A Case–Control Study of Quality of Life and Functional Impairment in Women with Long–Standing Vertebral Osteoporotic Fracture

There have been several studies of the impact of vertebral osteoporotic fracture on the quality of life and functionality of individual subjects. To date, however, no direct comparisons with age-matched normal subjects without vertebral fracture have been made. The radiographs of 145 female clinic patients with vertebral fractures were reviewed by the study physicians. The controls were recruited from the electoral role and by media appeal. One hundred and sixty-seven women had radiographs taken to determine those without vertebral fracture. Fracture subjects and controls had to be ambulant and were excluded if they had significant radiologic evidence of degenerative disk or joint disease of the spine. One hundred cases and one hundred controls were matched by 5-year age groups. The number, position and severity of the vertebral fracture on the lateral radiographs of the cases was recorded. Quality of life was measured using the Short Form-36 (SF-36) (maximum score 100) and a utility score calculated from thesese results (maximum score 1). Two measurements of functionality were employed: the Modified Barthel Index (MBI) to assess the activities of daily living (maximum score 100) and the Timed ‘Up & Go’ (TUG) that measured the time taken for the subject to rise from sitting in a chair, walk 3 m along a line, return to the chair and sit down. The fracture subjects had 2.9 + 1.6 (mean + SD) vertebral fractures and the time since last fracture was 5.1 + 4.8 years. The SF-36 physical function component summary index results were: fracture subjects 36 + 11, controls 48 + 9 (p < 0.001). The SF-36 mental health component summary index results were: fracture subjects 50 + 11, controls 54 + 8 (p <0.05). The utility scores were: fracture subjects 0.64 + 0.08, controls 0.72 + 0.07 (p <0.001). The MBI results were: fracture subjects 97 + 5, controls 99 + 1 (p< 0.01). The TUG results were: fracture subjects 13.8 + 7.3 s, controls 10.1 + 4.1 s (p <0.01). TUG and MBI scores correlated well with SF-36 scores; however, no domain of the SF-36 or functional measure correlated with either the number of vertebral fractures or the time since last vertebral fracture. Thus, clinically reported vertebral fractures impair both the quality of life and functionality of these subjects. The adverse impact of vertebral fracture on quality of life and functionality needs to be recognized by medical practitioners, subjects and the community, so that adequate health resources can be devoted to the prevention and treatment of this debilitating condition condition. Received: 17 June 1998 / Accepted: 28 October 1998     

Impact of Hip and Vertebral Fractures on Quality-Adjusted Life Years

The objective of the study was to estimate the impact of hip and vertebral fractures on quality of life in postmenopausal women using a preference-based health measure that is appropriate for economic evaluations and to investigate correlates of health outcome. Interviews to assess health-related quality of life, which also documented other health conditions and characteristics, were undertaken in women age 50 years and older without osteoporotic fractures compared with women with hip and/or vertebral fracture(s). Health status was characterized by self-reported physical limitations and the mental and physical component summary scores of the SF-36. Quality-adjusted life years (QALYs), which reflect each individual’s assessment of her overall health utility, were estimated with time tradeoff values. Regression methods were used to examine QALY correlates (e.g. time since fracture) for each fracture group and to estimate differences in QALYs between fracture and non-fracture subjects after accounting for other patient characteristics. Among 382 women ages 50–96 years, fracture subjects were significantly older, less likely to use hormone replacement therapy and more likely to report physical limitations than non-fracture subjects. On the QALY scale, where 1 represents perfect health and 0 represents death, mean QALY values were 0.82 (95% CI: 0.76, 0.87) among 114 women with one or more vertebral fractures and 0.63 (95% CI: 0.52, 0.74) among 67 with hip fracture compared with 0.91 (95% CI: 0.88, 0.94) among 201 women without fracture. No significant correlates of QALYs were identified among women with vertebral fracture alone. Among hip fracture subjects, time since hip fracture and presence of a vertebral fracture were significant correlates of QALYs. In multiple regression analyses, estimated QALY differences (fracture minus non-fracture subjects) ranged from –0.05 to –0.55 and were equivalent to losses of 20–58 days, 23–65 days and 115–202 days per year for vertebral fracture (p= 0.001), hip fracture (p= 0.009) and hip plus vertebral fracture (p<0.001) subjects, respectively, depending on age. Thus to adequately assess the cost-effectiveness of osteoporosis treatment, the negative impact of vertebral fractures on QALYs, even among women who have survived a hip fracture, must be considered. Received: 2 February 2001 / Accepted: 23 July 2001     

Intracapsular Hip Fracture: Increased Cortical Remodeling in the Thinned and Porous Anterior Region of the Femoral Neck

