effects of osteoporosis medications on bone quality

Joint Bone Spine 74 (2007) 39e47

http://france.elsevier.com/direct/BONSOI/

Review

Effects of osteoporosis medications on bone quality

Claude-Laurent Benhamou

CHR Orleans, Service de Rhumatologie, Unite INSERM U 658, 1 rue Porte Madeleine, BP 2439, 45032 Orleans Cedex 1, France

Received 3 January 2005; accepted 20 June 2006

Available online 28 November 2006

Abstract

In clinical practice, the quantitative evaluation of bone tissue relies on dual-energy X-ray absorptiometry (DXA) measurements of bone min-eral density (BMD) values, which are closely associated with the risk of osteoporotic fracture. However, only a small fraction of the antifractureeffect of bone resorption inhibitors is ascribable to BMD gains (4% with raloxifene and 16e28% with alendronate and risedronate). Bone qualityencompasses a number of bone tissue properties that govern mechanical resistance, such as bone geometry, cortical properties, trabecular micro-architecture, bone tissue mineralization, quality of collagen and bone apatite crystal, and presence of microcracks. All these properties are de-pendent on bone turnover and its variations. In populations, the decreases in bone resorption markers achieved with resorption inhibitors maypredict in part the decrease in fracture risk. At the spine, however, this correlation exists down to a 40% fall in bone resorption markers; largerdrops did not provide further protection against fractures in patients taking risedronate in one evaluation of this relationship.

Osteoporosis medications can exert favorable effects on bone size and cortical thickness. Such effects have been documented with teripara-tide (PTH 1e34), which is the unique purely anabolic treatment for osteoporosis available to date. More surprising are the favorable effects onbone size seen with some of the bone resorption inhibitors such as neridronate in adults with osteogenesis imperfecta. Similarly, estrogens andalendronate can increase femoral neck size in postmenopausal women. Preservation of the trabecular microarchitecture was demonstrated firstwith risedronate and subsequently with alendronate. In placebo-controlled studies, a deterioration in trabecular microarchitecture occurredwithin 1 to 3 years in the placebo groups but not in the bisphosphonate groups. Teriparatide, in contrast, improves trabecular microarchitecture,in particular by increasing connectivity and improving the plate-rod distribution.

The minerals within trabecular or cortical bone can be evaluated using microradiography or synchrotron micro-computed tomography.Marked or prolonged secondary mineralization may result in poor bone quality. Increased bone mineralization is among the key effects ofbone resorption inhibitors, most notably bisphosphonates. Prolonged use of the most potent bisphosphonates may lead to unwanted effects re-lated to excessive mineralization. Microcracks may play a physiological role; however, a large number of microcracks may be deleterious via aneffect on osteocytes. Excessive mineralization may promote the development of multiple microcracks. Studies of bone crystal and collagen prop-erties with several bone resorption inhibitors, including risedronate and raloxifene, showed no harmful effects.

An increasing number (several hundreds) of mandibular osteonecrosis associated with bisphosphonate therapy has been reported. The typicalpatient was receiving injectable bisphosphonate therapy for bone cancer and had undergone dental work shortly before bisphosphonate admin-istration. The mechanism of this adverse effect is poorly understood.� 2006 Elsevier Masson SAS. All rights reserved.

Keywords: Osteoporosis; Strontium ranelate; Selective estrogen receptor modulator (SERM); PTH; Bone quality; Bisphosphonates; Microarchitecture

1. Introduction

Quantitative bone tissue parameters were initially thought tobe acceptable surrogate markers for bone strength. Bone mass

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doi:10.1016/j.jbspin.2006.06.004

per unit volume can be determined, although the most widelyused parameter in clinical practice is bone density per unit sur-face area (bone mineral density, BMD) as measured by dual-energy X-ray absorptiometry (DXA). Over the years, however,BMD proved to be a less than ideal tool for diagnosing post-menopausal osteoporosis [1,2]. Furthermore, recent data alsochallenge the usefulness of BMD for diagnosing

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40 C.-L. Benhamou / Joint Bone Spine 74 (2007) 39e47

glucocorticoid-induced osteoporosis [3] and male osteoporosis[4]. Thus, the 1993 criteria for diagnosis and treatment guid-ance developed by the World Health Organization (WHO)[5] need to be revised in order to introduce clinical risk factorsand biophysical parameters related to other properties of bonetissue. Trabecular microarchitecture was considered a key fac-tor in the original WHO definition of postmenopausal osteopo-rosis [5]. A revised definition developed in 2001 by a consensuspanel at the National Institutes for Health [6] states that, in ad-dition to complementary quantitative parameters, qualitativeparameters play a role. This new definition emphasizes that mi-croarchitecture is not the only qualitative feature related tobone strength. Several reviews on this point have been pub-lished [7e10]. There is general agreement that bone turnoverorchestrates the qualitative and quantitative changes in bonetissue [7e10] (Fig. 1). Qualitative bone properties can be con-sidered at various levels, from bone shape and size to bone tis-sue molecular composition (Table 1)

Although the limitations of BMD measurements as a diag-nostic tool have been emphasized for many years, this param-eter remains a key determinant of bone strength that can beused to define the fracture risk [11]. In contrast, BMD isclearly inadequate for characterizing the effects of bone re-sorption inhibitors in patients with osteoporosis [12]. Thus,there is a need for new methods.

