Ten-year absolute risk of osteoporotic fractures according to BMD T score at menopause: the Danish Osteoporosis Prevention Study.

UNLABELLED: In the non-HRT arms of the DOPS study, 10-year fracture risk was higher at each level of T score than predicted by the Kanis algorithm. Under-reporting of fractures in registers and inclusion of HRT users are probable explanations for inappropriately low fracture risk estimates for younger women. INTRODUCTION: International recommendations highlight the importance of absolute fracture risk in establishing intervention thresholds. The available estimates of long-term risk have been derived by combining relative risks from meta-analyses with U.S. normative BMD data and Swedish fracture incidence records. We validated the 2001 Kanis risk algorithm using incident fractures observed in untreated women in the first 10 years of the Danish Osteoporosis Prevention Study (DOPS). Comparisons were also made with the relative risks derived from a recent meta-analysis of 12 cohort studies. MATERIALS AND METHODS: We analyzed DXA of the spine and hip from 872 women who were enrolled in the non-hormone replacement therapy (HRT) arms of the study and had not received HRT, bisphosphonates, or raloxifene. We collected verified reports of fractures at each visit. We focused on fractures of the hip, spine, shoulder, and forearm to provide risks comparable with the Kanis algorithm. Accordingly, asymptomatic radiographic vertebral fractures were not included. RESULTS: Seventy-eight women (9%) sustained relevant fractures. The risk of fracture increased by 1.32 (95% CI, 1.02; 1.70) for each unit decrease in femoral neck T score and by 1.30 (95% CI, 1.06; 1.58) for each unit decrease in lumbar spine T score at baseline. Absolute fracture risk was higher than expected from the Kanis algorithm at all T score levels. The difference was greatest for participants in the higher range of T scores. At T = -1, the observed risk was 10.9% as opposed to an expected risk of 5.7%. Relative risk gradients were similar to those of the recent meta-analysis. CONCLUSIONS: In healthy women, examined in the first year or two after menopause, 10-year fracture risk was higher at each level of BMD T score than expected from the model by Kanis et al. Inclusion of HRT users in the cohorts used may have led to higher BMD values and lower absolute fracture risk in the Kanis model. These longitudinal data can be used directly in estimating absolute fracture risk in untreated north European women from BMD at menopause.

Noninvasive measurement of bone strontium.

The strontium content of bone has hitherto been impossible to measure noninvasively. A novel dual-photon absorptiometry (DPA) method was developed. 241Am (59.5 keV) and 133Ba (356 keV) were used as radiation sources. The linearity of the DPA method was studied in monkey bones ex vivo after treatment over 52 wk with strontium ranelate. The bone strontium expressed in terms of the percentage molar ratio SrHA/(SrHA + CaHA) x 100%, where HA denotes hydroxyapatite, was measured (1) by the DPA method and (2) by inductively coupled plasma-atomic emission spectrophotometry at the same distal site of the femur. The results correlated significantly: y = 0.33%Sr + 1.086x; r = 0.976; standard error of the estimate (SEE) = 0.57%Sr. In order to measure the accuracy error of Sr%, 30 normal volunteers were measured. Their mean values did not differ significantly from zero and the SD was 0.5%. The radiation dose was small, the equivalent whole-body dose to human subjects being 0.005 micro Sv. This novel DPA method is likely to be successful for bone strontium measurement in humans.

Standardization of BMD T-Scores in the first five years after the menopause: do femoral neck-equivalent and older normative range T-Scores improve diagnostic agreement?

Calculating T-scores using an older reference population reduces inconsistency between measurement sites when osteoporosis is diagnosed in the elderly. The present analysis in a younger, early postmenopausal cohort examined 5-yr consistency of normalization by local and femoral neck-equivalent T-scores. NHANES (femur) and Hologic (spine and forearm) references were applied to baseline, 1-, 2-, 3-, and 5-yr scans in 925 untreated women in a national cohort study, and alternative local and neck-equivalent scores calculated. The baseline prevalence of osteopenia/osteoporosis was 35.5%/4.1% (spine), 31.0%/1.2% (neck), 31.3%/1.2% (total hip), and 37.2%/2.5% (forearm). It increased to 54.6%/7% by combining sites. The prevalences at 5-yr were 57.2%/12.4% (spine), 51.9%/5.0% (neck), 46.6%/3.7% (total hip), 52.5%/7.4% (forearm), and 77.3%/17.8% (any). A T-score cut-off at the lowest of four sites of -1.65 for osteopenia and -3.37 for osteoporosis was equivalent in patient numbers to T<-1 and T<-2.5 at the femoral neck. The proportion of inconsistently classified subjects decreased from 48% to 42% (p<0.05) with neck-equivalent scores. No improvement remained after 5 yr. Kappa scores did not improve by the use of local or femoral neck scores. In conclusion, adjusted thresholds cannot remove the anatomic discrepancy between T-scores. To overcome this problem, risk-based diagnostic cut-offs must therefore be calculated separately for each measurement site and fracture localization.

