P.J. Meunier

Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study

BACKGROUND The ability of ultrasonographic measurements to discriminate between patients with hip fracture and age-matched controls has until now been tested mainly through cross-sectional studies. We report the results of a prospective study to assess the value of measurements with ultrasound in predicting the risk of hip fracture. METHODS 5662 elderly women (mean age 80.4 years) had both baseline calcaneal ultrasonography measurements and femoral radiography (dual-photon X-ray absorptiometry, DPXA) to assess their bone quality. Follow-up every 4 months enabled us to identify incident fractures. 115 hip fractures were recorded during a mean follow-up duration of 2 years. FINDINGS Low calcaneal ultrasonographic variables (obtained from measurements of broadband ultrasound attenuation by, and speed of sound through the bone) were able to predict an increased risk of hip fracture, with similar accuracy to low femoral bone mineral density (BMD) obtained by DPXA. The relative risk of hip fracture for 1 SD reduction was 2.0 (95% CI 1.6-2.4) for ultrasound attenuation and 1.7 (1.4-2.1) for speed of sound, compared with 1.9 (1.6-2.4) for BMD. After control for the femoral neck BMD, ultrasonographic variables remained predictive of hip fracture. The incidence of hip fracture among women with values above the median for both calcaneal ultrasound attenuation and femoral neck BMD was 2.7 per 1000 woman-years, compared with 19.6 per 1000 woman-years for those with values below the median for both measures. INTERPRETATION Ultrasonographic measurements of the os calcis predict the risk of hip fracture in elderly women living at home as well as DPXA of the hip does, and the combination of both methods makes possible the identification of women at very high or very low risk of fracture.

Fall-related factors and risk of hip fracture: the EPIDOS prospective study

BACKGROUND Most hip fractures result from falls. However, the role of fall-related factors has seldom been examined. Comparison of the predictive value of these factors with that of bone mineral density (BMD) has important implications for the prevention of hip fractures. METHODS We assessed femoral-neck BMD by dual-photon X-ray absorptiometry and potential fall-related risk factors, which included self-reported physical capacity, neuromuscular function, mobility, visual function, and use of medication in 7575 women, aged 75 years or older, with no history of hip fracture recruited at five centres in France. We followed up these women every 4 months to record incident hip fractures. During an average of 1.9 years of follow-up 154 women suffered a first hip fracture. FINDINGS In age-adjusted multivariate analyses, we found four independent fall-related predictors of hip fracture: slower gait speed (relative risk = 1 . 4 for 1 SD decrease [95% Cl 1.1-1.6)]; difficulty in doing a tandem (heel-to-toe) walk (1.2 for 1 point on the difficulty score [1.0-1.5]); reduced visual acuity (2.0 for acuity < or = 2/10 [1.1-3.7]); and small calf circumference (1.5 [1.0-2.2]). After adjustment for femoral-neck BMD, neuromuscular impairment--gait speed, tandem walk--and poor vision remained significantly associated with an increased risk of subsequent hip fracture. With high risk defined as the top quartile of risk, the rate of hip fracture among women classified as high risk based on both a high fall-risk status and low BMD was 29 per 1000 women-years, compared with 11 per 1000 for women classified as high risk by either a high fall-risk status or low BMD; for women classified as low risk based on both criteria the rate was five per 1000. INTERPRETATION We conclude that neuromuscular and visual impairments, as well as femoral-neck BMD, are significant and independent predictors of the risk of hip fracture in elderly mobile women, and that their combined assessment improves the prediction of hip fractures.