2. Available medications for postmenopausal osteoporosis

Medications for postmenopausal osteoporosis include boneresorption inhibitors and bone formation enhancers.

2.1. Bone resorption inhibitors

Hormone replacement therapy (HRT) counters the boneturnover acceleration that occurs after the menopause.

Bone turnover

Bone strength

Quantitative factor

Bone mass Bone density

Qualitative factors

From macroscopic tonanoscopic

trabecular cortical

Falls

InjuriesFractures

--trabecular

cortical--

Fig. 1. Factors involved in osteoporotic fractures.

However, the use of HRT for preventing osteoporosis is de-clining. Bisphosphonates are the most potent bone resorptioninhibitors. Among them, etidronate is gradually being super-seded by risedronate and alendronate; all three drugs areused orally. Ibandronate has been licensed for use in Franceand will be available soon. Injectable bisphosphonates suchas zoledronate are being developed. A single selective estro-gen receptor modulator (SERM), called raloxifene, is availableto date, although other SERMs are being developed. Lastly,other drug classes such as RANK-ligand inhibitors are underinvestigation.

Calcium and vitamin D supplementation seeks chiefly tocorrect nutritional deficiencies. Bone resorption inhibition me-diates the effects of supplementation, most notably in older in-dividuals. However, calcium and vitamin D supplementation isnot usually classified among the bone resorption inhibitors.

2.2. Bone formation enhancers (anabolic agents)

Teriparatide, which is the 1e34 segment of parathyroidhormone, is the only bone formation enhancer available todate. Teriparatide exerts potent anabolic effects on bone. Itis reserved for patients who have severe postmenopausal oste-oporosis with at least two vertebral fractures.

2.3. Bone resorption inhibition plus boneformation enhancement

Strontium ranelate is a recently marketed agent that may becapable of both inhibiting bone resorption and enhancing bone

Table 1

Factors that determine bone quality [8]: a multiscale concept

Bone geometry Bone size (vertebrae, femur.)

Geometric variables Bone shape

Femoral neck length

Cortical thickness

Corticomedullary ratio

Fracture-related vertebral deformity

Coxa vara/coxa valga

Microarchitecture

Trabecular Connections among trabeculae

Cortical Perforationsedisconnections

Plate-rod distribution

Anisotropy

Microcracks

Mineral content within trabeculae

Nanoscopic level Collagen:

and molecular level Type

Linking peptides

Aging

Homogeneity

Bone crystal:

Mineral composition

Orientation

Homogeneity

Size

Aging

41C.-L. Benhamou / Joint Bone Spine 74 (2007) 39e47

formation [13,14]. It has been described as a decoupling agentto emphasize the opposite effects on resorption and formation.However, these effects are modest compared to those of boneresorption inhibitors or teriparatide.

3. Limitations of quantitative bone mineral densitymeasurements

Whereas antifracture efficacy at the spine is roughly similarwith all bone resorption inhibitors, BMD gains vary from onedrug to the next. Thus, the risk of vertebral fractures fell by30e50% over 3 years of treatment, whereas BMD gainsshowed far greater variability, from 3% to 9% [15,16]. Morespecifically, raloxifene provides limited BMD gains yet de-creases the fracture risk by 30e50% according to the studypopulation [12]. Mathematical models indicate that the pro-portion of the antifracture effect that is ascribable to BMDgains may be about 4% with raloxifene, 16% with alendronate[16], and 7e28% with risedronate [15,17]. Thus, most of thefracture-preventing effect of bone resorption inhibitors is inde-pendent from changes in BMD. In practice, however, a BMDgain of any magnitude indicates a fracture-preventing effect ina population, most notably with alendronate [18].

The rapid decrease in the fracture risk seen with bone re-sorption inhibitors is intriguing. The fracture risk decreasesbefore the maximum BMD values are achieved. For instance,risedronate decreases the fracture risk after 6 months [19] andraloxifene prevents symptomatic vertebral fractures after12 months [20]. In addition, the early fracture risk reductionsare larger than the reductions obtained after 3 years; thus,a 60e70% risk reduction is often seen after 1 year. Thesedata indicate that the BMD gain is not the only source ofthe fracture-preventing effect of bone resorption inhibitors.Other factors that are affected by these drugs and capable ofreducing bone turnover must be identified. In addition, the na-ture of the effects induced by bone formation enhancers needsto be characterized.

4. Bone turnover markers: indirect indicators ofbone quality

Bone turnover orchestrates the various factors that contrib-ute to bone quality (Fig. 1). Therefore, parameters that reflectbone turnover provide overall information on bone quality. Adrug that fails to significantly modify bone turnover is unlikelyto be effective in preventing fractures. On the other hand, ev-idence that a drug induces a marked and long-lasting decreasein bone turnover indicates a need for detailed studies of bonequality under treatment [21].

