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Byline: K. M. Knapp (1,2,3), G. M. Blake (2), T. D. Spector (3), I. Fogelman (2) Keywords: Axial transmission quantitative ultrasound; Bone density; Prevalence of osteoporosis; WHO criteria Abstract: Osteoporosis is a highly prevalent but preventable disease and, as such, it is important that there are appropriate diagnostic criteria to identify those at risk of low trauma fracture. In 1994 the World Health Organization (WHO) introduced definitions of osteoporosis and osteopenia using T-scores, which identified 30% of all Caucasian post-menopausal women as having osteoporosis. However, the use of the WHO T-score thresholds of -2.5 for osteoporosis and -1.0 for osteopenia may be inappropriate at skeletal sites other than the spine, hip and forearm or when other modalities, such as quantitative ultrasound (QUS) are used. The aim of this study was to evaluate the age-dependence of T-scores for speed of sound (SOS) measurements at the radius, tibia, phalanx and metatarsal by use of the Sunlight Omnisense, to evaluate the prevalence of osteoporosis and osteopenia at these sites by use of the WHO criteria, and calculate appropriate equivalent T-score thresholds. The study population consisted of 278 healthy pre-menopausal women, 194 healthy post-menopausal women and 115 women with atraumatic vertebral fractures. All women had SOS measurements at the radius, tibia, phalanx and metatarsal and bone mineral density (BMD) measurements at the lumbar spine and hip. A group of healthy pre-menopausal women aged 20--40 years from the pre-menopausal group were used to estimate the population mean and SD for each of the SOS and BMD measurement sites. Healthy post-menopausal women were classified into normal, osteopenic or osteoporotic, based upon the standard WHO definition of osteoporosis and expressed as a percentage. We investigated the age-related decline in T-scores from 20--79 by stratifying the healthy subjects into 10-year age groups and calculating the mean T-score for each of these groups. Finally, we estimated appropriate T-score thresholds, using five different approaches. The prevalence of osteoporosis in the post-menopausal women aged 50 years and over ranged from 1.4 to 12.7% for SOS and 1.3 to 5.2% for BMD. The age-related decline in T-scores ranged from -0.92 to -1.80 for SOS measurements in the 60 to 69-year age group and -0.60 to -1.19 for BMD measurements in the same age group. The WHO definition was not suitable for use with SOS measurements, and revised T-score thresholds for the diagnosis of osteoporosis of -2.6, -3.0, -3.0 and -2.2 and for osteopenia of -1.4, -1.6, -2.3, and -1.4, for the radius, tibia, phalanx and metatarsal, respectively, were recommended. Author Affiliation: (1) Osteoporosis Screening and Research Unit, Guy's Hospital, 16th Floor, Guy's Tower, St. Thomas Street, London, SE1 9RT, UK (2) Imaging Sciences, Guy's, Kings and St. Thomas' School of Medicine, Guy's Campus, London, UK (3) The Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London, UK Article History: Registration Date: 10/11/2003 Received Date: 11/06/2003 Accepted Date: 03/11/2003 Online Date: 18/12/2003

Byline: A. I. A. Rahmy (1), T. Gosens (2), G. M. Blake (3), A. Tonino (2), I. Fogelman (3) Keywords: Bone mineral density; Bone quality; Dual energy X-ray absorptiometry; Periprosthetic bone loss; Total hip arthroplasty Abstract: Periprosthetic bone loss is a major cause of concern in patients undergoing total hip arthroplasty (THA). Further studies are required to identify the factors determining the pattern of bone remodelling following THA and obtain improvements in the design and durability of prostheses. In this study, we monitored periprosthetic bone loss around two different types of hydroxyapatite coated femoral implant over a 3-year period to evaluate their design and investigate the relationship with the preoperative bone mineral density (BMD) at the spine, hip and forearm. Sixty patients (35 F, 25 M, mean age 63 years, range 46--75 years) undergoing THA were randomised to either the Anatomic Benoist Girard (ABG) or Mallory-Head (MH) femoral stem. Preoperative dual-energy X-ray absorptiometry (DXA) scans were acquired of the posteroanterior (PA) and lateral lumbar spine, the contralateral hip and the non-dominant forearm. Postoperative DXA scans were performed to measure periprosthetic BMD at 10 days (treated as baseline), 6 weeks, and 3, 6, 12, 24 and 36 months after THA using a standard Gruen zone analysis. Results were expressed as the percentage change from baseline and the data examined for the differences in bone loss between the different Gruen zones, between the ABG and MH stems, and the relationship with preoperative BMD. A total of 50 patients (24 ABG, 26 MH) completed the study. Three months after THA there was a statistically significant BMD decrease in every Gruen zone that varied between 5.6% and 13.8% for the ABG prosthesis and between 3.8% and 8.7% for the MH prosthesis. Subsequently, in most zones BMD reached a plateau or showed a small recovery. However, BMD continued to fall in Gruen zones 1 and 7 in ABG patients and Gruen zone 1 in MH patients. Bone loss was less in every Gruen zone in MH patients compared with ABG with the largest difference (10%, P=0.018) in Gruen zone 7. Highly significant relationships were found between periprosthetic bone loss and preoperative BMD measured at the PA spine (P&lt 0.001), total hip (P=0.004) and total distal radius (P&lt 0.001). This study showed differences between two different designs of hydroxyapatite-coated implant that confirmed that prosthesis design influences periprosthetic bone loss. The study also showed that patients' bone density measured at the spine, hip or forearm at the time of operation was a major factor influencing bone loss around the femoral stem. Author Affiliation: (1) Department of Nuclear Medicine, Atrium Medical Centre, Heerlen, The Netherlands (2) Department of Orthopaedics, Atrium Medical Centre, Heerlen, The Netherlands (3) Department of Nuclear Medicine, Guy's Hospital, St Thomas Street, London, SE1 9RT, United Kingdom Article History: Registration Date: 15/10/2003 Received Date: 27/05/2003 Accepted Date: 06/10/2003 Online Date: 06/12/2003

Byline: I. Fogelman (1), G. M. Blake (1), R. Blamey (2), M. Palmer (3), M. Schumacher (4), D. Serin (5), A. Stewart (6), W. Wilpshaar (3) Keywords: Bone mineral density; Goserelin; Node-positive early breast cancer; Premenopausal; ZEBRA Abstract: The purpose of this study was to compare changes in bone mineral density (BMD) in premenopausal patients with node-positive early breast cancer treated with goserelin (Zoladex) or cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients (n=1640) were randomized to goserelin (3.6 mg every 28 days for 2 years) or CMF (sixx28-day cycles) treatment. In a protocoled sub-study involving 96 patients from eight centers (goserelin: n=53 CMF: n=43), lumbar spine (L2--L4) and femoral neck BMD were assessed by dual X-ray absorptiometry at baseline and then annually for 3 years. At the end of the 2-year goserelin-treatment period, mean BMD losses for goserelin-treated and CMF-treated patients were -10.5% and -6.5% (P=0.0005) for lumbar spine and -6.4% and -4.5% (P=0.04) for femoral neck, respectively. At 3 years, partial recovery of BMD was observed in goserelin recipients. In contrast, mean BMD losses for the CMF group indicated persistent BMD loss. No significant differences in BMD were observed between groups at the 3-year assessment of the spine or femoral neck. In the CMF group, based on amenorrhea status at 48 weeks, BMD losses at the lumbar spine were greater for amenorrheic than non-amenorrheic patients. Ovarian suppression resulting in amenorrhea was closely related to BMD loss in both treatment groups. Overall, patients who received CMF did not show recovery of BMD throughout follow-up, whereas partial recovery was observed 1 year after cessation of goserelin therapy, associated with the return of ovarian function in the majority of patients. Author Affiliation: (1) Department of Nuclear Medicine, Guy's, Kings and St Thomas' Hospital Medical School, London, SE1 9RT, UK (2) Nottingham Hospital, Nottingham, UK (3) AstraZeneca, Macclesfield, UK (4) Institute fur Medizinische Biometrie und Informatik, University Hospital, Freiburg, Germany (5) Clinic Sainte Catherine, Avignon, France (6) Christie Hospital, Manchester, UK Article History: Received Date: 06/06/2003 Accepted Date: 19/08/2003 Online Date: 03/10/2003

Byline: K. M. Knapp (1,3), G. M. Blake (2), T. D. Spector (3), I. Fogelman (2) Keywords: Axial transmission ultrasound; Hormone replacement therapy; Postmenopausal age-related change; Precision Abstract: The menopause has a large effect on bone density, and hormone replacement therapy (HRT) has been shown to be an effective treatment for preventing postmenopausal bone loss. The aim of this study was to compare the effects of HRT use on speed of sound (SOS) measurements at the radius, tibia, phalanx, and metatarsal with bone mineral density (BMD) measurements of the lumbar spine and proximal femur. The study population consisted of 278 healthy premenopausal women, 194 healthy postmenopausal women, and 126 healthy postmenopausal women currently receiving HRT for one or more years. SOS measurements were taken at the radius, tibia, phalanx, and metatarsal using the Sunlight Omnisense, and BMD measurements at the lumbar spine and proximal femur using Hologic QDR-4500 densitometers. Z-scores were calculated using the postmenopausal control group. Z-score differences between the postmenopausal controls and HRT group, for the entire group and with the HRT group subdivided into three groups based on duration of HRT usage, were calculated. Significant postmenopausal bone loss was found for all SOS and BMD measurements. A positive effect of HRT usage was found for all SOS measurement sites and lumbar spine BMD, although only the radius and tibia SOS and lumbar spine BMD reached statistical significance. The Z-score differences between the two groups were 0.44, 0.37, 0.15, and 0.26 for the radius, tibia, phalanx, and metatarsal SOS respectively, and 0.28, 0.00, and -0.03 for the lumbar spine, femoral neck, and total hip BMD respectively. A clear effect of the duration of HRT use was seen for the radius measurements, the differences being less marked elsewhere. In conclusion, these results demonstrate a positive effect of HRT on SOS measurements at the radius and tibia and BMD measurements of the lumbar spine. Author Affiliation: (1) Osteoporosis Screening and Research Unit, 16th Floor, Guy's Tower, Guy's Hospital, St Thomas Street, London, SE1 9RT, UK (2) Imaging Sciences, Guy's Kings and St Thomas' School of Medicine, Guy's Campus, London, UK (3) The Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London, UK Article History: Received Date: 24/01/2002 Accepted Date: 28/10/2002 Online Date: 15/04/2003 Article note: Funded by a Research Fellowship from the National Osteoporosis Society.

Byline: R. P. Heaney (1), T. M. Zizic (2), I. Fogelman (3), W. P. Olszynski (4), P. Geusens (5), C. Kasibhatla (6), N. Alsayed (6), G. Isaia (7), M. W. Davie (8), C. H. Chesnut III (9) Keywords: Key words:Bone mineral density -- Osteoporosis -- Risedronate -- Vertebral fracture Abstract: Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =--3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90% P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90% P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96% P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Author Affiliation: (1) Creighton University, Omaha, Nebraska, USA, US (2) Chesapeake Medical Research, Baltimore, Maryland, USA, US (3) Guy's Hospital, London, UK, GB (4) Midtown Medical Center, Saskatoon, Saskatchewan, Canada, CA (5) Limburg University Center, Diepenbeek, Belgium, and University Hospital, Maastricht, The Netherlands, NL (6) Procter &amp Gamble Pharmaceuticals, Cincinnati, Ohio, USA, US (7) University of Turin, Turin, Italy, IT (8) Charles Salt Centre, Oswestry, Shropshire, UK , GB (9) University of Washington, Seattle, Washington, USA, US Article note: Received: 12 September 2001 / Accepted: 11 December 2001

Byline: K. M. Knapp (1), K. M. Knapp (2), G. M. Blake (1), I. Fogelman (1), D. V. Doyle (3), T. D. Spector (2) Keywords: Key words:Colles' fracture -- Multi-site ultrasound -- Postmenopausal women Abstract: Distal forearm fractures are the most common perimenopausal fracture and are generally associated with osteoporosis. The aim of this study was to evaluate the capability of speed of sound (SOS) measurements in cortical bone at the phalanx, radius, tibia and metatarsal to discriminate Colles' fracture cases from controls in postmenopausal women and to compare this with bone mineral density (BMD) measurements obtained by dual-energy X-ray absorptiometry (DXA). Sixty-three postmenpausal Colles' fracture cases and 191 postmenopausal controls had SOS measurements of the radius, tibia, phalanx and metatarsal using a semi-reflection ultrasound technique and BMD measurements of the lumbar spine and proximal femur using DXA. The age-adjusted odds ratios (ORs) for fracture for the SOS measurement sites were 1.50 [95% CI 1.07--2.10] for the radius, 1.23 [0.86-1.76] for the tibia, 1.85 [1.06--3.23] for the phalanx and 1.74 [1.12--2.71] for the metatarsal site. For the BMD measurements the ORs were 1.95 [1.34--2.85] for the lumbar spine, 2.21 [1.43--3.40] for the femoral neck and 2.62 [1.69--4.08] for the total hip. The benefits of combining sites either by taking their average Z-score or by using the manufacturer's ORI algorithm were evaluated. The two methods yielded similar results and the ORs for the combination of the radius and phalanx were 2.00 [1.21--3.33], for the radius and metatarsal 1.67 [1.05--2.67], for the phalanx and metatarsal 1.86 [1.11--3.08] and for the radius, phalanx and metatarsal 1.81 [1.07--3.06]. Combinations of DXA sites gave 2.22 [1.44--3.41] for the lumbar spine and femoral neck and 2.41 [1.57--3.70] for the lumbar spine and total hip. In conclusion, semi-reflection ultrasound measurements at the radius, phalanx or metatarsal demonstrated an ability to discriminate fracture cases from controls in postmenopausal Colles' fracture patients, although the odds ratios were lower than with spine and femur BMD. Author Affiliation: (1) Radiological Sciences, Guy's, Kings and St Thomas' Medical School, Guy's Hospital, London, GB (2) The Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London , GB (3) Department of Rheumatology, Whipps Cross Hospital, London, UK, GB Article note: Received: 6 July 2001 / Accepted: 11 December 2001

Byline: M. L. Frost (1), G. M. Blake (1), I. Fogelman (1) Keywords: Key words:Calcaneus -- DXA -- Fracture -- Osteoporosis -- Quantitative ultrasound Abstract: The widespread availability of quantitative ultrasound (QUS) and X-ray absorptiometry densitometers raises the question of whether a combination of QUS and bone mineral density (BMD) measurements could provide a clinically useful method of enhancing the prediction of fracture risk. The aim of this study was to examine whether a combination of axial BMD and calcaneal QUS measurements can enhance fracture discrimination compared with either method alone. The study population consisted of 154 postmenopausal women with a history of atraumatic fracture at the spine, hip or forearm and 221 healthy postmenopausal women with no clinical risk factors for osteoporosis. Subjects had dual-energy X-ray absorptiometry (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 (SAH) and Osteometer DTUone (DTU). Z-scores were calculated using the mean and SD obtained from the healthy postmenopausal group. Logistic regression analysis yielded odds ratios for BMD measurements at the LS, FN and THIP of 2.2, 2.2 and 2.3, respectively. The odds ratios obtained for QUS measurements ranged from 2.5 for DTU BUA to 3.3 for SAH SOS. While these odds ratios for QUS measurements were higher than those obtained for BMD measurements, the differences were not statistically significant. When the odds ratios for QUS were adjusted for BMD at the spine and hip, the odds ratios remained significant in all cases indicating that QUS and BMD variables contribute independently to fracture discrimination. When the BMD-adjusted odds ratios were compared with those for QUS alone, they were slightly lower but not significantly so. When the QUS measurements were adjusted for THIP BMD, the odds ratios for QUS tended to be lower than when adjusted for LS and FN BMD. The Z-scores for each of the QUS measurement variables were combined with spine or hip Z-scores. Logistic regression analysis of the QUS and BMD combined Z-scores yielded slightly higher odds ratios of approximately 3.1 (compared with 2.9 obtained for QUS alone) and increases in the area under the curve of approximately 2%. However, these increases were not clinically significant. In conclusion, the combination of axial BMD and calcaneal QUS measurements did not significantly improve fracture discrimination compared with either method alone. Author Affiliation: (1) Osteoporosis Screening and Research Unit, Guy's Hospital, London, UK, GB Article note: Received: 29 June 2000 / Accepted: 18 December 2000

Byline: J. Rymer (1), J. Robinson (2), I. Fogelman (3) Keywords: Key words:Bone loss -- Fracture -- Hormone replacement therapy -- Tibolone Abstract: The objective of this study was to assess the long-term effects of tibolone 2.5 mg daily (Livial.sup.1 Organon) on bone mineral density in recently postmenopausal women. An 8-year, open, nonrandomized, prospective study was designed to compare the effects of tibolone 2.5 mg daily (n= 59) with an untreated control group (n= 51). The subjects of this study were 110 recently postmenopausal women (6--36 months since last menstrual period). The main outcome measures were bone mineral density of the spine and femur, measured by dual-energy X-ray absorptiometry, and assessment of biochemical markers of bone metabolism. After 8 years of tibolone use, the mean (+- SEM) increase in bone mineral density compared with baseline was 4.1%+- 0.8% (p&lt 0.0001) in the spine and 4.6%+- 1.8% (p= 0.015) in the femoral neck. Over the same period, bone mineral density in the control group decreased in the spine by --7.5%+- 1.1%, (p&lt 0.0001) and in the femur by --6.7%+- 1.2% (p&lt 0.0001). The bone resorption marker, calcium/creatinine ratio, decreased in the tibolone group but not in the control group. Serum bone formation markers decreased (alkaline phosphatase) or stayed approximately the same (osteocalcin) in the tibolone group. Adherence was high, with 58% (34 of 59) of the tibolone group continuing treatment for 8 years. We conclude that tibolone 2.5 mg daily prevents bone loss in the lumbar spine and femoral neck over 8 years and adherence to treatment is high. The greater bone density compared with untreated women would be expected to reduce the risk of bone fractures. Author Affiliation: (1) Department of Obstetrics and Gynaecology, GB (2) Department of HRT Research Unit, GB (3) Department of Nuclear Medicine Unit, Guy's, King's and St Thomas' Medical School, London, UK, GB Article note: Received: September 2000 / Accepted: December 2000

Byline: K. M. Knapp (1), K. M. Knapp (2), G. M. Blake (1), T. D. Spector (2), I. Fogelman (1) Keywords: Key words:Correlation -- Fracture -- Multisite ultrasound -- Precision Abstract: This study evaluated the clinical utility of a new multisite ultrasound device capable of measuring speed of sound (SOS) at the phalanx, radius, tibia and metatarsal. The in vitro and in vivo short- and long-term precision were evaluated, reference data were collected for 409 healthy white women (236 premenopausal and 173 postmenopausal), and age and menopause related changes were calculated using linear regression. Fracture discrimination was evaluated using 109 women with vertebral fractures and the age-adjusted odds ratios calculated for each standard deviation decrease in SOS measurement. Correlations between SOS measurements and spine and femur bone mineral density (BMD) were calculated. T-score equivalence with BMD was also investigated together with the prevalence of osteoporosis as defined by the WHO criteria. The in vivo short-term precision standardized in T-score units ranged from 0.14 to 0.33 and long-term standardized precision was 0.35--0.65. Postmenopausal age-related bone loss expressed as the annual change in T-score ranged from 0.040 to 0.089 for SOS and 0.053 to 0.066 for BMD, whilst menopause-related annual loss ranged from 0.036 to 0.094 for SOS and 0.050 to 0.074 for BMD. Correlations between the different SOS sites ranged from r= 0.24 to 0.55, and between SOS and BMD from r= 0.12 to 0.47. The odds ratio (and 95% confidence intervals) for fracture per 1 SD decrease in SOS were 2.0 (1.22 to 3.23) for the phalanx 1.5 (1.01 to 2.24) for the metatarsal 1.4 (1.03 to 1.99) for the radius and 1.2 (0.87 to 1.66) for the tibia. Odds ratios for BMD in the same population ranged from 2.6 to 4.8 (1.70 to 8.29). The prevalence of osteoporosis as defined by T= &lt --2.5 in the age range 60--69 ranged from 7.1% to 20.6% for SOS and 6.4% to 12.1% for BMD. In conclusion, this study demonstrated that multisite ultrasound has adequate precision for investigating skeletal status, is capable of differentiating between pre- and postmenopausal women and women with vertebral fractures, has a T-score equivalence similar to that of dual-energy X-ray absorptiometry (DXA), and appears to be a promising new technique for evaluating skeletal status at clinically relevant sites. Author Affiliation: (1) Radiological Sciences, Guy's, Kings and St Thomas' Medical School, Guy's Hospital, London , GB (2) The Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London, UK, GB Article note: Received: 11 August 2000 / Accepted: 14 December 2000

Byline: R. Patel (1), D. Collins (2), S. Bullock (1), R. Swaminathan (3), G. M. Blake (1), I. Fogelman (1) Keywords: Key words:Bone density -- Bone markers -- Seasonal variation -- Vitamin D Abstract: Vitamin D status is known to be an important determinant of bone mineral density (BMD). There is a significant seasonal variation in serum vitamin D, and some studies have reported an associated seasonal variation in BMD. The present study was devised to investigate whether a seasonal variation in BMD could be detected in healthy normal subjects, along with associated variations in serum parathyroid hormone (PTH), intestinal calcium absorption and biochemical markers of bone turnover. A second aim was to investigate whether, if such variations were identified, they could be suppressed by vitamin D supplementation. The subjects were 70 healthy female volunteers (mean age 47.2 years, range 24--70 years) recruited into a double-masked crossover study and followed over 2 years. During the first year 35 subjects received a daily oral supplement containing 800 IU (20 mg) cholecalciferol (group 1) and 35 subjects received a placebo preparation (group 2). During the second year the treatment each group received was reversed. Lumbar spine (L1--L4), left proximal femur and total body BMD were measured by DXA at 3-month intervals. Serum 25-hydroxyvitamin D (25-OHD), serum PTH, bone markers (bone-specific ALP (BSAP) and urinary crosslinks (DYPD/creatinine)) and calcium absorption were also measured at each visit. Cholecalciferol treatment increased serum 25-OHD by 25.4 nmol/l (p &lt 0.001), while a reciprocal decrease in serum PTH of 6.6 ng/l (p=0.011) was seen in subjects in the lowest quartile of baseline serum 25-OHD. The treatment had no significant effect on spine, femur or total body BMD, calcium absorption or bone markers. When Fourier analysis was used to analyze the data for seasonal effect (defined as twice the amplitude of the 1-year period variation) a highly significant effect for 25-OHD of 18 nmol/l (p &lt 0.001) was found. However, no effect was found for BMD, PTH, calcium absorption or bone markers. The analysis set a 95% confidence limit to the seasonal effect of less than 0.6% for spine, total hip and total body BMD. It was concluded that in the population of healthy women studied there was no evidence of seasonal variation in spine, femur or total body BMD, serum PTH, calcium absorption or bone markers. Vitamin D supplementation was found to have no effect on BMD. Author Affiliation: (1) Department of Nuclear Medicine, Guy's Hospital, London, GB (2) Department of Chemical Pathology, Hemel Hempstead General Hospital, Herts , GB (3) Department of Clinical Chemistry, Guy's Hospital, London, UK, GB Article note: Received: 7 July 2000 / Accepted: 14 November 2000

Byline: J. A. Rea (1), M. B. Chen (2), J. Li (2), E. Marsh (3), B. Fan (2), G. M. Blake (1), P. Steiger (4), I. G. Smith (3), H. K. Genant (2), I. Fogelman (1) Keywords: Key words:Morphometric radiography -- Morphometric X-ray absorptiometry -- Osteoporosis -- Precision -- Vertebral deformities. Abstract: Vertebral morphometry, the quantification of vertebral body shape, has proved a useful tool in the identification and evaluation of osteoporotic vertebral deformities in both epidemiologic surveys and clinical trials. Although conventionally it has been performed on lateral radiographs of the thoracolumbar spine (morphometric radiography, MRX), it may now be accomplished on morphometric X-ray absorptiometry (MXA) scans, acquired on dual-energy X-ray absorptiometry (DXA) machines. In this study the long-term precision of vertebral height measurement using MXA and MRX was directly compared. Initially 24 postmenopausal women were recruited (mean age 67 +- 5.8 years): 12 normal subjects (group 1) and 12 with osteoporosis and known vertebral deformities (group 2). Each subject attended for a baseline visit at which they had a MXA examination and lateral thoracic and lumbar radiographs. Twenty-one subjects then returned 1.7 +- 0.4 years later (10 subjects from group 1 and 11 from group 2) for a follow-up visit to repeat both the MXA scans and conventional radiographs. The baseline MXA scans and conventional radiographs were each analyzed quantitatively by two observers in a masked fashion, using a standard six-point method. The follow-up images were then analyzed by the same observers. The MRX observers were masked to the baseline analyses, while the MXA observers utilized the manufacturer's 'compare' facility. On all scans and radiographs anterior (Ha), mid (Hm) and posterior (Hp) vertebral heights were measured and wedge (Ha/Hp) and mid-wedge (Hm/Hp) ratios calculated for each vertebral body, ideally from T4 to L4. MRX analyzed 129 of the 130 available vertebrae in group 1 at both visits and 141 of the 143 available in group 2, while MXA analyzed 124 vertebrae in group 1 at both visits and 127 in group 2. Intra- and inter-observer precision errors, particularly in terms of coefficient of variation (CV%), were larger for MXA than for MRX in both normal subjects and those with vertebral deformities. For example, intra-observer precision errors for vertebral height measurement were 0.62 mm (2.9%) for MXA compared with 0.63 mm (2.2%) for MRX in group 1 (normal) subjects and 0.82 mm (4.2%) for MXA compared with 0.85 mm (3.3%) for MRX for group 2 (osteoporosis and vertebral deformities) subjects. Both MXA and MRX inter-observer precision was clearly poorer than the intra-observer precision, a problem associated with any morphometric technique. This was particularly noticeable for MXA for example, precision of vertebral height measurement in group 1 subjects was 0.62 mm (2.9%) for intra-observer compared with 0.99 mm (4.6%) for inter-observer analyses. MXA and MRX intra- and inter-observer precision was significantly poorer for subjects with vertebral deformities compared with those without, with the CV% for subjects with vertebral deformity approximately 50% greater than that of normal subjects. For example, MRX intra-observer precision for the mid-wedge ratio was 2.6% for group 1 subjects compared with 3.8% for group 2 subjects. The precision of vertebral height measurement on deformed vertebrae of group 2 subjects was poorer than that for normal vertebrae in the same subjects using both MXA and MRX, as a result of increased variability in point placement. For example, MXA intra-observer precision (RMS SD) for the wedge ratio precision was 0.037 (3.9%) for normal vertebrae compared with 0.060 (6.6%) for deformed vertebrae. We conclude that MXA precision was generally poorer than MRX, although both techniques were adversely affected by the presence of vertebral deformities and the use of more than one observer. Although precision errors for both techniques were substantially smaller than the 20--25% reduction in vertebral height frequently proposed to identify incident deformities, the poorer precision of MXA may lead to an increased risk of erroneous classification of vertebrae as normal or deformed. Author Affiliation: (1) Osteoporosis Screening and Research Unit, Guy's Hospital, London, UK, UK (2) Osteoporosis and Arthritis Research Group, University of California, San Francisco, California, USA, US (3) Synexus Ltd, Chorley, Lancashire, UK, GB (4) Hologic Inc., Bedford, Massachusetts, USA, US Article note: Received: 17 December 2000 / Accepted: 12 September 2000

Byline: G. M. Blake (1), R. J. M. Herd (1), R. Patel (1), I. Fogelman (1) Keywords: Key words:Bone density -- Clinical trials -- Dual-energy X-ray absorptiometry -- Total body DXA -- Weight change Abstract: In the past decade dual-energy X-ray absorptiometry (DXA) scanning has assumed an important role in the evaluation of new treatments for osteoporosis. Although the spine and hip are the sites usually chosen for monitoring bone mineral density (BMD) changes, total body DXA is also of interest because of the comprehensive view it gives of the whole skeleton. However, recent studies have reported anomalies in total body DXA in subjects undergoing weight change, suggesting that the technique may not be valid in this circumstance. The present study evaluated total body DXA in a trial of cyclical etidronate therapy in which many subjects underwent significant weight change. The study population was 152 postmenopausal women who had spine, hip and total body DXA scans performed at baseline, 1 and 2 years. The total body scans were analyzed using two software options referred to as 'standard' and 'enhanced'. The following variables were studied: total body BMD, total body bone mineral content (BMC), and subregional BMD values for the following seven sites: lumbar spine, thoracic spine, pelvis, head, ribs, arms and legs. The percentage change from baseline was analyzed in a multivariate regression analysis to derive the treatment effect (defined as the difference in changes between the etidronate and placebo groups) and a coefficient that described the effect of weight change on the total body DXA variable. Mean weight change after 2 years was +1.1 kg (range -9.3 to +16.8 kg). Results for the weight change coefficient were significantly different from zero for five of nine total body variables using the standard analysis and seven of nine for the enhanced analysis with values (and standard errors) that varied from +0.67 (0.04) %/kg for standard total body BMC to -0.32 (0.11) %/kg for enhanced arm BMD. Results for the treatment effect at 2 years were significantly different from zero for total body BMD, total body BMC and for the lumbar spine, thoracic spine and pelvis BMD subregions, but were not significant for head, rib, arm or leg BMD. Findings for the standard and enhanced analyses agreed closely and the size of the treatment effect was related to the proportion of trabecular bone at the measurement site. We conclude that in a randomized study the effects of weight change can be corrected and total body DXA can give useful information about the response to treatment across the whole skeleton. Author Affiliation: (1) Department of Nuclear Medicine, Guy's Hospital, London, UK, GB Article note: Received: 18 February 2000 / Accepted: 12 April 2000

Byline: J. A. Rea (1), J. Li (2), G. M. Blake (1), P. Steiger (3), H. K. Genant (2), I. Fogelman (1) Keywords: Key words: Dual X-ray absorptiometry -- Morphometric X-ray absorptiometry -- Osteoporosis -- Vertebral fractures -- X-ray absorptiometry Abstract: The accurate identification of prevalent vertebral fractures is important in both the clinical and research setting as they are associated with increased risk of further fracture and irreversible clinical consequences. This study reports a direct comparison of prevalent vertebral deformity identification using X-ray absorptiometry (XA) scans, acquired on a dual-energy X-ray absorptiometry (DXA) machine, and conventional radiographs in a diverse group of 161 postmenopausal women, ranging from healthy subjects with normal bone mineral density (BMD) to osteoporotic subjects with multiple vertebral deformities. Deformities were identified by a trained operator by visual assessment of the XA scans (VXA) and semiquantitatively by an experienced radiologist on the conventional radiographs (XSQ). Subjects were recruited prospectively and were triaged according to their VXA results into normal, equivocal and definite deformity groups. VXA and XSQ demonstrated good agreement (96.3%, Io= 0.79) in classifying vertebrae as normal or deformed in the 1978 of 2093 vertebrae deemed analyzable on both the XA scans and conventional radiographs. VXA showed good sensitivity (91.9%) in the identification of moderate/severe XSQ deformities and an excellent negative predictive value (98.0%) was produced when VXA was used to distinguish subjects without vertebral deformities from those with possible or definite deformities on a per subject basis. The majority of disagreement between the two methods resulted from different classification of mild wedge and endplate deformities and the poor visualization of upper thoracic vertebrae on the XA scans. Agreement improved, particularly on a per subject basis, when analysis was restricted to the vertebral levels from L4 to T7. Visual triage of XA scans by a trained operator would seem to be swift, convenient and cost-effective method, with excellent negative predictive value, to distinguish subjects with very low risk of vertebral deformities from those with possible deformities. These 'normal' subjects can then be excluded prior to performing conventional radiographs and further time-consuming and costly methods of vertebral deformity assessment such as XSQ by an experienced radiologist and/or quantitative morphometry. VXA may prove useful in the clinical evaluation of patients at risk of osteoporosis as an adjunct to BMD scans or in the selection of subjects for osteoporosis-related clinical trials. Author Affiliation: (1) Osteoporosis Screening and Research Unit, Guy's Hospital, London, UK, GB (2) Osteoporosis and Arthritis Research Group, University of California, San Francisco, California, USA , US (3) Hologic Inc., Bedford, Massachusetts, USA, US Article note: Received: 27 July 1999 / Accepted: 4 February 2000

Byline: N. Crabtree (1), J. Wright (1), A. Walgrove (3), J. Rea (4), L. Hanratty (1), M. Lunt (5), I. Fogelman (4), R. Palmer (6), M. Vickers (3), J. E. Compston (2), J. Reeve (1) Keywords: Key words:Dual X-ray absorptiometry -- Osteoporosis prevention -- Radiographic vertebral morphometry -- Randomised controlled trial -- Statistical power Abstract: On radiation safety grounds there is concern about the morbidity attributable to routine radiographs of the spine for the identification of new fractures in large-scale trials of fracture prevention. However, the role of the potentially safer low-radiation-dose technique of vertebral morphometry performed by third generation dual-energy X-ray absorptiometry equipment requires evaluation for use in clinical trials. We have therefore investigated the short-term inter-scan imprecision as well as the imprecision attributable to different-day analyses by the same operator and differences in analyses by different operators. The volunteer subjects were participants in a pilot study for a randomized controlled trial of hormone replacement therapy (Women's International Study of long Duration Oestrogen after Menopause, WISDOM). Each subject had two morphometric X-ray analysis scans separated by 2--4 weeks. Exclusions were women with densitometrically defined osteoporosis, as defined by the WHO criterion, and women with a body mass index exceeding 30.9 kg/m.sup.2. On average, the women were 58.7 years of age and had bone mineral density values in the lumbar spine which were about 0.7 SD units higher than a reference US female age-matched population. Scans were assessed from vertebrae T7 through L4. In the study there were no clinically significant differences in performance between the Hologic QDR 4500A and the Lunar Expert XL equipment. Between-scan imprecision was significantly worse than imprecision attributable to reanalysis of the same scan by a different operator or the same operator after an interval. Vertebral level had an effect on measurement uncertainty, especially at the level of the diaphragm and at T7. Coefficients of variation, expressed as percentages of mean values, were better for absolute height measurements than for height ratios, ranging from 1.75% to 3.40% for the three heights measured on three separate machines and from 2.34% to 4.11% for the two height ratios. These results compared favorably with the equivalent figures from a parallel study of morphometry precision undertaken using standard lateral radiographs of the thoracic and lumbar spine (3.1--3.6% and 3.8--3.9%, respectively). We conclude that in trials of prevention therapy in women (or men) selected for not having osteoporosis, low-dose vertebral morphometry using the Hologic 4500A, the Lunar Expert XL or similar equipment is preferable on safety grounds to the classical technique based on standard radiographs, although conventional radiology may still be required in those with prevalent or incident deformities to exclude causes other than osteoporosis. The place of this low-dose technique in trials performed on patients with osteoporosis requires further study. Author Affiliation: (1) Bone Research Group (MRC), University Department of Medicine, Addenbrooke's Hospital, Cambridge, GB (2) Bone Research Group (Wellcome), University Department of Medicine, Addenbrooke's Hospital, Cambridge, GB (3) MRC Epidemiology &amp Medical Care Unit, Wolfson Institute for Preventive Medicine, London, GB (4) Bone Density Unit, Guys Hospital Trust, United Medical &amp Dental Schools, London, GB (5) University Institute of Public Health, Cambridge, GB (6) Department of Rheumatology, Birmingham Heartlands and Solihull NHS Trust, Birmingham, UK, GB Article note: Received: 29 June 1999 / Accepted: 15 December 1999

Byline: M. L. Frost (1), G. M. Blake (1), I. Fogelman (1) Keywords: Key words:Calcaneus -- Osteoporosis -- Precision -- QUS imaging Abstract: The aim of this study was to compare quantitative ultrasound (QUS) measurements obtained using a new calcaneal QUS imaging device with a conventional non-imaging device using fixed transducers. The study group consisted of 340 healthy women with no risk factors associated with osteoporosis (176 premenopausal and 164 postmenopausal) and 83 women with one or more vertebral fractures. All women had QUS measurements performed on the Osteometer DTU-one (imaging) and Walker-Sonix UBA575+ (non-imaging) devices and bone mineral density (BMD) measurements performed at the spine and hip. A subgroup of 81 women had additional dual-energy X-ray absorptiometry (DXA) scans at the calcaneus. Short-term standardized precision (SP = SD/young adult SD) based on duplicate measurements was significantly better on the DTU for broadband ultrasound attenuation (BUA) (SP: DTU 0.15 vs UBA 0.21, p= 0.01) and speed of sound (SOS) (SP: DTU 0.14 vs UBA 0.18, p= 0.01). However, long-term SP of the DTU was comparable to or significantly poorer than the SP of the UBA device. The BUA and SOS measurements obtained on the DTU and UBA were significantly correlated (r= 0.76 and 0.89 for BUA and SOS measurements respectively). The correlations between QUS and BMD measurements were all significant, ranging from 0.53 to 0.72. No significant improvements in the correlation with axial or peripheral BMD were observed using the imaging device. All the QUS measurement parameters showed a significant negative relationship between age and years since menopause in the postmenopausal group. Annual losses were lower for the DTU for BUA (DTU 0.22 dB/MHz per year vs UBA 0.44 dB/MHz per year) but comparable for SOS (DTU 0.29 m/s per year vs UBA 0.22 m/s per year). However, when these figures were standardized to take into account the clinical range, the annual losses were similar on the DTU and UBA. Age-adjusted odds ratios for each SD decline were similar on the DTU for BUA (DTU 3.2 vs UBA 3.3) and SOS (DTU 3.4 vs UBA 5.1). The corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip were 2.7, 2.9 and 3.3 respectively. Age-adjusted receiver-operating characteristics analysis yielded values for the area under the curve (AUC) ranging from 0.74 to 0.83. The DTU BUA AUC of 0.83 was significantly greater than the AUC obtained for UBA BUA and BMD measurements at the lumbar spine and femoral neck. Ultrasound imaging at the calcaneus was found to improve the standardized precision of BUA and SOS measurements in the short term but not in the long term. Neither the correlation with BMD nor the discriminatory ability of QUS was improved by utilizing QUS images at the calcaneus. The inconsistencies of the imaging system used for this study demonstrate that further development is required before it will be possible to show improvements in long-term precision. Author Affiliation: (1) Osteoporosis Research Unit, Guy's Hospital, London, UK., GB Article note: Received: 18 June 1999 / Accepted: 29 October 1999

Byline: M. L. Frost (1), G. M. Blake (1), I. Fogelman (1) Keywords: Key words:Calcaneus -- Osteoporosis -- Quantitative ultrasound --T-scores 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 a$?--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. Author Affiliation: (1) Osteoporosis Unit, Guy's Hospital, London, UK, GB Article note: Received: 25 June 1999 / Accepted: 29 September 1999

Byline: P. J. Ryan (1), G. M. Blake (1), M. Davie (3), M. Haddaway (3), T. Gibson (2), I. Fogelman (1) Keywords: Key words:Bisphosphonate -- Bone density -- Osteoporosis -- Pamidronate Abstract: The effect of oral pamidronate on bone mineral density and its adverse effect profile was investigated by a double-masked placebo-controlled study of 122 patients aged 55--75 years with established vertebral osteoporosis. Patients on active therapy received disodium pamidronate 300 mg/day (group A) for 4 weeks every 16 weeks, 150 mg/day (group B) for 4 weeks every 8 weeks or placebo (group C). All patients additionally received 500 mg of calcium and 400 IU vitamin D daily. Dual-energy X-ray absorptiometry measurements of the spine, hip, forearm and total body were performed at baseline and 6-monthly for 2 years using a Hologic QDR 1000 device at two sites. Serum osteocalcin and urinary deoxypyridinoline were measured at the above visits and at 3 months. The percentage change (SEM) in spine bone mineral density (BMD) at 2 years based on intention-to-treat analysis was 4.64 (1.01) in group A, 6.10 (0.87) in group B and 1.13 (1.32) in group C. Analysis of variance showed significant increases in group A and B compared with placebo (p&lt 0.01). There were also significant rises in femoral neck BMD for group A (p = 0.005), trochanter BMD for groups A and B (p&lt 0.01) and total-body BMD for groups A and B (p&lt 0.001). There was a significant reduction in serum osteocalcin and urinary deoxypyridinoline for groups A and B (p&lt 0.01). There was an excess of gastrointestinal side-effects in the treated groups, particularly group A. We conclude that intermittent pamidronate therapy can prevent bone loss at both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although due to gastrointestinal side-effects the 300 mg dose in particular does not appear suitable for clinical usage. Author Affiliation: (1) Departments of Nuclear Medicine, GB (2) Rheumatology, Guy's Hospital, London , GB (3) Charles Salt Centre, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK, GB Article note: Received: 12 January 1999 / Accepted: 30 August 1999

Byline: R. Patel (1), G. M. Blake (1), J. Rymer (2), I. Fogelman (1) Keywords: Key words:Bone mineral density -- Dual-energy X-ray absorptiometry -- Long-term precision Abstract: The reproducibility of dual-energy X-ray absorptiometry (DXA) measurements of bone mineral density (BMD) is an important factor for longitudinal studies. We assessed the long-term precision of posteroanterior lumbar spine, femoral neck and total hip BMD in 40 postmenopausal women who formed the control arm of a clinical trial of tibolone. BMD was measured at 0, 6 and 12 months and thereafter every 12 months up to 7 years. For each subject the trend of BMD with time was analyzed using linear regression. Each residual was expressed as the percentage difference from predicted BMD and the validity of assuming linear change with time was checked using the mean residuals for each visit number. For spine BMD a chi-squared test showed that the mean residuals were not statistically significantly different from zero. Although statistically significant deviations from linearity were found for the femoral neck and total hip sites the weighted root mean square residuals were small compared with the precision errors. When residuals were binned into histograms a statistical test for skewness was not significant for all three sites. However, a test for kurtosis yielded a statistically significant result for each histogram due to outlying residuals. To determine the standard deviation (SD) of the core gaussian distribution, outliers were trimmed using the method of Melton et al. For lumbar spine BMD outliers with residuals exceeding +- 3 SD arose mainly from subjects with a body mass index (BMI) &gt 28 kg/m.sup.2 or from subjects who had undergone a large change in BMI during the study. For femoral neck BMD and total hip BMD the outliers were frequently due to inconsistent rotation of the hip. Results for long-term precision calculated from the standard deviation of residuals using the trimmed (untrimmed) data were: lumbar spine BMD, 1.12% (1.65%) femoral neck BMD, 2.21% (2.48%) and total hip BMD, 1.32% (1.57%). These errors were only slightly worse than short-term errors despite changes of DXA scanner during the course of the study. However, obesity may have an adverse effect on precision errors in individual patients and particular care is necessary to ensure reproducible patient positioning for femur scans. Author Affiliation: (1) Department of Nuclear Medicine, GB (2) HRT Research Unit, Guy's Hospital, London, UK, GB Article note: Received: 30 March 1999 / Accepted: 22 June 1999

Byline: M. L. Frost (1), G. M. Blake (1), I. Fogelman (1) Keywords: Key words: Fracture -- Osteoporosis -- Precision -- Quantitative ultrasound 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/cm.sup.2 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&lt -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. Author Affiliation: (1) Osteoporosis Unit, Guy's Hospital, London, UK, GB Article note: Received: 8 February 1999 / Accepted: 5 May 1999

Byline: J. A. Rea (1), M. B. Chen (2), J. Li (2), E. Potts (3), B. Fan (2), G. M. Blake (1), P. Steiger (4), I. G. Smith (3), H. K. Genant (2), I. Fogelman (1) Keywords: Key words:Morphometric radiography -- Morphometric X-ray absorptiometry -- Osteoporosis -- Precision -- Vertebral deformities Abstract: Morphometric techniques, which use conventional lateral spine radiographs to quantify vertebral body shape (morphometric radiography, MRX), have proved a useful tool in the identification and evaluation of osteoporotic vertebral deformities. Recently a new method of acquiring the images required for vertebral morphometry using dual-energy X-ray absorptiometry scanners (morphometric X-ray absorptiometry, MXA) has been developed. In this study we compare repeat analysis precision of vertebral height measurement using MXA and MRX. Twenty-four postmenopausal women were recruited (mean age 67 + 5.8 years): 12 normal subjects and 12 with osteoporosis and vertebral deformities. Each subject had a MXA scan and lateral thoracic and lumbar radiographs at a single appointment, which were each analyzed quantitatively in a masked fashion, using a standard 6-point method, twice by one observer and once by a second observer. Anterior (Ha), mid (Hm) and posterior (Hp) vertebral heights were measured and wedge (Ha/Hp) and mid-wedge (Hm/Hp) ratios calculated for each vertebral body. Intra- and interobserver precision were consistently poorer in MXA compared with MRX in both normal subjects and those with vertebral deformities, with MXA CV% generally at least 50% higher than corresponding values for MRX. For both MXA and MRX interobserver precision was clearly poorer than intraobserver precision, a problem associated with any morphometric technique. MXA intra- and interobserver precision were significantly poorer for subjects with vertebral deformities compared with those without, with a CV% for deformity subjects up to twice that of normal subjects. Conversely, MRX showed little or no obvious worsening of intra- or interobserver precision for deformity subjects. Comparison of MXA precision in the normal and deformed vertebrae of the deformity subjects demonstrated that the poorer precision in these subjects compared with normal subjects was the result of increased variability in point placement on the deformed vertebrae themselves. However, the precision for normal vertebrae in these subjects was also somewhat poorer than the precision in normal subjects. We conclude that MXA precision is generally poorer than that of MRX and that the presence of vertebral deformities has a more pronounced effect on MXA precision than on MRX precision. Author Affiliation: (1) Osteoporosis Screening and Research Unit, Guy's Hospital, London, UK, GB (2) Osteoporosis and Arthritis Research Group, University of California, San Francisco, California, USA, US (3) Synexus Ltd, Chorley, Lancashire, UK, GB (4) Hologic Inc., Bedford, Massachusetts, USA, US Article note: Received: 21 July 1998 / Accepted: 13 November 1998

Byline: G. M. Blake (1), N. G. Preston (1), R. Patel (1), R. J. M. Herd (1), I. Fogelman (1) Keywords: Key words:Calibration change -- Dual-energy X-ray absorptiometry, Longitudinal studies Abstract: Since its commercial introduction a decade ago, the technique of dual-energy X-ray absorptiometry (DXA) has been widely recognized as a useful and sensitive method of measuring changes in bone mineral density (BMD) at selected sites in the skeleton such as the spine and proximal femur. Because of their high precision and stable calibration, DXA scanners are frequently used in clinical trials to evaluate new treatments for osteoporosis. Quality assurance procedures based on regular scanning of phantoms are widely adopted in such trials, and continuity of the phantom BMD measurements is generally believed to ensure continuity in the in-vivo calibration. We report a change in calibration of a DXA scanner that occurred during a clinical trial where the calibration shift was different for the spine and femur sites and was not predicted or explained by the standard quality control procedures using phantoms. However, we show that provided patients enrolled in studies are thoroughly randomized and the statistical analysis is confined to the differences between the treated and control groups, then the effects of such calibration shifts on conclusions regarding the efficacy of treatment are considerably smaller than the random statistical errors. Author Affiliation: (1) Department of Nuclear Medicine, Guy's Hospital, London, UK, GB Article note: Received: 12 February 1998 / Accepted: 20 May 1998