SERUM BONE GLA-PROTEIN: A SPECIFIC MARKER FOR BONE FORMATION IN POSTMENOPAUSAL OSTEOPOROSIS

Mean (+/- SD) serum bone Gla-protein (BGP or osteocalcin) was normal (7.0 +/- 3.3 ng/ml) in 26 patients with untreated postmenopausal osteoporosis ( PMO ). But 9 patients had values either above (4) or below (5) the normal values obtained in 35 age-matched control women (6.9 +/- 1.25 ng/ml). Serum BGP correlated positively with relative osteoid volume, relative osteoid surfaces, tetracycline labelled surfaces, and bone formation rate but not with resorption surfaces. Based on normal values for osteoid volume, patients were classified as having high (HF, 9 patients), normal (NF, 12 patients) and low osteoid formation (LF, 5 patients). Serum BGP (+/- SEM) was significantly lower in LF group (2.7 +/- 0.9 ng/ml) and significantly higher in HF group (9.7 +/- 0.8 ng/ml) than in the NF group (7.0 +/- 0.6 ng/ml). Serum alkaline phosphatase and urinary hydroxyproline did not discriminate between these three groups and did not correlate significantly with any of the measured histomorphometric indices in biopsy specimens in these patients. Serum BGP appears to be a specific marker for bone formation and can predict the histological profile in PMO . Serum BGP might be useful in investigating patients with PMO and should be valuable in assessing the effects of treatments that increase bone formation.

Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women.

The mean degree of mineralization of bone (MDMB) was measured by quantitative microradiography on transiliac bone biopsies taken from 53 postmenopausal osteoporotic women who had been treated with alendronate (ALN; 10 mg/day) during 2 (9 patients) or 3 years (16 patients) or with placebo (PLA; 15 and 13 patients, respectively). In the same patients, bone mineral density (BMD) values were obtained by dual-energy X-ray absorptiometry of the lumbar spine and femoral neck at the beginning and end of treatment. Histomorphometric parameters and activation frequency of new remodeling units were also measured on the iliac biopsies. After 2 years of ALN, MDMB in compact bone was 9.3% (p = 0.0035) and in cancellous bone was 7.3% (p = 0.0009) higher, respectively, than PLA. After 3 years of ALN, MDMB in compact bone was 11.6% (p = 0.0002) and in cancellous bone was 11.4% (p = 0.0001) higher, respectively, than PLA. After 2 and 3 years of ALN, and compared with the corresponding PLA, the distribution of the degree of mineralization in compact and cancellous bone showed a clear shift toward the highest mineralization values and a decrease in the number of bone structure units having low values of mineralization. The between-group differences in MDMB were similar to those of BMD at the lumbar spine BMD (+8.7% after 2 years and +9.6% after 3 years, respectively), suggesting that MDMB augmentation probably accounted for the majority of the increase in BMD seen with ALN. The data support the hypothesis that the reduction in activation frequency caused by the antiresorptive effect of ALN is followed by a prolonged secondary mineralization that increases the percentage of bone structure units having reached a maximum degree of secondary mineralization and, through this mechanism, MDMB. That these effects contribute to improved bone strength is demonstrated by the reduction in fracture incidence previously demonstrated in these patients.

How Hip and Whole-Body Bone Mineral Density Predict Hip Fracture in Elderly Women: The EPIDOS Prospective Study

Abstract: We conducted a population-based cohort study in 7598 white healthy women, aged 75 years and over, recruited from the voting lists. We measured at baseline bone mineral density (BMD g/cm2) of the proximal femur (neck, trochanter and Wards triangle) and the whole body, as well as fat and lean body mass, by dual-energy X-ray absorptiometry (DXA). One hundred and fifty-four women underwent a hip fracture during an average 2 years follow-up. Each standard deviation decrease in BMD increased the risk of hip fracture adjusted for age, weight and centre by 1.9 (95% CL 1.5, 2.3) for the femoral neck, 2.6 times (2.0, 3.3) for the trochanter, 1.8 times (1.4, 2.2) for Wards triangle, 1.6 times (1.2, 2.0) for the whole body, and 1.3 times (1.0, 1.5) for the fat mass. The areas under the receiver operating characteristic (ROC) curves were not significantly different between trochanter and femoral neck BMD, whereas ROC curves of femoral neck and trochanter BMD were significantly better than those for Wards triangle and whole-body BMD.emsp;Women who sustained an intertrochanteric fracture were older (84 ± 4.5 years) than women who had a cervical fracture (81 ± 4.5 years) and trochanter BMD seemed to be a stronger predictor of intertrochanteric ([RR = 4.5 (3.1, 6.5)] than cervical fractures ([RR = 1.8 (1.5, 2.3]).emsp;In very elderly women aged 80 years and more, hip BMD was still a significant predictor of hip fracture but the relative risk was significantly lower than in women younger than 80 years.emsp;In the 48% of women who had a femoral neck BMD T-score less than –2.5, the relative risk of hip fracture was increased by 3, and the unadjusted incidence of hip fracture was 16.4 per 1000 woman-years compared with 1.1 in the population with a femoral neck BMD T-score 5–1.