It has been shown previously that the antero-inferior cortex is subjected to maximal tensile stress during a fall onto the greater trochanter. We have recently shown that in cases of femoral neck fracture, cortical thinning and porosity is greatest in the anterior and antero-inferior region of the femoral neck. To investigate whether this is due to increased remodeling, we have quantified surface-based parameters associated with Haversian remodeling in femoral neck biopsies from women with intracapsular hip fracture and post-mortem controls. Cryostat sections of chilled biopsies were reacted for either tartrate-resistant acid phosphatase (TRAP) or alkaline phosphatase (ALP) activity. Proportions of active canals were determined in each quadrant (inferior, anterior, superior, posterior) of the femoral neck. The biopsies were then embedded in methacrylate to permit histomorphometry using Goldner’s and Solochrome sections. In the cases there was no significant increase in the proportion of canals undergoing remodeling in the cortex as a whole (p = 0.846), but the regional distribution of remodeling was markedly different from that in the controls. In the anterior cortex, the proportion of canals undergoing remodeling was increased by 56% (p = 0.0087); in contrast there was a relative decrease of 35% in the superior region (p = 0.0047). In the anterior cortex of cases there were 76% and 42% increases in the proportions of eroded (p = 0.019) and osteoid-bearing (p = 0.041) canals, respectively. In the superior region, the decrease in the proportion of remodeling sites was due to a marked decrease in canals with an osteoid surface (51%; p = 0.0031). Covariance analysis with cortical porosity as the dependent variable showed that porosity was significantly dependent on the regional distribution of eroded (p = 0.033) but not on the distribution of forming (p = 0.153) canals (R ²adj = 0.51). Cellular levels of TRAP and ALP were significantly elevated in the anterior region of cases compared with the controls (TRAP 55%, p = 0.006; ALP 36%, p = 0.003). For the posterior and inferior regions there were no marked differences in cellular TRAP and ALP levels compared with control values. These data show that the increased cortical thinning and increased porosity we have previously observed in the anterior cortex in cases of hip fracture are associated with increased indices of Haversian remodeling. These findings are consistent with the hypothesis that, in cases of hip fracture, remodeling imbalance in the anterior cortex is a continuing process up to the time of fracture and is due to increased osteoclastic cellular activity associated with an osteoblastic response that is inadequate to prevent bone loss. Received: 16 November 1998 / Accepted: 17 February 1999     

Six and Twelve Month Changes in Bone Turnover are Related to Reduction in Vertebral Fracture Risk During 3 Years of Raloxifene Treatment in Postmenopausal Osteoporosis

We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantely related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 mg/l in serum osteocalcin after 1 year’s raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54–0.88), p= 0.003. Similarly, for a decrease of 5.91 mg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62–0.92), p= 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture – even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture. Received: 2 January 2001 / Accepted: 30 May 2001     

Use of Bone Densitometry by Ontario Family Physicians

A stratified (urban/rural), computer-generated random sample of 797 Ontario members of the College of Family Physicians of Canada received a self-administered questionnaire by mail. The questionnaire examined current use of bone densitometry, focusing on reasons for its use, factors that limit use, and features of the report that are helpful to the family physician in subsequent patient management. The response rate was 64% (457/711) after excluding 77 physicians who no longer practice family medicine. Ninety-two percent of the physicians used densitometry; of these, 97% ordered the test in the past year. Compared with urban physicians, rural physicians were more likely to ‘never use densitometry’ (p = 0.04). Rural physicians who reported using densitometry used it less frequently (p = 0.002), were less likely to have local access (p = 0.001), and were less confident in its use (p = 0.004) than their urban counterparts. Risk factors and hormone replacement therapy decision-making were ranked equally as the most frequent reasons for ordering the test, followed by follow-up. Few physicians identified limits to their use of densitometry. Female physicians used densitometry more frequently (p = 0.03) and were more confident in its use (p = 0.02). Features of the bone density report found to be most helpful were the statement of fracture risk, suggestions for further investigation, management and follow-up, and percent reduction in bone density compared with age-matched controls. The use of bone densitometry by Ontario family physicians is consistent with published guidelines. These physicians identified the estimate of fracture risk and suggestions for investigation and management as the most helpful features of the bone density report. This suggests a role for the incorporation of clinical data in bone density reporting. Received: 23 May 1999 / Accepted: 19 September 1999     

Effects of Alendronate on Bone Density in Men with Primary and Secondary Osteoporosis

Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n= 23) or secondary osteoporosis (n= 18), (ii) postmenopausal women with primary (n= 18) or secondary (n= 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4%± 1.1% to 7.0%± 2.2% higher in the treated groups compared with baseline and controls (p<0.05 to 0.0001). Trochanteric BMD increased by 2.6%± 1.5% and 3.7%± 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9%± 1.3% in treated women with primary osteoporosis (p<0.01) after 12 months. No significant changes were detected at the femoral neck or Ward’s triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD – effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint. Received: 23 February 1999 / Accepted: 2 June 1999     