Bone turnover can be evaluated by histomorphometry ofbone biopsy specimens or by assays of markers for bone turn-over. These markers are suitable for use in clinical practice.Some markers reflect bone resorption (the most widely usedbeing serum crosslaps), and others bone formation (osteocal-cin, alkaline phosphatase, and N-terminal propeptide of typeI procollagen [PINP]). Bone turnover is governed in part bythe balance between apposition and resorption and in part by

the activation rate of bone remodeling units. Resorption inhi-bition varies considerably across drugs, as shown by the vari-ability in resorption marker decreases, which range from about30% with raloxifene to 50% with risedronate and 70% withalendronate.

In a study of patients taking risedronate for osteoporosis[22], the reduction in vertebral fracture risk was proportionalto the reduction in bone remodeling as long as this last didnot exceed about 40%. Further reductions in bone remodelingwere not associated with a further increase in antifracture effi-cacy; instead, the fracture risk reduction reached a plateau. Fur-thermore, marked and prolonged inhibition of bone resorptionmay exert deleterious effects [23,24]. However, with alendro-nate the plateau effect was not seen, although the decrease inbone remodeling was also closely associated with antifractureefficacy [25]. Bone remodeling markers may be useful for pre-dicting antifracture efficacy in populations with raloxifene [26].

5. Effects on bone geometry: the example of PTHdrecentdevelopments with bone resorption inhibitors

In postmenopausal women, teriparatide (1e34 PTH) in-jected daily for 18 months was associated with a 65% reduc-tion in vertebral fractures [27]. BMD gains varied acrossbone sites: with 20 mg/day, BMD increased by about 10% atthe lumbar spine and 3% at the hip but remained unchangedor tended to decrease at the radius [27]. Similar results wereobtained in men [28]. The absence of BMD increases at theradius may be ascribable to changes in bone size suggestinga lower mineral content of newly produced bone and/or wid-ening of the radius. A computed tomography (CT) study ofabout 100 women given teriparatide or a placebo [29] showedno significant BMD gains at the radius but disclosed a signifi-cant 5% increase in cortical surface area, which translated intoa trend toward an increase in bone mineral content (about 6%).

Thus, variations that occur with PTH therapy, most notablyat heavily cortical sites, should be interpreted in the light ofbone surface area changes. Similar findings were obtained inwomen on glucocorticoid therapy who were given PTH or a pla-cebo [30]. An about 5% increase in vertebral surface area at L1and L2 was noted after 1 year of PTH therapy [31], and onlyhalf of this gain was lost 1 year after treatment discontinuation.The antifracture effect may persist in part for at least 18 monthsafter treatment discontinuation, whereas the BMD values de-cline rapidly within the first year off treatment [32,33].

A somewhat unexpected finding is that bone resorption inhib-itors modify bone size. In adults with osteogenesis imperfecta,neridronate increased the cross-sectional area of the radius asevaluated by peripheral CT, compared to a placebo [34].

Femoral neck geometry can be evaluated on radiographs orDXA scans using a number of size measurements (outer diam-eter, cortical thickness, and surface area) or indirect indices(section modulus, which reflects bending strength; and buck-ling ratio, which is a measure of cortical bone stability).[35]. A comparison of HRT, alendronate, both drugs in combi-nation, and a placebo showed that the size parameters werelarger with the combination than with each active drug alone;


they were also larger in the three active-drug groups than inthe placebo group. Similar results were obtained for the buck-ling ratio and section modulus [35]. These data indicate bene-ficial effects of both HRT and alendronate on hip geometry.

The mechanisms of these beneficial effects on bone geom-etry remain poorly understood. They may involve endosteal orperiosteal changes. The relationships between bone size andbone strength were evaluated at the tissue level in tibiasfrom untreated men [36]. Tibias that were more slender ex-hibited lower mechanical resistance, suggesting that individ-uals with slender tibias may be at increased risk for fatiguefractures.

6. Influence on bone microarchitecture

Effects on bone microarchitecture undoubtedly contributeto the benefits brought about by osteoporosis medicationsvia pathways that do not involve bone mass. Microcomputedtomography (mCT) has proved an outstanding tool for evaluat-ing changes in bone microarchitecture (Figs. 2e4).

6.1. Effects of teriparatide on trabecularmicroarchitecture

Iliac crest biopsies from women with osteoporosis were ob-tained at baseline and after a mean-follow-up of 21 months,during which the patients took a placebo (n ¼ 19), teriparatide20 mg/day (n ¼ 18), or teriparatide 40 mg/day (n ¼ 14) [37]. Athree-dimensional analysis of the biopsy specimens was con-ducted using mCT. Teriparatide was associated not only withan increase in the amount of trabecular bone, but also withan about 22% increase in cortical thickness and with improve-ments in trabecular microarchitecture [37]. Trabecular connec-tivity increased by about 19% and the structural model index(SMI), which reflects plate-rod distribution, decreased by12% indicating a larger proportion of plates, a feature

Fig. 2. Scanning electron microscopy image of human trabecular bone (femo-

ral neck): note the plate-rod structure and the fenestrations in some of the

plates (Centre de Microscopie Electronique, Universite d’Orleans, France).

associated with greater mechanical strength. These data indi-cate that teriparatide therapy restores intertrabecular connec-tions. The mechanism of action of bone resorption inhibitorsdoes not suggest a similar effect.

