Long-term Alendronate Treatment Research Articles

Once-weekly parathyroid hormone combined with ongoing long-term alendronate treatment promotes osteoporotic fracture healing in ovariectomized rats.

This study examined the effect of once-weekly parathyroid hormone (PTH) combined with alendronate upon osteoporotic fracture healing after long-term alendronate anti-osteoporosis therapy. Seventy-six 12-week-old female Sprague-Dawley rats were either sham operated or bilaterally ovariectomized (OVX). Following confirmation of osteoporosis 3 months after OVX, the remaining 64 animals received alendronate therapy. After 3 months of alendronate treatment, all rats underwent unilateral transverse tibial osteotomy. Animals were immediately randomly assigned to one of four groups: (1) alendronate followed by vehicle (ALN-VEH), (2) continuation of alendronate (ALN-ALN), (3) alendronate followed by once-weekly PTH alone (ALN-PTH), (4) continuation of alendronate combined with once-weekly PTH (ALN-ALN + PTH) until collection at 4 or 8 weeks after osteotomy. The fractured tibia was assessed using x-ray, dual-energy x-ray absorptiometry, microcomputed tomography, biomechanical testing, histology, and sequential fluorescence labeling. The ALN-ALN + PTH treatment significantly increased total callus volume, mineralized callus volume, mineralized callus volume/total callus volume, and biomechanical strength of the callus relative to ALN-VEH and ALN-PTH treatments at both 4 and 8 weeks and produced more mature trabecular bone compared with ALN-ALN treatment at 8 weeks. RANKL/osteoprotegerin (OPG) are osteoclastogenesis markers, while cluster of differentiation 31 (CD31) is an important marker of angiogenesis. Qualitative immunohistochemical analysis revealed that CD31 and OPG expression was was strong after ALN-ALN + PTH compared with ALN-ALN treatment, whereas RANKL expression was weak after ALN-ALN + PTH versus ALN-PTH treatment. Our study showed that once-weekly PTH combined with alendronate was beneficial in promoting the healing of fractures acquired after long-term alendronate therapy in OVX-induced osteoporotic rats.

Effects of Long-Term Alendronate Treatment on a Large Sample of Pediatric Patients with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a group of inherited diseases characterized by reduced bone mass, recurrent bone fractures, and progressive bone deformities. Here, we evaluate the efficacy and safety of long-term treatment with alendronate in a large sample of Chinese children and adolescents with OI. In this prospective study, a total of 91 children and adolescents with OI were included. The patients received 3 years' treatment with 70 mg alendronate weekly and 500 mg calcium daily. During the treatment, fracture incidence, bone mineral density (BMD), and serum levels of the bone turnover biomarkers (alkaline phosphatase [ALP] and cross-linked C-telopeptide of type I collagen [β-CTX]) were evaluated. Linear growth speed and parameters of safety were also measured. After 3 years of treatment, the mean annual fracture incidence decreased from 1.2 ± 0.8 to 0.2 ± 0.3 (P<.01). BMD at the lumbar spine and femoral neck significantly increased by 74.6% and 39.5%, with their BMD Z-score increasing from -3.0 to 0.1 and from -4.2 to -1.3, respectively (both P<.01 vs. baseline). In addition, serum ALP and β-CTX levels decreased by 35.6% and 44.3%, respectively (both P<.05 vs. baseline). Height significantly increased, but without an obvious increase in its Z-score. Patient tolerance of alendronate was good. Three years' treatment with alendronate was demonstrated for the first time to significantly reduce fracture incidence, increase lumbar spine and femoral neck BMD, and decrease bone turnover biomarkers in Chinese children and adolescents with OI. ALP = alkaline phosphatase β-CTX = cross-linked C-telopeptide of type I collagen BMD = bone mineral density BP = bisphosphonate DXA = dual-energy X-ray absorptiometry 25OHD = 25-hydroxyvitamin D OI = osteogenesis imperfecta PTH = parathyroid hormone.

Effects of long-term alendronate treatment on postmenopausal osteoporosis bone material properties.