Intensive Insulin Therapy and Bone Mineral Density in Type 1 Diabetes Mellitus: A Prospective Study

To determine the effect of metabolic control on bone mineral density (BMD) in type 1 diabetes mellitus (type 1 DM), we studied BMD (by dual-energy X-ray energy absorptiometry) and bone remodeling parameters in 62 patients with type 1 DM both before and 7 years after commencement of intensive insulin therapy. Overall outcomes after the 7-year treatment included the stabilization of BMD at all sites, as well as a significant decrease in tartrate-resistant acid phosphatase (TRAP) (4.302 ± 2.62 vs 2.65 ± 0.97 IU/l; p = 0.0001) and increase in intact parathyroid hormone (PTHi) (28.05 ± 15.7 vs 39.78 ± 22.41 ng/l; p = 0.005). Presence of diabetic retinopathy (RTP) versus its absence (non-RTP) was associated with lower BMD in femoral neck (FN) (0.831 ± 0.142 vs 0.756 ± 0.153 mg/cm²; p = 0.03) and Ward’s triangle (WT) (0.736 ± 0.165 vs 0.632 ± 0.172 mg/cm²; p = 0.03), and with a lower T-score in FN (–0.93 ± 1.34 vs –1.70 ± 1.46; p = 0.04) and WT (–0.72 ± 1.42 vs –1.540 ± 1.55; p = 0.04) and Z-score in FN (–0.591 ± 1.23 vs –1.132 ± 1.46; p = 0.01). The percentage of patients with osteopenia or osteoporosis in the RTP group was significantly higher than in the non-RTP group (72% vs 53%, p = 0.05; RR= 3.2) and the glycosylated hemoglobin (HbA1c) levels of the RTP group were also higher (8.53 ± 1.6% vs 7.1 ± 1.1%; p = 0.05). The improvement in metabolic control, increase in body mass index and decrease in resorption parameters could contribute to the stabilization of bone mass in type 1 DM but the presence of retinopathy is a critical factor in the progression of diabetic osteopenia. Received: 4 June 1999 / Accepted: 16 November 1999     

Digital X-ray Radiogrammetry Predicts Hip,Wrist and Vertebral Fracture Risk in Elderly Women: A Prospective Analysis from the Study of Osteoporotic Fractures

Digital X-ray radiogrammetry (DXR) is a technique that uses automated image analysis of standard hand radiographs to estimate bone mineral density (DXR-BMD). Previous studies have shown that DXR-BMD measurements have high precision, are strongly correlated with forearm BMD and are lower in individuals with prevalent fractures. To determine whether DXR-BMD measurements predict wrist, hip and vertebral fracture risk we conducted a case–cohort study within a prospective study of 9704 community-dwelling elderly women (the Study of Osteoporotic Fractures). We compared DXR-BMD, and BMD of the radius (proximal and distal), calcaneus, femoral neck and posteroanterior lumbar spine in women who subsequently suffered a wrist (n= 192), hip (n= 195), or vertebral fracture (n= 193) with randomly selected controls from the same cohort (n= 392–398). DXR-BMD was estimated from hand radiographs acquired at the baseline visit. The radiographs were digitized and the Pronosco X-posure System was used to compute DXR-BMD from the second through fourth metacarpals. Wrist fractures were confirmed by radiographic reports and hip fractures were confirmed by radiographs. Vertebral fractures were defined using morphometric analysis of lateral spine radiographs acquired at baseline and an average of 3.7 years later. Age-adjusted odds ratio (OR, vertebral fracture) or relative hazard (RH, wrist and hip fracture) for a 1 SD decrease in BMD were computed. All BMD measurements were similar for prediction of wrist (RH = 1.5–2.1) and vertebral fracture (OR = 1.8–2.5). Femoral neck BMD best predicted hip fracture (RH = 3.0), while the relative hazards for all other BMD measurements were similar (RH = 1.5–1.9). These prospective data indicate that DXR-BMD performs as well as other peripheral BMD measurements for prediction of wrist, hip and vertebral fractures. Therefore, DXR-BMD may be useful for prediction of fracture risk in clinical settings where hip BMD is not available. Received: 27 April 2001 / Accepted: 10 October 2001     

High-Resolution Computed Tomography for Architectural Characterization of Human Lumbar Cancellous Bone: Relationships with Histomorphometry and Biomechanics