In a group of women given teriparatide, we found beneficialeffects on parameters from fractal analysis of texture of thecalcaneus [38]. The improvements with teriparatide were sig-nificantly larger than those obtained with bone resorption in-hibitors. Fractal analysis of texture was validated many yearsago in our center [39], and we have shown that fractal analysisparameters correlate with connectivity evaluated by three-dimensional analysis of the same bone volume [40].

6.2. Effects of bisphosphonates on trabecularmicroarchitecture

Risedronate was studied in a minipig model. Oophorectom-ized females were given a placebo, risedronate 0.5 mg/kg/day,or risedronate 2.5 mg/kg/day [39] for 18 months. Bone micro-architecture was evaluated using mCT. Bone mass increasedwith both risedronate dosages. In addition, trabecular micro-architecture was better in the two risedronate groups than inthe placebo group. In particular, risedronate preserved verte-bral trabeculae that were orthogonal to the cranialecaudalaxis [41].

A study in postmenopausal women without osteoporosiscompared risedronate 5 mg/kg/day (n ¼ 14) to a placebo(n ¼ 12) [42]. In each patient, an iliac crest biopsy was takenafter 1 year. Trabecular microarchitecture deteriorated in theplacebo group, illustrating the adverse effects of estrogen dep-rivation on bone [42]. In contrast, microarchitecture was pre-served in the risedronate group. More specifically, the starvolume remained normal or decreased [42].

Fig. 3. Micro-computed tomography image of human trabecular bone from the

femoral head of an 87-year-old man with osteoporosis (Skyscan 1072 e In-

serm U 658).


Fig. 4. Micro-computed tomography image of rat bone tissue (Skyscan 1072). The specimen on the left is from a rat given the beta-adrenoceptor agonist salbu-

tamol. The specimen on the right was from a control rat.

In another study, bone biopsies were obtained at baselineand after 3 years of treatment with risedronate (n ¼ 17) ora placebo (n ¼ 17) [43]. Three-dimensional mCT showed pres-ervation of bone microarchitecture in the risedronate group. Inaddition, cortical bone loss was less marked with risedronatethan with the placebo [43]. These findings suggest that risedr-onate therapy may protect from the rapid deterioration in bonemicroarchitecture that occurs after the cessation of menses butfails to restore perforated or disconnected trabeculae, in con-trast to teriparatide.

A comparison of bone biopsies in patients given alendro-nate or a placebo produced similar results [44]. However, a sin-gle biopsy was taken in each patient, after treatment. Weconfirmed the beneficial effects of alendronate compared toa placebo on the topological parameters derived by skeletongraph analysis, after 2e3 years of treatment [45]. In particular,alendronate was significantly better than the placebo in in-creasing the number of nodes. The degree of anisotropy wasnot significantly different in the two groups [45].

A 2005 study report describes the results of an in vivo mag-netic resonance imaging (MRI) evaluation of bone microarch-itecture in postmenopausal women with osteoporosis treatedwith nasal calcitonin (n ¼ 46) or a placebo (n ¼ 45) [46].Measurements were done at the hip, radius, and calcaneus.

The results suggested preservation of bone microarchitectureat the hip. Few changes were noted at the calcaneus [46].

Using the texture analysis method developed in our centerto examine the calcaneus [39,40], we conducted a cross-sectional study of postmenopausal women to compare HRTusers and nonusers [47]. Texture analysis parameters were betterin the women taking HRT [47], suggesting better trabecularmicroarchitecture (Fig. 5).

6.3. Effects of bone resorption inhibitors onmineralization

Bone tissue mineralization occurs in two separate phases,primary mineralization and secondary mineralization. Duringprimary mineralization, minerals are laid down on the miner-alization front. This phase lasts about 3 months and accountsfor about half the total mineral content. Secondary mineraliza-tion occurs over 2 to 3 years, during which the apatite crystalsincrease in number and size [48,49]. The link between bonemineralization and mechanical resistance has been abundantlydocumented [50].

Bone mineralization can be evaluated by microradiographyof bone specimens. Focal mineralization measurements can beused to assess the uniformity of tissue mineralization. Aging

Radiograph

Fractalparameter

D: fractal dimension

H = 2-D

Unidirectionalanalysis

Digitization

ROI

2.7 2.7 cm²

Anatomic landmarks

0

50

100

150

200

0 50 100 150 200 250

Abscisse

Niv

eau

de g

ris

Fractional Brownianmotion

Maximum likelihood

Hmean

Multidirectionalanalysis

Fig. 5. Principle of fractal texture analysis on radiographs of the calcaneus [39].

44 C.-L. Benhamou / Joint Bo

bone is characterized by increased mineralization with greateruniformity, compared to younger individuals. Greater unifor-mity of mineralization may be associated with poor bone qual-ity and decreased bone strength [50].

With alendronate, the BMD increase (about 8% at the lum-bar spine) was largely ascribable to increases in mineralizationcompared to the placebo group, of about 7% after 2 years and11% after 3 years [51], accompanied with an increase in theuniformity of bone mineralization.