Raman microspectroscopic analysis of iliac crest from patients that were treated with alendronate (ALN) for 10years revealed minimal, transient alterations in bone material properties confined to actively forming bone surfaces compared to patients that were on ALN for 5years. These changes were not encountered in the bulk tissue. Alendronate (ALN) and other bisphosphonates (BPs) are the most widely prescribed therapy for postmenopausal osteoporosis. Despite their overall excellent safety record and efficacy in reducing fractures, questions have been raised regarding potential detrimental effects that may be related to prolonged bone turnover reduction, although no definite cause-effect relationship has been established to date. The purpose of the present study was to evaluate bone material properties in patients that were receiving ALN for 5 or 10years. Raman microspectroscopic analysis was used to analyze iliac crest biopsies from postmenopausal women with osteoporosis who had been treated with ALN for 5years and were then re-randomized to placebo (PBO, N = 14), 5mg/day ALN (N = 10), or 10mg/day ALN (N = 6) for another 5years. The parameters monitored and expressed as a function of tissue age were (i) the mineral/matrix ratio (MM), (ii) the relative proteoglycan content (PG), (iii) the relative lipid content (LPD), (iv) the mineral maturity/crystallinity (MMC), and (v) the relative pyridinoline content (PYD). The obtained data indicate that 10-year ALN use results in minimal, transient bone tissue composition changes compared to use for 5years, confined to actively forming trabecular surfaces, implying potential differences in bone matrix maturation that nevertheless did not result in differences of these values in bulk tissue. The data suggest that prolonged reduction in bone turnover during 10years of therapy with ALN by itself is unlikely to be associated with adverse effects on bone material properties.

Atypical femoral fracture after long-term alendronate treatment: Report of a case evidenced with magnetic resonance imaging

Postmenopausal osteoporosis is commonly treated with alendronate, one of the bisphosphonates used for the prevention and treatment of osteoporotic fractures. However, the correlation between atypical femoral fractures and long-term bisphosphonate therapy has not been clearly identified. We report here the case of a 69-year-old woman with postmenopausal osteoporosis who presented with an atypical femoral subtrochanteric fracture on magnetic resonance imaging (MRI) confirmation after having received alendronate therapy for about 3 years. The fracture united after refixation and after administration of alendronate was stopped. Several published reports were reviewed, and some clinical characteristics of this atraumatic fracture were revealed, including the clinical symptoms of thigh pain, stress reaction or stress fracture, and transverse fracture with unicortical beak in an area of cortical hypertrophy. In addition to a regular radiographic survey, MRI, which may provide early information, and bone biopsy for pathologic analysis may be used as tools for early detection and final diagnosis. Once an insufficiency fracture is suspected or proved to be related to bisphosphonate, the withholding of bisphosphonate should be highly recommended to enhance fracture healing. Prophylactic fixation should be considered if fracture healing is not good or if the patient cannot tolerate protection of weight-bearing.

Atypical Femoral Fracture Risk in Patients Treated With Bisphosphonates

There is increasing evidence that the use of bisphosphonates to prevent osteoporotic fractures, particularly long-term use, is associated with an increased risk of unusual fractures of the proximal femur. Numerous case reports of these “atypical” fractures of the femur among bisphosphonate-treated women have appeared over the last 5 years or more.1,2 A case definition for atypical femur fractures has now been proposed3 that includes subtrochanteric (below the lesser trochanter) or diaphyseal (above the distal metaphysis) location, transverse or nearly transverse “chalklike” fracture line (as opposed to the more typical spiral or comminuted fractures), and paucity of trauma. Additional features may include the presence of prodromal thigh pain, bilateral involvement, cortical thickening, and the presence of other selected diseases (such as rheumatoid arthritis or diabetes) or medication use (such as corticosteroids or proton pump inhibitors). Some reports, but certainly not all, suggest marked suppression of bone turnover as assessed by bone turnover markers and iliac crest histomorphometry.1 Even if causally related, these atypical fractures must be quite rare among osteoporotic women treated with bisphosphonates, as a recent pooled analysis of 3 large clinical trials (FIT, FLEX, and HORIZON) with up to 10 years of follow-up4 found that all types of subtrochanteric and diaphyseal fractures were infrequent and similar among placebo- and bisphospho-nate-treated women. Although these findings are reassuring, important limitations were that relatively few women received more than 5 years of bisphosphonate treatment, information on atypical features was not specifically collected, and only radiographic reports were reviewed. Clearly, because atypical subtrochanteric fractures occur infrequently, they are unlikely to be easily studied in randomized trials, and other study designs will be necessary.

