Disease activity was followed at three-monthly clinic visits at which the haemoglobin, erythrocyte sedimentation rate, and platelet count were measured. The urinary hydroxyproline to creatinine ratio and plasma osteocalcin were measured at the beginning and end of the observation period. RESULTS: Eleven patients required treatment with disease modifying drugs but none was given corticosteroids. Those whose physical activity did not improve lost radial diaphysial bone at about 4% annually. There was, however, a statistically significant inverse relation, accounting for 48.5% of the variance, between bone loss at this site and improvement in physical activity as assessed by the Framingham index. The other two sites showed much weaker associations. Adjusting for indices of disease activity hardly affected the first relation. Three biochemical indices related to bone turnover showed weak tendencies to decrease with increasing physical activity. CONCLUSIONS: Peripheral cortical bone, distant from inflamed joints, is conserved more successfully in patients who achieve higher levels of physical rehabilitation. This may have implications for avoiding long bone fractures later in the disease.
Biochemical prediction of changes in spinal bone mass in juvenile chronic (or rheumatoid) arthritis treated with glucocorticoids.
OBJECTIVE: To identify biochemical predictors of spinal bone mineral growth and the development of spinal osteoporosis in children with juvenile chronic arthritis (JCA) treated with glucocorticoids. METHODS: Bone mass measurements were made at 3 monthly intervals for one year in 31 children. At each visit, blood and urine were obtained for assessment of laboratory indices related to the acute phase response and bone remodelling rates. Assessments were also made of joint inflammation (simple joint count). RESULTS: Plasma albumin and C-reactive protein (CRP) concentrations contributed independently of height velocity to the prediction of lumbar spinal bone mineral growth, but only when averaged over the year of observation. The simple joint count did not usefully predict spinal bone mineral changes in the individual patient, nor did any measured index normally related to bone turnover (plasma osteocalcin, 25 (OH) vitamin D, urinary hydroxyproline). Mean values of the simple joint count were predicted by mean CRP and CRP trends. Joint count trends were predicted by hemoglobin trends. None of these relationships, although statistically significant, was strong enough to predict individual outcomes precisely. CONCLUSIONS: Failure of spinal bone mineral growth is related to failure of growth in height and weight but also to biochemical markers for the activation of the acute phase response. Failure of bone growth to correlate with increased hydroxyprolinuria or plasma osteocalcin concentrations may be attributed to the confounding effect of glucocorticoid treatment on plasma osteocalcin levels in children whose bone resorption is little changed from normal levels despite their reduced growth. Biochemical measurements are weak substitutes for bone densitometry in monitoring spinal growth in these children.
Deflazacort in juvenile chronic arthritis.
Vertebral crush fracture associated with glucocorticoid therapy causes major morbidity in juvenile chronic arthritis (JCA). Deflazacort (DFZ) may have an advantage over prednisone (PRED) because of its alleged bone sparing properties. Of 34 children with JCA receiving more than 5 mg PRED/day, 31 completed a 1-year, double blind, randomized, comparative trial of DFZ and PRED. Patient characteristics at trial entry were well matched. DFZ and PRED were prescribed in equivalent amounts. DFZ achieved similar disease control to PRED, and was not associated with untoward effects. Joint counts, hematological indices and biochemical values did not differ between treatment groups initially or during the trial. Bone density trends (velocities) in the lumbar spine were measured using dual photon absorptiometry at 3-monthly intervals and trends in bone and soft tissue growth calculated. Lumbar spine bone growth correlated with indices of somatic growth, with wide ranges in each group. Co-variance analysis showed a significant advantage (p < 0.007) of DFZ over PRED when spinal bone density was compared to body surface area and weight. Children taking DFZ showed less weight gain but similar height gain to children taking PRED. Children with poor or no somatic growth showed significant lumbar bone loss only in the PRED group. Of the children originally treated with PRED; 11 were switched to DFZ after completing the double blind study. Data for 26 children treated with DFZ for 1 year were thus available and confirmed a significantly greater rate of spinal bone growth relative to somatic growth, p < 0.002.(ABSTRACT TRUNCATED AT 250 WORDS)
Temporal variations in iliac trabecular bone formation in vertebral osteoporosis.
