Bisphosphonates are the most commonly prescribed type of medication for the treatment of osteoporosis. Studies have shown that bisphosphonates reduce the incidence of vertebral and nonvertebral fractures when used to treat postmenopausal osteoporosis1-4. The indications for use of bisphosphonates also extend to other metabolic bone diseases such as glucocorticoid-induced osteoporosis, Paget disease, hypercalcemia due to a variety of causes, and skeletal metastases5-7. Treatment with bisphosphonates, however, is not without adverse effects. Because bisphosphonates act by inhibiting osteoclast function and inducing osteoclast apoptosis8,9, there is a substantial concern regarding the potential side effects related to severe suppression of the bone turnover rate.
Several case reports and case series have indicated an association between a unique fracture type, so-called “atypical femoral fractures,” and prolonged bisphosphonate use10-14. These fractures differ from typical osteoporotic femoral fractures in many respects, including the mechanism of injury, location, and fracture configuration. Although the American Society for Bone and Mineral Research (ASBMR) published a task force report on atypical femoral fractures in 201015, little information about this type of fracture is known. The present report will critically review current evidence on the characteristics, epidemiology, pathogenesis, and treatment outcomes of atypical femoral fractures to identify gaps in knowledge calling for future research and to provide guidance for orthopaedic surgeons.
Many case reports and case reviews have described several common radiographic features of atypical femoral fractures associated with bisphosphonate use, including a transverse, noncomminuted fracture at the subtrochanteric or femoral shaft region with a medial cortical spike at the fracture area (Fig. 1). Other features include prodromal pain and generalized thickening of the femoral cortices on radiographs13,14,16,17. Because of the lack of clear criteria to define atypical femoral fractures, the ASBMR task force established major and minor features for both complete and incomplete atypical fractures of the femur15 (Table I). All of the major features should be present to designate a fracture as atypical and distinguish it from more common osteoporotic hip fractures (Fig. 2). The minor features have also been described in association with atypical femoral fractures, but they are not required for diagnosis.
Although the ASBMR criteria are useful for defining atypical femoral fractures and allowing consistent diagnosis across studies, some features remain controversial. For instance, generalized cortical thickening (one of the minor radiographic features) is believed to result from an impaired ability of bone to remodel because of prolonged bisphosphonate use, leading to an accumulation of microdamage and compromised bone strength17-19. However, a recent study by our group found that prolonged alendronate treatment (≥5 years) did not cause thickened femoral cortices20. This result suggested that femoral cortices in patients who have undergone long-term bisphosphonate treatment may have already been thick prior to the initiation of bisphosphonate treatment. Another recent study by Feldstein et al. found that individuals with atypical femoral fractures who exhibited only the major radiographic features tended to be older and thinner than those who exhibited both major and minor criteria. In addition, the incidence of atypical femoral fractures exhibiting only the major radiographic features appeared relatively constant over the study period (cumulative incidence, 5.9 per 100,000 person-years) while the proportion of atypical femoral fractures with both major and minor features increased over time21. Thus, it may be more accurate to diagnose atypical femoral fractures only in patients who exhibit both major and minor features. Nevertheless, that study and ours support the need for a more precise measure to define atypical femoral fractures. As the pathogenesis and clinical presentation of such fractures become better elucidated, future refinement of the current ASBMR criteria for atypical femoral fractures will be necessary.
Over twenty-five case reports and series related to atypical femoral fractures, as well as a number of controlled studies and several larger studies using national registries and Phase-III trial data, have been published15,22,23. In this section we will consider the incidence of atypical femoral fractures; their relationship to bisphosphonate use is discussed later in this article.
All current evidence indicates that atypical femoral fractures represent a rare subset of subtrochanteric and femoral shaft fractures. The average incidence of subtrochanteric and femoral shaft fractures, ranging from twenty to thirty per 100,000 person-years in the United States24,25, represents the upper bound for an estimate of the incidence of atypical femoral fractures. In a Finnish registry, femoral shaft fractures had an incidence of 2.5 to 9.9 per 100,000 person-years, but 75% occurred with high-energy trauma26 and the majority were comminuted and had a spiral configuration26,27. Thus, the actual incidence of atypical femoral fractures is expected to be considerably less than the total incidence of subtrochanteric and femoral shaft fractures. In the osteoporotic population, subtrochanteric and femoral shaft fractures account for 3% and 5% of femoral fractures, respectively24,28.
Atypical femoral fractures have been associated with various factors, including Asian descent, bilateral fractures, prodromal pain, the use of glucocorticoids and proton pump inhibitors, and delayed fracture-healing (Table II). Other factors that have been reported to be associated with such fractures include the presence of rheumatoid arthritis or diabetes mellitus as well as vitamin-D3 deficiencies15. However, Lo et al. showed that women with atypical femoral fractures were less likely to have diabetes and chronic kidney disease29. Giusti et al. found that cortical thickness was comparable between patients with and without atypical fractures, and they also found an association between atypical femoral fractures and a history of glucocorticoids use30.
Incidence estimates made on the basis of reviews of radiographs have ranged from 0.9 to seventy-eight atypical femoral fractures per 100,000 person-years15,21,30-32. The ASBMR task force reported an incidence of two per 100,000 cases per year after two years of bisphosphonate use, increasing to seventy-eight per 100,000 cases per year after eight years of use (n = 15,000)15. A review of radiographs by Girgis and Seibel indicated an incidence of 2.3 to sixteen atypical femoral fractures per 100,000 person-years, with a higher incidence in patients who were sixty-five years or older (n = 174,448)31. As described above, a review of radiographs by Feldstein et al. found that fractures characterized by the presence of only the ASBMR major criteria occurred at a rate of 5.9 per 100,000 person-years (n = 5034), and the number of such atypical fractures was stable over the study period despite an increase in the use of bisphosphonates21. A review of radiographs of 906 femoral fractures by Giusti et al. found ten atypical fractures that also met some of the minor criteria, accounting for 1.1% of all of the femoral fractures and 10.4% of the subtrochanteric and femoral shaft fractures30. A review of radiographs by Schilcher et al. found an incidence of fifty-five atypical fractures per 100,000 person-years among bisphosphonate users compared with 0.9 per 100,000 person-years among those with no bisphosphonate use (age-adjusted relative risk = 47.3; 95% confidence interval [CI], 25.6 to 87.3) (n = 12,777)32.