Byline: A.I.H. Ahmed (1), G.M. Blake (2), J.M. Rymer (1), I. Fogelman (2) Keywords: Key words: Bone mineral density Lumbar spine Femoral neck Osteopenia Reference Data Abstract: Osteoporosis is a common disease which causes significant morbidity and mortality and in many cases may be preventable. In the absence of fragility fractures the accepted method of identifying those at high risk is based upon bone mineral density (BMD) measurements with defined cut-off points. To correctly delineate normal from abnormal, reliable reference ranges appropriate to the observed population are required. We have studied the age-dependent changes in mean BMD and standard deviation at the lumbar spine and femoral neck in a normal population extracted from 4280 women screened for osteopenia and compared our findings with the manufacturer's normal range (MNR). The recent World Health Organization criteria for the diagnosis of osteopenia and osteoporosis using the 'manufacturer's young normal' (MYN) values and our 'study young normal' (SYN) values have been applied. The study normal population (SNP) included 2068 women (mixes social class mean age 53 years, range 30--79 years). The distribution of mean lumbar spine BMD with age in SNP was generally similar to the MNR. In contrast mean femoral neck bone density from SNP was significantly different from the MNR, ranging from 3% to 12% lower in each 5-year group analysed (p &lt 0.05). Comparison of standard deviations in spine BMD in SNP against the fixed MNR standard deviation showed a statistically significant increase commencing at 45 years of age. The magnitude of this increase appeared to rise with age and remained significant in the 75-to-79-year group (p &lt 0.05). In contrast, standard deviation in femoral neck BMD in SNP appeared relatively constant with age except in the group of women at and around the time of the menopause. The SYN value for mean lumbar spine BMD was 0.994 g/cm.sup.2 (cf. MYN value 1.047, p &lt 0.0001) with a standard deviation of 0.122 g/cm.sup.2 (cf. MYN 0.11, p = 0.0005). Similarly our SYN value for femoral neck BMD was 0.787 (cf. MYN value 0.895, p &lt 0.0001) with a standard deviation of 0.109 (cf. MYN value 0.10, p = 0.0027). Using SYN values 36% (748) for the spine and 33% for the hip of our normal population are classified as osteopenic or osteoporotic. Using MYN values increases the proportion of women classified as osteopenic or osteoporotic to 52% (1078) for the spine and 68% (1409) for the femur. If both sites of measurement are considered simultaneously SYN classifies 46% (952) as either osteopenic or osteoporotic at one or other site, which is increased to 73% (1513) when the MYN values are used. We observe that manufacturer's reference ranges may not be appropriate for the local population and may lead to an erroneously high diagnosis of osteopenia and osteoporosis, which would lead to unnecessary patient anxiety and perhaps errors regarding treatment. Author Affiliation: (1) Department of Gynaecology, Guy's Hospital, London, UK, GB (2) Department of Nuclear Medicine, Guy's Hospital, London, UK, GB

Summary: This study showed that regional bone blood flow and F-fluoride bone plasma clearance measured by positron emission tomography are three times lower at the hip than the lumbar spine. Introduction: Measurements of effective bone plasma flow ( K), bone plasma clearance ( K) and standardised uptake values (SUV) using F-fluoride positron emission tomography (F-PET) provide a useful means of studying regional bone metabolism at different sites in the skeleton. This study compares the regional F-fluoride kinetics and SUV at the hip and lumbar spine (LS). Methods: Twelve healthy postmenopausal women with no history of metabolic bone disease apart from two with untreated osteoporosis were recruited. Each subject underwent 60-min dynamic F-PET scans at the LS and proximal femur two weeks apart. K, K and SUV were measured at the LS (mean of L-L), femoral neck (FN), total hip (TH) and femoral shaft (FS). Differences between sites were assessed using the nonparametric Kruskal-Wallis test with a Bonferroni correction for multiple comparisons. Results: Values of K, K and SUV at the FN, TH and FS were three times lower than at the LS ( p = 0.003). Amongst the proximal femur sites, K and SUV were lower at the FS compared with the FN and TH, and SUV was lower at the TH compared with the FN (all p < 0.05). The volume of distribution was lower at the TH and FS compared with the LS ( p < 0.05). Conclusion: The lower values of K, K and SUV at the hip suggest that lower bone blood flow in the proximal femur is an important factor explaining the principal reason for the differences in bone fluoride kinetics between the LS and hip sites. [ABSTRACT FROM AUTHOR]

Summary: We assessed the precision of lumbar spine F-PET measurements based on 58 scans performed on 20 postmenopausal women. The percentage coefficient of variation (%CV) (95% confidence interval) was 9.2% (7.5-11.8) for standardised uptake values, 11.7% (9.5-14.9) for plasma clearance measurements using the Patlak method and 14.5% (11.7-18.5) for plasma clearance measurements using the Hawkins three-compartment model. Introduction: F-Fluoride positron emission tomography (F-PET) is a non-invasive technique that allows the assessment of regional bone turnover in patients with metabolic bone disease. Knowledge of the precision errors of F-PET measurements is important for planning the number of subjects required for research studies. Methods: Twenty osteoporotic postmenopausal women had F-PET scans of the lumbar spine at 0, 6 and 12 months after stopping long-term bisphosphonate treatment. No significant changes in the PET measurements were seen over the 12-month period, and the data were deemed suitable for a precision study. Precision errors were evaluated for standardised uptake values (SUVs) and for the fluoride plasma clearance to bone mineral ( K) determined using the Patlak and Hawkins methods. Precision errors were expressed as the %CV and were calculated for the mean L1-L4 region and for individual vertebrae. Results: %CV (95% confidence interval) for the L1-L4 region was 9.2% (7.5-11.8) for SUV, 11.7% (9.5-14.9) for K measured using the Patlak method and 14.5% (11.7-18.5) for K measured using the Hawkins method. There was no significant difference between precision errors obtained for the L1-L4 region and those obtained for a single vertebra. Conclusions: SUV measurements showed the smallest precision error followed by the Patlak method, while the Hawkins method gave the largest error. Measuring a smaller region of interest did not increase the precision error, suggesting that the factor determining the errors may be scanner calibration. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1 year but increased in the hip in the alendronate group only. Introduction: Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation. Methods: Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN ( n = 11) or RIS ( n = 9) for a minimum of 3 years at screening (range 3-9 years, mean 5 years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12 months following treatment discontinuation. F-fluoride plasma clearance (K) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed. Results: With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12 months for both study groups. Measurements of K and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% ( p = 0.028) and 24.0% ( p = 0.013), respectively. Conclusions: Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12 months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment. [ABSTRACT FROM AUTHOR]

Summary: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m, p < 0.001). Conclusion: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis" by P. J. Marie, D. Felsenberg, and M.-L. Brandi that was published in the July 14, 2011 online issue.