Comparison of Trabecular Bone Microarchitecture and Remodeling in Glucocorticoid‐Induced and Postmenopausal Osteoporosis

Long‐term treatment with glucocorticoids (GCs) leads to a rapid bone loss and to a greater risk of fractures. To evaluate the specific effects of this treatment on cancellous bone remodeling, structure, and microarchitecture, we compared 22 transiliac biopsy specimens taken in postmenopausal women (65 ± 6 years) receiving GCs (≥7.5 mg/day, for at least 6 months) and 22 biopsy specimens taken in age‐matched women with postmenopausal osteoporosis (PMOP), all untreated and having either at least one vertebral fracture or a T score < −2.5 SD. On these biopsy specimens, we measured static and dynamic parameters reflecting trabecular bone formation and resorption. Also, we performed the strut analysis and evaluated the trabecular bone pattern factor (TBPf), Euler number/tissue volume (E/TV), interconnectivity index (ICI), and marrow star volume (MaSV). Glucocorticoid‐induced osteoporosis (GIOP), when compared with PMOP, was characterized by lower bone volume (BV/TV), trabecular thickness (Tb.Th), wall thickness (W.Th), osteoid thickness (O.Th), bone formation rate/bone surface (BFR/BS), adjusted mineral apposition rate/bone surface (Aj.AR/BS), and higher ICI and resorption parameters. After adjustment for BV/TV, the W.Th remained significantly lower in GIOP (p < 0.0001). The active formation period [FP(a+)] was not different. Patients with GIOP were divided into two groups: high cumulative dose GCs (HGCs; 23.7 ± 9.7 g) and low cumulative dose GCs (LGCs; 2.7 ± 1.2 g). HGC when compared with LGC was characterized by lower W.Th (p < 0.05), BV/TV (p < 0.001), Tb.Th (p < 0.05), trabecular number (Tb.N; p < 0.05), FP(a+) (p < 0.05), and nodes (p < 0.05), and higher E/TV (p < 0.05), ICI (p < 0.005), and TBPf (p < 0.05). When HGC was compared with PMOP, the results were similar except for the MaSV, which was significantly higher (p < 0.005). In summary, GIOP was characterized by lower formation and higher resorption than in PMOP, already present after LGC. With HGCs, these changes were associated with a more dramatic bone loss caused by a major loss of trabecular connectivity.

Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: A three year follow-up study

We have previously shown that elderly women with an increased serum undercarboxylated osteocalcin (ucOC) level have an increased risk of sustaining a hip fracture as compared to those with normal serum ucOC. We reassessed our findings on a larger number of hip fractures that occurred over 3 years in 183 institutionalized women (aged 70-97 years) belonging to a large prospective clinical trial. Total OC, carboxylated OC, ucOC, and alkaline phosphatase were significantly higher at baseline in those who sustained a hip fracture during the follow-up. The age-adjusted odds ratio for hip fracture was three times higher in women with increased ucOC at baseline (odds ratio = 3.1, 99.9% C.I. = 1.7-6.0, p < 0.001). In the logistic regression, ucOC was still predictive of the hip fracture when age and parathyroid hormone concentration were included into the model (odds ratio = 2.6, 95% C.I. = 1.05-6.4). These data confirm that ucOC is a marker of the increased risk of hip fracture in elderly institutionalized women. Serum ucOC may reflect some nutritional deficiency associated with increased bone fragility.

