An unusual cause of spinal bone loss detected by DXA scanning.

Routine DXA scanning in a 68-year-old asymptomatic man undergoing long-term bisphosphonate treatment for osteogenesis imperfecta showed unexplained loss of bone mineral density in two lumbar vertebrae. Subsequent radiographs revealed a 14-cm abdominal aortic aneurysm eroding the vertebrae. The importance of reviewing all the vertebrae in DXA scans is emphasized, and reasons for the absence of symptoms suggested.

Health-related quality of life in patients with osteoporosis in the absence of vertebral fracture: a systematic review.

To review whether osteoporosis in the absence of vertebral fracture (VFX) affects health-related quality of life (HRQoL), a systematic search of the main literature databases for HRQoL in patients with osteoporosis without VFX was undertaken. This was undertaken. This identified 1,327 articles as potentially relevant to the review. After screening of abstracts and reviewing 168 articles in detail, 27 were considered relevant. HRQoL data were extracted and collated into tables and, where possible, were converted into normative scores and further analysed. Data relating to the associations between HRQoL and bone mineral density (BMD) were also collated. Of the 27 articles included, only 5 directly compared osteoporosis without VFX with a control group (BMD T-score > -1.0, without VFX). Extracted raw data from 21 articles demonstrated that patients with osteoporosis without VFX had clinically relevant reductions in role physical, general health, vitality, mental health domains and the mental component summary score, using SF36. Using Qualeffo-41, pain and physical function were worse in these patients. Also, HRQoL was related to upper femur, but not lumbar spine BMD. HRQoL data in patients with osteoporosis without VFX are limited and variable but suggest that HRQoL is adversely affected by osteoporosis in the absence of VFX. The association of lower BMD and worse HRQoL suggests that more attention should be paid to HRQoL in those without VFX. Future studies are needed to investigate HRQoL in patients with osteoporosis in the absence of fracture, controlling for co-morbidities and social and economic status.

Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells.

Glucocorticoids are effective anti-inflammatory and immunosuppressive agents, but their use is often associated with debilitating side effects such as glucocorticoid-induced osteoporosis. Newly developed glucocorticoid analogues such as the so-called dissociated glucocorticoids are potent immunosuppressants and have the potential for fewer side effects. The effects of these new analogues on osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) in osteoblastic cells have not been studied. OPG and RANKL are osteoblast-derived proteins pivotal to the regulation of bone mass. RANKL stimulates bone resorption by increasing osteoclast differentiation, activation and survival. OPG is the decoy receptor for RANKL and thus inhibits bone resorption. Here, we show that dexamethasone, prednisolone, deflazacort and the dissociated glucocorticoids, RU24858, RU40066, RU24782, AL438-F1 and ZK216348 significantly inhibit OPG production in two human osteoblastic cell lines (MG63 and hFOB). The potency for OPG inhibition was ligand and cell-type specific. In both cell types, dexamethasone and prednisolone were the most potent ligands inhibiting OPG production with IC(50)s of approximately 0.1 nM and 10 nM respectively. In MG63 cells, deflazacort and the RU compounds were the next most potent ligands followed by AL438-F1 and ZK216348. In hFOB cells, however, the RU compounds were the least potent ligands with an IC(50) 74 times higher than in MG63 cells. In contrast, the level of maximum inhibition or effectiveness of OPG inhibition did not vary between cell types but did vary according to the ligand. Dexamethasone, prednisolone, deflazacort and the RU compounds all inhibited OPG production by a maximum of approximately 70-80%, whereas AL438-F1 and ZK 216348 inhibited OPG production by a maximum of only 40-50% at 1 microM. All of the dissociated glucocorticoids and deflazacort were poor stimulators of RANKL gene expression stimulating by only approximately 1-3-fold compared to 7-fold by prednisolone. These data demonstrate that deflazacort and the dissociated glucocorticoids are weak stimulators of the RANKL:OPG ratio compared to prednisolone. Therefore, these compounds have the potential to cause less bone loss than that seen with prednisolone, though this was not investigated here.

A bio-assay for effectors of osteoclast differentiation in serum from patients with bone disease.