The aim of the present study on human vertebral cancellous bone was to validate structural parameters measured with high-resolution (150 μm) computed tomography (HRCT) by referring to histomorphometry and to try to predict mechanical properties of bone using HRCT. Two adjacent vertical cores were removed from the central part of human L2 vertebral body taken after necropsy in 22 subjects aged 47–95 years (10 women, 12 men; mean age 79 ± 14 years). The right core was used for structural analysis performed by both HRCT and histomorphometry. Two cancellous bone specimens were extracted from the left core: a cube for HRCT and a compression test, and a cylinder for a shear test. Significant correlations were found between HRCT and histomorphometric measurements (BV/TV, trabecular thickness, separation and number, and node-strut analysis), but with higher values for most of the tomographic parameters (BV/TV and trabecular thickness determined by HRCT were overestimated by a factor 3.5 and 2.5 respectively, as compared with histomorphometry). The maximum compressive strength and Young’s modulus were highly correlated (ρ= 0.99, p<0.0005). Significant correlation was obtained between bone mineral density (determined using dual-energy X-ray absorptiometry) and the maximum compressive strength (ρ= 0.64, p= 0.002). In addition the maximum compressive strength and architectural parameters determined by HRCT or histomorphometry showed significant correlations (e.g., for HRCT, BV/TV: ρ = 0.88, p<0.0005, N.Nd/TV: ρ= 0.73, p<0.001). The shear strength was significantly correlated with BV/TV (ρ= 0.62, p= 0.002), Tb.Sp (ρ=−0.58, p= 0.004) and TSL (ρ= 0.55, p= 0.006) measured by HRCT. In conclusion, an HRCT system with 150 μm resolution is not sufficient to predict the true values of the structural parameters measured by histomorphometry, although high correlations were found between the two methods. However, we showed that a resolution of 150 μm allowed us to predict the mechanical properties of human cancellous bone. In vivo peripheral systems with such a resolution should be of interest and would deliver an acceptable radiation dose to the patient. Received: 13 October 1998 / Accepted: 16 March 1999     

A Randomized Trial of Sodium Fluoride (60 mg) ± Estrogen in Postmenopausal Osteoporotic Vertebral Fractures: Increased Vertebral Fractures and Peripheral Bone Loss with Sodium Fluoride; Concurrent Estrogen Prevents Peripheral Loss, But Not Vertebral Fractures

Postmenopausal Caucasian women aged less than 80 years (n= 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (–E study), age 70.8 ± 0.8 years (mean ± SEM) were all treated with calcium (Ca) 1.0–1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on, 3 months off, initial dose 60 mg/day; group F CaD, n= 34) or no NaF (group CaD, n= 31). In the second study 34 patients, age 65.5 ± 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n= 17; E CaD, n= 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to ± NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p= 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft –7.3% (p= 0.005); femoral shaft –7.1% (p= 0.004); distal forearm –4.0% (p = 0.004); total hip –4.1% (p = 0.003); and femoral neck –3.5% (p= 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p<0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox’s proportional hazards model, in the –E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p= 0.008, 95% CI 2.3–255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: –23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups; there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts, if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor. Received: 22 August 2000 / Accepted: 23 July 2001     

Quality of Life in Patients with Vertebral Fractures: Validation of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO)

Vertebral fractures may be minor or lead to pain, decreased physical function, immobility, social isolation and depression, which together contribute to quality of life. A Working Party of the European Foundation for Osteoporosis has developed a specfic questionnaire for patients with vertebral fractures. This questionnaire, QUALEFFO, includes questions in the domains pain, physical function, social function, general health perception and mental function. QUALEFFO was validated in a multicenter study in seven countries. The study was done in 159 patients aged 55–80 years with clinical osteoporosis, i.e., back pain and other complaints with at least one vertebral fracture and lumbar bone mineral density T-score <−1. Patients with a recent vertebral fracture were excluded because of unstable disease. Controls were age- and sex-matched, and did not have chronic back pain or vertebral fractures. Subjects with conditions exerting a major influence on quality of life were excluded. The QUALEFFO was administered twice within 4 weeks and compared with a generic questionnaire, the Short Form 36 of the Medical Outcomes Study (SF-36). Standard spinal radiographs were made for assessment of vertebral height. Seven questions were removed from the analysis because of low response rate, linguistic ambiguities or redundancy. The 41 remaining questions were analyzed for repeatability, internal consistency and the capacity to discriminate between patients with vertebral fractures and controls. Comparison with the SF-36 was performed within similar domains by conditional logistic regression and by receiver operating characteristic (ROC) curves. The repeatability of QUALEFFO was good (kappa statistics 0.54–0.90) and 26 of 41 questions had a kappa score ≥0.70. The internal consistency of the five domains was adequate, with Crohnbach α around 0.80. All except five questions discriminated significantly between patients and controls. The median scores of QUALEFFO were significantly higher in patients with vertebral fractures than in controls in all five domain (p<0.001), which is consistent with decreased quality of life in patients with osteoporosis. Spinal radiographs were assessed using the McCloskey–Kanis algorithm. According to this, 124 patients (78%) had vertebral fractures of ≥3 SD severity, in contrast with 7 controls (4%). Significant correlations existed between scores of similar domains of QUALEFFO and the SF-36, especially for pain, physical function and mental function. All five domains within each questionnaire discriminated significantly between fracture cases and controls. The odds ratios for pain and social function were greater for QUALEFFO, while general health perception was more discriminating using the SF-36. The ROC curve analysis of QUALEFFO indicated that all five domains were significantly predictive of vertebral fractures. When comparing similar domains of the two questionnaires, QUALEFFO domains demonstrated significantly better performance for pain, physical function and social function. The QUALEFFO total score and SF-36 physical composite score showed similar performance. In conclusion, QUALEFFO is repeatable, coherent and discriminates well between patients with vertebral fractures and control subjects. The results of this study confirm the decreased quality of life in patients with vertebral fractures. Received: 4 August 1998 / Accepted: 28 December 1998     