Discordant results have also been published. In a matched control analysis within a cross-sectional study of 11,944 patients, the hazard ratio (HR) for subtrochanteric fractures in alendronate-exposed patients (HR = 1.46; 95% CI, 0.91 to 2.35) was similar to the hazard ratio for proximal femoral fractures (HR = 1.45; 95% CI, 1.21 to 1.74)33. A similar study using Danish national health care data on 39,567 alendronate users and 158,268 untreated controls, however, found subtrochanteric and diaphyseal fracture rates of thirteen per 10,000 person-years in untreated women and thirty-one per 10,000 person-years in women receiving alendronate (HR = 1.88; 95% CI, 1.62 to 2.17)34. A post hoc analysis of data from three randomized trials of bisphosphonates for postmenopausal osteoporosis identified twelve subtrochanteric or diaphyseal femoral fractures in ten of the 14,195 study participants35, yielding a rate of twenty-three per 100,000 person-years. The relative hazard for subtrochanteric or diaphyseal fracture in the intervention group compared with the control subjects was not significant in any trial, indicating no association between bisphosphonate use and subtrochanteric or diaphyseal fracture even among women who were treated for as long as ten years35. These studies, however, were limited by the unavailability of radiographs for review, leaving the atypical nature of fractures unconfirmed, and most patients had an exposure of less than four years. The statistical power of the study was also low, with a reduced chance of detecting rare events such as atypical fractures.
Atypical femoral fractures, although rare, are important to consider in patients who present with thigh pain. Case reports provided the first evidence of such fractures but had limitations of historical bias, varying definitions of the fracture type, and inability to directly compare the risk of these fractures according to bisphosphonate use. In addition, administrative data and register-based studies do not capture all atypical fractures, as they rely on identification by diagnostic codes that may misclassify fracture location, and they do not assess the radiographic hallmarks of atypia15. In various studies, 2.3% to 34% of atypical femoral fractures were misidentified on the basis of International Classification of Diseases, Ninth Revision (ICD-9) codes21,24,30.
An association between bisphosphonate use and the occurrence of atypical femoral fractures has been suggested10. According to a task force report from the ASBMR, this relationship has not yet been shown to be causal15. Pharmacoepidemiologic studies involving the monitoring of, detection of, evaluation of, and response to adverse drug events have used the Bradford-Hill criteria. These criteria provide a better perspective on the lines of evidence in a given drug-disease association, thus helping to determine whether an apparent association between a medicine and an effect is likely to represent a causal relationship36 (Table III).
The first criterion, the strength of the association, refers to the extent to which the risk of the disease is greater than that resulting from chance alone37,38. Bisphosphonates substantially increase the risk of atypical femoral fracture (with estimates of the odds ratio ranging from 2.29 to 139.33)13,21,32,39. Almost 40% of patients who sustained a subtrochanteric or femoral shaft fracture had used bisphosphonates for a significantly longer period of time than subjects who sustained an intertrochanteric or femoral neck fracture (odds ratio = 4.44, p = 0.002)14. Despite these results, reanalysis of the data in three major randomized controlled trials showed no statistically significant increase in the risk of subtrochanteric femoral fracture in patients treated with bisphosphonates for as long as ten years35. Given the mixture of results and the different methodologies used in these studies, it is difficult to demonstrate consistency of this association. Furthermore, not all fractures located in the femoral subtrochanteric or diaphyseal region of patients taking bisphosphonates are atypical. Only 17% to 29% of subtrochanteric or diaphyseal fractures can be classified as atypical fractures15. Additionally, some atypical femoral fractures occur in patients who have not taken bisphosphonates34,40. Therefore, there is a lack of specificity for associating bisphosphonate use with atypical femoral fractures.
Studies have shown an increased risk of atypical femoral fractures in patients taking bisphosphonates for five or more years, suggesting a dose-response relationship13,14,39. Despite this, an analysis of patients with skeletal malignant involvement who received a minimum of twenty-four doses of intravenous bisphosphonates revealed no difference in the dosage or the duration of therapy between those who sustained atypical femoral fractures and those who did not41. The authors of the study cite the lack of long-term follow-up as a limitation of their study and their ability to draw conclusions about the long-term effects of bisphosphonate usage41. Thus, there is no dose-response relationship on the basis of higher bisphosphonate dosage; however, there appears to be a dose-response relationship on the basis of the cumulative dose over time, which can be explained by the fact that bisphosphonates bind to bone for many years42.
The cause-effect relationship between bisphosphonate use and atypical femoral fractures is plausible given the hypothesized pathologic mechanisms involving bisphosphonate-induced microdamage accumulation, decreased spatial variation in the bone mineral density distribution, and decreased bone heterogeneity43-46. In addition, the potential for a causal relationship between bisphosphonate use and the risk of atypical femoral fractures is supported by analogous examples of drug-enhanced fracture risk, including effects in patients taking corticosteroids, antiepileptic drugs, and antidepressants47,48. Nevertheless, there is a dearth of experimental evidence that supports the causation of atypical femoral fractures in patients on bisphosphonate therapy, and many of the studies are observational. On the basis of the currently available data, a mechanistic cause-and-effect relationship between bisphosphonate usage and atypical femoral fractures has not been established.
