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1.  Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries 
Summary
Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates.
Introduction
Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated.
Methods
Among all Medicare fee-for-service female beneficiaries from 2006–2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/ femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR<1/3 as less compliant, MPR≥1/3–<2/3 as compliant, and MPR≥2/3 as highly compliant. Alternative cutoff points at 50 and 80 % were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures.
Results
There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray’s test, P<0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95 % Confidence Interval [CI] 1.06–1.43) overall, became significant after 2 years of follow-up (HR=1.51, 95 % CI 1.06–2.15) and reached the highest risk in the fifth year (HR=4.06, 95 % CI 1.47–11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR=0.69, 95 % CI 0.66–0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively.
Conclusions
Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (≥3 years) oral bisphosphonates in the elderly female Medicare population.
doi:10.1007/s00198-014-2738-x
PMCID: PMC4254800  PMID: 24846316
Bisphosphonates; Fracture; Osteoporosis; Atypical femur fracture
2.  Bisphosphonates and Risk of Subtrochanteric, Femoral Shaft, and Atypical Femur Fracture: A Systematic Review and Meta-analysis 
While there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral fractures (AFF). Recent published studies examining this potential association are conflicting in regards to the existence and strength of this association. We conducted a systematic review and meta-analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random-effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta-analysis: five case-control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF with adjusted RR of 1.70 (95% CI 1.22–2.37). Subgroup analysis of studies using the ASBMR-criteria to define AFF suggests a higher risk of AFF with bisphosphonate use with RR of 11.78 (95% CI 0.39–359.69) as compared to studies using mainly diagnosis codes (RR 1.62, 95% CI 1.18–2.22), although there is a wide confidence interval and severe heterogeneity (I2=96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI 1.29–2.04). This meta-analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long-term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.
doi:10.1002/jbmr.1893
PMCID: PMC3713078  PMID: 23408697
Atypical femur fracture; bisphosphonates; osteoporosis; subtrochanteric fracture; femoral shaft fracture
3.  Oral bisphosphonates are associated with increased risk of subtrochanteric and diaphyseal fractures in elderly women: a nested case–control study 
BMJ Open  2013;3(1):e002091.
Objectives
To evaluate the association between bisphosphonate use and the risk of atypical femoral fractures among women aged 65 or older.
Design
Nested case–control study.
Setting
General practice research database in Spain.
Exposures
Use of oral bisphosphonates before the occurrence of atypical fractures among cases or the corresponding index date among controls. Bisphosphonate use was categorised as ever versus never users. Ever users were divided according to the total time since first prescription.
Main outcome measures
Cases were defined as women aged 65 years or older with a first diagnosis of subtrochanteric or diaphyseal fracture, recorded in the BIFAP database between 1 January 2005 and 31 December 2008, and with at least 1 year of follow-up before the index date. For each case, five age-matched and calendar-year-matched controls without a history of hip or atypical fracture were randomly selected from the database.
Statistical analysis
OR of atypical femoral fracture by bisphosphonate use was determined using conditional logistic regression. Models were adjusted for comorbidities and use of other medications.
Results
The analysis included 44 cases and 220 matched controls (mean age, 82 years). Ever use of bisphosphonates was more frequent in cases than controls (29.6% vs 10.5%). In multivariate analyses, OR (95% CI) of atypical femoral fracture was 4.30 (1.55 to 11.9) in ever versus never users of bisphosphonates. The risk increased with long-term use, with an OR of 9.46 (2.17 to 41.3) comparing those using bisphosphonates over 3 years versus no users (p for trend=0.01).
Conclusions
Bisphosphonate use was associated with an increased risk of subtrochanteric or diaphyseal fractures in elderly women in a low fracture risk population, with a higher risk among long-term bisphosphonate users.