Sex Difference in the Validity of Vertebral Deformities as an Index of Prevalent Vertebral Osteoporotic Fractures: A Population Survey of Older Men and Women

Morphometric methods have been developed for standardized assessment of vertebral deformities in clinical and epidemiologic studies of spinal osteoporosis. However, vertebral deformity may be caused by a variety of other conditions. To examine the validity of morphometrically assessed vertebral deformities as an index of osteoporotic vertebral fractures, we developed an algorithm for radiological differential classification (RDC) based on a combination of quantitative and qualitative assessment of lateral spinal radiographs. Radiographs were obtained in a population of 50- to 80-year-old German women (n= 283) and men (n = 297) surveyed in the context of the European Vertebral Osteoporosis Study (EVOS). Morphometric methods (Eastell 3 SD and 4 SD criteria, McCloskey) were validated against RDC and against bone mineral density (BMD) at the femur and the lumbar spine. According to RDC 36 persons (6.2%) had at least one osteoporotic vertebral fracture; among 516 (88.9%) nonosteoporotics 154 had severe spondylosis, 132 had other spinal disease and 219 had normal findings; 14 persons (2.4%) could not be unequivocally classified. The prevalence of morphometrically assessed vertebral deformities ranged from 7.3% to 19.2% in women and from 3.5% to 16.6% in men, depending on the stringency of the morphometric criteria. The agreement between RDC and morphometric methods was poor. In men, 62–86% of cases with vertebral deformities were classified as nonosteoporotic (severe spondylosis or other spinal disease) by RDC, compared with 31–68% in women. Among these, most had wedge deformities of the thoracic spine. On the other hand, up to 80% of osteoporotic vertebral fractures in men and up to 48% in women were missed by morphometry, in particular endplate fractures at the lumbar spine. In the group with osteoporotic vertebral fractures by RDC the proportion of persons with osteoporosis according to the WHO criteria (T-score <−2.5 SD) was 90.0% in women and 86.6% in men, compared with 67.9–85.0% in women and 20.8–50.0% in men with vertebral deformities by various methods. Although vertebral deformities by most definitions were significantly and inversely related to BMD as a continuous variable in both sexes [OR; 95% CI ranged between (1.70; 1.07–2.70) and (3.69; 1.33–10.25)], a much stronger association existed between BMD and osteoporotic fractures defined by RDC [OR; 95% CI between (4.85; 2.30–10.24) and (15.40; 4.65–51.02)]. In the nonosteoporotic group individuals with severe spondylosis had significantly higher BMD values at the femoral neck (p <0.01) and lumbar spine (p <0.0004) compared with the normal group. On the basis of internal (RDC) and external (BMD) validation, we conclude that assessment of vertebral osteoporotic fracture by quantitative methods alone will result in considerable misclassification, especially in men. Criteria for differential diagnosis as used within RDC can be helpful for a standardized subclassification of vertebral deformities in studies of spinal osteoporosis. Received: 5 February 1999 / Accepted: 24 June 1999     

Vitamin D and Bone Mineral Density in Ambulatory Women Living in Buenos Aires, Argentina

The aim of this study was to determine possible associations between bone mineral density (BMD), 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (PTH). In a retrospective study we examined the case notes of free-living postmenopausal women living in our city (34° S). We also report a low prevalence of vitamin D deficiency (25(OH)D <25 nmol/l, 5.6%) and of secondary hyperparathyroidism (intact PTH >65 pg/ml, 7.5%). Age was correlated with BMD at the lumbar spine (r=−0.25, p = 0.00038) and femoral neck (r=−0.252, p = 0.0003). Body mass index (BMI) was correlated with BMD at the femoral neck (r= 0.177, p = 0.021) but not at the lumbar spine. 25(OH)D was positively correlated with BMD at the femoral neck (r = 0.149, p=0.036) but not at the lumbar spine. PTH was positively correlated with age (r= 0.279, p = 0.012) and negatively correlated with 25(OH)D (r=−0.322, p = 0.0036). PTH was also negatively correlated with BMD at the lumbar spine (r=−0.258, p=0.02) and the femoral neck (r=−0.282, p = 0.011). Forward stepwise multiple regression showed that BMI, age and 25(OH)D made significant contributions to BMD at the femoral neck. PTH also showed a significant contribution to BMD at both sites. In conclusion, weak correlations found between PTH and 25(OH)D and BMD suggest these biochemical variables, among other factors, contribute to lumbar spine and femoral neck BMD. Received: 19 February 2000 / Accepted: 20 June 2000     