Various pathogenic mechanisms that could explain the relationship between prolonged bisphosphonate therapy and atypical femoral fractures have been the subject of extensive research. Prolonged bisphosphonate treatment may be responsible for deleterious effects on bone quality by inhibiting bone remodeling at the cellular level. Although increased bone remodeling predisposes to bone fragility, overly suppressed bone remodeling can also lead to microdamage accumulation and impaired stress-fracture-healing, a reduction in matrix heterogeneity, and an increase in advanced glycation end-products (Fig. 3).
Microdamage Accumulation and Impaired Stress-Fracture-Healing
Bisphosphonates reduce the risk of fractures by suppressing osteoclast-mediated bone resorption, thereby interrupting the normally coupled resorption-formation process of bone remodeling. Since bone remodeling is essential for continuous bone renewal and repair of microdamage, severe suppression of bone remodeling can lead to microdamage accumulation49,50. It should be noted, however, that microdamage accumulation alone does not explain the decline in bone toughness, as minimal association between changes in microdamage accumulation and bone toughness was found in preclinical studies51,52.
Studies on stress fractures induced in the rat ulna showed that bisphosphonates impair stress-fracture-healing by reducing the volume of bone resorbed and replaced during the remodeling process53,54. Several clinical reports also showed that a periosteal stress reaction and a transverse radiolucent line indicative of stress fracture usually preceded the complete atypical fracture in patients taking bisphosphonates, indicating a possible role for bisphosphonates in impaired stress-fracture-healing55-57 (Fig. 4).
Reduced Heterogeneity of Organic Matrix and Mineral Properties
Bone maintains its compositional heterogeneity through the continuing process of bone remodeling. Heterogeneity of bone matrix and mineral density is preferable to homogeneity. Computational models of trabecular and cortical bone showed that a heterogeneous tissue distribution reduces local stress and enhances energy dissipation58,59, whereas a homogeneous distribution is associated with greater propensity for crack formation and propagation, thereby increasing the risk of fracture60. By inhibiting the process of bone remodeling, bisphosphonates lead to a less heterogeneous structure with narrowed distributions of mineral and collagen properties45,61,62. Boskey et al. found that treatment with alendronate for three years increased tissue mineral content and decreased the spatial heterogeneity of mineral properties of iliac crest tissue in healthy postmenopausal women without fractures61. In addition, Donnelly et al. used Fourier transform infrared (FTIR) imaging to compare the mineral and collagen properties of corticocancellous bone biopsies from forty patients diagnosed with proximal femoral fractures62. The authors found that FTIR-measured parameters in the twenty bisphosphonate-treated patients were similar to those in the twenty patients who had not received bisphosphonate treatment. However, the distributions of collagen maturity and crystal perfection were narrowed by 28% and 17%, respectively, in the bisphosphonate-treated patients compared with those without a history of bisphosphonate therapy (Fig. 5).
Increased Advanced Glycation End-Products
Collagen in the extracellular bone matrix contains both enzymatic and nonenzymatic crosslinks63. Enzymatic crosslinks, mediated by the actions of lysyl and prolyl hydroxylases, have a substantial impact on bone mechanical properties and are essential to stabilize the bone matrix. Nonenzymatic crosslinks are formed through the interaction of collagen and sugars in a series of glycation and oxidation reactions, leading to the formation of advanced glycation end-products64,65. Bisphosphonate treatment increased advanced glycation end-products in the ribs of dogs66, and such an increase has been associated in animals with deleterious effects on bone mechanical properties, including a lower threshold of energy to fracture67.
The bulk of evidence on the pathogenesis of these atypical fractures stems from animal models, with few studies of human bone. Furthermore, multiple biomechanical considerations and patient risk factors may play a role in the pathogenesis of these fractures. The subtrochanteric region of the femur is subjected to the greatest tensile loading68. It is possible that Asian populations have a higher risk of developing these fractures because of their greater femoral bowing29,69. Patients with atypical fractures may also have a preexisting defect in bone quality that is exacerbated by bisphosphonate use. Therefore, an atypical femoral fracture should be considered pathologic, and further work-up is warranted to identify an underlying skeletal abnormality.
The management of atypical femoral fractures requires a specific protocol that includes both medical and surgical treatment. Because we are aware of no prospective controlled studies evaluating treatment protocols in patients with atypical femoral fractures, the guidelines proposed in this article are based on the recommendations outlined by the ASBMR task force and several recently published case series.
Management of Patients with Atypical Femoral Fractures
Management of patients with atypical femoral fractures includes fracture fixation and initiation of medical management (Table IV). Once a patient is diagnosed with an atypical femoral fracture, bisphosphonates must be discontinued. In a large observational study including a total of 126 patients with atypical femoral fractures, the incidence of bilateral atypical femoral fractures was 41.2% in patients who continued bisphosphonates for three or more years after the index atypical femoral fracture compared with 19.3% in patients who continued bisphosphonates for less than three years after the index atypical femoral fracture70. The risk of a contralateral atypical femoral fracture decreased by approximately 53% (p = 0.042) if bisphosphonates were discontinued after the index atypical femoral fracture70.
In addition, all patients should receive daily calcium and vitamin-D supplementation. Recommendations for optimal treatment include a daily calcium intake of 1000 to 1200 mg/day71. Although current recommendations from the Institute of Medicine state that 400 to 800 IU/day of vitamin D3 is adequate71, many experts and studies have shown these recommendations to be insufficient72-74. The minimum adult intake of vitamin D3 should be 1000 to 2000 IU/day75. Recombinant parathyroid hormone (teriparatide) should also be considered, especially as there is evidence to suggest that teriparatide improves bone turnover and microarchitecture in patients on long-term alendronate treatment76,77. Furthermore, teriparatide enhances and accelerates fracture-healing by increasing callus formation and mechanical strength78-82. Additional clinical trials also showed that teriparatide shortened the time to healing in patients with osteoporotic fractures83,84. Therefore, teriparatide may be beneficial to enhance fracture-healing in patients with atypical femoral fractures.
