Michelle Frost

Can the WHO criteria for diagnosing osteoporosis be applied to calcaneal quantitative ultrasound

Abstract: With the increasing number of quantitative ultrasound (QUS) devices in use worldwide it is important to develop strategies for the clinical use of QUS. The aims of this study were to examine the age-dependence of T-scores and the prevalence of osteoporosis using the World Health Organization Study Group criteria for diagnosing osteoporosis and to examine the T-score threshold that would be appropriate to identify women at risk of osteoporosis using QUS. Two groups of women were studied: (i) 420 healthy women aged 20–79 years with no known risk factors associated with osteoporosis; (ii) 97 postmenopausal women with vertebral fractures. All subjects had dual-energy X-ray absorptiometry (DXA) measurements of the spine and hip and QUS measurements on three calcaneal ultrasound devices (Hologic Sahara, Hologic UBA575+, Osteometer DTUone). A subgroup of 102 (76 on the DTUone) healthy women aged 20–40 years was used to estimate the young adult mean and SD for each QUS and DXA measurement parameter to calculate T-scores. The age-related decline in T-scores for QUS measurement parameters was half the rate observed for the bone mineral density (BMD) measurements. The average T-score for a woman aged 65 years was –1.2 for QUS measurements and –1.75 for the BMD measurements. When osteoporosis was defined by a T-score ≤–2.5 the prevalence of osteoporosis in healthy postmenopausal women was 17%, 16% and 12% for lumbar spine, femoral neck and total hip BMD respectively. When the same definition was used for QUS measurements the prevalence of osteoporosis ranged from 2% to 8% depending on which ultrasound device and measurement parameter was used. Four different approaches, based on DXA-equivalent prevalence rates of osteoporosis, were utilized to examine which T-score threshold would be appropriate for identifying postmenopausal women at risk of osteoporosis using QUS measurements. These ranged from –1.05 to –2.12 depending upon the approach used to estimate the threshold and on which QUS device the measurements were performed, but all were significantly lower than the threshold of –2.5 used for BMD measurements. In conclusion, the WHO threshold of T=–2.5 for diagnosing osteoporosis requires modification when using QUS to assess skeletal status. For the three QUS devices used in this study, a T-score threshold of –1.80 would result in the same percentage of postmenopausal women classified as osteoporotic as the WHO threshold for BMD measurements. Corresponding T-score thresholds for individual measurement parameters on the two commercially available devices were –1.61, –1.94 and –1.90 for Sahara BUA, SOS and estimated heel BMD respectively and –1.45 and –2.10 for DTU BUA and SOS respectively Additional studies are needed to determine suitable T-score thresholds for other commercial QUS devices.

Quantitative ultrasound and bone mineral density are equally strongly associated with risk factors for osteoporosis

Because resources do not allow all women to be screened for osteoporosis, clinical risk factors are often used to identify those individuals at increased risk of fracture who are then assessed by bone densitometry. The aim of this study was to compare calcaneal quantitative ultrasound (QUS) and axial bone mineral density (BMD) T and Z scores in a large group of women, some with no clinical risk factors and others with one or more risk factors for osteoporosis. The study population consisted of 1115 pre‐ and postmenopausal women. A subgroup of 530 women was used to construct reference data for calculating T and Z scores. A total of 786 women was found to have one or more of the following risk factors: (i) atraumatic fracture since the age of 25 years, (ii) report of X‐ray osteopenia, (iii) predisposing medical condition or use of therapy known to affect bone metabolism, (iv) premature menopause before the age of 45 years or a history of amenorrhea of longer than 6 months duration, (v) family history of osteoporosis, (vi) body mass index (BMI) <20 kg/m2, and (vii) current smoking habit. Calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements were performed on a Hologic Sahara and a DTUone and BMD was measured at the spine and hip using dual‐energy X‐ray absorptiometry (DXA). The Z score decrements associated with the seven risk factors calculated using multivariate regression analysis were similar for QUS and BMD measurements. Z score decrements (mean of BMD and QUS measurements combined) associated with a history of atraumatic fracture (−0.67), X‐ray osteopenia (−0.36), a family history of osteoporosis (−0.23), and a low BMI (−0.53) were all statistically significant compared with women with no risk factors. Z score decrements associated with a medical condition or use of therapy known to affect bone metabolism, a premature menopause or prolonged amenorrhea, or those who were current smokers were not significantly different from zero. As the number of risk factors present in each individual increased, the mean Z score decrements became more negative, increasing from −0.28 for women with one risk factor to −1.19 for those with four or more risk factors. QUS and BMD measurements yielded similar mean Z scores for women with one, two, three, or more than four risk factors. Using the World Health Organization (WHO) criteria to diagnose osteoporosis for BMD measurements and revised diagnostic criteria for QUS, approximately one‐third of postmenopausal women aged 50+ years with clinical risk factors were classified as osteoporotic compared with only 12% of women without clinical risk factors. Over two‐thirds of postmenopausal women with risk factors were classified as osteopenic or osteoporotic and approximately 28% were classified as normal. The proportion of women classified into each diagnostic category was similar for BMD and QUS. In conclusion, clinical risk factors for osteoporosis affected calcaneal BUA and SOS Z score measurements to the same extent as axial BMD Z score measurements. Provided revised diagnostic criteria are adopted for QUS, similar proportions of postmenopausal women are identified as osteopenic or osteoporotic as with BMD.