Microradiography studies showed increased mineralizationwith zoledronate [52] and HRT [53]. Uniformity of mineraliza-tion did not increase with HRT, even after more than 10 years ofuse. Similarly, with raloxifene, mineralization increased by 7%over 3 years, whereas uniformity remained unchanged [54].

Bone mineralization increases both during aging and duringbone resorption inhibitor therapy, which may seem contradic-tory. Greater mineralization seems beneficial, at least up toa certain extent, although excessive mineralization is difficultto define [20].

Synchrotron micro-CT has been used to evaluate bone min-eralization [55]. In a study of bone biopsies from women givenrisedronate or a placebo, bone mineralization increased byabout 5% with risedronate, compared to 1.6e2% with the pla-cebo (and calcium-vitamin D supplementation) [56]. In the ri-sedronate group, mineralization was negatively correlated withbone turnover. Risedronate therapy increased the ratio of low-to high-mineralized bone fractions [56].

Teriparatide therapy was associated with decreased miner-alization and with a slight increase in the heterogeneity index[57]. There is an overall increase in bone turnover with an in-creased proportion of newly formed bone having a low min-eral content, at least initially.

7. Properties of bone apatite crystal and collagen

The properties of bone apatite crystal (maturation, size, andorientation) can be evaluated using Fourier transform infraredimaging (FTIRI) or X-ray back-scattering under electron mi-croscopy. FTIRI is generally used to evaluate the propertiesof collagen such as the D pyridinoline/dihydroxylysylnorleu-cine ratio and the uniformity of collagen fibers [58].

FTIRI studies of bone biopsies from patients given risedro-nate therapy showed decreased apatite crystal and collagenmaturation, with better preservation of bone tissue heterogene-ity in this respect, compared to a placebo [59]. Similarly,FTIRI studies established that the intrinsic qualities of bonetissue were preserved after raloxifene therapy.

8. Impact of osteoporosis medications on other bonequality parameters

8.1. Microcracks (Figs. 6,7)

Excessive mineralization may promote the development ofmicrocracks in trabecular or cortical bone [60,61]. In beagledogs, incadronate and etidronate were associated not onlywith marked inhibition of bone remodeling, but also with the

development of microcracks [62e64]. The nature, frequency,and role of microcracks are being investigated. Microcracksshould be differentiated from artifacts related to preparation ofthe bone specimens, which can cause tissue damage; to thisend, specific stains such as fuchsin should be used. The dosagesper kg used in the dogs were far greater than those used in hu-mans [62e64]. Dosages comparable to those given to human pa-tients may increase the number of microcracks withoutmodifying the mechanical properties of bone [65]. Microcracksexert unwanted effects on osteocytes, which act as mechanore-ceptors within the bone tissue [66]. Their role in clinical practiceremains controversial and is being investigated [24].

8.2. A specific complication: osteonecrosis of the jawwith bisphosphonates

This is a very rare complication of bisphosphonate therapy,with 63 cases as of 2004 [67]. The incidence was 9.9% in

Fig. 6. Scanning electron microscopy image of trabecular bone from the fem-

oral neck of a woman with osteoporosis. Note the microcallus. Panel B is

a close-up of the upper left part of the image in Panel A (Centre de Microsco-

pie Electronique, Universite d’Orleans).

ne Spine 74 (2007) 39e47


patients with myeloma and 2.9% in those with breast cancer inone study [69]; corresponding figures in another study were6.8% and 4.4% [68]. Most of the patients were receiving in-jectable bisphosphonate therapy to treat cancer or myeloma.

Bisphosphonate-induced osteonecrosis of the jaw can leadto severe bone loss. The mechanism is poorly understood. Inpractice, great caution is in order in patients who require den-tal care, which increases the risk, most notably when teeth areextracted. Injectable bisphosphonate therapy may deserve tobe interrupted or postponed in patients who require dental pro-cedures; however, there is no proof that this measure decreasesor eliminates the risk of osteonecrosis of the jaw [68,70]. Den-tal procedures should be performed prior to the initiation of bi-sphosphonate therapy, together with prophylactic care ifneeded [70]. Finally, a key role for the cumulative exposureto glucocorticoids has been reported [68e70].

9. Conclusion

An increasingly strong body of evidence indicates thatBMD measurements cannot fully characterize the effects ofosteoporosis medications. Among the qualitative parametersdiscussed in this article, bone geometry and trabecular archi-tecture are good candidates for use in everyday practice.New tools are being developed, such as peripheral CT (withor without high resolution), MRI, structural analyses on radio-graphs or DXA scans, texture analysis on radiographs, and as-says of peptides released during collagen breakdown. Oncevalidated, these tools can be expected to supply valuable infor-mation on osteoporosis, particularly regarding its course andthe effects of treatment.

References

[1] Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of

bone mineral density predict occurrence of osteoporotic fractures. BMJ

1996;312:1254e9.

Fig. 7. X-ray micro-computed tomography image of a biopsy from a human

mandible: in the center of the sample microcallus (Skyscan 1072, resolution

7 mm; C. Chappard, INSERM U 658, Orleans).