doi:10.1136/bmjopen-2012-002091
PMCID: PMC3563115  PMID: 23370011
Clinical Pharmacology; Epidemiology; Primary Care
4.  Bisphosphonate-induced reductions in rat femoral bone energy absorption and toughness are testing rate-dependent 
Bisphosphonates have been used for years to suppress bone turnover and reduce fracture risk. Bisphosphonates have recently been associated with atypical femoral fractures, which are catastrophic, low trauma, brittle fractures that appear to occur more frequently than in untreated individuals. Previous work using a dog model has demonstrated bisphosphonate-induced reductions in bone toughness (the inverse of brittleness), yet data are lacking to show this occurs in rodents. The goal of this study was to determine if bisphosphonate-induced alterations in toughness could be quantified in rats. At 26 weeks of age, skeletally mature rats (n=32 total) were given an injection of either zoledronate (100 µg /kg body weight) or vehicle (0.5 mL saline). Five weeks post-injection, both femora were collected and analyzed for geometry and mechanical properties. To assess the effect of testing rate on the biomechanical outcomes, the left femora were broken at 2 mm/min, while the right femora were broken at 20 mm/min. The results showed a significantly lower energy to failure in zoledronate-treated animals compared to vehicle at the slow testing rate (−15%, p < 0.05) with no difference at the faster rate. While there was not a significant interaction between drug and testing rate for toughness to fracture (p = 0.07), toughness between ultimate stress and fracture was significantly lower with zoledronate only at the slow rate (−40%, p < 0.05). These data document that bisphosphonate-induced reductions in energy absorption and toughness can be quantified in rats yet they are highly dependent on testing rate.
doi:10.1002/jor.22343
PMCID: PMC4048838  PMID: 23494860
zoledronate; mechanical testing; atypical femoral fractures; sub-trochanteric fracture
5.  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 
Osteoporosis International  2010;22(2):373-390.
Summary
This paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case–control studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven.
Introduction
A Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians.
Methods
A PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed.
Results
Several clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these ‘atypical’ fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case–control studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks.
Conclusions
Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk–benefit ratio still remains favourable for use of bisphosphonates to prevent fractures.
doi:10.1007/s00198-010-1453-5
PMCID: PMC3020314  PMID: 21085935
Atypical; Bisphosphonate; Femur; Low trauma; Osteoporosis; Subtrochanteric
6.  Management Strategy for Symptomatic Bisphosphonate-Associated Incomplete Atypical Femoral Fractures 
HSS Journal  2012;8(2):103-110.
Background
Long-term bisphosphonate use has often been associated with atypical femoral fractures. These fractures evolve from incomplete femoral fractures. A previous study demonstrated that the presence of a radiolucent line in an incomplete fracture can indicate a high risk of progression to complete fracture.
Questions/Purposes
The aim of this study is to present a management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. Specific study questions include the following: (1) Is there a difference in the prognosis of these fractures based on the presence or absence of a radiolucent fracture line? (2) Can treatment with teriparatide assist in clinical/radiographic healing of these incomplete fractures? (3) Is there a characteristic biochemical profile in these patients?
Patients and Methods
We retrospectively examined all femur radiographs ordered by the metabolic bone disease service at our hospital between July 1, 2006 and July 1, 2011 and identified 10 patients with a total of 14 incomplete fractures. Nine patients received bisphosphonates for a mean duration of 10 ± 5 years (range, 4–17). The mean follow-up since the time of diagnosis was 20 ± 11 months (range, 6–36 months).
Results
Five fractures did not have a radiolucent fracture line and were treated conservatively with partial weight-bearing restrictions and pharmacologic therapy. All five of these fractures healed with conservative management. Nine fractures had a radiolucent fracture line, and only two of these were treated successfully with conservative management including teriparatide. Six of the eight patients with a radiolucent line elected for surgical prophylaxis after 3 months of conservative management, whereas one patient underwent surgical prophylaxis without a trial of conservative management. Regarding the biochemical profiles, bone turnover markers for our patient cohort were in the lower quartile.
Conclusions
Fractures without a radiolucent line appear to respond to conservative management and not require surgical prophylaxis. Teriparatide treatment may hold promise in promoting healing of these fractures.
doi:10.1007/s11420-012-9275-y
PMCID: PMC3715620  PMID: 23874247
bisphosphonates; atypical femoral fractures; incomplete fractures; teriparatide; radiolucent fracture line
7.  Predictors of atypical femoral fractures during long term bisphosphonate therapy: A case series & review of literature 
Background & objectives:
Bisphosphonates (BPs) are the most widely prescribed medicines for the treatment of osteoporosis because of their efficacy and favourable safety profile. There have been, several reports on an increased incidence of atypical femoral fractures after long term treatment with BPs. The objective of this study was to evaluate the clinical presentation including prodromal symptoms, skeletal radiograph findings, type and duration of BPs received and treatment outcome of patients who developed atypical femoral fractures during bisphosphonate therapy.
Methods:
In this retrospective study, eight patients with atypical femoral fractures were analysed based on clinical features, biochemical and radiological investigations.