Although there are no randomized controlled trials comparing a plate-and-screw construct and intramedullary nail fixation for the treatment of atypical femoral fractures, most orthopaedic surgeons recommend an intramedullary full-length reconstruction nail as the preferred method of treatment. A fracture treated by intramedullary nailing heals by endochondral repair, whereas a plate-and-screw construct generally precludes the endochondral repair process and is not recommended for these fractures. The outcome of surgical treatment in patients with bisphosphonate-related atypical femoral fractures is poor (Fig. 6). Weil et al. showed that seven (44%) of sixteen fractures treated with intramedullary nail fixation required secondary operative procedures85. Although some studies suggested a potential negative effect of bisphosphonates on the fracture-healing process, current evidence shows conflicting results17,57,86,87. Visekruna et al. reported on three patients with atypical subtrochanteric fractures, one of whom had no radiographic evidence of union at twenty-two months17. Conversely, Ha et al. reported that ten atypical femoral fractures all healed, with osseous union after internal fixation during the follow-up period of twelve to sixty months57. These differing results may be due to differences in preoperative status and in the medication type or dose used in these patients.
We recommend careful surveillance of patients with atypical femoral fractures because 28% to 44.2% of patients with atypical femoral fractures have bilateral involvement15,22,29. Radiographs of the contralateral femur must be evaluated for evidence of a stress fracture. Technetium bone scintigraphy or magnetic resonance imaging (MRI) should be considered if a stress fracture is suspected (Fig. 7).
If the patient has an incomplete fracture with no or minimal pain, a period of conservative therapy may be considered. This includes partial weight-bearing with use of a cane, crutches, or walker; avoidance of strenuous activity; and the use of teriparatide. The failure rate of this conservative treatment, however, is high56,57. Banffy et al. reviewed patients with nondisplaced stress fractures that were initially treated nonoperatively. Five of six patients had progression of the lesion to complete fracture at a mean of ten months56. Thus, close monitoring is necessary in this particular group of patients. Prophylactic intramedullary nail fixation should be considered when there is moderate to severe pain in the affected limb, persistent or worsening pain after a period of conservative treatment, or progression of the fracture line observed on serial radiographs57 (Fig. 8).
Management of Patients with Prolonged Bisphosphonate Therapy
Once administered, bisphosphonates accumulate in the bone and continue to be released for months or years after treatment is discontinued. Data from the Fracture Intervention Trial Long-term Extension (FLEX) study showed that the fracture risk in postmenopausal women who discontinued alendronate after five years of treatment was not higher than in those who continued alendronate for a total of ten years, despite a moderate decline in bone mineral density at both the spine and femoral neck and a rise in bone markers in the former1. For risedronate, the extension of the Vertebral Efficacy with Risedronate Therapy (VERT)-North America study showed that one year after discontinuation of a three-year protocol of risedronate treatment, bone mineral density decreased (but remained higher than baseline and higher than in the former placebo subjects) and bone turnover markers increased (to levels no different from those in the former placebo subjects). Despite these changes, the incidence of new morphometric vertebral fractures was 46% lower in the former risedronate group compared with the former placebo group88. This information supports the hypothesis that there is continued release of bisphosphonate from bone resulting in statistically significant and clinically important fracture prevention following discontinuation of bisphosphonates. Thus, there may be some lingering effects on bone even after bisphosphonates are discontinued.
Because of a concern regarding oversuppression of bone turnover with prolonged bisphosphonate therapy, it is recommended that osteoporosis treatment with bisphosphonates be stopped after a period of five years to provide patients a so-called “drug holiday.” The duration of bisphosphonate treatment and the length of the drug holiday are based on fracture risk and the pharmacokinetics of the bisphosphonate used89. The four bisphosphonates commonly used in clinical practice (alendronate, risedronate, ibandronate, and zoledronate) have different binding affinities and different antiresorptive potencies, depending on their side chains. The order of binding affinity to bone, from highest to lowest, is zoledronate, alendronate, ibandronate, and risedronate90, whereas the order of potency for inhibiting the enzyme farnesyl pyrophosphate synthase, from highest to lowest, is zoledronate, risedronate, ibandronate, and alendronate91. Because of the differences in binding affinity and antiresorptive potency, each bisphosphonate has a unique profile of the speed of onset and offset of its effect, as well as a unique degree of bone turnover suppression. Park-Wyllie et al. performed a nested case-control study to explore the association between bisphosphonate use and femoral fractures, and they reported that bisphosphonate treatment of more than five years was associated with an increased risk of atypical subtrochanteric or femoral shaft fractures (adjusted odds ratio = 2.74; 95% CI, 1.25 to 6.02)39. Therefore, it may be appropriate to consider a drug holiday in patients with a cumulative duration of bisphosphonate treatment of more than five years.
By stratifying patients on the basis of the fracture risk, a logistic approach to providing management guidelines for patients with prolonged bisphosphonate use can be established (Fig. 9). Although there are no clear criteria to define the risk of fracture, fracture risk can be estimated with use of the World Health Organization’s fracture risk assessment tool (FRAX) as well as bone turnover markers92. For patients at low risk of fracture, bisphosphonates can be discontinued and the patients placed on a drug holiday. Patients should nevertheless take daily calcium and vitamin-D supplements. For those at high risk of fracture, it may be beneficial to continue bisphosphonate treatment beyond five years. Alternatively, other medications such as denosumab or teriparatide may be provided during the holiday from bisphosphonates. For patients at moderate risk of fracture, the management plan can be further divided on the basis of the bone turnover state (low and high-turnover states). Patients who are at moderate risk of fracture and in a low-turnover state can be managed in a fashion that is similar to those at low risk of fracture. However, patients who are at moderate risk but in a high-turnover state should be managed as if they have high risk of fracture (Fig. 9). In general, the drug holiday should be continued until there is substantial loss of bone mineral density, marked increase in bone turnover markers, or the occurrence of a new fracture89.
Given that the incidence of atypical femoral fractures is low and the actual incidence of abnormal radiographic features in the entire patient population taking bisphosphonates is not known, it may not be appropriate to screen all patients with a history of prolonged bisphosphonate treatment by means of radiographs of the femur. Nevertheless, the development of groin or thigh pain in a patient on long-term bisphosphonate treatment should raise the index of suspicion of an atypical femoral fracture, particularly if the patient has a history of rheumatoid arthritis, diabetes, or exposure to glucocorticoid therapy11,12. Further work-up with serial radiography, bone scintigraphy, and MRI should be considered in this setting to facilitate the early diagnosis of bone fragility.
The causal relationship between prolonged bisphosphonate use and the occurrence of atypical femoral fractures has not yet been established. If a patient sustains an atypical femoral fracture, bisphosphonates must be stopped and an anabolic agent should be employed. These patients should also have daily calcium and vitamin-D supplementation. As fractures treated by intramedullary nailing heal by endochondral repair, such nailing is a preferred method of fixation for atypical femoral fractures. Atypical femoral fractures are relatively rare events, and the balance between patient efficacy and safety still favors bisphosphonate therapy for the treatment of osteoporosis. Bisphosphonates appear to have lingering efficacy against fractures even after the treatment is discontinued, so a drug holiday should be considered for most patients who take bisphosphonates for five years or more.
Because many questions regarding atypical femoral fractures are unanswered, future studies should focus on bone histomorphometry and biomechanical properties of the femoral cortices as well as clinical drug trials regarding this particular problem. The small number of reported fractures may warrant development of a national registry of atypical femoral fractures.
Black
DM;
Schwartz
AV;
Ensrud
KE;
Cauley
JA;
Levis
S;
Quandt
SA;
Satterfield
S;
Wallace
RB;
Bauer
DC;
Palermo
L;
Wehren
LE;
Lombardi
A;
Santora
AC;
Cummings
SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA.
2006 Dec 27;296(
24):2927-38.[CrossRef]
Black
DM;
Delmas
PD;
Eastell
R;
Reid
IR;
Boonen
S;
Cauley
JA;
Cosman
F;
Lakatos
P;
Leung
PC;
Man
Z;
Mautalen
C;
Mesenbrink
P;
Hu
H;
Caminis
J;
Tong
K;
Rosario-Jansen
T;
Krasnow
J;
Hue
TF;
Sellmeyer
D;
Eriksen
EF;
Cummings
SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med.
2007 May 3;356(
18):1809-22.[CrossRef]
Chesnut III
CH;
Skag
A;
Christiansen
C;
Recker
R;
Stakkestad
JA;
Hoiseth
A;
Felsenberg
D;
Huss
H;
Gilbride
J;
Schimmer
RC;
Delmas
PD; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res.
2004 Aug;19(
8):1241-9. .[CrossRef]
Harris
ST;
Watts
NB;
Genant
HK;
McKeever
CD;
Hangartner
T;
Keller
M;
Chesnut
CH
3rd;
Brown
J;
Eriksen
EF;
Hoseyni
MS;
Axelrod
DW;
Miller
PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA.
1999 Oct 13;282(
14):1344-52.[CrossRef]
Reid
DM;
Devogelaer
JP;
Saag
K;
Roux
C;
Lau
CS;
Reginster
JY;
Papanastasiou
P;
Ferreira
A;
Hartl
F;
Fashola
T;
Mesenbrink
P;
Sambrook
PN; HORIZON investigators. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet.
2009 Apr 11;373(
9671):1253-63.[CrossRef]
Devogelaer
JP. Modern therapy for Paget's disease of bone: focus on bisphosphonates. Treat Endocrinol.
2002;1(
4):241-57.[CrossRef][PubMed]
Polascik
TJ. Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases. Drug Des Devel Ther.
2009 Sep 21;3:27-40.
Reszka
AA;
Rodan
GA. Bisphosphonate mechanism of action. Curr Rheumatol Rep.
2003 Feb;5(
1):65-74.[CrossRef]
Russell
RG;
Xia
Z;
Dunford
JE;
Oppermann
U;
Kwaasi
A;
Hulley
PA;
Kavanagh
KL;
Triffitt
JT;
Lundy
MW;
Phipps
RJ;
Barnett
BL;
Coxon
FP;
Rogers
MJ;
Watts
NB;
Ebetino
FH. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci.
2007 Nov;1117:209-57.[CrossRef]
Odvina
CV;
Zerwekh
JE;
Rao
DS;
Maalouf
N;
Gottschalk
FA;
Pak
CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab.
2005 Mar;90(
3):1294-301. .[CrossRef]
Goh
SK;
Yang
KY;
Koh
JS;
Wong
MK;
Chua
SY;
Chua
DT;
Howe
TS. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br.
2007 Mar;89(
3):349-53.[CrossRef]
Kwek
EB;
Goh
SK;
Koh
JS;
Png
MA;
Howe
TS. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy?Injury.
2008 Feb;39(
2):224-31. .[CrossRef]
Neviaser
AS;
Lane
JM;
Lenart
BA;
Edobor-Osula
F;
Lorich
DG. Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma.
2008 May-Jun;22(
5):346-50.[CrossRef]
Lenart
BA;
Neviaser
AS;
Lyman
S;
Chang
CC;
Edobor-Osula
F;
Steele
B;
van der Meulen
MC;
Lorich
DG;
Lane
JM. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int.