[2] Melton LJ, Kan SH, Frye MA, Wahner HW, O’Fallon WM, Riggs BL.

Epidemiology of vertebral fractures in women. Am J Epidemiol 1989;

129:1000e11.

[3] Kanis JA, Johansson H, Oden A, Johnell O, de Lact C, Melton III LJ,

et al. A meta-analysis of prior corticosteroid use and fracture risk.

J Bone Miner Res 2004;19:893e9.

[4] Szulc P, Beck TJ, Marchand F, Delmas PD. Low skeletal muscle mass is

associated with poor structural parameters of bone and impaired balance

in elderly men. The Minos Study. J Bone Miner Res 2005;20:721e9.

[5] Consensus Development conference. Prophylaxis and treatment of oste-

oporosis. Am J Med 1993;94:646e50.

[6] NIH Consensus Development Panel in osteoporosis prevention, diagno-

sis, and therapy. JAMA 2001;285:785e95.

[7] GRIO (C.L. Benhamou coord.). Les osteoporoses. 2e edition. Paris: Doin

Editeur; 2005.

[8] (C.L. Benhamou, coord.). Les determinants multi echelle de la fragilite

osseusedComite d’Interface InsermdAppareil. Laboratoires Servier

Editeur; 2005.

[9] Chesnut III CH, Rosen CJ. Reconsidering the effects of antiresorptive

therapies in reducing osteoporotic fracture. J Bone Miner Res 2001;16:

2163e72.

[10] Bone Quality. What is it and can we measure it? NIH and ASBMR Meet-

ing. ASBMR; May 2005.

[11] Kanis JA, Johnell O, Oden A, de Laet C, Jonsson B, Dawson A. Ten-year

risk of osteoporotic fracture and the effect of risk factors on screening

strategies. Bone 2002;30:251e9.

[12] Sarkar S, Mitlab B, Wong M, Stock JL, Black DM, Harper KD. Relation-

ships between bone mineral density and incident vertebral fracture risk

with raloxifene therapy. J Bone Miner Res 2002;17:1e10.

[13] Meunier P, Roux C, Seeman E, Ortolani S, Badurski J, Spector T, et al.

Effects of strontium ranelate on vertebral fracture risk in postmenopausal

women. N Engl J Med 2004;350:459e68.

[14] Reginster JY, Seeman E, de Vernejoul MC, Adami S, Compston J,

Phenekos C, et al. Strontium ranelate reduces the risk of nonvertebral

fractures in postmenopausal women with osteoporosis. J Clin Endrocri-

nol Metab 2005;90:2816e22.

[15] Watts NB, Cooper C, Lindsay R, Eastell R, Manhart M, Barton IP, et al.

Relationship between changes in bone mineral density and vertebral frac-

ture risk associated with risedronate. J Clin Densitom 2004;7:256e61.

[16] Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, Lacroix AZ,

et al. Improvement in spine bone density and reduction in risk of verte-

bral fractures during treatment with antiresorptive drugs. Am J Med

2002;112:281e9.

[17] Li Z, Meredith MP, Hoseyni MS. A method to assess the proportion of

treatment effect explained by surrogate endpoint. Stat Med 2001;20:

3175e88.

[18] Hochberg M, Greenspan S, Wasnich R, Miller P, Thomson D, Ross P.

Changes in bone density and turnover explain the reductions in incidence

of nonvertebral fractures that occur during treatment with antiresorptive

agents. J Clin Endocrinol Metab 2002;87:1586e92.

[19] Roux C, Seeman E, Eastell R, Adachi J, Jackson R, Felsenberg D, et al.

Efficacy of risedronate on clinical vertebral fractures within six months.

Curr Med Res Opin 2004;20:433e9.

[20] Maricic M, Adachi JD, Sarkar S, Wu W, Wong M, Harper KD. Early effects

of raloxifene on clinical vertebral fractures at 12 months in post-meno-

pausal women with osteoporosis. Arch Intern Med 2002;162:1140e3.

[21] Weinstein RS. True strength. J Bone Miner Res 2000;15:621e7.

[22] Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD.

Relationship of early changes in bone resorption to the reduction in

fracture risk with risedronate. J Bone Miner Res 2003;18:051e6.

[23] Cummings SR. How drugs decrease fracture risk: lessons from trials.

J Musculoskel Neuron Interact 2002;2:198e200.

[24] Ott S. Long-term safety of bisphosphonates. J Clin Endocrinol Metab

2005;90:1897e9.

[25] Bauer D, Black D, Garnero P, Hochberg M, Ott S, Orloff J, , et al., for the

fracture intervention trial study group. Changes in bone turnover and hip,

non-spine and vertebral fracture in alendronate-treated women: the frac-

ture intervention trial. J Bone Miner Res 2004;19:1250e8.


[26] Bjarnason NH, Sarkar S, Duong T, Mitlak B, Delmas PD, Christiansen C.

Six and twelve month changes in bone turnover are related to reduction

in vertebral fracture risk during 3 years of raloxifene treatment in post-

menopausal osteoporosis. Osteoporosis Int 2001;12:922e30.

