Long-term Alendronate Therapy Research Articles

Comparative Fracture Risk During Osteoporosis Drug Holidays After Long-Term Risedronate Versus Alendronate Therapy : A Propensity Score-Matched Cohort Study.

An osteoporosis drug holiday is recommended for most patients after 3 to 5 years of therapy. Risedronate has a shorter half-life than alendronate, and thus the residual length of fracture protection may be shorter. To examine the comparative risks of drug holidays after long-term (≥3 years) risedronate versus alendronate therapy. Population-based, matched, cohort study. Province-wide health care administrative databases providing comprehensive coverage to Ontario residents aged 65 years or older between November 2000 and March 2020. Persons aged 66 years or older who had long-term risedronate therapy and a drug holiday were matched 1:1 on propensity score to those who had long-term alendronate therapy and a drug holiday. The primary outcome was hip fracture within 3 years after a 120-day ascertainment period. Secondary analyses included shorter follow-up and sex-specific estimates. Cox proportional hazards models were used to estimate hazard ratios (HRs) for fracture risk between groups. A total of 25077 propensity score-matched pairs were eligible (mean age, 81 years; 81% women). Hip fracture rates were higher among risedronate than alendronate drug holidays (12.4 and 10.6 events, respectively, per 1000 patient-years; HR, 1.18 [95% CI, 1.04 to 1.34]; 915 total hip fractures). The association was attenuated when any fracture was included as the outcome (HR, 1.07 [CI, 1.00 to 1.16]) and with shorter drug holidays (1 year: HR, 1.03 [CI, 0.85 to 1.24]; 2 years: HR, 1.14 [CI, 0.96 to 1.32]). Analyses were limited to health care administrative data (potential unmeasured confounding), and some secondary analyses contained few events. Drug holidays after long-term therapy with risedronate were associated with a small increase in risk for hip fracture compared with alendronate drug holidays. Future research should examine how best to mitigate this risk. Canadian Institutes of Health Research.

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.

Nontraumatic bilateral atypical femoral fractures associated with long-term alendronate therapy

Alendronate is a bisphosphonate commonly used in the treatment of post-menopausal and steroid-associated osteoporosis. Bisphosphonates have an evidence base for reducing the occurrence of typical osteoporotic fractures. However, there has been growing recognition of a correlation with the use of long-term therapy with bisphosphonates, and rare occurrence of atypical femoral fractures (AFFs). This report describes a 72-year-old caucasian woman presenting with evolving groin and thigh pains of two weeks duration. Plain X-rays noted features compatible with bilateral impending femoral subtrochanteric fractures. She had been taking oral alendronate 70mg weekly for ten consecutive years as treatment for osteoporosis. Based on the medication history, the absence of preceding trauma or a fall, and the presence of supportive radiological findings, the diagnosis was made of impending bilateral proximal femur fractures secondary to long-term bisphosphonate therapy. The alendronate was discontinued, and the patient managed with two planned successive surgeries involving the insertion of intertrochanteric antegrade nails (inter-TAN) to both femurs. Following a period of rehabilitation, she was successfully discharged home. Some pharmacokinetic and pharmacodynamic considerations of bisphosphonates are discussed. The write-up presents a brief literature review of AFFs. The index report is further reviewed in relation to the American society for bone and mineral research (ASBMR) task force’s recommended case definition of what constitutes AFFs. The discussion concludes with the application of two previously validated causality assessment systems (CAS). In this instance, both CAS indicated a ‘probable’ classification for the adverse drug reaction (ADR) to prolonged usage of oral alendronate.

Patients' reasons for adhering to long-term alendronate therapy.

Aim of this study was to investigate patients' reasons for adhering to long-term alendronate therapy (more than 5years), as data is not available in the current literature regarding the reasons behind long-term adherence. We studied 204 long-term adherent alendronate users: 65 postmenopausal outpatients still adherent (group C, years on treatment = 8.70 ± 1.31) were compared to 139 age-matched patients who discontinued therapy (group S, years on treatment = 8.64 ± 1.43). We evaluated main biochemical parameters, BMD values, fractures, and Charlson comorbidity index (CCI). A questionnaire was administered to analyze the reasons for long-term adherence. There were no significant differences between groups concerning baseline DXA values, number of fractures, and CCI. A higher education level was observed in group C (C 54% vs S 35% of patients, p = 0.001). At the time of interview, there was a significantly higher number of patients with a CCI of two in group S compared to the beginning of treatment (56% vs 43%, p = 0.04), together with a higher number of patients taking more than 3 drugs (22% vs 11%, p = 0.01) compared to basal evaluation. Forty-seven percent of patients reported new diseases during the treatment as the main reason for stopping alendronate. A multivariate, stepwise logistic regression analysis showed that awareness of the disease was highly associated with adherence (OR = 0.20; 95% CI 0.045-0.93, p = 0.04) followed by higher education (OR = 0.526, 95% CI 0.345-0.801, p = 0.003). Worsening of CCI was associated with discontinuation (OR = 2.75, 95% CI 1.033-7.324, p = 0.04). Education and disease awareness are associated with long-term alendronate adherence while competing health problems negatively impact adherence.

The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects.

BackgroundAlthough bisphosphonate-related osteonecrosis of the jaw (ONJ) develops mainly after tooth extractions (TEs), the strength of the association between them and how the existence of the disease among bisphosphonate (BP)-treated osteoporotic patients exposed to TE remain uncertain.MethodsA nationwide retrospective cohort study investigated the influence of alendronate and TE on the development of ONJ.ResultsIncidence of ONJ following long-term alendronate therapy was 262/100,000 person-years, while no event developed in the control group on raloxifene. Overall prevalence of ONJ in osteoporotic subjects receiving alendronate was estimated at 0.34% which rose to 2.16% after TE. Multiple logistic regression analysis, adjusted for the potential confounders, showed TE (adjusted odds ratio, 9.60 [4.33–21.29]), drug duration exceeding 3 years (3.00 [1.33–6.76]), and concomitant rheumatoid arthritis (4.94 [1.64–14.90]) were independent predictors of ONJ.ConclusionsThis article strengthens the relationship between ONJ and BPs. Among osteoporotic patients exposed to alendronate, TE confers a 9.6-fold increased risk for ONJ and it should be performed with caution irrespective of drug duration.

Does Long-Term Alendronate Therapy May Lead to Atypical Femoral Fracture near the Hip Prosthesis?

Osteoporotic fractures are a major public health problem, affecting millions of people worldwide, with oral bisphosphonates favored for their prevention and treatment. Bisphosphonate is a potent inhibitor of osteoclast-mediated bone resorption and is widely used as first-line therapy for the prevention of osteoporotic fractures. It acts by suppressing osteoclastic activity and inducing apoptosis of the osteoclasts.

Bilateral Simultaneous Femoral Fragility Fractures after Long-term Alendronate Therapy

Bilateral Simultaneous Femoral Fragility Fractures after Long-term Alendronate Therapy

Atypical periprosthetic acetabular fracture in long-term alendronate therapy.

Bisphosphonates have been commonly used in the treatment of osteoporosis, demonstrating its efficacy in fracture risk reduction. However, even if are generally safe and well tolerated, concerns have emerged about atypical fractures related to its prolonged use. Although atypical femoral fracture are more common, case reports demonstrated that even other skeletal areas can be involved by unusual pattern of fracture. We report a atypical acetabular periprosthetic fracture in a 83-year-old female patient after prolonged alendronate treatment for osteoporosis and isolated acetabular revision surgery. The patient underwent to clinical, bioumoral and radiological evaluation and all the history cases were fully reported. We believe this periprosthetic fracture, according to the available data, may have similar underlying pathology to atypical femoral fractures. Awareness of symptoms, in addition to a regular radiographic survey may facilitate early diagnosis and possible prevention of spontaneous periprosthetic fractures, in patients receiving bisphosphonate therapy beyond 5 years. The treatment of this atypical periprosthetic fracture should include both surgical than pharmacological therapy to obtained bone healing.

Bilateral Simultaneous Femoral Fragility Fractures after Long - Term Alendronate Therapy

Yalcin Turhan Department of Orthopaedics and Traumatology, School of Medicine, Duzce University, Duzce, Turkey. e-mail: yturhan_2000@yahoo.com INTRODUCTION Osteoporosis is a major public health problem with a significant economic burden on the society (1–4). The main clinical manifestations of osteoporosis are low-energy fractures of the proximal femur, vertebrae, and distal radius. Nearly two million osteoporotic fractures occur annually in the United States at an estimated cost of more than $17 billion (5,6). Subtrochanteric and diaphyseal areas are considered to be the strongest parts of femur subjected to the highest stresses of the body (7). The strongest bone of the body, femur diaphysis, is an unusual site for fracture due to minor trauma, and raises significant suspicion regarding the pathogenesis of the fracture. In recent years, some cases of subtrochanteric and diaphyseal fractures due to minor trauma have been reported in association with long-term alendronate therapy (8-10). This pattern of fracture is defined as alendronate-induced atypical fracture. This study presents a case of bilateral femoral insufficiency fracture in a woman receiving long-term alendronate therapy.

Effect of Long-Term Use of Bisphosphonates on Forearm Bone: Atypical Ulna Fractures in Elderly Woman with Osteoporosis.

Osteoporosis is a common musculoskeletal disease of the elderly population characterized by decreased bone mineral density and subsequent fractures. Bisphosphonates are a widely accepted drug therapy which act through inhibition of bone resorption and prevent fractures. However, in long-term use, atypical bisphosphonate induced fractures may occur, particularly involving the lower weight bearing extremity. Atypical ulna fracture associated with long-term bisphosphonate use is rarely reported in current literature. We present a 62-year-old woman with atypical ulna due to long-term alendronate therapy without a history of trauma or fall. Clinicians should be aware of stress fracture in a patient who has complaints of upper extremity pain and history of long-term bisphosphonate therapy.

Teriparatide for the rapid resolution of delayed healing of atypical fractures associated with long-term bisphosphonate use.

Bisphosphonates (BPs) are the most widely used drugs to treat osteoporosis. However, recent reports associated to long-term BPs use with atypical low-impact fractures and prodromal pain. It is estimated that 26% of the cases of atypical fractures associated with the long-term use of BPs show delayed healing or nonunion. Teriparatide [PTH1-34] (TPTD) is an anabolic drug shown to be effective in stimulating bone formation. The aim was to describe the course of a right diaphyseal femoral fracture sustained by a patient on long-term BPs treatment. A 57-year-old postmenopausal Caucasian female presented with delayed healing of a right femoral diaphyseal fracture 10 months after the fracture, despite having received orthopedic treatment. The fracture was preceded by progressive, severe, and bilateral thigh pain. Her medical history included osteopenia that was treated with alendronate over 7 years. On presentation at our clinic, the patient ambulated with the aid of a walking cane. The diagnosis was an atypical right femoral fracture associated with long-term alendronate use. The levels of the following parameters were measured: mineral metabolism laboratory: intact parathormone, 40 ng/mL (reference values (rv): 10-65 ng/mL); 25-hydroxyvitamin D, 40 ng/mL (rv: >30 ng/mL); serum Crosslaps, 318 ng/mL (rv: 80-590 ng/mL); and bone-specific alkaline phosphatase, 76UI/L (rv: 31-95UI/L)]. Magnetic resonance imaging of the left femur was performed, which revealed a diaphyseal stress fracture. She was prescribed 20 μg/day of subcutaneous (s.c.) TPTD (PTH1-34, Forteo; Eli Lilly Co., Indianapolis, IN, United States). A computed tomography scan performed 3 months later showed that the fracture had healed; the patient was able to resume her usual activities. Twenty micrograms per day of s.c. TPD accelerated the healing of the atypical fracture associated with long-term alendronate therapy, allowing a fast recovery of ambulation and quality of life.

An Atypical Femoral Fracture in a Patient on Long-term Alendronate Therapy

Background: Biphosphonates, especially alendronate, are used extensively and successfully for the treatment of osteoporosis. However, there are numerous recent studies that indicate low-energy subt...

Do atypical femoral fractures in patients with prolonged alendronate treatment heal?

Osteoporosis, which is a major health problem, may have an adverse impact on the economic status of the society and the quality of the life of the patients. Long-term alendronate use may cause an increased susceptibility to fractures with an increased risk of delayed union. In this article, we describe two patients on long-term alendronate therapy which were treated for atypical femoral fractures healed with surgical treatment plus calcium, vitamin D support, and alendronate discontinuation.