Contact Quantitative Ultrasound: An Evaluation of Precision, Fracture Discrimination, Age-Related Bone Loss and Applicability of the WHO Criteria

Abstract: The aim of this study was to assess a dry calcaneal quantitative ultrasound (QUS) device by examining: (i) short- and long-term precision; (ii) the ability of the ultrasound parameters to identify women with vertebral fractures; (iii) age- and menopause-related bone loss; (iv) applicability of the WHO criteria in scan interpretation. The study group consisted of 422 healthy women with no risk factors associated with osteoporosis (227 premenopausal and 195 postmenopausal) and 93 women with one or more vertebral fractures. All women had calcaneal QUS and bone mineral density (BMD) measurements of the lumbar spine and hip performed. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements in the heel were combined and expressed as estimated heel BMD. Short-term precision studies yielded coefficient of variations of 0.3% for SOS, 4% for BUA and 3.3% for estimated heel BMD. Standardized short-term precision values were approximately 0.2 SD. Long-term standardized precision errors ranged from 0.17 to 0.38 SD. All the QUS and BMD measurement parameters showed significant negative relationships with age in the postmenopausal group. Annual losses were 0.35 dB/MHz per year for BUA, 0.56 m/s per year for SOS and 0.002 g/cm2 per year for estimated heel BMD. All the QUS and BMD parameters were able to discriminate between healthy postmenopausal women and women with vertebral fracture. Age-adjusted odds ratios for each SD decline in QUS measurements were 3.63, 5.25 and 4.79 for BUA, SOS and estimated heel BMD respectively. Corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip were 2.39, 2.51 and 2.95 respectively. When the QUS and BMD parameters were expressed as T-scores, estimated heel BMD showed the least age-related decline, while femoral neck BMD displayed the greatest decrease with age. The mean T-score and prevalence of osteoporosis (T<−2.5) for a Caucasian woman aged 60–65 years were −1.35 and 21% respectively for the lumbar spine compared with −0.59 and 2% for estimated heel BMD. In conclusion, this study revealed that contact ultrasound can detect age- and menopause-related influences on bone status and was able to discriminate between healthy individuals and women with vertebral fracture. However, the widely accepted threshold of a T-score of less than −2.5 for the definition of osteoporosis may need modifying for the interpretation of QUS scans.

Arterial Stiffening Relates to Arterial Calcification But Not to Noncalcified Atheroma in Women A Twin Study

Objectives Our aim was to examine the relationship of arterial stiffness to measures of atherosclerosis, arterial calcification, and bone mineral density (BMD); the heritability of these measures; and the degree to which they are explained by common genetic influences. Background Arterial stiffening relates to arterial calcification, but this association could result from coexistent atherosclerosis. A reciprocal relationship between arterial stiffening/calcification and BMD could explain the association between cardiovascular morbidity and osteoporosis. Methods We examined, in 900 women from the Twins UK cohort, the relationship of carotid-femoral pulse wave velocity (cfPWV) to measures of atherosclerosis (carotid intima-media thickening; carotid/femoral plaque), calcification (calcified plaque [CP]; aortic calcification by computed tomography, performed in subsample of 40 age-matched women with low and high cfPWV), and BMD. Results The cfPWV independently correlated with CP but not with intima-media thickness or noncalcified plaque. Total aortic calcium, determined by computed tomography, was significantly greater in subjects with high cfPWV (median Agatston score 450.4 compared with 63.2 arbitrary units in subjects with low cfPWV, p = 0.001). There was no independent association between cfPWV and BMD. Adjusted heritability estimates of cfPWV and CP were 0.38 (95% confidence interval: 0.19 to 0.59) and 0.61 (95% confidence interval: 0.04 to 0.83), respectively. Shared genetic factors accounted for 92% of the observed correlation (0.38) between cfPWV and CP. Conclusions These results suggest that the association between increased arterial stiffness and the propensity of the arterial wall to calcify is explained by a common genetic etiology and is independent of noncalcified atheromatous plaque and independent of BMD.