Reply to Letter to the Editor: The Effect of Long-term Alendronate Treatment on Cortical Thickness of the Proximal Femur

We thank Dr. Koh and colleagues for their well-taken comments to our article, “The Effect of Long-term Alendronate Treatment on Cortical Thickness of the Proximal Femur” [7]. Our results interestingly showed that the majority of patients treated with alendronate at a minimum of 5 years had stable or decreased cortical thickness. This finding is contradictory to the results from Lenart et al. [3]. Although the method used to calculate a cortical thickness ratio from dual energy x-ray absorptiometry images in our study is similar to that of the plain radiographs used by Lenart et al., a so-called normalized cortical thickness, some differences must be underscored between their study and ours regarding the methodology and patient population. First, Lenart et al. [3] reported the normalized cortical thickness in only patients with subtrochanteric fractures, whereas we included only patients without a history of fractures around the lower extremities. Thus, our findings may not be applicable to those with atypical femoral insufficiency fractures. As we discussed in the original article [7], our study strongly supports the concept that patients with atypical femoral insufficiency fractures had thickened femoral cortices at the onset of bisphosphonate therapy. Second, we determined the cortical thickness ratio only at the subtrochanteric region, whereas Lenart et al. [3] measured femoral cortices just distal to the fracture site, which may not always be synonymous with the subtrochanteric area. Thus, the average value of the normalized cortical thickness from their study may differ from ours. Third, the mean ages of patients in their study were much older (70 and 83 years in patients with and without x-ray pattern for atypical femoral insufficiency fracture, respectively) than our patients (62 and 63 years in patients with and without history of long-term bisphosphonate therapy, respectively). It is possible that patients of different ages may respond to alendronate treatment differently. In addition, we do not have rigorous detail available regarding the adherence and compliance of patients with long-term bisphosphonate treatment in our study. However, the bone mineral density responses in our patients with long-term alendronate therapy were consistent with a compliant population based on previous reports [1, 5]. The majority of patients with atypical femoral insufficiency fractures have enlarged femoral cortices. In addition, they also have localized femoral thickening that may represent a true stress fracture [1–3]. We speculate that a stress fracture occurs at an area of abnormal stress concentration, such as at the lateral aspect of the femur attributable to anterolateral femoral bowing. As prolonged bisphosphonate therapy may lead to inhibition of the fracture healing process and deposition of poor-quality bony tissue [4], these stress fractures can propagate to simple transverse or short oblique fractures with beaking. Nevertheless, we agree with Koh and colleagues that the American Society for Bone and Mineral Research criteria [6] to define atypical femoral insufficiency fractures needs further refinement. As we gain a greater understanding of the pathophysiology, we will be able to better define the critical elements of this unique disorder.

Letter to the Editor: The Effect of Long-term Alendronate Treatment on Cortical Thickness of the Proximal Femur

To the Editor: We read with interest the recent article by Unnanuntana et al. [8], who found no increase in proximal femoral cortical thickness in patients receiving prolonged alendronate therapy. Given the contrast to earlier observations by Lenart et al. [6], we raise the question of whether the technique of assessing proximal femoral cortical thickness and cortical thickness ratio on dual-energy x-ray absorptiometry are comparable to that of measuring off plain radiographs as performed by Lenart et al. [6]. Further, in light of the current findings reported by Unnanuntana et al., should a generalized increase in cortical thickness of the femoral diaphysis still be included as a minor criterion for atypical fractures, as previously proposed by Shane et al. and a task force for the American Society for Bone and Mineral Research [7]? The issue of cortical thickness after alendronate treatment has been a somewhat confusing entity in the recent orthopaedic literature [1, 5, 6, 8]. One study had documented an increased mean percentage of cortical thickness after alendronate treatment for 1 to 2 years [1]. Initially thought to be a beneficial effect of osteoclastic suppression, cortical thickening began to be viewed as a double-edged sword when lateral thickening was observed in atypical femur fractures [5]. Generalized increased cortical thickness in the proximal femur was first observed by Lenart et al. [6] in femurs with atypical fractures. This led to the notion that alendronate therapy may cause changes in cortical thickness around the subtrochanteric region of the femur, which may in turn predispose to atypical fractures. The recent study by Unnanuntana et al. [8] seems to show the contrary—that long-term alendronate therapy does not lead to increased cortical thickness. This raises the question of whether the increased cortical thickness observed in some patients with atypical femoral fractures is coincidental or causative. It is possible these patients already have increased cortical thickness before commencing alendronate therapy or that susceptible individuals have increased cortical thickness develop in response to alendronate therapy. However, increased normalized cortical thickness per se may not be pathologic and is to be expected in young, healthy individuals. Since atypical fractures first caught the attention of the medical community owing to their occurrence in otherwise healthy, postmenopausal women [2], many of whom had no documentation of osteoporosis observed on bone mineral density measurements [3], the observed increase in cortical thickness could represent radiographic evidence of good bone stock. Further, it is uncertain whether the original technique described by Lenart et al. [6] for measuring cortical thickness just below the fracture line is an appropriate indicator of general cortical thickening or part of the distal periosteal reaction. This latter supposition is consistent with our observations of only localized thickening in the lateral cortex and not generalized thickening in atypical femoral fractures [4]. Atypical fractures reportedly cluster in regions subject to maximal tensile loading in the femur [4] and the CT/MRI of contralateral cortical thickening reported by Kwek et al. [5] in patients with atypical fractures showed a localized region of resorptive cavities and bone marrow invasion into these lesions associated with thinning of the overlying cortex. Therefore, cortical thickening associated with atypical fractures appears to be a local phenomenon, possibly representing callus formation in response to microfractures in regions subject to abnormal stress. Cortical thickening in atypical fractures requires a more precise definition and analysis. The observed general cortical thickening is open to further discussion and research. Localized cortical thickening, however, heralds bone remodeling in response to stress and should be treated with caution [3].