2009 Aug;20(
8):1353-62. .[CrossRef]
Shane
E;
Burr
D;
Ebeling
PR;
Abrahamsen
B;
Adler
RA;
Brown
TD;
Cheung
AM;
Cosman
F;
Curtis
JR;
Dell
R;
Dempster
D;
Einhorn
TA;
Genant
HK;
Geusens
P;
Klaushofer
K;
Koval
K;
Lane
JM;
McKiernan
F;
McKinney
R;
Ng
A;
Nieves
J;
O’Keefe
R;
Papapoulos
S;
Sen
HT;
van der Meulen
MC;
Weinstein
RS;
Whyte
M; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res.
2010 Nov;25(
11):2267-94.[CrossRef]
Schneider
JP. Should bisphosphonates be continued indefinitely? An unusual fracture in a healthy woman on long-term alendronate. Geriatrics.
2006 Jan;61(
1):31-3.
Visekruna
M;
Wilson
D;
McKiernan
FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab.
2008 Aug;93(
8):2948-52. .[CrossRef]
Armamento-Villareal
R;
Napoli
N;
Diemer
K;
Watkins
M;
Civitelli
R;
Teitelbaum
S;
Novack
D. Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif Tissue Int.
2009 Jul;85(
1):37-44. .[CrossRef]
Mashiba
T;
Hirano
T;
Turner
CH;
Forwood
MR;
Johnston
CC;
Burr
DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res.
2000 Apr;15(
4):613-20.[CrossRef]
Unnanuntana
A;
Ashfaq
K;
Ton
QV;
Kleimeyer
JP;
Lane
JM. The effect of long-term alendronate treatment on cortical thickness of the proximal femur. Clin Orthop Relat Res.
2012 Jan;470(
1):291-8. .[CrossRef]
Feldstein
AC;
Black
D;
Perrin
N;
Rosales
AG;
Friess
D;
Boardman
D;
Dell
R;
Santora
A;
Chandler
JM;
Rix
MM;
Orwoll
E. Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res.
2012 May;27(
5):977-86. .[CrossRef]
Giusti
A;
Hamdy
NA;
Papapoulos
SE. Atypical fractures of the femur and bisphosphonate therapy: A systematic review of case/case series studies. Bone.
2010 Aug;47(
2):169-80. .[CrossRef]
Rizzoli
R;
Akesson
K;
Bouxsein
M;
Kanis
JA;
Napoli
N;
Papapoulos
S;
Reginster
JY;
Cooper
C. Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int.
2011 Feb;22(
2):373-90. .[CrossRef]
Nieves
JW;
Bilezikian
JP;
Lane
JM;
Einhorn
TA;
Wang
Y;
Steinbuch
M;
Cosman
F. Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int.
2010 Mar;21(
3):399-408. .[CrossRef]
Wang
Z;
Bhattacharyya
T. Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996-2007. J Bone Miner Res.
2011 Mar;26(
3):553-60. .[CrossRef]
Salminen
ST;
Pihlajamäki
HK;
Avikainen
VJ;
Böstman
OM. Population based epidemiologic and morphologic study of femoral shaft fractures. Clin Orthop Relat Res.
2000 Mar;(
372):241-9.
Salminen
S;
Pihlajamäki
H;
Avikainen
V;
Kyrö
A;
Böstman
O. Specific features associated with femoral shaft fractures caused by low-energy trauma. J Trauma.
1997 Jul;43(
1):117-22.[CrossRef]
Martinet
O;
Cordey
J;
Harder
Y;
Maier
A;
Bühler
M;
Barraud
GE. The epidemiology of fractures of the distal femur. Injury.
2000 Sep;31
Suppl 3:C62-3.[CrossRef]
Lo
JC;
Huang
SY;
Lee
GA;
Khandewal
S;
Provus
J;
Ettinger
B;
Gonzalez
JR;
Hui
RL;
Grimsrud
CD. Clinical correlates of atypical femoral fracture. Bone.
2012 Jul;51(
1):181-4. .[CrossRef]
Giusti
A;
Hamdy
NA;
Dekkers
OM;
Ramautar
SR;
Dijkstra
S;
Papapoulos
SE. Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone.
2011 May 1;48(
5):966-71. .[CrossRef]
Girgis
CM;
Seibel
MJ. Population and treatment-based incidence estimates of atypical fractures. Med J Aust.
2011 Jun 20;194(
12):666.
Schilcher
J;
Michaëlsson
K;
Aspenberg
P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med.
2011 May 5;364(
18):1728-37. .[CrossRef]
Abrahamsen
B;
Eiken
P;
Eastell
R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res.
2009 Jun;24(
6):1095-102.[CrossRef]
Abrahamsen
B;
Eiken
P;
Eastell
R. Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol Metab.
2010 Dec;95(
12):5258-65. .[CrossRef]
Black
DM;
Kelly
MP;
Genant
HK;
Palermo
L;
Eastell
R;
Bucci-Rechtweg
C;
Cauley
J;
Leung
PC;
Boonen
S;
Santora
A;
de Papp
A;
Bauer
DC; Fracture Intervention Trial Steering Committee; HORIZON Pivotal Fracture Trial Steering Committee. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med.
2010 May 13;362(
19):1761-71. .[CrossRef]
Shakir
SA;
Layton
D. Causal association in pharmacovigilance and pharmacoepidemiology: thoughts on the application of the Austin Bradford-Hill criteria. Drug Saf.
2002;25(
6):467-71.[CrossRef][PubMed]
Hill
AB. The environment and disease: association or causation?Proc R Soc Med.
1965 May;58:295-300.
Holt
RI;
Peveler
RC. Antipsychotic drugs and diabetes—an application of the Austin Bradford Hill criteria. Diabetologia.