The relationship between inhibitors of the Wnt signalling pathway (Dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial stiffness in post-menopausal women

Epidemiological studies have shown an association between bone loss/osteoporosis and vascular calcification (VC). Recent studies have implicated the Wnt signalling pathway in the pathogenesis of VC. We investigated the association between circulating concentrations of Wnt inhibitors; DKK1 and sclerostin with bone mineral density (BMD), abdominal aortic calcification (AAC) and arterial stiffness in post-menopausal women. One hundred and forty six post-menopausal women aged (mean [SD]) 61.5[6.5] years were studied. Sclerostin and DKK1 were measured in serum. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH). AAC was detected by Vertebral Fracture Assessment (VFA) imaging and quantified using an 8- and 24- point scoring methods. Arterial stiffness was determined by aortic pulse wave velocity (PWV). A significant positive correlation was observed between sclerostin and BMD at the FN (r = 0.166, p = 0.043) and TH (r = 0.165, p = 0.044). The association remained significant at the FN (p = 0.045) and TH (p = 0.026) following adjustment for confounders. No significant correlation was observed between DKK1 and BMD. In contrast, there was a significant negative correlation between log DKK1 and AAC (24-point score: r = -0.25, p = 0.008 and 8-point score: r = -0.21, p = 0.024). Subjects with AAC score of 1 or less had significantly higher DKK1 (p = 0.01). The association between DKK1 and AAC remained significant following correction for age, blood pressure, cholesterol (24-point score: p = 0.017, 8-point score: p = 0.044). In adjusted linear regression analysis, sclerostin was positively associated with AAC (24-point score: p = 0.048, 8-point score: p = 0.031). Subjects with a PWV>9 m/s had significantly higher sclerostin than those with PWV <9 m/s: 23.8[12.3], vs 29.7 [14] pmol/l, p = 0.03). No association was observed between DKK1 and PWV. The opposite association between AAC and the 2 Wnt signaling inhibitors is of interest and merits further investigations. Future longitudinal studies are needed to establish the precise role of sclerostin and DKK1 in the pathogenesis of VC.

A prospective study of risedronate on regional bone metabolism and blood flow at the lumbar spine measured by 18F-fluoride positron emission tomography.

The effect of risedronate on bone metabolism at the lumbar spine was assessed in 18 women who had a18F‐fluoride PET scan at baseline and after 6 months of therapy. The net plasma clearance of fluoride to bone mineral reflecting osteoblastic activity decreased significantly after therapy.

Long-Term Precision of 18F-Fluoride PET Skeletal Kinetic Studies in the Assessment of Bone Metabolism

18F-Fluoride PET allows noninvasive evaluation of regional bone metabolism and has the potential to become a useful tool for assessing patients with metabolic bone disease and evaluating novel drugs being developed for these diseases. The main PET parameter of interest, termed Ki, reflects regional bone metabolism. The aim of this study was to compare the long-term precision of 18F-fluoride PET with that of biochemical markers of bone turnover assessed over 6 mo. Methods: Sixteen postmenopausal women with osteoporosis or significant osteopenia and a mean age of 64 y underwent 18F-fluoride PET of the lumbar spine and measurements of biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (urinary deoxypyridinoline) at baseline and 6 mo later. Four different methods for analyzing the 18F-fluoride PET data were compared: a 4k 3-compartmental model using nonlinear regression analysis (Ki-4k), a 3k 3-compartmental model using nonlinear regression analysis (Ki-3k), Patlak analysis (Ki-PAT), and standardized uptake values. Results: With the exception of a small but significant decrease in Ki-3k at 6 mo, there were no significant differences between the baseline and 6-mo values for the PET parameters or biochemical markers. The long-term precision, expressed as the coefficient of variation (with 95% confidence interval in parentheses), was 12.2% (9%–19%), 13.8% (10%–22%), 14.4% (11%–22%), and 26.6% (19%–40%) for Ki-3k, Ki-PAT, mean standardized uptake value, and Ki-4k, respectively. For comparison, the precision of the biochemical markers was 10% (7%–15%), 18% (13%–27%), and 14% (10%–21%) for bone-specific alkaline phosphatase, osteocalcin, and urinary deoxypyridinoline, respectively. Intraclass correlation between the baseline and 6-mo values ranged from 0.44 for Ki-4k to 0.85 for Ki-3k. No significant correlation was found between the repeated mean standardized uptake value measurements. Conclusion: The precision and intraclass correlation observed for Ki-3k and Ki-PAT was equivalent to that observed for biochemical markers. This study provided initial data on the long-term precision of 18F-fluoride PET measured at the lumbar spine, which will aid in the accurate interpretation of changes in regional bone metabolism in response to treatment.

Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis.

Regional bone metabolism measured using18F‐fluoride PET was assessed in 72 postmenopausal women classified as normal, osteopenic, or osteoporotic. Lower values of regional bone formation activity at the lumbar spine were seen in osteoporotic women, whereas global markers of bone formation were significantly increased.

A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual X-ray absorptiometry in women with a history of fracture at sites other than the spine and hip

AbstractThe 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.

Differential effects of teriparatide on regional bone formation using 18F-fluoride positron emission tomography

Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study 18F‐fluoride plasma clearance (Ki) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1‐hour dynamic scan of the lumbar spine and a 10‐minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 µg/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine Ki values evaluated using a three‐compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine Ki values increased by 24% (p = .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k3/[k2 + k3]), which increased by 23% (p = .0006). In contrast to Ki, spine SUVs increased by only 3% (p = .84). The discrepancy between changes in Ki and SUVs was explained by a 20% decrease in 18F− plasma concentration. SUVs increased by 37% at the femoral shaft (p = .0019), 20% at the total hip (p = .032), and 11% at the pelvis (p = .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by 18F− PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites.