ORIGINAL ARTICLE

Reduction in normalized bone elasticity following long-termbisphosphonate treatment as measured by ultrasound critical anglereflectometry

Edmond Richer Æ Matthew A. Lewis Æ Clarita V. Odvina

Miguel A. Vazquez Æ Billy J. Smith Æ Roy D. Peterson

John R. Poindexter Æ Peter P. AntichCharles Y. C. Pak

Received: 4 August 2004 / Accepted: 28 December 2004 / Published online: 22 February 2005� International Osteoporosis Foundation and National Osteoporosis Foundation 2005

Abstract Using an improved version of ultrasound crit-ical angle reflectometry, the bone quality of cortical andtrabecular bone was assessed in vivo by measuringelastic moduli (normalized for bone density) at bothprincipal axes, referred to as the minimum and maxi-mum normalized elasticities. The measurements weremade in 30 normal premenopausal women, 30 normalpostmenopausal women, 22 untreated postmenopausalwomen with osteoporosis, 74 postmenopausal womenwith osteoporosis or osteopenia on bisphosphonatetreatment, and 32 patients with renal transplantation (16women and 16 men) taking steroids. Cortical elasticitywas higher than trabecular elasticity; both declinedslightly and non-significantly with age in normal women.Among untreated postmenopausal women with osteo-porosis, cortical maximum normalized elasticity (Ecmax)remained within 95% prediction intervals of normalwomen. Among patients on bisphosphonate, Ecmax waslow in the majority of patients. Ecmax was significantlymore depressed among those taking the drug ‡3 yearsthan <3 years (22.1% below normal premenopausalwomen versus 17.2%, P =0.001), and among those withincident non-spinal fractures than without (75.9 vs.81.5%, P =0.008). Ecmax was independent of bone

mineral density at the calcaneus. Most patients withrenal transplantation had low Ecmax, with a mean 20.8%below the normal premenopausal mean. Qualitativelysimilar findings were found with cortical minimumelasticity and with trabecular minimum and maximumelasticities. Thus, the material bone quality of corticaland trabecular bone may be impaired following bis-phosphonate treatment, as in renal transplantation onsteroids.

Keywords Bisphosphonate Æ Bone elasticity ÆOsteoporosis Æ Renal transplantation Æ Ultrasound

Introduction

There is increased recognition of the importance of bonestrength in the development of osteoporotic fractures [1].Bone strength is determined by the density of bone aswell as its quality. Bone density defines the amount ofbone in a bone volume being analyzed; it is typicallydetermined by bone mineral density (BMD) [2]. Bonequality is affected by the architecture of the whole organ(such as trabecular connectivity and cortical porosity)and by material property (crystalline composition-ori-entation and organic matrix), and by the integrity of thematerial (for example, presence of microcracks) of dis-crete parts of bone [3, 4].

Bone strength can be only measured directly bymechanical testing, but such methods are not applicableclinically due to their destructive nature [5]. It has beenshown that the modulus of elasticity (the parameter thatdescribes the relationship between stress and strain) canbe indicative of the ultimate bone strength. Thus, non-invasive approaches based on ultrasound have beenproposed to assess bone strength by measuring ultra-sound velocity [6]. The available methods are based ontransmission ultrasound, wherein the time or the speed

Osteoporos Int (2005) 16: 1384–1392DOI 10.1007/s00198-005-1848-x

E. Richer (&) Æ M.A. Lewis Æ B.J. Smith Æ P.P. AntichAdvanced Radiological Sciences Department of Radiology,University of Texas Southwestern Medical Center,Dallas, TXE-mail: edmond.richer@utsouthwestern.edu

C.V. Odvina Æ R.D. Peterson Æ J.R. PoindexterP.P. Antich Æ C.Y.C. PakCenter for Mineral Metabolism and Clinical Research,University of Texas Southwestern Medical Center,5323 Harry Hines Boulevard, 75390 Dallas, TX

M.A. VazquezDivision of Nephrology,University of Texas Southwestern Medical Center,Dallas, TX

of ultrasound traversing across bone tissue is measured[7]. Unfortunately, the data obtained therein are influ-enced by bone density at the organ level, overlying softtissue, bone marrow content, and only partly revealmaterial bone quality.