2006 Jul;49(
7):1467-76. .[CrossRef]
Park-Wyllie
LY;
Mamdani
MM;
Juurlink
DN;
Hawker
GA;
Gunraj
N;
Austin
PC;
Whelan
DB;
Weiler
PJ;
Laupacis
A. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA.
2011 Feb 23;305(
8):783-9.[CrossRef]
Adachi
JD;
Lyles
K;
Boonen
S;
Colón-Emeric
C;
Hyldstrup
L;
Nordsletten
L;
Pieper
C;
Recknor
C;
Su
G;
Bucci-Rechtweg
C;
Magaziner
J. Subtrochanteric fractures in bisphosphonate-naive patients: results from the HORIZON-recurrent fracture trial. Calcif Tissue Int.
2011 Dec;89(
6):427-33. .[CrossRef]
Puhaindran
ME;
Farooki
A;
Steensma
MR;
Hameed
M;
Healey
JH;
Boland
PJ. Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am.
2011 Jul 6;93(
13):1235-42.[CrossRef]
Weaver
MJ;
Miller
MA;
Vrahas
MS. The orthopaedic implications of diphosphonate therapy. J Am Acad Orthop Surg.
2010 Jun;18(
6):367-74.
Li
J;
Mashiba
T;
Burr
DB. Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int.
2001 Nov;69(
5):281-6.[CrossRef]
Parfitt
AM. Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone.
2002 Jan;30(
1):5-7.[CrossRef]
Roschger
P;
Rinnerthaler
S;
Yates
J;
Rodan
GA;
Fratzl
P;
Klaushofer
K. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone.
2001 Aug;29(
2):185-91.[CrossRef]
Boivin
GY;
Chavassieux
PM;
Santora
AC;
Yates
J;
Meunier
PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone.
2000 Nov;27(
5):687-94.[CrossRef]
Templeton
K. Secondary osteoporosis. J Am Acad Orthop Surg.
2005 Nov;13(
7):475-86.
Vestergaard
P;
Rejnmark
L;
Mosekilde
L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int.
2006;17(
6):807-16. .[CrossRef][PubMed]
Allen
MR;
Burr
DB. Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res.
2007 Nov;22(
11):1759-65.[CrossRef]
Brennan
O;
Kennedy
OD;
Lee
TC;
Rackard
SM;
O’Brien
FJ. Effects of estrogen deficiency and bisphosphonate therapy on osteocyte viability and microdamage accumulation in an ovine model of osteoporosis. J Orthop Res.
2011 Mar;29(
3):419-24. .[CrossRef]
Allen
MR;
Iwata
K;
Phipps
R;
Burr
DB. Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone.
2006 Oct;39(
4):872-9. .[CrossRef]
Allen
MR;
Reinwald
S;
Burr
DB. Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment. Calcif Tissue Int.
2008 May;82(
5):354-60. .[CrossRef]
Kidd
LJ;
Cowling
NR;
Wu
AC;
Kelly
WL;
Forwood
MR. Bisphosphonate treatment delays stress fracture remodeling in the rat ulna. J Orthop Res.
2011 Dec;29(
12):1827-33. .[CrossRef]
Sloan
AV;
Martin
JR;
Li
S;
Li
J. Parathyroid hormone and bisphosphonate have opposite effects on stress fracture repair. Bone.
2010 Aug;47(
2):235-40. .[CrossRef]
Koh
JS;
Goh
SK;
Png
MA;
Kwek
EB;
Howe
TS. Femoral cortical stress lesions in long-term bisphosphonate therapy: a herald of impending fracture?J Orthop Trauma.
2010 Feb;24(
2):75-81.[CrossRef]
Banffy
MB;
Vrahas
MS;
Ready
JE;
Abraham
JA. Nonoperative versus prophylactic treatment of bisphosphonate-associated femoral stress fractures. Clin Orthop Relat Res.
2011 Jul;469(
7):2028-34. .[CrossRef]
Ha
YC;
Cho
MR;
Park
KH;
Kim
SY;
Koo
KH. Is surgery necessary for femoral insufficiency fractures after long-term bisphosphonate therapy?Clin Orthop Relat Res.
2010 Dec;468(
12):3393-8. .[CrossRef]
Renders
GA;
Mulder
L;
van Ruijven
LJ;
Langenbach
GE;
van Eijden
TM. Mineral heterogeneity affects predictions of intratrabecular stress and strain. J Biomech.
2011 Feb 3;44(
3):402-7. .[CrossRef]
Tai
K;
Dao
M;
Suresh
S;
Palazoglu
A;
Ortiz
C. Nanoscale heterogeneity promotes energy dissipation in bone. Nat Mater.
2007 Jun;6(
6):454-62. .[CrossRef]
Roschger
P;
Paschalis
EP;
Fratzl
P;
Klaushofer
K. Bone mineralization density distribution in health and disease. Bone.
2008 Mar;42(
3):456-66. .[CrossRef]
Boskey
AL;
Spevak
L;
Weinstein
RS. Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int.
2009 May;20(
5):793-800. .[CrossRef]
Donnelly
E;
Meredith
DS;
Nguyen
JT;
Gladnick
BP;
Rebolledo
BJ;
Shaffer
AD;
Lorich
DG;
Lane
JM;
Boskey
AL. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res.
2012 Mar;27(
3):672-8.[CrossRef]
Viguet-Carrin
S;
Garnero
P;
Delmas
PD. The role of collagen in bone strength. Osteoporos Int.
2006;17(
3):319-36. .[CrossRef][PubMed]
Schmidt
AM;
Hori
O;
Brett
J;
Yan
SD;
Wautier
JL;
Stern
D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb.
1994 Oct;14(
10):1521-8.[CrossRef]
Singh
R;
Barden
A;
Mori
T;
Beilin
L. Advanced glycation end-products: a review. Diabetologia.
2001 Feb;44(
2):129-46.[CrossRef]
Saito
M;
Mori
S;
Mashiba
T;
Komatsubara
S;
Marumo
K. Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int.