UNLABELLED: Osteoclast differentiation and activity, and hence bone loss, depend on two opposing cytokines. Receptor activator of NF-(kappa)B ligand (RANKL) produced by osteoblasts and T-cells stimulates, while osteoprotegerin inhibits. Both of these cytokines are found in serum. Our aim was to develop a functional assay for any factors present in human serum that can affect osteoclast differentiation and to assess whether any such factors vary in diseases in which bone loss occurs. METHODS: Using a culture model of osteoclast differentiation in the presence of macrophage colony stimulating factor and soluble RANKL, we have measured the effects of different human sera on osteoclast differentiation. The production of a marker enzyme for the osteoclast, tartrate-resistant acid phosphatase (TRAP), was used to follow osteoclast differentiation. RESULTS: In general, human serum stimulates osteoclast differentiation as indicated by TRAP activity, but in patients with low bone density this stimulation was attenuated. Sera from 40 female subjects with low bone mineral density showed significantly lower TRAP cell differentiation activity than sera from the healthy female controls. CONCLUSION: We describe a functional bio-assay for factors in human serum which can affect osteoclast differentiation. This assay may have application in monitoring the effects of therapy in bone disease.

Effects of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate on mouse osteoclasts.

A group of 5-day-old mice were injected intraperitoneally with (3-amino-1-hydroxypropylidine)-1,1-bisphosphonate (APD). Morphologic changes were observed in vitally stained osteoclasts on parietal bones 3 days later, and these were judged to be degenerative. At this time significantly increased numbers of nuclei per osteoclast and total numbers of osteoclast nuclei were observed. However, at 4 days after the injection of APD, the total numbers of osteoclasts were significantly reduced relative to controls. When parietal bones were maintained in culture, APD reduced osteoclast numbers and inhibited cell-mediated 45Ca2+ release. Exposure of bones to parathyroid hormone increased the number of osteoclasts counted 1 day later. This effect was not blocked by APD. Calcitonin prevented the reduction in osteoclast numbers due to APD in vitro. We conclude that APD has a direct effect on resorbing mouse osteoclasts.

Isoforms of bone alkaline phosphatase: characterization and origin in human trabecular and cortical bone.

Alkaline phosphatase (ALP) is a glycoprotein and functions as an ectoenzyme attached to the cell membrane by a hydrophobic glycosyl-phosphatidylinositol (GPI) anchor. Three bone ALP (BALP) isoforms in human serum were separated and quantitated by high-performance liquid chromatography. B/I, a minor fraction, is composed on average of bone (70%) and intestinal (30%) ALP, and two major isoforms, B1 and B2. Treatment with GPI-specific phospholipase C (GPI-PLC) did not influence the activities or retention times for B1 and B2, indicating that the biochemical differences between B1 and B2 are likely to be due to different glycosylation patterns. The B/I fraction in serum, on average 4% of total ALP, was found to be composed of B1 and B2 isoforms, each with an intact hydrophobic GPI cell membrane anchor. We investigated the origin of these three BALP isoforms and osteocalcin in human femora from five healthy individuals (four males), mean age 51 years, obtained from a tissue bank. Bone was sampled from three sites: cortical bone, trabecular bone from the diaphysis, and trabecular bone from the greater trochanter. Trabecular bone, from both sites, had higher BALP activities compared with cortical bone. Conversely, the osteocalcin content of cortical bone was more than 3-fold greater than that of trabecular bone. Cortical bone had approximately 2-fold higher activity of B1 compared with B2, whereas trabecular bone had approximately 2-fold higher activity of B2 compared with B1. We observed a previously undescribed BALP isoform (B1x) in all bone samples. B1x was also observed in sera from some patients (60%) with severe renal insufficiency and on chronic dialysis therapy (n = 20). The isoforms of BALP may provide information relating to bone metabolism within specific bone compartments.

Mechanical properties of bone from iliac crest and relationship to L5 vertebral bone.