Effect of long-term treatment with strontium ranelate on bone strontium content.

AIM: To investigate the kinetics and magnitude of human bone strontium uptake and retention during and after long-time treatment with strontium ranelate (SrR). METHODS: Bone strontium was measured by a novel DPA method developed by us. 32 osteoporotic female patients volunteered to participate in a 3 years open study of the effect on bone Sr. The group was treated with 2 g SrR/day, 17 of the group had received active treatment for 4-5 years before the study. DXA BMD measurements and DPA measurements of the relative bone strontium hydroxy apatite termed %Sr (SrHA/(CaHA+SrHA)) were done simultaneously ultra-distally (UD) on the non-dominant radius every six months during the study and three and six months after treatment stop. RESULTS: The highest relative Sr content was found in patients who had been treated for 7-8 years. The variability was pronounced; a mean of 1.1 % Sr was measured at the end of treatment. No effect was demonstrated on distal radius relative bone Ca hydroxy apatite. Bone strontium uptake and retention data were compatible with a power function model. Withdrawal of SrR resulted in a decline in bone Sr, but 73 %Sr and 67 %Sr, respectively remained in UD-radius three and six months after drug withdrawal. CONCLUSION: The rise in bone Sr content measured by DPA as well as BMD measured by DXA was most marked initially. After the treatment was stopped bone Sr decreased rapidly only during the first months. In UD-radius the apparent BMD corrected for the influence of %Sr measured by DPA showed a slight decline like in an untreated population. Strontium containing drugs may influence DXA bone mineral measurements several years after treatment withdrawal. According to the power function model the skeletal retention three and six months after stopping the treatment would average 66% and 58%, respectively after three years of treatment, and 76% and 70%, respectively after eight years of treatment. However, individual predictions are uncertain due to large inter-individual variations, and the values cannot be extrapolated to other bone sites.

Ten-year prediction of osteoporosis from baseline bone mineral density: development of prognostic thresholds in healthy postmenopausal women. The Danish Osteoporosis Prevention Study.

Osteopenia is common in healthy women examined in the first year or two following menopause. Short-term fracture risk is low, but we lack algorithms to assess long-term risk of osteoporosis. Because bone loss proceeds at only a few percent per year, we speculated that baseline bone mineral density (BMD) would predict a large proportion of 10-year BMD and be useful for deriving predictive thresholds. We aimed to identify prognostic thresholds associated with less than 10% risk of osteoporosis by 10 years in the individual participant, in order to allow rational osteodensitometry and intervention. We analyzed dual energy X-ray absorptometry (DXA) of the lumbar spine (LS) and femoral neck (FN) from 872 women, who participated in the non-HRT arms of the Danish Osteoporosis Prevention Study and had remained on no HRT, bisphosphonates or raloxifene since inclusion 10 years ago. We defined development of a T -score below -2.5 at the LS and/or FN or incident fracture as end-point, and we derived prognostic thresholds for baseline BMD, defining 90% NPV (negative predictive value) and 90% sensitivity, respectively. Seventy-six percent of the variation in BMD of the LS at 10 years was predicted by baseline BMD. In an individual participant, a baseline BMD T -score above -1.4 (FN or LS, whichever was lower) was associated with a 10-year risk of less than 10% of developing osteoporotic BMD or fracture. This covered 69% of the population. By contrast, participants with T -scores below -1.4 had a 56% risk of fracture or low BMD within 10 years. At the population level, baseline T -score cutoffs below 0 at the LS (68% of the population), 0 at the FN (72%) or -0.6 (62%) at the lower of the two sites capture 90% of the population that developed osteoporosis during the following 10 years. A BMD measurement, performed in the first two years following menopause, is a strong long-term predictor of BMD in healthy women. The association is strong enough to provide robust prognostic thresholds, which can be used to divide the population into two prognostic classes at menopause.