The Presence and Severity of Vertebral Fractures is Associated with the Presence of Esophageal Hiatal Hernia in Postmenopausal Women

We examined the relationship between the presence of esophageal hiatal hernia (HH) assessed by endoscopy and the presence of vertebral fractures (VFs) in 87 Japanese postmenopausal women (age range 52–87 years). We found that 29 (63%) of 46 patients with HH (71.2 ± 6.1 years, mean ± SD) had one or more VFs, compared with 14 (34%) of 41 patients without HH (70.8 ± 6.8 years), which was a significant difference in the frequency of VFs (c²= 7.242; p= 0.0071). The average number of VFs per patient was significantly higher for the patients with HH than for those without HH (1.67 ± 1.75 vs 0.68 ± 1.21, p= 0.0032). There were no significant differences in absolute or age-matched bone mineral density (BMD) values at the lumbar spine (0.656 ± 0.131 vs 0.662 ± 0.148 g/cm²; Z-score, –0.35 ± 1.17 vs –0.26 ± 1.00) and there were no significant differences in biochemical parameters, age, years since menopause or body mass index (BMI) between the two groups. When patients were divided into those with reflux esophagitis (RE) (n= 30, 70.2 ± 7.3 years) and those without RE (n= 57, 71.4 ± 5.9 years), no significant differences were detected in any of the above parameters including the presence or number of VFs. The patients were further subdivided into four groups: those with ‘HH only’ (n= 23, 72.3 ± 4.6 years), with ‘RE only’ (n= 7, 70.9 ± 7.7 years), with ‘both’ (n= 23, 70.0 ± 7.3 years) and with ‘neither’ (n= 34, 70.8 ± 6.7 years). One or more VFs were found in 12 (52%), 1 (14%), 17 (74%), and 13 (38%) patients in each group, respectively, and the difference in frequency was significant (c²= 10.748; p= 0.0132). The average number of VFs per patient in each group was 1.57 ± 2.06, 0.14 ± 0.38, 1.78 ± 1.41 and 0.79 ± 1.30, respectively, and there were significant differences between the ‘both’ and ‘neither’ groups, and between the ‘both’ and ‘RE only’ groups (p<0.05). When univariate logistic regression analysis was performed with the presence of HH as a dependent variable and each of the presence of VFs, the number of VFs per patient, absolute or age-matched BMD values at the lumbar spine, BMI and plasma albumin as independent variables, the presence of VFs and the number of VFs per patient were selected as indices affecting the presence of HH (odds ratio: 3.29 and 1.59, 95% confidence interval: 1.36–7.94 and 1.14–2.23; p = 0.0080 and 0.0064, respectively). These results show that the presence and severity of VFs are associated with the presence of HH but not of RE in Japanese postmenopausal women, and suggest that kyphosis induced by multiple VFs might predispose elderly women to a complication with HH. Received: 2 March 2001 / Accepted: 11 June 2001     

Changes in Levels of Biochemical Markers and Ultrasound Indices of Os Calcis Across the Menopausal Transition

The aim of this longitudinal study was to investigate the changes in the levels of biochemical markers and ultrasound indices of os calcis across the menopausal transition. One hundred and ten healthy women (age 35–59 years at the 1992 baseline) participated in this 4-year population-based longitudinal study. Serum intact osteocalcin (IOC), urinary pyridinoline (Pyr), urinary deoxypyridinoline (Dpyr) and ultrasound indices were measured at baseline and after 4 years. The percentage changes in biochemical markers (%DIOC, %DPyr and %DDpyr) and the percentage decreases in the ultrasound indices (%DSOS, %DBUA and %DStiffness) were calculated. The values of %DIOC and %DDpyr in the perimenopausal subgroup (−4 to−3 years since menopause) and the values of %DSOS and %DStiffness in the perimenopausal subgroup (−2 to 0 years since menopause) were significantly higher than those in other groups. Pyr was significantly correlated with %DSOS (r=−0.467, p<0.01) and %DStiffness (r = −0.330, p<0.05) and Dpyr was significantly correlated with %DSOS (r=−0.390, p<0.05), %DBUA (r=−0.353, p<0.05) and %DStiffness (r = −0.454, p<0.05), while %DIOC was significantly correlated with %DSOS (r=−0.278, p<0.05), %DBUA (r=−0.369, p<0.01) and %DStiffness (r = −0.383, p<0.01) in the peri- and postmenopausal groups. These results indicate that the increase in bone turnover occurs 4 years before menopause. However, the correlations between biochemical markers and ultrasound indices were too low to allow prediction of bone change in the individual patient. Received: 12 October 1999 / Accepted: 30 June 1999     