Low-energy femoral shaft fractures after long-term alendronate therapy: report of seven cases

There is increasing evidence suggesting a high incidence of low-energy fractures of the diaphysis or the proximal femur in patients receiving bisphosphonates for a long time. Bisphosphonate-related femoral fractures occur after low-energy trauma and have a typical simple transverse or oblique radiographic pattern, with focal or generalized increased cortical thickness, cortical beaking, and medial spiking. This article presents six female patients who experienced seven transverse femoral diaphysis and subtrochanteric fractures with cortical thickening and beaking; all patients had alendronate treatment for 4-10 years (average, 9 years) before their fracture. The typical radiographic findings, long-term administration of alendronate, low-energy mechanism of fracture, and related literature support the fact that the fractures in the patients presented in this series should be related to alendronate treatment. Until definite evidence is available, alendronate treatment in patients with osteoporosis is not now prohibited by the healthcare authorities, probably because its beneficial influence outweighs the adverse effects. However, this adverse effect deserves attention of medical practitioners; physicians should be alert on alendronate's possible suppressive effect on bone turnover, which in turn may be responsible for the occurrence of femoral fractures.

Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment

Cortical bone, the dominant component of the human skeleton by volume, plays a key role in protecting bones from fracture. We analyzed the cortical bone effects of teriparatide treatment in postmenopausal women with osteoporosis who had previously received long-term alendronate (ALN) therapy or were treatment naïve (TN). Tetracycline-labeled paired iliac crest biopsies obtained from 29 ALN-pretreated and 16 TN women were evaluated for dynamic histomorphometric parameters of bone formation at the periosteal, endocortical and intracortical bone compartments, before and after 24months of teriparatide treatment. At baseline, the frequency of specimens without any endocortical and periosteal tetracycline labeling, and the percentage of quiescent osteons, was higher in the ALN than the TN group. Endocortical and periosteal mineralizing surface (MS/BS%), periosteal bone formation rate (BFR/BS), mineral apposition rate (MAR) and the number of intracortical forming osteons were significantly lower in the ALN-pretreated patients than in the TN group. Following teriparatide treatment, the frequency of endocortical and periosteal unlabeled biopsies decreased; in the ALN-pretreated group the percentage of quiescent osteons decreased and, in contrast, forming and resorbing osteons were increased. Teriparatide treatment resulted in significant increases of MAR in the endocortical, and MS/BS% in the periosteal compartment in the ALN-pretreated group. Most indices of bone formation remained lower in the ALN-pretreated group compared with the TN group at study end. Endocortical wall width was increased in both ALN-pretreated and TN groups. Cortical porosity and cortical thickness were significantly increased in the ALN-pretreated group after teriparatide treatment. Our results suggest that 24months of teriparatide treatment increases cortical bone formation and cortical turnover in patients who were either TN or had previous ALN therapy.

Atypical femoral fractures bilaterally in a patient receiving denosumab

We present a case of bilateral low-energy femoral shaft fractures over a 1-year period in a woman after discontinuation of long-term alendronate therapy and initiation of treatment with denosumab. A 73-year-old woman with diabetes mellitus and an 8-year history of post-menopausal osteoporosis presented to the emergency department in June 2011 with a spontaneous left femur fracture. It was 3 weeks after the discontinuation of an 8-year therapy with vitamin D supplement and 70 mg alendronate weekly, and 1 week after the first subcutaneous injection of denosumab. Radiographs revealed a transverse femoral shaft fracture with lateral cortical hypertrophy and medial spiking (Figure 1). Figure 1. The patient’s left femur at the time of the first fracture. A transverse femoral shaft fracture with lateral cortical hypertrophy and medial spiking. The fracture was stabilized with a cephalomedullary nail. Routine blood investigations were within normal range and myeloma was excluded. Bone densitometry revealed an increase in bone density relative to baseline values before the initiation of alendronate therapy, but the T-score of at least 1 site was still in the osteoporotic range (femoral neck T-score: –2.95). 5 months postoperatively, the fracture had healed with callus formation. 1 year after the first fracture, the patient sustained a similar atypical fracture of the right femoral shaft (Figure 2) and she described mild, diffuse pain in the thigh during the previous 6–7 months. She was still on treatment with denosumab 12 months after the first injection (she had received 3 injections of denosumab at 6-month intervals). This fracture was also stabilized with a cephalomedullary nail and a pathological fracture was excluded. Figure 2. Both femurs at the time of the right femoral shaft fracture. This fracture also healed in 5 months with callus formation (Figure 3). In view of reports linking this pattern of femoral shaft fractures to long-term alendronate therapy (Neviaser et al. 2008) and considering the anti-resorptive mechanism of action of the denosumab, treatment with teriparatide (20 µg subcutaneously once a day) and vitamin D was commenced and denosumab was stopped. Figure 3. Anteroposterior radiograph of both femurs 5 months after the second operation, showing healing of the fracture with callus formation.