Results:
Of the eight patients, who sustained atypical femoral fractures, six were on alendronate and two were on zoledronate therapy before the fractures. In addition to BPs, two patients were on long term corticosteroid therapy for rheumatoid arthritis and Addison's disease. Three patients had bilateral atypical femoral fractures. Except one, all of them had prodromal symptoms prior to fracture. Skeletal radiograph showed cortical thickening, pointed (beaking of) cortical margin and transverse fracture in meta-diaphyseal location. Serum calcium, phosphate, alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) concentrations were within the reference range in all patients.
Interpretation & conclusions:
Long term bisphosphonate therapy may increase the risk of atypical femoral fractures. Presence of prodromal pain, thickened cortex with cortical beaking may be an early clue for predicting the atypical fractures. High risk patients need periodical skeletal survey and a close follow up for early detection of cases.
PMCID: PMC4181159  PMID: 25222777
Atypical; bisphosphonates; femoral shaft; fracture; subtrochanteric
8.  Bisphosphonate-associated Femur Fractures Have High Complication Rates with Operative Fixation 
Background
Bisphosphonate-associated femur fractures have been well described but the preoperative patient factors, treatment modalities, and complications of treatment are unclear.
Questions/purposes
We asked whether a diagnosis of osteoporosis, the characteristic radiographic features of bisphosphonate-related femur fractures, and complication rates differed in patients with operatively treated femoral shaft fractures receiving bisphosphonates and in patients not receiving bisphosphonates.
Methods
We retrospectively reviewed 43 patients with bisphosphonate-associated femoral shaft fractures (including subtrochanteric) from 2002 to 2008 and 20 patients with similar fractures but not treated with bisphosphonates. Similar implants were used in both groups, but a greater number of adjuvants were used in the bisphosphonate cohort. We recorded preoperative osteoporosis and radiographic findings of the characteristic bisphosphonate femur fracture and early complications. The minimum followup was 5 months (mean, 29 months; range 5–60 months).
Results
Preoperatively a greater percentage of patients treated with bisphosphonates had confirmed osteoporosis than those not treated with bisphosphonates (24% versus 5%, respectively), a greater percentage had a proximal fracture location (48% versus 40%, respectively), and their mean cortex to shaft diameter ratio was greater (24% versus 15%, respectively). The bisphosphonate cohort had a higher rate of intraoperative fractures (21% versus 0%) and postoperative plate failures (30% versus 0%).
Conclusions
Despite low rates of other risk factors and ample use of biologic adjuvants, patients treated with bisphosphonates having femur fractures have more complications.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-012-2412-6
PMCID: PMC3392377  PMID: 22669553
9.  Spontaneous Incomplete transverse subtrochanteric femoral fracture with cortical thickening possibly secondary to risedronate use: a case report 
Introduction
Osteoporosis is an asymptomatic disease characterized by bone weakening and predisposition to fragility (insufficiency) fractures and can have devastating effects on individual life and great financial impact on the economy. Bisphosphonates are used worldwide for the primary and secondary prevention of osteoporotic fractures. However, increasing evidence raises concern that bisphosphonates can be associated with atypical fractures.
Case presentation
A 65-year-old Caucasian woman on long-term steroid treatment for polymyalgia rheumatica was admitted with severe and constant pain in the right hip, radiating to the right knee. She had a history of steroid-induced osteoporosis, for which she was started on risedronate four years earlier. She had no history of trauma. Her blood results were unremarkable. Her X-rays confirmed that she had an incomplete right subtrochanteric femoral fracture. A bone scan confirmed the diagnosis and also ruled out any other associated fractures. Our patient successfully underwent internal nail fixation of the fracture. She was reviewed by a rheumatology team, which stopped the risedronate. She was started on treatment with denosumab injection.