The Effect of Long-term Alendronate Treatment on Cortical Thickness of the Proximal Femur

One of the radiographic hallmarks in patients with atypical femoral insufficiency fractures after prolonged bisphosphonate treatment is generalized cortical hypertrophy. Whether cortical thickening in the proximal femur is caused by long-term alendronate therapy, however, remains unknown. We asked whether long-term alendronate use of 5 years or more results in progressive thickening of the subtrochanteric femoral cortices. We retrospectively evaluated changes in cortical thickness and cortical thickness ratio (ratio of cortical to femoral shaft diameter) at the subtrochanteric region of the proximal femur in baseline and latest hip dual-energy xray absorptiometry (DXA) scans of 131 patients. The mean followup was 7.3 years. Patients were divided into two groups: control (no history of alendronate, 45 patients) and alendronate (history of alendronate ≥ 5 years, 86 patients). We determined cortical thickness and cortical thickness ratio at 3.5 and 4.0 cm below the tip of the greater trochanter, representing the subtrochanteric region. After a minimum of 5 years followup, mean cortical thickness decreased approximately 3% in the alendronate and control groups. The cortical thickness at the subtrochanteric femoral region changed less than 1 mm in greater than 90% of the patients with long-term alendronate treatment. We observed no differences in mean changes of cortical thickness and percent changes of cortical thickness between the two groups. Long-term alendronate treatment did not appear to cause thickened femoral cortices within the detection limits of our method. This finding contrasts with the notion that long-term alendronate treatment leads to generalized cortical thickening.

Non-traumatic fracture of femur in healthy women after long-term alendronate treatment. A case report

Non-traumatic fracture of femur in healthy women after long-term alendronate treatment. A case report

Subtrochanteric and diaphyseal fractures in patients during long-term alendronate treatment: Expanded and extended national register based cohort study

Subtrochanteric and diaphyseal fractures in patients during long-term alendronate treatment: Expanded and extended national register based cohort study

The effects of high-dose, long-term alendronate treatment on microarchitecture and bone mineral density of compact and trabecular bone in the proximal femur of adult male rabbits

Despite the widespread use of bisphosphonates, its effects on normal bone microarchitecture of the proximal femur are still poorly studied. The purpose of this study was to determine the effects of long-term high-dose treatment of alendronate on microstructure and bone mineral density of cancellous, cortical compact and subchondral compact bone of the femoral head and neck region in normal adult male rabbits. Thirty-two adult, male rabbits were randomized into and were treated with either alendronate or placebo for 6 and 12 months. Micro-QCT measurements were taken in the (1) trabecular region, (2) cortical region of the femoral neck and (3) the subchondral region of the femoral head. In the trabecular region of the femoral head, alendronate treatment significantly increased vBMD at 6 and 12 months (+21.0%, p < 0.05 and +26.8%, p < 0.05, respectively) and BVF (29.6%, p < 0.05 and 35.6%, p < 0.05, respectively) with significantly altered bone microarchitecture when compared with their placebo group; 6- and 12-month alendronate treatment significantly increased the vBMD and thickness and decreased the porosity of the subchondral bone in the femoral head. High-dose alendronate treatment led to significant and differential changes in bone microarchitecture in trabecular, cortical and subchondral bone of the proximal femur of adult male rabbits.

Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis

The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1-34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone turnover initially due to previous alendronate (ALN) therapy. Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment. Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5 ± 16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end. Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11-0.34 cycles per year, 3.96-9.8% in the ALN-pretreated group and 0.19-0.33 cycles per year, 6.2-11.3% (p < 0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r = 0.57, p < 0.001 and r = 0.48, p < 0.01) and OS (r = 0.51, p < 0.01 and r = 0.56, p < 0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r = 0.52, p < 0.01) and OS (r = 0.54, p < 0.01) after 24 months. The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.

The Effect of Raloxifene after Discontinuation of Long-Term Alendronate Treatment of Postmenopausal Osteoporosis

The aim of this study was to compare bone mineral density (BMD) and biochemical markers of bone turnover in patients receiving long-term alendronate therapy who continued alendronate, were switched to raloxifene, or discontinued antiresorptive therapy. Ninety-nine ambulatory women who were diagnosed with postmenopausal osteoporosis and treated with alendronate (10 mg/d) for a mean period of 43 months were randomized to double-blind raloxifene (60 mg/d; n = 33), placebo (n = 33), or continuation of open-label alendronate (n = 33) for 12 months. Patients continued their assigned treatment in a subsequent 12-month, open-label extension phase. All patients received supplemental calcium (500 mg/d) and vitamin D (800 IU/d). BMD (lumbar spine, total femur, femoral neck, distal forearm, and total body) and biochemical markers (serum intact amino-terminal propeptide of type I procollagen, type 1 collagen cross-linked C-telopeptide, and osteocalcin) were measured at baseline and follow-up visits. Discontinuation of alendronate therapy resulted in a decrease in lumbar spine BMD at 12 months (-2.66%; P < 0.05), but did not change total femur BMD (+0.35%; nonsignificant). Raloxifene and alendronate, compared with discontinuation, prevented lumbar spine BMD loss (-0.75% and -0.54% at 12 months, respectively; P < 0.05). Raloxifene and alendronate caused a similar increase in total femur BMD at 12 months (1.45% and 1.56%; both P < 0.05 vs. baseline; nonsignificant vs. discontinuation). Patients, who discontinued alendronate therapy experienced an increase in bone turnover. Bone turnover increases were less pronounced in patients taking raloxifene and were absent in those who continued alendronate. Of the three groups, mean bone turnover in raloxifene patients was the closest to premenopausal mean values. BMD preservation and increase were most pronounced in patients continuing alendronate. Raloxifene treatment, compared with placebo, demonstrated beneficial effects on BMD and bone turnover after discontinuation of long-term alendronate therapy.

A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment

In patients with osteoporosis, alendronate treatment causes an increase in bone mineral density (BMD) and a decrease in fracture incidence. Alendronate acts by changing the bone remodeling process. Changes in bone remodeling resulting in decreased remodeling space, increased bone balance per remodeling cycle, and increased mineralization (ash mass/bone mass) have all been associated with alendronate treatment. Understanding the relative contributions of these parameters to BMD increases could help predict the utility of long-term (>10 years) or intermittent treatment strategies, as well as treatment strategies in which another pharmaceutical is administered concurrently. We have developed a computer simulation of bone remodeling to compare the contributions of focal bone balance and mineralization on BMD by simulating alendronate treatment using a bone balance method (decreased remodeling space, increased focal bone balance, uniform bone mineralization) and a mineralization method (decreased remodeling space, neutral focal bone balance, varying bone mineralization). Although both methods are able to predict BMD increases caused by alendronate over short periods, our findings suggest that the mineralization method may be more descriptive of long-term alendronate treatment. This implies that mineralization may be a larger contributor to BMD changes caused by alendronate than the focal bone balance. Based on this finding we offer a hypothesis to describe how remodeling space, focal bone balance, and mineralization each contribute to alendronate-induced BMD changes. Future analyses with this method could be used to identify improved dosing regimens and to predict which osteoporosis treatments would best complement each other.

Effects of long-term alendronate treatment on bone histomorphometry in postmenopausal osteoporosis

Effects of long-term alendronate treatment on bone histomorphometry in postmenopausal osteoporosis

Effects at the basic structure unit level of longterm alendronate treatment in post-menopausal osteoporosis

Effects at the basic structure unit level of longterm alendronate treatment in post-menopausal osteoporosis