Ultrasound critical-angle reflectometry (UCR) intro-duced by us in 1992 can overcome these shortcomings,since it can provide a measure of material bone qualityfrom the ‘‘reflected’’ ultrasound amplitude [8, 9]. Re-cently modified and refined [10], this device can estimatematerial bone quality from the square of ultrasoundvelocity, yielding elasticity normalized for density(henceforth called normalized elasticity or simply elas-ticity). Not only can this approach analyze cortical andtrabecular bone separately, but it can also determine theminimum as well as maximum elasticities correspondingto principal axes of bone [11].

In this communication, the new UCR device wasapplied to two clinical conditions believed to be associ-ated with impaired bone quality. One is long-term bis-phosphonate treatment that may produce severesuppression of bone turnover [12]. The other is renaltransplantation for which adrenocorticosteroids are gi-ven to avert organ rejection [13].

Materials and methods

Patient data

The UCR measurements at the calcaneus were made invivo in 30 normal premenopausal women, 30 normalpostmenopausal women, 22 postmenopausal womenwith osteoporosis not treated with bisphosphonate, ter-iparatide or fluoride (untreated postmenopausal osteo-porosis), 74 postmenopausal women with osteoporosisor osteopenia on bisphosphonate treatment, and 32patients with renal transplantation (16 women and 16

men) taking steroids (Table 1). None of the subjects hadsecondary causes of bone loss, such as primary hyper-parathyroidism, distal renal tubular acidosis, fatmalabsorption, chronic diarrheal states, adrenocortico-steroid excess or treatment, anticonvulsant therapy, orthyrotoxicosis. Except in patients with renal transplan-tation, endogenous creatinine clearance exceeded 0.6 ml/min/kg. All subjects were Caucasian. Except for renaltransplantation, the study groups comprised only wo-men.

Normal premenopausal women were healthy sub-jects who were still menstruating without skeletalfractures. Normal postmenopausal women comprisedthose without prevalent skeletal fractures with L2–L4BMD T-score >)2.5. None of the normal women tookbisphosphonate, teriparatide or fluoride, but 14 of 30normal postmenopausal women were on estrogen or aselective estrogen receptor modulator (SERM). Amongthose with untreated postmenopausal osteoporosis, 4patients had prevalent spinal fractures, and 18 hadosteoporosis by density criteria. For the whole group,the mean L2–L4 BMD was about 25% depressed fromnormal peak value (T-score )2.49, Table 1). Amongpatients on bisphosphonate, 68 had osteoporosis and 6osteopenia; 36 patients took the drug for less than3 years, and 38 for 3 or more years. Sixteen patientshad non-traumatic non-spinal fractures (of the meta-tarsal, pelvis, femur, radius, and rib), which occurredafter 2–6 years of bisphosphonate treatment in 13 pa-tients and 6 months–2 years of treatment in 6 patients.Fifty-seven patients took alendronate (10 mg/day or70 mg/week) and 17 received risedronate (35 mg/week).In the renal transplantation group, renal transplanta-tion was performed at least 2 years and a mean of7.4 years before the UCR measurement. They had ta-ken prednisolone at a dose of 0.1 mg/kg/day. Averageserum creatinine at the time of UCR measurement was1.5 mg/dl.

Table 1 Patient data. Valuesare presented as mean ± SD.Numbers within parenthesisindicate the range

No. patients Age, years T-score L2–L4BMD

Normal premenopausal women 30 36.8±9.1 )0.4±1.1(22–51)

Normal postmenopausal women 30 60.2±8.8 0.00±1.7(43–77)

Untreated postmenopausal osteoporosis 22 67.7±8.7 )2.49±1.17(51–78)

Bisphosphonate treatment combined 74 62.2±10.6 )1.97±1.16(44–84)

Bisphosphonate treatment <3 years 36 61.1±11.0 )1.99±1.02(44–82)

Bisphosphonate treatment ‡3 years 38 63.2±10.3 )1.95±1.31(47–84)

Renal transplantation combined 32 47.9±10.8 )1.93±1.26(30–68)

Renal transplantation women 16 46.4±12.7 )1.97±1.43(30–68)

Renal transplantation men 16 49.4±8.6 )1.85±1.02(35–63)

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UCR device and measurement

UCR device

UCR is a method for the measurement of velocity ofultrasound in bone by analyzing reflected sound waves[8, 9]. At the critical angle, the reflected wave experiencesan abrupt change in amplitude due to total internalreflection of the refracted pressure wave. This changeidentifies the critical angle hc and permits derivation ofthe velocity in bone V as V=c/sin hc, where c is thevelocity in the medium in which the ultrasound elementsare placed. In an elastic solid model, this method givesa measure of elasticity, since E=qV2 implies thatV2=E/q, where E is the elastic modulus and q is thedensity. The elastic modulus normalized for density canthus be obtained as the square of velocity. The nor-malized elasticity so-derived represents a materialproperty of bone [9, 11]. We reported previously that theelasticity correlates with the breaking strength of bone,and that the correlation differs between sites containingmainly cortical bone and those comprised of a mixtureof cortical and trabecular bone [11, 14, 15].