Conclusions
Previous case series have reported that long-term bisphosphonate use is associated with atypical fractures of the femur, and certain criteria have been established to help identify such rare fractures. Delayed union or non-union is expected in such fractures following definitive orthopedic treatment because of the long half life of bisphosphonates. In this case report, we try to raise questions related to this important subject, like the duration and safety of bisphosphonate use and the alternative medications used in osteoporosis in this rare condition. We consider this case report not only interesting but also important and unusual because it is about a patient who developed a potentially rare and serious side effect of long-term bisphosphonate use, estimated to affect 2.3 in every 10,000 patients, and who presented with a pelvic X-ray that showed the characteristic features of atypical fractures secondary to risedronate use. In addition, most of the documented cases have been associated with many years of bisphosphonate use whereas our patient had been on risedronate for only four years.
doi:10.1186/1752-1947-6-272
PMCID: PMC3459800  PMID: 22943389
10.  Current perspectives on bisphosphonate treatment in Paget’s disease of bone 
Paget’s disease of bone is a chronic metabolic bone disease with focal increase in bone turnover. The exact etiology of the disease is uncertain, although genetic and environmental factors are believed to be important. Bisphosphonate is the main class of medication being used to control disease activity via its antiresorptive effect. This review discusses the controversies concerning the use of bisphosphonates in the treatment of Paget’s disease of bone, the efficacy of different bisphosphonates in controlling disease activity, and the possible rare side effects of bisphosphonates. Symptoms are the main indication for treatment in Paget’s disease of bone. As treatment benefits in asymptomatic individuals remain controversial and nonevidence based, the decision to treat these patients should be individualized to their risk and benefit profiles. There are several trials conducted to evaluate and compare the efficacy of different regimes of bisphosphonates for treating Paget’s disease of bone. Most trials used biochemical markers rather than clinical symptoms or outcomes as parameters for comparison. Zoledronate is an attractive option as it can achieve high rates of biochemical remission and sustain long duration of suppression by a single dose. Atypical femoral fracture and osteonecrosis of the jaw are two rare and severe side effects reported, possibly related to the use of bisphosphonates in patients with osteoporosis and malignancy-induced hypercalcemia. As the regimes of bisphosphonates used for treating Paget’s disease of bone are different from those two diseases, the risks of developing these two possible side effects are expected to be very low, although this remains unknown. Vitamin D and calcium supplement should be given to patients at risk of vitamin D insufficiency when given zoledronate, as symptomatic hypocalcemia may develop. For those intolerant of bisphosphonates, subcutaneous calcitonin can be used for a limited period due to its associated risk of malignancy.
doi:10.2147/TCRM.S58367
PMCID: PMC4242688  PMID: 25429226
osteitis deformans; antiresorptive; alkaline phosphatase
11.  Atypical subtrochanteric femoral shaft fractures: role for mechanics and bone quality 
Bisphosphonates are highly effective agents for reducing osteoporotic fractures in women and men, decreasing fracture incidence at the hip and spine up to 50%. In a small subset of patients, however, these agents have recently been associated with 'atypical femoral fractures' (AFFs) in the subtrochanteric region or the diaphysis. These fractures have several atypical characteristics, including occurrence with minimal trauma; younger age than typical osteoporotic fractures; occurrence at cortical, rather than cancellous sites; early radiographic appearance similar to that of a stress fracture; transverse fracture pattern rather than the familiar spiral or transverse-oblique morphologies; initiation on the lateral cortex; and high risk of fracture on the contralateral side, at the same location as the initial fracture. Fracture is a mechanical phenomenon that occurs when the loads applied to a structure such as a long bone exceed its load-bearing capacity, either due to a single catastrophic overload (traumatic failure) or as a result of accumulated damage and crack propagation at sub-failure loads (fatigue failure). The association of AFFs with no or minimal trauma suggests a fatigue-based mechanism that depends on cortical cross-sectional geometry and tissue material properties. In the case of AFFs, bisphosphonate treatment may alter cortical tissue properties, as these agents are known to alter bone remodeling. This review discusses the use of bisphosphonates, their effects on bone remodeling, mechanics and tissue composition, their significance as an effective therapy for osteoporosis, and why these agents may increase fracture risk in a small population of patients.
doi:10.1186/ar4013
PMCID: PMC3580578  PMID: 22958475
12.  Managing osteoporosis in ulcerative colitis: Something new? 
World Journal of Gastroenterology : WJG  2014;20(39):14087-14098.