Apparent density, yield stress and yield energy were measured in transiliac cores of trabecular bone from iliac crest and craniocaudal cores of L5 vertebra from 26 cadavers. In the iliac crest, bone from the anterior superior spine region had significantly greater apparent density and had greater yield energy than bone from the center of the crest. Yield stress was greater at the anterior superior spine than either the center or at the posterior spine. Lumbar vertebral bone was uniform in its characteristics. Apparent density was the property showing the best correlation between iliac crest and L5 (r = 0.79), while yield energy was less well associated (r = 0.67). In L5, mechanical properties decline more rapidly with age than apparent density. Between the ages of 25 and 75 years the rate of fall of yield stress was twice and yield energy 2.6 times compared with the rate of fall of apparent density. Iliac crest behaved similarly. Yield stress in iliac crest paired for density in subjects less than 40 years and greater than 60 years was 40.7% lower in the older subjects (p = 0.03), suggesting a specific mechanical defect in old age. The yield stress advantage accruing to orientated lumbar bone was more marked at lower values of yield stress in the iliac crest when cores from the same cadaver were matched for apparent density. Mechanical properties of iliac crest bone are very dependent upon site and at no one site in the iliac crest do the physical properties satisfactorily predict those in the lumbar spine.

Osteoclasts are not the major source of interleukin-6 in mouse parietal bones.

Interleukin-6 (IL-6) is produced by bone cells and has been shown to stimulate the proliferation of osteoclast progenitors. Which cells in bone produce IL-6 is controversial. This article tests the hypothesis that tartrate-resistant acid phosphatase-positive osteoclasts (TRAP + OC) in neonatal mouse parietal bones are the major source of IL-6. Bones were preincubated with indomethacin to decrease the number of TRAP + OC and the amount of IL-6 produced. Incubation with parathyroid hormone or prostaglandin E2 increased the number of TRAP + OC and the amount of IL-6 produced. Calcitonin and 17 beta-estradiol inhibited this increase in TRAP + OC but had no effect on IL-6 production. 1,25-dihydroxy-vitamin D3 also stimulated an increase in TRAP + OC number but did not cause increased IL-6 production. Both the endocranial and ectocranial membranes of these bones produced large amounts of IL-6. TRAP activity in extracts of endocranial membranes was 14-fold that of the ectocranial membrane and, histochemically, some TRAP + cells could be detected here. However, the ectocranial membranes produced more IL-6 than the endocranial membranes. We conclude that TRAP + OC are not a major source of IL-6 in this system.

Serum osteocalcin and other indices of bone formation: an 8-decade population study in healthy men and women.

In a study of 435 healthy men and women aged 17-97 yr, serum osteocalcin and alkaline phosphatase were measured together with 99TcMDP retention in women. In women, serum osteocalcin falls to a nadir at 35-39 yr, and the mean then rapidly rises 2-fold to a plateau from 50-75 yr. 99TcMDP retention falls to a minimum at 40-45 yr and then rises steadily with increasing age. Serum alkaline phosphatase rises in an indeterminate fashion from 20-25 yr onwards. Osteocalcin in men fell until age 60-70 yr and hardly changed thereafter, whereas serum alkaline phosphatase reached a minimum at age 30-40 yr and thereafter rose with age, as in women.

The use of tonebursts as an alternative to broadband signals in the measurement of speed of sound in human cancellous bone.

Speed of sound (SOS) measurements, typically made using 1 MHz broadband pulses, are increasingly used in the clinical diagnosis of bone disorders. Previous in vitro studies indicate that broadband ultrasound pulses are susceptible to distortion in cancellous bone, leading to imprecise arrival time and SOS measurements. We investigated the effect of bandwidth and frequency on SOS by comparing measurements made using 1 MHz broadband with 1 MHz and 300 kHz narrowband toneburst signals in 15 human proximal femur cancellous bone specimens. There was no significant difference in the value of SOS measured from the leading edge of 1 MHz broadband, 1 MHz toneburst and 300 kHz toneburst signals. Values of SOS in later regions of 1 MHz and 300 kHz tonebursts fell significantly (p < 0.001) when compared to earlier regions. This decrease in SOS levelled off by the third complete cycle of 300 kHz toneburst signals, reaching a plateau value of 1961 +/- 239 m s-1. No plateau SOS value was obtained in 1 MHz tonebursts. The reproducibility of SOS, as measured by the coefficient of variation, was higher for later regions of 300 kHz tonebursts than for the leading edge of 300 kHz toneburst and 1 MHz broadband signals (p < 0.005). The correlation between ultrasound measured modulus and compressive Young's modulus improved when 300 kHz tonebursts (r2 = 0.83) rather than 1 MHz broadband (r2 = 0.77) signals were used to calculate SOS. The improved SOS reproducibility of later regions 300 kHz tonebursts suggest that it may be beneficial to use such signals rather than 1 MHz broadband pulses in SOS measurement. Since no reliable SOS measurements could be obtained from any region of 1 MHz tonebursts, the use of high frequency toneburst signals in cancellous bone has little value.

