Journal of Clinical Densitometry: Assessment of Skeletal Health, vol. 15, no. 4, 472e474, 2012� Copyright 2012 by The International Society for Clinical Densitometry1094-6950/15:472e474/$36.00

Letter to the Editor

Can Dual-Energy X-Ray Absorptiometry-Based Hip Structural Analysis Be Used

in Patients Treated With Strontium Ranelate?

We read with interest the recent article by Briot et al(1) describing the analysis of dual-energy X-ray absorp-tiometry (DXA) scans from the Treatment of PeripheralOsteoporosis Trial (TROPOS) (2,3) using Tom Beck’ship structural analysis (HSA) software (4). In Table 5of the article by Briot et al, the authors demonstratethat, after adjustment for bone mineral density (BMD)changes, there were statistically significant improve-ments in most HSA indices of hip strength in subjectswho received 5-yr treatment with strontium ranelate(1). We write to question the validity of using regressionanalysis to adjust HSA measurements for the BMDchanges caused by the accumulation of strontium inbone. We believe that one cannot use the HSA softwareto draw reliable conclusions about improvements in hipstrength due to strontium ranelate without explicitknowledge of the bone strontium content in the hip.

To explain our reasoning, we first consider the sim-pler problem of interpreting the large BMD increasesseen in strontium ranelate-treated patients to distinguishthe true biological increase in bone mass from the en-hanced X-ray attenuation caused by the introductionof strontium into bone tissue (5). It is not possible to re-solve this question without knowing the molar percent-age (Sr/[Caþ Sr]� 100%) of strontium in bone (6). Forexample, a 1% molar concentration of strontium causesa 10% increase in BMD due to its physical effect on theDXA measurements (5). Hence, to infer the true biolog-ical effect of treatment, one needs to adjust the observedBMD changes based on reliable knowledge of the bonestrontium content (6).

A similar conclusion applies when interpreting DXA-based HSA measurements in strontium-treated patients.An important limitation of HSA is that DXA scans are2-dimensional rather than 3-dimensional images, andhence, point-by-point measurements of BMD are con-verted into the equivalent thickness of mineralizedbone tissue assuming a volumetric bone density of1.85 g/cm3 (4). For bone tissue containing 1% stron-tium, the appropriate volumetric density for the HSA

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model is 1.85 � 1.105 2.035 g/cm3. For valid resultsin this circumstance, it is necessary to run the HSA pro-gram using the correct volumetric bone density parame-ter for each individual patient.

We turn now to the shortcomings of the BMD adjust-ment applied by Briot et al (1). The easiest way to demon-strate that this failed to achieve its intended aim is toconsider the calculation of the HSA cross-sectional area(CSA) parameter. CSA is calculated by integrating thethickness of bone tissue inferred from the point-by-point measurement of BMD across the bone mass profilethrough the hip section (7,8). In their report, Briot et al didnot comment on whether any changes were observed inthe outer diameter of the bone profiles, but we assumethat, as with other osteoporosis treatments such as alendr-onate, denosumab, raloxifene, and hormone replacementtherapy, no change was found in bone size (8e10). In thiscircumstance, provided the adjustment for the BMDchange was performed correctly, the change in CSA re-ported by Briot et al should of necessity be zero becausechanges can occur only as a result of changes in bonesize or BMD and, according to the authors, the latterwas eliminated from the analysis.

The finding of statistically significant changes in CSAat the three measurement sites (narrow neck, intertro-chanteric, and femoral shaft) (1) therefore suggests anerror in data analysis. Without access to the raw data,it is difficult to judge, but a likely issue is the well-known limitation of regression analysis, which is basedon the assumption that all the errors are in the y-axisvalues of the scatter plot when in reality both x- andy-axis values are affected by measurement errors. Asa result, regression analysis tends to underestimate thetrue slope of the relationship in proportion to the corre-lation coefficient falling below r5 1.0 (Fig. 1). Perhapspredictably, when the strontium ranelate and placebogroups were pooled, the apparent effect of strontiumtreatment on the HSA indices disappeared (1).

Whether strontium ranelate treatment truly has a ben-eficial effect on bone strength in the hip is an important

Fig. 1. Simulation illustrating the problem of using linear regression analysis to adjust hip structural analysis CSA data for thechanges in BMD associated with bone strontium content when there are significant measurement errors on both axes. (A) Whenthe random measurement errors are small (r5 0.98), the best fitting regression line passes close to the origin, and the intercept isnot statistically significantly different from 0. (B, C, and D) As the errors become larger and the correlation coefficient de-creases, the slope of the regression line is smaller and the intercept appears to be statistically significant. Solid line: regressionline; dashed lines: 95% confidence limits on regression line. CSA, cross-sectional area; BMD, bone mineral density.

Letter to the Editor 473

question, and such a claim rightly demands a high stan-dard of proof. Unfortunately, the analysis of Briot et alfails to convincingly prove this point.

Glen M. BlakeIgnac Fogelman

Osteoporosis Research UnitKing’s College LondonKing’s Health Partners

Guy’s Hospital, London, UK

References

1. Briot K, Benhamou CL, Roux C. 2012 Hip cortical thicknessassessment in postmenopausal women with osteoporosis andstrontium ranelate effect on hip geometry. J Clin Densitom15:176e185.

2. Reginster JY, Seeman E, De Vernejoul MC, et al. 2005 Stron-tium ranelate reduces the risk of nonvertebral fractures in post-menopausal women with osteoporosis: TROPOS Study. J ClinEndocrinol Metab 90:2816e2822.

Journal of Clinical Densitometry: Assessment of Skeletal Health

3. Reginster J-Y, Felsenberg D, Booen S, et al. 2008 Effects oflong-term strontium ranelate treatment on the risk of non-vertebral and vertebral fractures in postmenopausal osteoporo-sis of a 5-year, randomized, placebo controlled trial. ArthritisRheum 58:1687e1695.

4. Beck TJ, Ruff CB, Warden KE, et al. 1990 Predicting femoralneck strength from bone mineral data. A structural approach.Invest Radiol 25:6e18.

5. Pors Nielsen S, Slosman D, Sorensen OH, et al. 1999 Influenceof strontium on bone mineral density and bone mineral contentmeasurements by dual X-ray absorptiometry. J Clin Densitom2:371e379.

6. Meunier PJ, Roux C, Seeman E, et al. 2004 The effects of stron-tium ranelate on the risk of vertebral fracture in women withpostmenopausal osteoporosis. N Engl J Med 350:459e468.

7. Martin RB, Burr D. 1984 Non-invasive measurement of longbone cross-sectional moment of inertia by photon absorptiom-etry. J Biomech 17:195e201.

8. Beck TJ, Michael Lewiecki E, Miller PD, et al. 2008 Effects ofdenosumab on the geometry of the proximal femur in postmen-opausal women in comparison with alendronate. J Clin Densi-tom 11:351e359.

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9. Uusi-Rasi K, Beck TJ, Semanick LM, et al. 2006 Structural ef-fects of raloxifene on the proximal femur: results from the mul-tiple outcomes of raloxifene evaluation trial. Osteoporos Int 17:575e586.

Journal of Clinical Densitometry: Assessment of Skeletal Health

10. Chen Z, Beck TJ, Cauley JA, et al. 2008 Hormone therapy im-proves femur geometry among ethnically diverse postmeno-pausal participants in the Women’s Health Initiative hormoneintervention trials. J Bone Miner Res 23:1935e1945.

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