The authors revise the latest evidence in the literature regarding managing of osteoporosis in ulcerative colitis (UC), paying particular attention to the latest tendency of the research concerning the management of bone damage in the patient affected by UC. It is wise to assess vitamin D status in ulcerative colitis patients to recognize who is predisposed to low levels of vitamin D, whose deficiency has to be treated with oral or parenteral vitamin D supplementation. An adequate dietary calcium intake or supplementation and physical activity, if possible, should be guaranteed. Osteoporotic risk factors, such as smoking and excessive alcohol intake, must be avoided. Steroid has to be prescribed at the lowest possible dosage and for the shortest possible time. Moreover, conditions favoring falling have to been minimized, like carpets, low illumination, sedatives assumption, vitamin D deficiency. It is advisable to assess the fracture risk in all UC patient by the fracture assessment risk tool (FRAX® tool), that calculates the ten years risk of fracture for the population aged from 40 to 90 years in many countries of the world. A high risk value could indicate the necessity of treatment, whereas a low risk value suggests a follow-up only. An intermediate risk supports the decision to prescribe bone mineral density (BMD) assessment and a subsequent patient revaluation for treatment. Dual energy X-ray absorptiometry bone densitometry can be used not only for BMD measurement, but also to collect data about bone quality by the means of trabecular bone score and hip structural analysis assessment. These two indices could represent a method of interesting perspectives in evaluating bone status in patients affected by diseases like UC, which may present an impairment of bone quality as well as of bone quantity. In literature there is no strong evidence for instituting pharmacological therapy of bone impairment in UC patients for clinical indications other than those that are also applied to the patients with osteoporosis. Therefore, a reasonable advice is to consider pharmacological treatment for osteoporosis in those UC patients who already present fragility fractures, which bring a high risk of subsequent fractures. Therapy has also to be considered in patients with a high risk of fracture even if it did not yet happen, and particularly when they had long periods of corticosteroid therapy or cumulative high dosages. In patients without fragility fractures or steroid treatment, a medical decision about treatment could be guided by the FRAX tool to determine the intervention threshold. Among drugs for osteoporosis treatment, the bisphosphonates are the most studied ones, with the best and longest evidence of efficacy and safety. Despite this, several questions are still open, such as the duration of treatment, the necessity to discontinue it, the indication of therapy in young patients, particularly in those without previous fractures. Further, it has to be mentioned that a long-term bisphosphonates use in primary osteoporosis has been associated with an increased incidence of dramatic side-effects, even if uncommon, like osteonecrosis of the jaw and atypical sub-trochanteric and diaphyseal femoral fractures. UC is a long-lasting disease and the majority of patients is relatively young. In this scenario primary prevention of fragility fracture is the best cost-effective strategy. Vitamin D supplementation, adequate calcium intake, suitable physical activity (when possible), removing of risk factors for osteoporosis like smoking, and avoiding falling are the best medical acts.
doi:10.3748/wjg.v20.i39.14087
PMCID: PMC4202340  PMID: 25339798
Ulcerative colitis; Osteoporosis; Fragility fracture; Bone mineral density; Trabecular bone score; Hip structural analysis; Fracture assessment risk tool; Dual energy X-ray absorptiometry
13.  Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate 
Acta Orthopaedica  2009;80(4):413-415.
Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined.
Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005.
Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200).
Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial (Black et al. 1996).
doi:10.3109/17453670903139914
PMCID: PMC2823197  PMID: 19568963
14.  The Benefit of Adherence with Bisphosphonates Depends on Age and Fracture Type: Results from an Analysis of 101,038 New Bisphosphonate Users 
The relationship between high adherence to oral bisphosphonates and the risk of different types of fractures has not been well studied among adults of different ages.
Using claims data from a large U.S. health care organization, we quantified adherence after initiating bisphosphonate therapy using the Medication Possession Ratio (MPR) and identified fractures. Cox proportional hazards models were used to evaluate the rate of fracture among non-adherent persons (MPR < 50%) compared to highly adherent persons (MPR ≥ 80%) across several age strata and a variety of types of clinical fractures. In conjunction with fracture incidence rates among the non-adherent, these estimates were used to compute the number needed to treat with high adherence in order to prevent one fracture, by age and fracture type.
Among 101,038 new bisphosphonate users, the proportion of persons with high adherence at 1, 2, and 3 years was 44, 39, and 35%, respectively. Among 65–78 year old persons with a physician diagnosis of osteoporosis, the crude and adjusted rate of hip fracture among the non-adherent was 1.96 (95% CI 1.48–2.60) and 1.74 (95% CI 1.30–2.31), resulting in a number needed to treat with high adherence to prevent one hip fracture of 107. The impact of high adherence was substantially less for other types of fractures and for younger persons. Analysis of adherence in a non-time dependent fashion artifactually magnified differences in fracture rates between adherent and non-adherent persons.