2008 Sep;19(
9):1343-54. .[CrossRef]
Tang
SY;
Allen
MR;
Phipps
R;
Burr
DB;
Vashishth
D. Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate. Osteoporos Int.
2009 Jun;20(
6):887-94. .[CrossRef]
Koh
JS;
Goh
SK;
Png
MA;
Ng
AC;
Howe
TS. Distribution of atypical fractures and cortical stress lesions in the femur: implications on pathophysiology. Singapore Med J.
2011 Feb;52(
2):77-80.
Tang
WM;
Chiu
KY;
Kwan
MF;
Ng
TP;
Yau
WP. Sagittal bowing of the distal femur in Chinese patients who require total knee arthroplasty. J Orthop Res.
2005 Jan;23(
1):41-5.[CrossRef]
Dell
R;
Greene
D;
Tran
D. .
Ross
CA;
Taylor
CL;
Yaktine
AL;
Del Valle
HB. Dietary reference intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011. .
Priemel
M;
von Domarus
C;
Klatte
TO;
Kessler
S;
Schlie
J;
Meier
S;
Proksch
N;
Pastor
F;
Netter
C;
Streichert
T;
Püschel
K;
Amling
M. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res.
2010 Feb;25(
2):305-12.[CrossRef]
Heaney
RP;
Holick
MF. Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res.
2011 Mar;26(
3):455-7. .[CrossRef]
Whiting
SJ;
Calvo
MS. Correcting poor vitamin D status: do older adults need higher repletion doses of vitamin D3 than younger adults?Mol Nutr Food Res.
2010 Aug;54(
8):1077-84.
Gehrig
L;
Lane
J;
O’Connor
MI. Osteoporosis: management and treatment strategies for orthopaedic surgeons. J Bone Joint Surg Am.
2008 Jun;90(
6):1362-74.
Ettinger
B;
San Martin
J;
Crans
G;
Pavo
I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res.
2004 May;19(
5):745-51. .[CrossRef]
Gomberg
SJ;
Wustrack
RL;
Napoli
N;
Arnaud
CD;
Black
DM. Teriparatide, vitamin D, and calcium healed bilateral subtrochanteric stress fractures in a postmenopausal woman with a 13-year history of continuous alendronate therapy. J Clin Endocrinol Metab.
2011 Jun;96(
6):1627-32. .[CrossRef]
Andreassen
TT;
Ejersted
C;
Oxlund
H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res.
1999 Jun;14(
6):960-8.[CrossRef]
Andreassen
TT;
Fledelius
C;
Ejersted
C;
Oxlund
H. Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand.
2001 Jun;72(
3):304-7.[CrossRef]
Holzer
G;
Majeska
RJ;
Lundy
MW;
Hartke
JR;
Einhorn
TA. Parathyroid hormone enhances fracture healing. A preliminary report. Clin Orthop Relat Res.
1999 Sep;(
366):258-63.
Skripitz
R;
Andreassen
TT;
Aspenberg
P. Parathyroid hormone (1-34) increases the density of rat cancellous bone in a bone chamber. A dose-response study. J Bone Joint Surg Br.
2000 Jan;82(
1):138-41.[CrossRef]
Zanchetta
JR;
Bogado
CE;
Ferretti
JL;
Wang
O;
Wilson
MG;
Sato
M;
Gaich
GA;
Dalsky
GP;
Myers
SL. Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res.
2003 Mar;18(
3):539-43.[CrossRef]
Aspenberg
P;
Genant
HK;
Johansson
T;
Nino
AJ;
See
K;
Krohn
K;
García-Hernández
PA;
Recknor
CP;
Einhorn
TA;
Dalsky
GP;
Mitlak
BH;
Fierlinger
A;
Lakshmanan
MC. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res.
2010 Feb;25(
2):404-14.[CrossRef]
Peichl
P;
Holzer
LA;
Maier
R;
Holzer
G. Parathyroid hormone 1-84 accelerates fracture-healing in pubic bones of elderly osteoporotic women. J Bone Joint Surg Am.
2011 Sep 7;93(
17):1583-7.[CrossRef]
Weil
YA;
Rivkin
G;
Safran
O;
Liebergall
M;
Foldes
AJ. The outcome of surgically treated femur fractures associated with long-term bisphosphonate use. J Trauma.
2011 Jul;71(
1):186-90.[CrossRef]
Sayed-Noor
AS;
Sjödén
GO. Case reports: two femoral insufficiency fractures after long-term alendronate therapy. Clin Orthop Relat Res.
2009 Jul;467(
7):1921-6. .[CrossRef]
Capeci
CM;
Tejwani
NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am.
2009 Nov;91(
11):2556-61.[CrossRef]
Watts
NB;
Chines
A;
Olszynski
WP;
McKeever
CD;
McClung
MR;
Zhou
X;
Grauer
A. Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int.
2008 Mar;19(
3):365-72. .[CrossRef]
Watts
NB;
Diab
DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab.
2010 Apr;95(
4):1555-65. .[CrossRef]
Nancollas
GH;
Tang
R;
Phipps
RJ;
Henneman
Z;
Gulde
S;
Wu
W;
Mangood
A;
Russell
RG;
Ebetino
FH. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone.
2006 May;38(
5):617-27. .[CrossRef]
Dunford
JE;
Thompson
K;
Coxon
FP;
Luckman
SP;
Hahn
FM;
Poulter
CD;
Ebetino
FH;
Rogers
MJ. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther.
2001 Feb;296(
2):235-42.
Unnanuntana
A;
Gladnick
BP;
Donnelly
E;
Lane
JM. The assessment of fracture risk. J Bone Joint Surg Am.
2010 Mar;92(
3):743-53.[CrossRef]
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.