The current device was designed to make the mea-surement more practical and faster than in our previousdevices [8, 9], thus permitting measurements at multiplepoints and leading to greater precision. Moreover, itexpands the method to take explicitly into account theanisotropy of bone, and allows measurement of nor-malized elasticity at two principal directions orthogonalto each other. The ultrasound transducer head devel-oped for use in the clinic consists of a concave trans-mitter, spanning 100 degrees, concentric to a 48-channelreceiver array capable of analyzing multiple reflectionsfrom mineralized tissues over angles from )45 to45 degrees. A single wave train is emitted by the trans-mitter and detected after reflection from the body. Thereceiving array detects the reflected amplitude at theangles of reflection corresponding to the successivepositions of the elements. An interpolating motion isused to increase the angular resolution. The critical an-gle, used in ultrasound velocity calculation, correspondsto a maximum in the reflected amplitude distribution.The signal is recorded using specially designed, multi-channel amplifier and digitization systems.

In order to ensure accurate UCR measurements it isimportant for the ultrasound head to be oriented per-pendicular to the bone surface. A robotic arm has beenconstructed to permit the rapid orientation of theultrasound transducer along the ‘‘normal’’ to the bonesurface and to automate the measurement of spectra atdifferent orientations (Fig. 1). Two orthogonal rotating(pivoting) motions around the center of the transmitter,one longitudinal and the other transversal (angles / andh), are employed for normal alignment. Once the per-pendicular direction has been determined, the head canbe rotated using the normal as the axis of rotation toobtain the spectra at different orientations w. Theultrasound transducer can be positioned at multiple

measurement locations using three orthogonal rectilin-ear motions, X, Y and Z.

UCR indices measured

In each patient, UCR analysis was conducted in vivo atthree sites of bone on the lateral aspect of the calcaneus.At each site, critical angle velocity (reflected velocity)was obtained at orientations spanning 165 degrees atboth cortical and trabecular surfaces. By fitting the datainto a theoretical curve based on hexagonal symmetry[16], minimum and maximum velocities were derivedallowing calculation of corresponding elasticities nor-malized for density.

Four indices were obtained: cortical minimum elas-ticity (Ecmin), cortical maximum elasticity (Ecmax), tra-becular minimum elasticity (Etmin) and trabecularmaximum elasticity (Etmax). In each patient, the mean ofvalues from three sites was taken. The precision ofmeasurement was <2% in view of the intrinsic varia-bility of bone at the scale explored.

Other tests

At the time of UCR analysis, BMD of the calcaneus wasobtained by X-ray absorptiometry (Apollo DXA, Nor-land Medical Systems, White Plains, N.Y.), and that ofL2–L4 vertebrae was measured by dual photon X-rayabsorptiometry (Hologic QDR, Waltham, Mass.).

Statistical analysis

The mean values for each elasticity index were deter-mined for each patient group. One way analysis ofvariance (ANOVA) was used to assess significant dif-ferences between the seven groups. When the ANOVA

Fig. 1 Kinematics of the UCR device

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reached significance, the least squares means probabili-ties employing Bonferroni corrections were used tocompare data of the premenopausal normal group withthose of other groups. In addition, the mean elasticityfrom normal premenopausal women was obtained, andelasticity from subjects in other groups was then calcu-lated as the percentage of normal premenopausal mean.Group means expressed as percentages were then com-pared by using Student’s t -test, in assessing differencesbetween estrogen versus non-estrogen, varying durationof bisphosphonate treatment, with and without pre-valent fractures, presence or absence of incident non-spinal fractures and types of bisphosphonate. Linearregression and 95% prediction interval were used todescribe the relationship between age and elasticity.Data showing the relationship of Ecmax with the dura-tion of bisphosphonate treatment were fitted into acurve by exponential decay. Data are presented as mean± SD. Statistical analysis was performed with SASversion 9.1 (SAS Institute, Cary, N.C.) and SigmaPlotversion 8.02 (SPSS Inc., Chicago, Ill.).