Femoral Shaft Cortical Pathology associated with longterm Alendronate Therapy: A New Classification.

There are reported cases of cortical reaction over the tension side of the normal femoral shafts in patients on long term treatment with alendronate, leading to subsequent femoral shaft fractures. We performed a retrospective review of patients with low-energy femoral shaft fracture on alendronate, admitted to our institution during the period 2004 to May 2009. The presence of radiological changes of cortical hypertrophy with or without Looser's zone over the tension side of the femoral bone (normal limb) was determined and correlated with clinical symptoms. Thirteen patients were identified. Average duration of alendronate use was 6.5 ± 3.3 years (ranges, two to 10 years). These radiological changes were noted in four patients. Average duration of alendronate usage in these four patients was 6.5 ± 2.4 years (ranges, 5 to10 years). Prodromal thigh pain was present in a patient, who had cortical hypertrophy with the presence of a Looser's zone traversing the cortex on the femoral shaft. One patient had Looser's zone limited at the lateral hypertrophied cortex without prodromal pain. The interobserver kappa coefficient was 0.96. A femoral radiograph should be performed in all patients who are on long-term alendronate therapy who present with thigh pain. We propose a new grading system based on our observation of the radiological features in these four cases. This new grading of the radiological spectrum of femoral shaft cortical pathology has the potential to stratify the risk of low energy femoral fracture for patients treated with long-term alendronate therapy. Femur, Cortical Hypertrophy, Looser Zone, Alendronate.

Spontaneous subtrochanteric femoral stress fracture related to alendronate : a case report.

Spontaneous atypical fractures of the femur have been reported in patients on long-term antiresorptive bisphosphonate therapy. Here, we report a case of subtrochanteric stress fracture in a seventy-year-old female patient on long-term alendronate therapy, and accompanying management challenges. Potential measures to prevent this complication of antiresorptive treatment for osteoporosis include the following: setting strict criteria for prescribing antiresorptive therapy, limiting the duration of continuous antiresorptive therapy, and increasing the use of bone anabolic agents. atypical femoral fractures, alendronate, osteoporosis.

Discontinuation of alendronate and administration of bone-forming agents after surgical nailing may promote union of atypical femoral fractures in patients on long-term alendronate therapy

BackgroundLong-term alendronate therapy may lead to atypical femoral fractures in a very few patients. However, the management protocol to optimize fracture healing remains undetermined. The purpose of this study was to describe the time to union of atypical femoral fractures after surgical nailing in patients on long-term alendronate therapy, with continuation of alendronate or discontinuation of alendronate, and administration of bone-forming agents.FindingsFrom January 2004 to December 2011, the records of patients at our institution on long-term alendronate therapy for more than 36 months and sustaining atypical femoral fractures that had undergone surgical nailing, with continuation of alendronate or discontinuation of alendronate and administration of bone-forming agents were reviewed.During the 8-year study period, we treated 10 atypical femoral fractures with surgical nailing in 7 consecutive osteopenic or osteoporotic patients on long-term alendronate therapy for more than 36 months. There were no post-operative complications or needs for revision surgery. All fractures achieved union during follow-up. Mean union time was 23.5 months (range, 18–31 months) for 6 fractures with continuation of alendronate after surgery, and 4.5 months (range, 4–5 months) for 4 fractures with discontinuation of alendronate and administration of bone-forming agents after surgery.ConclusionsDiscontinuation of alendronate and administration of bone-forming agents after surgical nailing may promote union of atypical femoral fractures in patients on long-term alendronate therapy.

Alendronate-Associated Ulnar and Tibial Fractures: A Case Report

Bisphosphonates are widely used to prevent osteoporotic fractures. Long-term use has resulted in unexpected subtrochanteric fractures in some elderly patients. We report a patient on long-term alendronate therapy who sustained fractures of the ulna and tibia sequentially over a 7-month period, without any trauma or fall.