Discrimination of Proximal Hip Fracture by Quantitative Ultrasound Measurement at the Radius

Osteoporosis is a disease that culminates in fragility fractures and, therefore, imposes major burden on the health economy. In dealing with this worldwide condition, it is prudent to use a reliable, inexpensive, portable diagnostic means that does not use ionizing radiation and is capable of measuring bone properties at several sites. Recently, a quantitative ultrasound device (Omnisense) that measures speed of sound (SOS) at multiple skeletal sites was introduced. The Omnisense combines the “axial transmission” mode and the critical angle concept. Preliminary reports suggested that of the different skeletal sites measured by this device, the distal third of the radius is the preferred measurement site for osteoporosis. In this cross-sectional study, SOS was determined at the radius using Omnisense in 50 hip-fractured elderly women (group F, age 76.1 ± 6.0 years), 130 elderly controls (group NF, age 71.5 ± 5.2 years) and 185 young healthy controls (group YH, age 40.6 ± 3.0 years). Actual SOS was significantly lower in group F compared with group NF (p = 0.0001). Whereas SOS T-scores calculated for each woman and stratified into age subgroups within each of the study groups indicate decline from –2.22 to –3.56 in group F and from –1.56 to –3.17 in group NF, there was an increase from –0.02 to 0.03 in group YH. Age- and BMI-adjusted logistic regression for hip fracture discrimination indicated an area under the receiver operating characteristic curve for hip fracture of 0.79 (95% CI, 0.73–0.86; p = 0.005) and an odds ratio of 1.92 (95% CI, 1.22–3.02; p = 0.005). We conclude that SOS measured at the radius by Omnisense discriminates subjects with hip fracture from controls. Prospective studies are needed to support the role of Omnisense in assessing the risk of hip fracture. Received: 16 March 1999Accepted: 29 October 1999     

Effects of Gender and Age on the Association of Apolipoprotein E ε4 with Bone Mineral Density,Bone Turnover and the Risk of Fractures in Older People*

The aim of this study was to examine whether the presence of apolipoprotein E ε4 (ApoE ε4) is associated with a lower bone mineral density (BMD), lower quantitative ultrasound (QUS) measurements, higher bone turnover and fracture risk, and whether these relations are modified by gender and age. A total of 1406 elderly men and women (≥65 years) of the Longitudinal Aging Study Amsterdam (LASA) participated in this study. In all participants, QUS measurements were assessed, as well as serum osteocalcin (OC) and urine deoxypyridinolin (DPD/Cr urine). Follow-up of fractures was done each three months. In a subsample (n = 604), total body bone mineral content (BMC) and BMD of the hip and lumbar spine were measured. In addition, prevalent vertebral deformities were identified on radiographs. In women, the presence of ApoE ε4 was associated with significantly lower femoral neck BMD (g/cm²; mean ± SEM; ε4+, 0.64 ± 0.01 vs. ε4−, 0.67 ± 0.01; p= 0.04), lower trochanter BMD (g/cm²; mean ± SEM; ε4+, 0.58 ± 0.01 vs. ε4–, 0.61 ± 0.01; p= 0.01) and lower total body BMC (g; mean ± SEM; ε4+, 1787 ± 40.0 vs. ε4–, 1863 ± 23.8; p= 0.04). Women with ApoE ε4 also had a higher risk of severe vertebral deformities (OR=2.78; 95%CI: 1.21–6.34). In men, the associations between ApoE status and both hip BMD and QUS depended on age. Only among the younger men (65–69 years) was the presence of ApoE ε4 associated with lower BMD values. Bone markers and fractures were not associated with ApoE ε4 in either women, or men. In conclusion, this large community-based study confirms the importance of ApoE ε4 as a possible genetic risk factor related to BMD and vertebral deformities and demonstrates that its effect is gender related, and depends on age in men only. Received: 6 July 2001 / Accepted: 2 April 2002     

In Vivo MRI Measurements of Bone Quality in the Calcaneus: A Comparison with DXA and Ultrasound