Results

Overall results

Data for four elasticity indices in various patient groupsare summarized in Table 2. Actual group means areshown for each study group. For each group other thanthe premenopausal group, the value expressed as per-centage of the mean normal premenopausal value isdisplayed in parenthesis. The normalized elasticity valueof cortical bone was greater than the correspondingvalue of trabecular bone. In general, the percentagedecline in elasticity from the normal premenopausalmean following bisphosphonate treatment or in renaltransplantation was more prominent in cortical bonethan trabecular bone. In bisphosphonate treatment or

renal transplantation, the percentage decline of mini-mum elasticity was similar to that of maximum elastic-ity. For simplicity we chose Ecmax and Etmax in thedetailed comparison between groups.

UCR data in normal women

In normal women without osteoporosis either by frac-ture or density criteria, the decline in Ecmax was modestand non-significant, with a decrease of 4.9% from 20 to80 years of age (Fig. 2, left). Similarly, E tmax declinednon-significantly by 2.6% from 20 to 80 years of age.Postmenopausal women who took estrogen or SERMdisplayed Ecmax and Etmax unchanged from those ofsubjects who did not receive this treatment (data notshown).

UCR data in untreated postmenopausal osteoporosis

In untreated postmenopausal osteoporosis (withoutbisphosphonate, fluoride, and PTH peptide), E cmax wasin the low normal range, with the decline from normalpremenopausal state being only about 5.4% (Fig. 3,left). Etmax clustered within the 95% prediction intervalof normal women (Fig. 3, right). Values from patientswith prevalent fractures did not differ from those with-out fractures.

UCR data during bisphosphonate treatment

Among patients treated with bisphosphonate, Ecmax wasbelow the low normal limit in the majority of patients(Fig. 4, left). The remaining 1/5 of patients had Ecmax

that was largely in the low normal range. Sixteen of 74women developed spontaneous non-spinal fracturesduring bisphosphonate treatment. Their mean E cmax

Table 2 Minimum and maximum elasticities of cortical and tra-becular bone. Normalized elasticities, expressed in (km/s)2, arepresented as mean ± SD. Numbers within parenthesis indicatepercentage of mean value in normal premenopausal women. For

each elasticity index, statistical significance from the normal pre-menopausal group is indicated by * for P<0.0083 (0.05/6 to ac-count for multiplicity of testing)

Ecmin, corticalminimum elasticity

Ecmax, corticalmaximum elasticity

Etmin, trabecularminimum elasticity

Etmax, trabecularmaximum elasticity

Normal premenopausal women 14.1±0.9 15.6±0.8 7.4±0.3 8.0±0.3Normal postmenopausal women 13.7±0.7* 15.2±0.9 7.3±0.3 7.9±0.4

(96.7±5.1) (97.7±5.6) (99.1±4.6) (98.7±4.7)Untreated postmenopausal osteoporosis 13.5±0.7* 14.7±0.7* 7.2±0.3 7.8±0.4

(95.4±5.2) (94.6±4.5) (97.9±4.2) (97.3±5.5)Bisphosphonate treatment <3 years 11.7±1.1* 12.9±1.2* 6.6±0.8* 7.1±0.7*

(82.8±7.9) (82.8±7.7) (89.5±10.5) (88.8±8.3)Bisphosphonate treatment ‡3 years 11.0±0.8* 12.1±1.1* 6.2±0.4* 6.7±0.4*

(78.0±5.6) (77.9±6.8) (84.7±5.0) (84.1±5.1)Renal transplantation women 11.1±0.6* 12.2±1.1* 6.3±0.2* 6.9±0.3*

(78.5±4.4) (78.3±6.9) (86.1±3.0) (86.2±3.5)Renal transplantation men 11.2±0.6* 12.5±1.0* 6.3±0.3* 6.9±0.2*

(79.2±4.2) (80.1±6.4) (85.8±3.4) (86.9±3.0)ANOVA P <0.0001 <0.0001 <0.0001 <0.0001

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was significantly lower than among those without inci-dent non-spinal fractures (75.9±5.7% vs. 81.5±7.6% ofnormal premenopausal value, P =0.008). E cmax wasmarginally lower among 57 patients taking alendronatethan in 17 patients on risedronate (79.6±7.2% versus82.7±8.4%, P =0.13), but those on alendronate hadbeen on treatment longer (3.0 years alendronate and1.4 years on risedronate).