The anti-fracture effectiveness associated with high adherence to oral bisphosphonates varied substantially by age and fracture type. These results provide estimates of absolute fracture effectiveness across age subgroups and fracture types that have been minimally evaluated in clinical trials and may be useful for future cost-effectiveness studies.
doi:10.1359/JBMR.080418
PMCID: PMC2574615  PMID: 18442318
bisphosphonate; adherence; compliance; fracture; osteoporosis
15.  Mechanical property and tissue mineral density differences among severely suppressed bone turnover (SSBT) patients, osteoporotic patients, and normal subjects 
Bone  2011;49(6):1279-1289.
Pathogenesis of atypical fractures in patients on long term bisphosphonate therapy is poorly understood, and the type, the manner in which they occur and the fracture sites are quite different from the usual osteoporotic fractures. We hypothesized that the tissue-level mechanical properties and mean degree of mineralization of the iliac bone would differ among 1) patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy, 2) age-matched, treatment-naïve osteoporotic patients with vertebral fracture, 3) age-matched normals and 4) young normals. Large differences in tissue-level mechanical properties and/or mineralization among these groups could help explain the underlying mechanism(s) for the occurrence of typical osteoporotic and the atypical femoral shaft fractures. Elastic modulus, contact hardness, plastic deformation resistance, and tissue mineral densities of cortical and trabecular bone regions of 55 iliac bone biopsies—12 SSBT patients (SSBT; aged 49–77), 11 age-matched untreated osteoporotic patients with vertebral fracture (Osteoporotic), 12 age-matched subjects without bone fracture (Age-Matched Normal), and 20 younger subjects without bone fracture (Young Normal)—were measured using nanoindentation and quantitative backscattered electron microscopy. For cortical bone nanoindentation properties, only plastic deformation resistance was different among the groups (p<0.05), with greater resistance to plastic deformation in the SSBT group compared to all other groups. For trabecular bone, all nanoindentation properties and mineral density of the trabecular bone were different among the groups (p<0.05). The SSBT group had greater plastic deformation resistance and harder trabecular bone compared to the other three groups, stiffer bone compared to the Osteoporotic and Young Normal groups, and a trend of higher mineral density compared to the Age-Matched Normal and Osteoporotic groups. Lower heterogeneity of modulus and contact hardness for cortical bone of the SSBT and trabecular bone of the Osteoporotic fracture groups, respectively, compared to the non-fractured groups, may contribute to fracture susceptibility due to lowered ability to prevent crack propagation. We tentatively conclude that, in addition to extremely low bone formation rate, atypical fractures in SSBT and/or long-term bisphosphonate treatment may be associated with greater mean plastic deformation resistance properties and less heterogeneous elastic properties of the bone.
doi:10.1016/j.bone.2011.09.042
PMCID: PMC3221814  PMID: 21958843
Bisphosphonate; Atypical fracture; Severely suppressed bone turnover; Nanoindentation; Mechanical properties; Mineral density
16.  Subtrochanteric Fractures in Bisphosphonate-Naive Patients: Results from the HORIZON-Recurrent Fracture Trial 
Calcified Tissue International  2011;89(6):427-433.
Our purpose was to characterize the risks of osteoporosis-related subtrochanteric fractures in bisphosphonate-naive individuals. Baseline characteristics of patients enrolled in the HORIZON-Recurrent Fracture Trial with a study-qualifying hip fracture were examined, comparing those who sustained incident subtrochanteric fractures with those sustaining other hip fractures. Subjects were bisphosphonate-naive or had a bisphosphonate washout period of 6–24 months and subsequently received an annual infusion of zoledronic acid 5 mg or placebo after low-trauma hip-fracture repair. In total, 2,127 men and women were included. Of the qualifying hip fractures, 5.2% were subtrochanteric, 54.8% femoral neck, 33.0% intertrochanteric, and 7.1% other (generally complex fractures of mixed type). Significant baseline (pre-hip fracture) differences were seen between index hip-fracture types, with the percentage of patients with extreme mobility problems being twofold higher in patients with index subtrochanteric fracture (9.9%) compared to other patients. The distribution of hip-fracture types was similar between the treatment groups at baseline. No patients with index subtrochanteric fractures and six patients with other qualifying hip fractures reported prior bisphosphonate use. Only one further subtrochanteric fracture occurred in each treatment group over an average 2-year patient follow-up. Subtrochanteric fractures are not uncommon in bisphosphonate-naive patients. Extreme difficulties with mobility may be a unique risk factor predisposing to development of incident subtrochanteric fractures rather than other types of hip fracture. In patients with recent hip fracture who received zoledronic acid therapy, the incidence of new subtrochanteric fractures was too small to draw any meaningful conclusions.
doi:10.1007/s00223-011-9543-8
PMCID: PMC3215881  PMID: 22038744
Bisphosphonate; Hip fracture; Osteoporosis; Subtrochanteric; Zoledronic acid
17.  Adherence to osteoporosis drugs and fracture prevention: no evidence of healthy adherer bias in a frail cohort of seniors 
Osteoporosis International  2010;22(3):943-954.