The histologic heterogeneity of osteoporosis relative to normal controls has attracted great interest. There has been controversy as to whether patients with high turnover osteoporosis may convert to a normal or low turnover form, and vice versa. We have studied 44 patients over 12 years by dynamic histomorphometry and 85Sr kinetics+calcium balance performed within 60 days in 20 patients (Group 1) and 75-808 days apart in the remainder (Group 2). In the first group, the histologic tissue level bone formation rate (BFR/BV or BFR/BS) was predictive of the 85Sr measurements of bone formation (r = 0.66 P < 0.01). There was no statistically significant correlation in Group 2 and the regression coefficients were significantly different (P = 0.01). Periodic regression was used to determine if seasonal changes were responsible for this loss of correlation; none was found that was of statistical significance. No systematic changes with time in bone formation were found in Group 2 during the period of observation; nor were consistent secular changes detected when the data for both groups were examined according to procedure date. In conclusion, bone formation may change with time in postmenopausal osteoporosis. Evidence that these changes are systematic was not found and this has implications for the design of treatment studies.
Spinal and somatic growth in patients with juvenile chronic arthritis treated for up to 2 years with deflazacort.
We previously reported a double-blind controlled trial of Deflazacort vs Prednisone in patients with Juvenile Chronic Arthritis who had required corticosteroid therapy for at least one year. This paper presents further results on an additional 11 patients, making 26 altogether, who were treated for one year with deflazacort. Fourteen of these went on to a second year of deflazacort treatment. As previously reported, the relative rate of spinal bone mineral growth in the first year was greater for the spinal bone mineral content than for the body surface by about 70%. In the second year of treatment spinal bone mineral continued, with wide variations, to grow at the same or a very slightly greater rate. However, somatic growth recovered so that there was no significant difference between the relative growth rates in the spinal bone mineral and the body surface area in year 2 (P = 0.78). Deflazacort therapy appears to permit appropriate growth of the spine in relation to the rest of the body against a background of variable growth impairment due to the disease process and the treatment required to control it.
Whole-body and site-specific bone remodelling in patients with previous femoral fractures: relationships between reduced physical activity, reduced bone mass and increased bone resorption.
1. A new tracer method is described for the non-invasive measurement of bone formation in the proximal femur. The method is based on our previously described whole-body method using 85Sr as the tracer (Reeve, J., Hesp, R. & Wootton, R. Calcif. Tissue Res. 1976; 22, 191-206). It allows correction to be made for long-term exchange processes within the skeleton. 2. The method has been applied in a study of regional and whole-body bone formation in 12 rehabilitated patients who had previously suffered a fracture of the proximal femur. Twelve healthy control subjects were studied, who were selected for their good health and continued physical activity. The aim was to explore the relationship between bone formation and physical activity. 3. Bone formation was similar in the two groups, both regionally and in the whole body. Based on analyses of four cadaver specimens, bone formation in the proximal femur was about one and two-thirds times that in the whole skeleton when related to mass of calcium in the region of interest. 4. Whole-body bone resorption, estimated from five measurements per subject of hydroxyproline excretion in relation to creatinine excretion, was significantly higher in the fracture patients (P < 0.01, Wilcoxon's test). 5. Estimates of current physical activity (and immediate pre-fracture physical activity) were made with a newly devised questionnaire. Historical levels of physical activity (at ages 15-45 years) were determined with Astrom's questionnaire. No bone formation index correlated with any index of physical activity. Urinary hydroxyproline excretion correlated inversely both with current physical activity and historical physical activity (for both regression coefficients P < 0.01). 6. The results are discussed in the light of our current understanding of the control of bone remodelling by the discrete basic multicellular units of bone. The opportunity to study regional bone resorption by the additional use of serial dual X-ray absorptiometry of the same region will in future allow the direct monitoring of the effects of therapeutic interventions which have been designed to prevent contralateral hip fracture.