Similarly, Etmax was below the low normal range in themajority of patients on bisphosphonate treatment (Fig. 4,

right). The remainingminority of patients had values thatwere mostly in the low normal range. The mean value ofpatients with incident non-spinal fractures was signifi-cantly lower than that of patients who were fracture-free(82.3±3.9% vs. 87.6±7.5% of normal premenopausalvalue, P =0.0004). Eighteen of 74 patients were takingestrogenor SERM; their Etmax aswell asEcmaxwere nearlyidentical to those of patients not on this treatment.

In Fig. 5A and B, individual data for Ecmax and Etmax

are plotted against the duration of bisphosphonate

Fig. 2 Maximum elasticities ofcortical and trabecular bone innormal women. Dashed linesindicate the 95% predictioninterval of normal women. Thesolid line is the regression line.R2=0.05, P =0.09 formaximum cortical elasticity.R2=0.02, P=0.3 for maximumtrabecular elasticity

Fig. 4 Maximum elasticities ofcortical and trabecular boneduring bisphosphonatetreatment. Closed circles =women with non-spinalfractures developing duringbisphosphonate treatment; opencircles = women withoutfractures. Dashed lines indicatethe 95% confidence intervalsfor normal women

Fig. 3 Maximum elasticities of cortical bone ( left) and trabecularbone ( right) in untreated postmenopausal osteoporosis and renaltransplantation. Closed circle = untreated postmenopausalosteoporosis with prevalent fracture; open circles = untreated

postmenopausal osteoporosis without prevalent fractures (diagno-sis of osteoporosis by density criteria); + = women with renaltransplantation; x = men with renal transplantation. Dashed linesindicate the 95% prediction interval of normal women

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treatment. Among patients treated for less than 3 years,the decline in Ecmax of 17.2% (from below the mean ofnormal premenopausal women) was significantly lessthan that of 22.1% disclosed among patients who hadbeen treated longer ( P <0.001, Table 2). Similarly, thedecline in Etmax was significantly lower during treatment<3 years than ‡3 years (11.2 versus 15.9%, P <0.005).Among patients taking bisphosphonate, Ecmax and Etmax

were plotted against corresponding heel BMD (Fig. 5Cand D). Both elasticities were independent of BMD.

UCR data in renal transplantation

All 16 women with renal transplantation taking steroidshad E cmax that was below the lower limit of normalwomen (symbol +, Fig. 3). In 16 men with renaltransplantation, Ecmax was below the range of normalwomen in 15 patients (symbol x, Fig. 3). Values in wo-men overlapped with those of men with renal trans-plantation. (The 95% prediction interval for normalmen is not yet available, but appears to be similar to thatof women.) Similar findings were disclosed with Etmax.Virtually all values from women and men with renaltransplantation were below the range of normal women.

Relationship between T-scores of normalizedelasticities and of BMD

In Fig. 6A and B, mean values for E cmax and Etmax

(expressed as % normal premenopausal mean) are

plotted against the corresponding values for L2–L4BMD (as % normal peak). For both cortical and tra-becular elasticities, values in normal women clustered tothe upper right. (Normal postmenopausal women hadslightly higher L2–L4 BMD than premenopausal wo-men, since they were selected for having normal density.)Untreated postmenopausal osteoporosis had a modestdecline in elasticity, but the most severe decline in L2–L4BMD. Patients on short-term bisphosphonate treatment(<3 years) had moderate reduction in both elasticityand BMD. Patients on bisphosphonate treatment‡3 years had a similar decline in elasticity and BMD asthose with renal transplantation. Their BMD was higherthan in short-term bisphosphonate treatment, but theirelasticity displayed the most decline. A similar depen-dence of elasticities was disclosed when L2–L4 BMDwas replaced by heel BMD (Fig. 6C and D).