The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography.

Strength of bones depends on bone matrix volume (BMV), bone microarchitecture, but also bone mineralization, and we have recently shown in osteoporotic patients treated with alendronate that fracture risk and bone mineral density (BMD) were changed without modifications of BMV or bone microarchitecture. Mineralization of bone matrix implies two successive steps: a rapid primary mineralization on the calcification front followed by a slow process of secondary mineralization progressively adding about one-half of the mineral content on bone matrix. These two steps are clearly illustrated by microradiographs of compact and cancellous bone tissue from transiliac human biopsies. Our working hypothesis is based on the impact of changes in bone remodeling rate on the degree of mineralization of bone, i.e., on the BMD measured at the tissue level. Contact quantitative microradiography using a computerized microdensitometric method, is described and allows the measurement of the mean degree of mineralization of bone (MDMB). This parameter may be quantitatively evaluated by exposing an aluminum calibration step-wedge and a plane-parallel calcified tissue section simultaneously to the same beam of X-rays, then determining, from the resulting microradiograph, the thickness of aluminum that produces the same X-ray absorption as a given region of the bone tissue section. To be used as a control group, iliac bone samples were taken at necropsy from 43 subjects (30 women aged 48.4 +/- 3.7 years and 13 men aged 66.0 +/- 4.4 years) who died suddenly showing no apparent bone disease. A control MDMB, which does not change with age, and a control distribution of these values are thus established. These control values are necessary for interpreting the changes in MDMB observed in bone conditions untreated or treated.

Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis

The risk-benefit ratio of combined fluoride-calcium therapy in primary vertebral osteoporosis was examined prospectively in patients with at least one vertebral fracture. 257 patients were randomised to receive sodium fluoride 25 mg twice daily plus elemental calcium 1 g daily and a vitamin D2 supplement, and 209 received one of the alternative therapies usually prescribed in France. After a follow-up of 24 months the fluoride-calcium group showed a significantly lower rate of new vertebral fractures, the main adverse effect of the regimen being a higher incidence of osteoarticular pains in the ankle and foot; the risk of non-vertebral fractures was not increased, and digestive disorders arose with equal frequency in the two groups. Sodium fluoride 50 mg daily seems to represent a reasonable compromise in terms of anti-fracture effectiveness and side-effects.

Do ultrasound measurements on the os calcis reflect more the bone microarchitecture than the bone mass?: A two-dimensional histomorphometric study

Few studies have analyzed the relationship between ultrasound measurements (US) and corresponding histomorphometric parameters of the calcaneus. To address this question we have compared US and histomorphometric parameters in 17 whole human os calcis from amputation or necropsy. Speed of sound (SOS), broadband ultrasound attenuation (BUA), and bone mineral density (BMD) were measured on the whole foot at the calcaneal site using an Achilles device and a DPX-L densitometer (Lunar). The os calcis was dissected and a 1-cm-wide transcortical parallelepiped extracted with a biopsy needle, focused on the center of the measured area. Histomorphometry was performed on undecalcified biopsies. Structural and connectivity parameters were measured on 7-microns-thick sections with both automatic (Biocom) and semiautomatic analyzers (Ibas 1, Kontron). We found that all ultrasonic and densitometric parameters reflected the true amount of bone and were correlated with only some of the parameters reflecting bone microarchitecture. From stepwise regression analysis, we found that 68%, 67%, 72%, and 74% of the variance of SOS, BUA stiffness, and BMD, respectively, were explained significantly by trabeculae thickness only. Ultrasonic measurements appear to reflect bone quantity rather than bone microarchitecture. The current conclusion is fairly negative with respect to the ability of ultrasound to assess structural parameters, but our limited sample size did not give enough power to our study to reach statistically significant correlations. In addition, the calcaneus is anisotropic and the ultrasound interaction in bone is a three-dimensional phenomenon. So, a three-dimensional study rather than a two-dimensional one should be performed.