Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women

Roschger, Paul; Rinnerthaler, S; Yates, John; Rodan, Gideon A.; Fratzl, Peter; Klaushofer, Klaus

doi:10.1016/s8756-3282(01)00485-9

Cited by 359 publications

(217 citation statements)

References 28 publications

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“…(36)(37)(38) Nevertheless, cotreatment with zoledronic acid may prevent the teriparatide-induced increase in cortical porosity, thus potentially strengthening the cortex and, as observed in this study, increasing hip BMD beyond values achieved with teriparatide alone. (39) The lack of continued increase in BMD at the hip during the latter 6 months in the combination group of our study may be due to increased cortical remodeling and resulting increases in cortical porosity as the effect of zoledronic acid wanes.…”

Section: Discussionmentioning

confidence: 58%

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Cosman

Eriksen

Recknor

et al. 2010

Journal of Bone and Mineral Research

309

173

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Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20 mg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 AE 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 mg (n ¼ 137), zoledronic acid alone (n ¼ 137), or teriparatide alone (n ¼ 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively ( p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone ( p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks ( p < .05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum b-C-telopeptide of type I collagen [b-CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone ( p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA-based BMD (e.g., quantitative computed tomography and finite-element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. ß

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Section: Discussionmentioning

confidence: 58%

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Cosman

Eriksen

Recknor

et al. 2010

Journal of Bone and Mineral Research

309

173

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“…BMDD is a measure of the degree and heterogeneity of mineralization in bone tissue. (33)(34)(35) In the healthy adult population, BMDD of cancellous bone shows only minor variations with age, gender, ethnicity, and skeletal site, (36) indicating that the normal BMDD corresponds to a biologic and mechanical optimum. Therefore, even small deviations from the normal BMDD may have biologic meaning.…”

Section: Insights Into the Pathogenesis Of Atypical Femoral Fracturesmentioning

confidence: 99%

“…(37) BP treatment reduces bone turnover, increases overall mineralization, but leaves mineral particle shape, thickness, and orientation unaffected, narrows the BMDD, and increases bone strength and stiffness. (33,34) BP effects on BMDD have been studied only in transiliac bone biopsies, so there is limited knowledge about their effects on cortical bone from other sites. However, Donnelly and colleagues (38,39) have shown that the range of mineral distribution at the proximal femur is significantly narrower than that in the iliac crest and that postmenopausal women treated with BPs for an average of 8 years demonstrated substantially less tissue heterogeneity in terms of mineralization, crystal size, and crystal perfection than those who had not been treated.…”

Section: Insights Into the Pathogenesis Of Atypical Femoral Fracturesmentioning

confidence: 99%

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

Shane

Burr

Ebeling

et al. 2010

Journal of Bone and Mineral Research

986

679

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Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. ß

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“…In iliac crest bone biopsies from osteoporotic women, the degree of mineralization was decreased while the mineral crystal size and perfection was increased, as compared to the non-osteoporotic controls [9,10]. Treatment of osteoporotic women with the bisphosphonate alendronate, was reported to increase the mean degree of mineralization and the homogeneity of the mineral distribution in the cancellous bone of compared to placebo treated subjects [9,11]. Apart from affecting bone mineral distribution, bisphosphonates have non-hydrolysable P-C-P bonds with high affinities for the hydroxyapatite crystals (mineral); moreover, they have been reported to regulate crystal growth and dissolution [12].…”

Section: Introductionmentioning

confidence: 99%

The degree of bone mineralization is maintained with single intravenous bisphosphonates in aged estrogen-deficient rats and is a strong predictor of bone strength

Yao

Cheng

Koester

et al. 2007

Bone

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The treatment of osteoporotic women with bisphosphonates significantly reduces the incidence of bone fractures to a degree greater than can be explained by an increase in bone mineral density. In this Study, 18 month Fischer 344 rats were ovariectomized and treated with a single dose of risedronate (intravenous, iv, 500μg), zoledronic acid (iv, 100μg) or continuous raloxifene (2mg/ kg, po., 3x/wk). High resolution microCT was used to measure lumbar vertebral bone microarchitecture, the degree of bone mineralization (DBM) and the distribution of mineral. Small angle x-ray scattering was used to investigate mineral crystallinity. We found prolonged estrogen deficiency, reduced trabecular bone volume, and increased micro architecture bone compression strength. lowered the degree of mineralization. Treatment with resorptive agents (bisphosphonates > raloxifene) prevented the loss of mineralization, trabecular bone volume and bone compression strength. Crystal size was not changed with OVX or with anti-resorptive treatments. In conclusion, in the aged estrogen deficient rat model, single intravenous doses of two bisphosphonates were effective in maintaining the compressive bone strength for 180 days by reducing bone turnover, and maintaining the DBM to a greater degree than with raloxifene.

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Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women

Cited by 359 publications

References 28 publications

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

The degree of bone mineralization is maintained with single intravenous bisphosphonates in aged estrogen-deficient rats and is a strong predictor of bone strength

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