Discussion

The material quality of cortical and trabecular bone ofthe calcaneus was assessed from normalized elasticmoduli determined in vivo by a refinement of ultrasoundcritical angle reflectometry. Elastic moduli declinedslightly with normal ageing and in untreated postmen-opaual osteoporosis. However, elastic moduli weresubstantially reduced by bisphosphonate treatment andin renal transplantation, more so in cortical bone than intrabecular bone. Among patients treated with bis-phosphonate, the decline in elastic moduli was moremarked among those taking the drug ‡3 years than for a

Fig. 5 Individual data fornormalized elasticity plottedagainst corresponding durationof bisphonate treatment andBMD. Panel A shows therelationship between maximumcortical elasticity and durationof treatment, whereas panel Bdepicts that between maximumtrabecular elasticity andduration. Panels C and Ddisplay the plots of maximumcortical and maximumtrabecular elasticities againstcorresponding heel BMD

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shorter period, and among patients who developed non-spinal fractures than those who did not.

Earlier, our group had introduced a novel method formeasuring intrinsic quality of bone [8, 9] from theultrasound velocity measured in the amplitude reflectedat discrete bone surfaces. Unfortunately, the initial invivo device was cumbersome and slow in operation [9].Moreover, it could not ascertain velocities correspond-ing to principal axes of bone, an important factor sincein vitro studies showed that the velocity along theprincipal axis was the best velocity predictor of bonestrength [14].

For this study, a new device was constructed that hasthe capability for measuring reflected ultrasound veloc-ities at various orientations easily and rapidly on eithercortical or trabecular surfaces of the calcaneus in vivo.This device thereby allowed determination of velocitiesat principal axes of bone (perpendicular and parallel toweight-bearing). The square of ultrasound velocity wasthen calculated in order to derive elastic modulus nor-malized for bone density. Since the UCR method mea-sures bone surfaces of submillimeter size [9], thenormalized elasticity from UCR yielded a measure ofmaterial quality of discrete parts of bone. This conclu-sion is supported by the independence of normalizedelasticity from organ BMD, as shown before [9].Moreover, in normal postmenopausal women and inuntreated postmenopausal osteoporosis, the decline inelasticity from the normal premenopausal mean wasslight and non-significant, showing relatively unaffectedbone in the area investigated [9]. The clinical relevance

of UCR was indicated by a strong correlation betweenthe normalized elasticity and elasticity obtained fromdirect mechanical testing [11, 14, 15].

The key finding of this study was the reduction innormalized bone elasticity by bisphosphonate. There isemerging evidence that long-term bisphosphonatetreatment may cause oversuppression of bone turnover,may impair bone quality and cause fractures [12]. In-creased crystallinity of bone crystals and microdamagehave been reported in experimental animal exposed tobisphosphonate [17]. In human beings, bisphosphonatetreatment in excessive doses or of long duration has beenassociated with marble bone disease [18], osteonecrosisof the jaw [19], histomorphometric evidence of severesuppression of bone turnover [12], and spontaneousnon-spinal fractures displaying delayed healing [12].

Previous studies with bisphosphonate studies in ani-mal models did not reveal statistically significantreductions in bone elasticity [4]; rather, the anti-resorp-tive agent was shown to significantly increase the frac-tional trabecular bone volume (BV/TV) and the ultimateload. However, a significant decrease in modulus oftoughness (density-normalized, using BV/TV) was alsoreported, indicative of reduced energy absorptioncapacity for bone. Norman et al. [20] have shown thattoughness was correlated with microdamage accumula-tion. Unfortunately, the reduced normalized toughnessof trabecular bone without corresponding reductions innormalized ultimate stress [ultimate stress/(BV/TV)] orin normalized elastic modulus [E/(BV/TV)] is not wellcharacterized or understood. Other researchers found

Fig. 6 Relationship betweennormalized elasticity and BMD.Panels A and B depict the groupmeans for maximum corticaland trabecular elasticitiesplotted against mean L2-L4BMD. Panels C and D show therelationship between meanmaximum elasticities and heelBMD. Elasticities are expressedas percent of the mean value innormal postmenopausalwomen, and bone densities areexpressed as percent of normalpeak value for women.Horizontal bars indicate mean± SD for BMD of L2-L4 spineand heel and vertical barsrepresent mean ± SD forelasticity

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that while the apparent elastic modulus of bone (at theorgan level) was increased in normal dogs followingbisphosphonate treatment, the effect was mostly due toan increase in overall bone mass and not to changes atthe material level [20]. Indeed, the elasticity of the cal-cified matrix was reduced by up to 5%, suggestive ofimpaired material bone quality.