Magnetic resonance imaging (MRI) has shown promise in the assessment of bone architecture. The precision and feasibility of MRI measurements in osteoporosis in vivo have been assessed in this study. T2′ was calculated from measurements of T2 and T2* in the calcaneus of 32 postmenopausal women using a gradient-echo sequence PRIME (Partially Refocused Interleaved Multiple Echo). This sequence allows the measurement of T2 and T2* in one acquisition. In vivo measurements of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were made in the calcaneus, spine and femoral neck. The ultrasound parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were also measured in the calcaneus. These three techniques have not previously been compared in the same study population. The precision of the MRI technique was poor relative to the DXA and ultrasound techniques, with a CV of 6.9%± 4.4% for T2′ and 5.5%± 3.6% for T2*. Approximately 4% of this is due to system error as determined by phantom measurements. The postmenopausal women were classified as having low BMD if they had a lumbar spine (L2–4) BMD of less than 0.96 g/cm² (more than 2 standard deviations below normal peak bone mass). Calcaneal T2′ was significantly correlated with calcaneal BMD (r = –0.79, p <0.0001), BUA (r = –0.59, p = 0.0004) and SOS (r = –0.58, p = 0.0006). T2′ was significantly different in postmenopausal women with normal BMD and those with low BMD (p <0.01). However, the difference was of only borderline significance (p <0.06) after adjustment for age and years since menopause. Received: 8 July 1997 / Accepted: 29 April 1998     

Osteocalcin Gene Polymorphism is Related to Bone Density in Healthy Adolescent Females

Recently a polymorphism was found in the human osteocalcin gene, and its association with bone mass was investigated in healthy postmenopausal Japanese women. The osteocalcin gene allelic variant HH was found to be overrepresented in women with osteopenia. The purpose of this study was to investigate whether the previously demonstrated polymorphism of the osteocalcin gene was related to bone mineral density (BMD; g/cm²) or osteopenia in a group of 97 healthy Caucasian adolescent females (aged 16.9 ± 1.2 years, mean ± SD). BMD of the left humerus, right femoral neck, lumbar spine and total body was measured using dual-energy X-ray absorptiometry. The relation between the allelic variants and bone density was analyzed as presence or absence of the H allele. Presence of the H allele was found to be related to a lower BMD of the humerus (0.97 vs 1.02, p = 0.03). There was also a strong tendency towards significance at the femoral neck (p = 0.06) and total body (p = 0.11). Using a multiple linear regression and including physical activity, weight, height and years since menarche, presence of the H allele was found to be an independent predictor of humerus BMD (β=−0.21, p<0.05) and femoral neck BMD (β=−0.23, p<0.01). Using logistic regression, presence of the H allele was also independently associated with a 4.5 times increased risk of osteopenia (p = 0.03) in the whole group. Osteopenia was defined as at least 1 SD lower bone density than the mean for the whole group of at least one of the BMD sites measured. We have demonstrated that the osteocalcin HindIII genotype is independently related to bone density in healthy adolescent females. The present study also suggests that presence of the H allele is predictive of osteopenia at an early age. Received: 31 January 2000 / Accepted: 25 April 2000     

Bone Density in an Immigrant Population from Southeast Asia

The epidemiology of bone loss in populations of Asian heritage is still poorly known. This study compared the skeletal status of a convenience sample of 396 Southeast Asian immigrants (172 Vietnamese, 171 Cambodians and 53 Laotians) residing in Rochester, Minnesota in 1997 with 684 white subjects previously recruited from an age-stratified random sample of community residents. Areal bone mineral density (BMD, g/cm²) and volumetric bone mineral apparent density (BMAD, g/cm³) were determined for lumbar spine and proximal femur using the Hologic QDR 2000 instrument for the white population and the QDR 4500 for Southeast Asian subjects; the machines were cross-calibrated from data on 20 volunteers. Lumbar spine BMD was 7% higher in white than Southeast Asian women ( p < 0.001), and similar results were observed for the femoral neck; lumbar spine BMD was 12% higher in white than nonwhite men ( p < 0.001). Race-specific discrepancies were reduced by calculating BMAD: for premenopausal women, lumbar spine and femoral neck differences between whites and Southeast Asians were eliminated; for postmenopausal women the lumbar spine differences persisted ( p < 0.0001), while femoral neck BMAD was actually higher for Southeast Asians. There were no race-specific differences in femoral neck BMAD among men of any age ( p= 0.312), but lumbar spine BMAD was less for younger ( p= 0.042) but not older ( p= 0.693) Southeast Asian men. There were differences among the Southeast Asian subgroups, but no clear pattern emerged. Predictors of lumbar spine BMAD in Southeast Asian women were age ( p < 0.001), weight ( p= 0.015) and gravidity ( p= 0.037). Even after adjusting for bone size using BMAD, 32% and 9% of Southeast Asian women and men, respectively, would be considered to have osteoporosis at the femoral neck and 25% and 4%, respectively, at the lumbar spine. These findings indicate a need for culturally sensitive educational interventions for Southeast Asians and for physicians to pursue diagnosis and treatment to prevent osteoporosis-related disabilities in this population. Received: 12 October 2000 / Accepted: 15 February 2001