Summary
We examined new users of osteoporosis drugs among seniors in Pennsylvania and found no evidence of healthy adherer bias on observed associations between adherence to treatment and non-vertebral fracture risk; we document fracture reduction with better adherence to bisphosphonates, yet no fracture reduction with better adherence to calcitonin or raloxifene.
Introduction
We examined the potential for “healthy adherer bias” when studying the effects of adherence to osteoporosis pharmacotherapy on fracture risk. Based on clinical trial evidence, bisphosphonates, calcitonin, and raloxifene reduce vertebral fracture risk; yet only bisphosphonates are documented to reduce non-vertebral fracture risk.
Methods
This is a cohort study of older women in Pennsylvania who initiated osteoporosis drugs between 1995 and 2005. We included new users of bisphosphonates, calcitonin, and raloxifene. Adherence was categorized based on a measure of compliance as high [proportion of days covered (PDC) ≥ 80%], intermediate (50% < PDC < 80%), or low (PDC ≤ 50%) according to a 180-day ascertainment period. Non-vertebral fracture rates within 365 days after the ascertainment period were compared between adherence categories (reference = low) using Cox proportional hazard models and adjusting for fracture risk factors. Primary and secondary prevention cohorts were examined separately. Adherence to calcitonin and ralox-ifene were control analyses.
Results
We found little difference in fracture rates between levels of adherence to calcitonin, bisphosphonates for primary prevention, or raloxifene for secondary prevention. We document lower fracture rates among high versus low adherent bisphosphonate users for secondary prevention (HR = 0.53, 95%CI = 0.38–0.74) and higher fracture rates among high versus low adherent raloxifene users for primary prevention (HR = 2.01, 95% CI = 1.04–3.87).
Conclusions
We document little evidence of healthy adherer bias when studying the association between better adherence to osteoporosis drugs and fracture risk reduction, with only better adherence to bisphosphonates reducing fracture risk. The higher fracture risk among highly adherent raloxifene users for primary prevention is likely due to residual confounding.
doi:10.1007/s00198-010-1309-z
PMCID: PMC3277855  PMID: 20532481
Bones; Fractures; Medication adherence; Osteoporosis; Selection bias
18.  Validation of Diagnostic Codes for Subtrochanteric, Diaphyseal, and Atypical Femoral Fractures Using Administrative Claims Data 
Purpose
Administrative claims databases have large samples and high generalizability. They have been used to evaluate associations of atypical subtrochanteric fractures with bisphosphonates. We developed and assessed accuracy of claims-based algorithms with hospital and physician diagnosis codes for these fractures.
Methods
Medical records and radiology reports of all adults admitted at University of Alabama at Birmingham Hospital from 2004-2008 with ICD-9 hospital discharges and surgeons' fracture repair codes for subtrochanteric femoral fractures, and random sample of other femoral fractures were reviewed. An expert panel adjudicated any discordance.
Results
We identified 137 persons with suspected subtrochanteric femoral fractures and randomly selected 50 persons with either suspected diaphyseal femoral fractures or hip fractures other than subtrochanteric and diaphyseal femoral fracture (typical hip fracture). Eleven patients had radiographic features indicative of atypical femoral fractures. The positive predictive value (PPV) of claims-based algorithms varied with primary or secondary positions on discharge diagnoses, and the sources of diagnosis codes. The PPV for fractures ranged 69-89% for subtrochanteric femoral, 89-98% for diaphyseal femoral and 85-98% for typical hip fractures. The PPV of administrative codes for defining a femoral fracture as atypical was low and imprecise.