In the present study, bisphosphonate treatment ofpatients with postmenopausal osteoporosis was found toproduce a marked decline in normalized elasticity, par-ticularly of cortical bone. Moreover, the reduction inelasticity was more marked among those who sustainednon-spinal fractures than those who did not. The resultssuggested that the development of non-spinal fracturesmay be related to the impaired material bone quality,especially of cortical bone.

Despite widespread depression of bone elasticity bybisphosphonate shown here, only some patients devel-oped non-spinal fractures. Moreover, bisphosphonatetreatment has been reported to be efficacious in inhib-iting spinal fractures and even appendicular fracturesduring early periods of treatment [21, 22]. While bis-phosphonate may impair the material quality of discreteparts of the bone, it is also known to increase the BMDat the organ [21] and material [23] level. This rise couldhave offset the reduction in normalized elasticity,thereby increasing the overall bone strength andaccounting for the reported positive clinical response.

To dissect the effect of bisphosphonate, we assumedtypical values of trabecular bone density (q=1.8 g/cm3)and normalized elasticity (Etmax=7.8 (km/s2) for un-treated postmenopausal osteoporosis). In the elasticmodulus formula a 10% increase in density (optimumvalue achieved with bisphosphonate) would be offset bya decline in the normalized elasticity of 9%. However,the decline in Etmax found in this study with bis-phosphonate treatment ‡3 years was 16%. By insertingthese values into the elasticity formula presented in theprevious section, a reduction in the elastic modulus(predictive of material strength) of 5.5% was obtained.In other words, the rise in density mollified the declinein material quality (as indicated by the normalizedelasticity) measured by this technique, but did not offsetit. The same analysis applied to cortical bone yields a9.5% reduction in the elastic modulus. Because BMDdoes not directly measure physical density, a futurechallenge is to devise a method that would measurenon-invasively the density at the material level, so as toaccount for the remaining component of materialstrength.

The minimum and maximum normalized elasticitieswere similarly reduced during bisphosphonate treatmentat both cortical and trabecular bone surfaces. Thus,anisotropy, represented by the ratio of minimum andmaximum elasticities, was maintained during this treat-ment. The result suggests that a suppressed bone turn-over by bisphosphonate affects bone elements alongboth principal axes. This is compatible with the isotropicreduction found by inducing defects in the mineralized

phase of bone by EDTA, a manipulation which mimicsmicrofractures [24].

The finding of low bone elasticity in renal transplan-tation was not unexpected [13]. In this condition, boneformation may be suppressed, especially among thosetaking steroids. The so-called ‘‘adynamic bone disease’’with virtual loss of bone cellular activity has been de-scribed in this entity [25]. Other forms of bone disease,such as osteitis or osteomalacia, may be present due tochronic renal disease prior to renal transplantation.Clinically, increased susceptibility to fractures and im-paired healing of fractures have been described [26]. Inthis study, all 16 women with renal transplantation hadinvariably low elasticity, with virtually all subjects havingEcmax below the low normal limits. Values in 16 menoverlapped with those of women. The elasticity in menwith renal transplantation was probably reduced, sincepreliminary data indicated that elasticity in normalmen isequivalent to, and not lower than, that of normal women.The decline in elasticity was greater for cortical than tra-becular bone. The above findings in renal transplantationwere remarkably similar to those disclosed in long-termbisphosphonate treatment, supporting the contentionthat this treatment may impair material bone quality.

A drawback of this study was that the relatively shortavailability of the new UCR device did not allow serialmeasurements in the same subjects. Thus, the reducedelasticity by bisphosphonate treatment was inferred bycomparison with the untreated patients. However, thefinding of a much lower elasticity after ‡3 years oftreatment compared with earlier periods of treatmentsuggests a role for bisphosphonate.

In summary, the improved UCR approach allowedthe estimation of the material quality of cortical andtrabecular bone in vivo. Elasticity so-measured wasindependent of BMD, and was only slightly affected bynormal ageing and in untreated postmenopausal osteo-porosis. However, it was significantly and substantiallydepressed following bisphosphonate treatment and inrenal transplantation, especially in cortical bone.

Acknowledgements This study was supported by a GCRC grantfrom NIH M01-RR00633, and by the discretionary funds of theCenter for Mineral Metabolism and Clinical Research and theBone Quality Research Institute. The new UCR device is beingdeveloped by a non-profit entity, the Bone Quality ResearchInstitute, in cooperation with the sponsor, the University of TexasSouthwestern Medical Center. None of the authors own equity inthe Bone Quality Research Institute.

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