The dependence of ultrasonic properties on orientation in human vertebral bone.

Speed of sound (SOS) and broad-band ultrasound attenuation (BUA) were measured in cubes of human trabecular bone from lumbar vertebrae, in the three major anatomical axes. There were significant differences in sos and in BUA when measured in the different axes, indicating a structural component to the ultrasonic measurement. Qualitatively different behaviour was observed in the cranio-caudal (CC) axis compared to the transverse directions: SOS was approximately 500 m s(-1) greater than in either the lateral (LT) or antero-posterior (AP) axes, and BUA was approximately 23 dB MHz(-1) cm(-1) greater. Small, but significant, differences existed between the AP and LT axes for both SOS and BUA. In the AP and LT directions, strong linear correlations existed between sos and apparent density (r = 0.90), and between BUA and apparent density (r = 0.96). In the cc axis, correlations with density were poorer. The anomalous behaviour in the cc axis was due to a transient travelling ahead of the main wavefront, and it is suggested that this represents propagation of ultrasound directly through the trabecular framework as a bar wave. This can only occur in the cc axis where the majority of trabeculae are orientated parallel to the direction of propagation. Measurements on cubes in air, as opposed to water, supported this hypothesis. Modifications to the experimental technique necessary to consistently detect this phenomenon are described.

Differential response of serum alkaline phosphatase and serum osteocalcin in Paget's osteosarcoma.

Serum osteocalcin did not show any response to the onset of osteosarcoma in Paget's disease of bone whereas serum alkaline phosphatase increased rapidly. This suggests that osteocalcin is not useful in the diagnosis and management of Paget's osteosarcoma and does not reflect the same osteoblastic processes in bone as serum alkaline phosphatase.

Bone mineral density in healthy normal women and reproducibility of measurements in spine and hip using dual-energy X-ray absorptiometry.

Bone mineral density (BMD) using dual-energy X-ray absorptiometry (DEXA) has been measured in 394 healthy normal women. BMD is highest at the end of the 3rd decade and declines from 45 to 75 years by 0.0095 g/cm2/year in the lumbar spine and by 0.0052-0.0078 g/cm2/year in the upper femur depending on the site. BMD appears to increase in the 8th decade. Reproducibility (coefficient of variation (CV) of repeated measurements) was lowest in the lumbar spine (1.45%) and highest in Ward's triangle (4.29%). CV was not influenced by age at any site and by osteoporosis only in the femoral neck. BMD increased from L2 to L4 but the increase could not wholly be accounted for by the size of the vertebra, suggesting that the posterior elements were contributing to the observed increase of bone density.

Effect of Paget's disease of bone on areal lumbar spine bone mineral density measured by DXA, and density of cortical and trabecular bone measured by quantitative CT.