Treatment of osteoporosis with parathyroid peptide (hPTH 1-34) and oestrogen: increase in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone.
OBJECTIVE: We wished to determine whether treatment of vertebral osteoporosis with human parathyroid peptide 1-34 (hPTH 1-34), given as a daily injection with supplementary treatment with hormone replacement therapy (HRT), increases cancellous bone area in the ilium by increasing the size of packets of new bone. DESIGN AND MEASUREMENTS: The width of packets of cancellous bone (wall width) was measured at random intercepts and mean values calculated. Cancellous bone area and perimeter were also measured. Indices of trabecular separation and the complementary quantity trabecular number were derived according to Parfitt's method, as well as trabecular width. Patients were used as their own controls and changes in these indices calculated. Correlations were calculated for data obtained from independent measurements. PATIENTS: We studied eleven women with post-menopausal osteoporosis, diagnosed by fractures after exclusion of causes of secondary osteoporosis. RESULTS: One woman did not comply with her HRT therapy. In the others, treatment with hPTH 1-34 + HRT restored the characteristically depressed pre-treatment values of wall width to normal. Trabecular width increased approximately four times more than wall width. Changes in wall width correlated with changes in cancellous bone area; however, bone area increased considerably more than could be accounted for statistically by changes in wall width. A decrease in trabecular separation was found to account for the additional increase in bone area (P = 0.056). CONCLUSION: hPTH 1-34 + oestrogen and progestagen therapy increases the width of packets of new cancellous bone with consequent increases in the width of trabecular plates.
Relationship between the location of osteoblastic alkaline phosphatase activity and bone formation in human iliac crest bone.
It is not feasible to use in vivo tetracycline double labeling to study bone formation in biopsies taken during the emergency fixation of fractures. We therefore compared the trabecular localization and extent of osteoblastic alkaline phosphatase (AP) perimeters with tetracycline and osteoid perimeters in iliac crest biopsies from 7 women with postmenopausal osteoporosis and 13 women without metabolic bone disease. Fresh biopsies were chilled to -70 degrees C, and triplicate serial unfixed undecalcified cryostat sections were cut and reacted for AP, stained for osteoid, or mounted unstained. At individual remodeling sites, the mineralizing perimeter (M.Pm) was measured as the extent of a double or single label accompanied by greater than or equal to 1 lamella of osteoid and greater than or equal to 1 lamella of mineralized matrix between the mineralization front and the adjacent label. Osteoid perimeters (O.Pm) and AP perimeters (AP.Pm) were also measured. In each biopsy there was good agreement between the location of AP and bone formation (kappa statistic, range 0.71-1.0). The overall sensitivity and specificity of AP as an indicator of the location of bone formation were 0.963 and 0.902, respectively. At the level of the basic multicellular unit, in those samples in which greater than 3 active BMUs were found, there was (1) significant positive correlation between the M.Pm and both AP.Pm and AP-positive O.Pm (except 1 patient) and (2) no significant difference between the M.Pm and AP-positive O.Pm (17 of 18 patients and 18 of 18 patients at the tissue level).(ABSTRACT TRUNCATED AT 250 WORDS)
Dietary calcium as a statistical determinant of spinal trabecular bone density in amenorrhoeic and oestrogen-replete athletes.
A study investigating the relationship between spinal trabecular bone density (measured by QCT), dietary calcium (measured by questionnaire) and menstrual status in 67 elite female athletes was undertaken. Twenty-five athletes were amenorrhoeic, 27 eumenorrhoeic and 15 were taking an oral contraceptive. The mean bone density was significantly lower (P less than 0.0001) in the amenorrhoeics (168 mg/cm3; 95% confidence interval 154-182) than in the eumenorrhoeics (211 mg/cm3; 197-224) and oral contraceptive takers (215 mg/cm3; 197-233). There was also a significant positive linear correlation between trabecular bone density. However, factors with which calcium intake may be linked, such as energy intake and expenditure, were not measured and therefore it is possible that this relationship is indirect. Further studies on the relationship between dietary calcium and bone mineral density in young women are needed.