[27] Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY,

et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral

density in postmenopausal women with osteoporosis. N Engl J Med

2001;344:1434e41.

[28] Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A,

et al. The effect of teriparatide [Human Parathyroid Hormone (1-34)].


[29] Zanchetta J, Bogado C, Ferretti J, Wang O, Wilson MG. Sato M et al.

Effects of teriparatide [recombinant human parathyroid hormone (1-

34)] on cortical bone in postmenopausal women with osteoporosis.


[30] Rehman Q, Lang TF, Arnaud CD, Modin GW, Lane NE. Daily treatment

with parathyroid hormone is associated with an increase in vertebral

cross-sectional area in postmenopausal women with glucocorticoid-

induced osteoporosis. Osteoporosis Int 2003;14:77e81.

[31] Lindsay R, Scheele WH, Neer R, Pohl G, Adami S, Carlos Mautalen,

et al. Sustained vertebral fracture risk reduction after withdrawal of ter-

iparatide in postmenopausal women with osteoporosis. Arch Intern Med

2004;164:2024e30.

[32] Rittmaster RS, Bolognese M, Ettinger M, Hanley DA, Hodsman AB,

Kendler DL, et al. Enhancement of bone mass in osteoporotic women

with parathyroid hormone followed by alendronate. J Clin Endocrinol

Metab 2000;85:2129e34.

[33] Prince R, Sipos A, Hossain A, Syversen U, Ish-Shalom S,

Marcinowska E, et al. Sustained nonvertebral fragility fracture risk re-

duction after discontinuation of teriparatide treatment. J Bone Miner

Res 2005;20:1507e13.

[34] Gatti D, Viapiana O, Lippolis I, Braga V, Prizzi R, Rossini M, et al.

Intravenous bisphosphonate therapy increases radial width in adults

with osteogenesis imperfecta. J Bone Miner Res 2005;20:1323e6.

[35] Greenspan SL, Beck TJ, Resnick NM, Bhattacharya R, Parker RA. Effect

of hormone replacement alendronate, or combination therapy on hip

structural geometry: a 3-year, double-blind, placebo-controlled clinical

trial. J. Bone Miner Res 2005;20:1525e32.

[36] Tommasini SM, Nasser P, Schaffler MB, Jepsen KJ. Relationship be-

tween bone morphology and bone quality in male tibias. J Bone Miner.

Res 2005;20:1372e80.

[37] Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF. Recombi-

nant human parathyroid hormone (1-34) [teriparatide] improves both

cortical and cancellous bone structure. J Bone Miner Res 2003;18:

1932e41.

[38] Benhamou CL, Chappard C, Gadois C, Lemineur G, Lespessailles E, de

Vernejoul MC, et al. Characterization of trabecular micro-architecture

improvement under teriparatide by a fractal analysis of texture on calca-

neus radiographs. J Bone Miner Res 2004;1(Suppl):S126.

[39] Benhamou CL, Lespessailles E, Jacquet G, Harba R, Jennane R,

Loussot T, et al. Fractal organization of trabecular bone images on calca-

neus radiographs. J Bone Miner Res 1994;9:1909e18.

[40] Pothuaud L, Benhamou CL, Porion P, Lespessailles E, Harba R, Levitz P,

et al. Fractal dimension of trabecular bone projection texture is related

to three-dimensional microarchitecture. J Bone Miner Res 2000;15:

691e9.

[41] Borah B, Dufresne TE, Chmielewski PA, Gross GJ, Prenger MC,

Phipps RJ. Risedronate preserves trabecular architecture and increases

bone strength in vertebra of ovariectomized minipigs as measured by

3-D computed tomography. J Bone Miner Res 2002;17:1139e47.

[42] Dufresne TE, Chmielewski PA, Mannhart MD, Johnson TD, Borah B.

Risedronate preserves bone architecture in early postmenopausal women

in 1 year as measured by 3-D microcomputed tomography. Calcif Tissue

Int 2003;73:423e32.

[43] Borah B, Dufresne TE, Chmielewski PA, Johnson TD, Chines A,

Mannhart MD. Risedronate preserves bone architecture in postmeno-

pausal women with osteoporosis as measured by 3-D micro computed to-

mography. Bone 2004;34:736e46.

[44] Recker R, Masarachia P, Santora A, Howard T, Chavassieux P, Arlot M.

Trabecular bone microarchitecture after alendronate treatment of osteo-

porotic women. Curr Med Res Opin 2005;21:185e94.

[45] Benhamou C.L., Basillais A., Aufort G., Chappard C., Jennane R., Ma-

sarachia P., et al. Application of a three dimensional skeleton graph anal-

ysis to patients treated by alendronate on placebo on micro-computed

tomography images. NIAMS-ASBMR Scientific MeetingdBone Qual-

ity: What is it and can we measure it? May 2-3, 2005, Bethesda, MD,

USA. p. 34e36.

[46] Chesnut III CH, Majumdar S, Newitt DC, Shields A, Van Pelt J,

Laschansky E, et al. Effects of salmon calcitonin on trabecular micro-

architecture as determined by MRI: results from the QUEST study.