Although bone density may be increased in bone that is affected by Paget's disease, density changes in cortical and trabecular bone and the effect on bone that is apparently unaffected by Paget's disease are relatively unexplored. We have investigated 81 vertebrae (28 affected, 53 unaffected) in 27 patients with Paget's disease, by dual X-ray absorptiometry (DXA) and by quantitative CT (QCT) bone density measurements of trabecular and cortical bone. DXA bone density was high (mean z-score = 1.62, p < 0.001) in vertebrae affected by Paget's disease, but not significantly different from normal in unaffected vertebrae (mean z-score = 0.07, ns). Mean QCT z-score in Paget's vertebrae was 2.07 (p = 0.009) for cortical bone and 1.37 (p = 0.008) for trabecular bone. DXA correlated with QCT cortical values in affected and unaffected bone (r = 0.8 and 0.56, respectively), and with QCT trabecular values (r = 0.72 and 0.48, respectively). There was no significant difference in the slopes for the correlations in affected or unaffected bone. Cortical QCT values are underestimated in Paget's disease compared with physical measurements of density, owing to the computer algorithm used. High DXA values may alert to the possibility of Paget's disease, especially if the value deviates from the expected normal sequence in lumbar vertebrae. Osteoporotic vertebrae may be overlooked if the average value of bone mineral density is taken in the lumbar spine without reviewing each vertebra.

A computerized technique for vertebral morphometry.

A new technique for morphometric measurement of vertebral bodies has been described, in which a computerized image analysis system was used to digitize and measure standardized lateral radiographs of the thoracic and lumbar spine. The sources of error in the radiographic system and the image analysis system were assessed using vertebral phantoms and test images. Oblique projection in the radiographic image of a vertebra did not produce a significant error in the measured area. The radiographic magnification was approximately 35%. Optical non-uniformity was detected in the image analysis system, and was ascribed to the lens optics. The maximum intra-observer and inter-observer variations in vertebral area were 3.1% and 5.3% respectively for experienced observers. The technique is applicable to clinical studies of large populations, and has value in investigating vertebral deformity in the management of metabolic bone disease.

Structural and material mechanical properties of human vertebral cancellous bone.

The structural Young's modulus (i.e. that of the cancellous framework) was determined by non-destructive compressive mechanical testing in the three orthogonal axes of 48 vertebral bone cubes. In addition, the material Young's modulus (i.e. of the trabeculae themselves) was estimated using an ultrasonic technique. Apparent and true density were determined by direct physical measurements. Significant mechanical anisotropy was observed: mean structural Young's modulus varied from 165 MPa in the supero-inferior direction to 43 MPa in the lateral direction. Structural Young's modulus correlated with apparent density, with power-law regression models giving the best correlations (r2 = 0.52-0.88). Mechanical anisotropy increased as a function of decreasing apparent density (p < 0.001). Material Young's modulus was 10.0 +/- 1.3 GPa, and was negatively correlated with apparent density (p < 0.001). In multiple regression models, material Young's modulus was a significant independent predictor of structural Young's modulus only in the supero-inferior direction. The data suggest the presence of two effects in vertebral bone associated with decreasing apparent density and, by implication, bone loss in general: (a) increased mechanical anisotropy, such that there is relative conservation of stiffness in the axial direction compared with the transverse directions; and (b) increased stiffness of the trabeculae themselves.

Uptake of treatment for osteoporosis and compliance after bone density measurement in the community.

BACKGROUND: Management of osteoporosis is imperfect because patients may not start, persist or comply with treatment. This study was aimed to identify baseline variables associated with women failing to start, persist or comply with bisphosphonate treatment. METHODS: 254 women >50 years old were selected 5 years after having a bone densitometry (bone mineral density (BMD)) diagnosis of osteoporosis. At the outset, information about osteoporosis was sent to the general practitioner (GP). Women were not under pressure at the outset to start or comply, and they and their GP were unaware that follow-up studies would take place. Patient survival was identified from the National Health Service Strategic Tracing Service, prescription data from GP records and baseline data from the initial questionnaire. Persistence was defined as at least one prescription issued per year and compliance as having a medicine possession ratio of >or=80% for each of 5 years. RESULTS: 38% failed to start treatment. Failure was associated with higher BMD Z score and residence in a nursing/residential home. Half of those starting and alive at 5 years persisted with treatment, whereas only 23% achieved a medicine possession ratio of >or=80%. Persistence was associated with a lower comorbidity index and compliance with a lower BMD Z score and a fall before starting treatment. CONCLUSIONS: Treatment was low, especially in nursing/residential homes where known low treatment prevalence appears to be associated with non-initiation. The degree of depression of BMD (not just low BMD) was associated with better initiation and compliance. The association of falls with compliance suggests that fall clinics may be able to play a part in improving osteoporosis management.