[47] Lespessailles E, Poupon S, Niamane R, Loiseau-Peres S,

Derommelaere G, Harba R, et al. Fractal analysis of trabecular bone tex-

ture on calcaneus radiographs: effects of age, time since menopause and

hormonal replacement therapy on microarchitectural changes. Osteopo-

rosis Int 2002;13:366e72.

[48] Boivin G, Meunier PJ. The degree of mineralization of bone tissue mea-

sured by computerized quantitative contact microradiography. Calcif Tis-

sue Int 2000;70:503e11.

[49] Boivin G, Meunier PJ. Methodological considerations in measurement of

bone mineral content. Osteoporosis Int 2003;5(Suppl):22e8.

[50] Turner CH. Biomechanics of bone: determinants of skeletal fragility and

bone quality. Osteoporosis Int 2002;13:97e104.

[51] Boivin G, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendro-

nate increases bone strength by increasing the mean degree of minerali-

zation of bone tissue in osteoporotic women. Bone 2000;27:687e94.

[52] Boivin G, Arlot M, Trechsel U, Meunier PJ. Effects of intravenous zole-

dronic acid on the degree of mineralization of bone in post-menopausal

osteoporosis: a quantitative microradiographic analysis of transiliac biop-

sies after one year. J Bone Miner Res 2003;2(Suppl):S261.

[53] Boivin G, Vedi S, Purdie DW, Compston JE, Meunier PJ. Influence of

estrogen therapy at conventional and high doses on the degree of miner-

alization of iliac bone tissue: a quantitative microradiographic analysis in

postmenopausal women. Bone 2005;36:562e7.

[54] Boivin G, Lips P, Ott SM, Harper KB, Sarkar S, Pinette V, et al. Contri-

bution of raloxifene and calcium and vitamin D. Supplementation to the

increase of the degree of mineralization of bone in postmenopausal

women. J Clin Endocrinol Metab 2003;88:4199e205.

[55] Nuzzo S, Peyrin F, Cloetens P, Bachurel J, Boivin G. Quantification of

the degree of mineralization of bone in three dimension using synchro-

tron radiation microtomography. Med Phys 2002;29:2672e81.

[56] Borah B, Ritman E, Dufresne T, Jorgensen S, Liu S, Sacha J, et al. The

effect of risedronate on bone mineralization as measured by micro-CT

with synchrotron radiation: correlation to histomorphometric indices of

turnover. Bone 2005;37:1e9.

[57] Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, Messmer P,

et al. Effects of intermittent parathyroid hormone administration on

bone mineralization density in iliac crest biopsies from patients with

osteoporosis: a paired study before and after treatment. J Clin Endocrinol

Metab 2003;88:1150e6.

[58] Paschalis EP, Betts F, Dicarlo E, Mendelson R, Boskey AL. FTIR Micro-

spectroscopic analysis of normal human cortical and trabecular bone.

Calcif Tissue Int 1997;61:480e6.

[59] Paschalis EP, Phipps R. Long-term treatment with risedronate preserves

bone quality. International Conference on Progress in Bone and Mineral

Research, Vienna, November 27; 2003.

[60] Burr D. Microdamage and bone strength. Osteoporosis Int 2003;5(Sup-

pl):S67e72.

[61] Hirano T, Turner CH, Forwood H, Johnston C, Burr D. Does suppression

of bone turnover impair mechanical properties by allowing microdamage

accumulation? Bone 2000;27:13e20.

[62] Burr D, Miller L, Grynpas M, Li J, Boyde A, Mashiba T, et al. Tissue

mineralization is increased following 1-year treatment with high doses

of bisphosphonates in dogs. Bone 2003;33:960e9.

[63] Komatsubara S, Mori S, Mashiba T, Li J, Nonaka K, Kaji Y, et al. Sup-

pressed bone turnover by long-term bisphosphonate treatment


accumulates microdamage but maintains intrinsic material properties in

cortical bone of dog rib. J Bone Miner Res 2004;19:999e1005.

[64] Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB.

Effects of suppressed bone turnover by bisphosphonates on microdamage

accumulation and biomechanical properties in clinically relevant skeletal

sites in beagles. Bone 2001;28:524e31.

[65] Allen MR, Iwata K, Phipps R, Burr D. Risedronate and alendronate

similarly suppress remodelling and increase microdamage in beagles

after 1 year of treatment at clinical doses. J Bone Miner Res 2005;

1081:S22.

[66] Martin RB. Fatigue microdamage as an essential element of bone me-

chanics and biology. Calcif Tissue Int 2003;73:101e7.

[67] Ruggiero S, Mebrotra B, Rosenberg T, Engroff S. Osteonecrosis of the

jaws associated with the use of bisphosphonates: a review of 63 cases.

J Oral Maxillofac Surg 2004;62:527e34.

[68] Durie BG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med

2005;353:99e102.

[69] Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I,

Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with

bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23:

8580e7.

[70] Afssaps. Lettre aux prescripteurs. Information de pharmacovigilance.

Acide zoledronique/pamidronate de sodium et osteonecrose de la ma-

choire. 24 juin 2005.

effects of osteoporosis medications on bone quality

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