Conclusions
Claims-based algorithms combining hospital discharges with surgeon's diagnosis codes had high PPV to identify the site of subtrochanteric or diaphyseal femoral fractures versus typical hip fractures. However, claims-based data were not accurate in identifying atypical femoral fractures. These claims algorithms will be useful in future population-based observational studies to evaluate associations between osteoporosis medications and subtrochanteric and diaphyseal femoral fractures.
doi:10.1016/j.jocd.2011.09.001
PMCID: PMC4112756  PMID: 22071028
Atypical femoral fracture; Diagnostic Codes; Administrative Claims Data
19.  Longitudinal change in clinical fracture incidence after initiation of bisphosphonates 
Osteoporosis International  2009;21(6):1021-1029.
Summary
There are differences in the risk profile of patients prescribed alendronate, risedronate, or ibandronate. Observed reductions in fracture incidence over time suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.
Introduction
Observational studies of bisphosphonate effectiveness for fracture prevention are subject to bias from unknown characteristics of baseline fracture risk at the start of therapy. The fracture incidence during the short period after starting a bisphosphonate and before any expected clinical benefit likely reflects baseline fracture risk. Bisphosphonate effectiveness may then be estimated by measuring the change in fracture incidence over time on therapy.
Methods
Administrative billing data were used to follow three cohorts of women aged 65 and older (total n = 210,144) after starting therapy either on alendronate, risedronate, or ibandronate in the USA between market introduction and 2006. Within each cohort, the baseline incidence of clinical fractures at the hip, vertebral, and nonvertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baselines, we then compared the fracture incidence during the subsequent 12 months on therapy.
Results
At the start of therapy, the ibandronate cohort was younger and had fewer prior fractures than either the risedronate or alendronate cohorts. Accordingly, the baseline incidence of hip fractures was higher in the risedronate cohort (0.90 per 100 person-years) and in the alendronate cohort (0.77) than in the ibandronate cohort (0.64). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (18% lower at hip, 28% at nonvertebral sites, and 57% at vertebral sites) and risedronate (27% lower at hip, 21% at nonvertebral sites, and 54% at vertebral sites). In the ibandronate cohort, the fracture incidence was lower (31%) only at vertebral sites.
Conclusions
Differences in the baseline fracture incidence among the cohorts may reflect differences in the risk profile of patients prescribed each bisphosphonate. The reductions observed in fracture incidence over time within each cohort suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.
doi:10.1007/s00198-009-1046-3
PMCID: PMC2861765  PMID: 19722103
Bisphosphonates; Clinical fractures; Effectiveness; Epidemiology; Osteoporosis
20.  Dichotomous location of 160 atypical femoral fractures 
Acta Orthopaedica  2013;84(6):561-564.
Background and purpose
The risk of atypical fracture of the femur is associated with bisphosphonate use. While characterizing atypical fractures from a previous nationwide study in radiographic detail, we had the impression that the fractures were located either in the subtrochanteric region or in the shaft. We determined whether there is a dichotomy in this respect.
Patients and methods
The distance between the atypical fractures and the lesser trochanter was measured on plain radiographs from 129 of 160 patients with atypical fractures, taken from 2008 through 2010. Analysis of the distances measured showed 2 clusters, which were then analyzed with regard to bisphosphonate use and age.
Results
The distribution of the distances would be best described as 2 clusters, with a dichotomy at 8 cm. The proximal (subtrochanteric) cluster comprised 25 patients who were generally younger (median 71 years) than the 104 patients in the cluster with shaft fractures (median 80 years). The 95% CI for the difference between medians was 4–11 years. Of the patients with subtrochanteric fractures, 18 of 25 used bisphosphonates as compared to 89 of 104 with shaft fractures.
Interpretation
The younger age and possibly smaller proportion of bisphosphonate users in the subtrochanteric cluster may be compatible with a greater influence of mechanical stress in the underlying pathophysiology of proximal fractures.
doi:10.3109/17453674.2013.866193
PMCID: PMC3851670  PMID: 24286566
21.  Spontaneous Non-Traumatic Stress Fractures in Bilateral Femoral Shafts in a Patient Treated with Bisphosphonates 
Bisphosphonates are potent inhibitors of bone resorption and widely used to treat osteoporosis. Extensive studies have shown that therapy with bisphosphonates improves bone density and decreases fracture risk. However, concerns have been raised about potential over-suppression of bone turnover during long-term use of bisphosphonates, resulting in increased susceptibility to and delayed healing of non-spinal fractures. We report a patient who sustained non-traumatic stress fractures in bilateral femoral shafts with delayed healing after long-term bisphosphonate therapy. She underwent open reduction and surgical internal fixation. Although bisphosphonates effectively prevent vertebral fractures, and their safety has been tested in randomized trials, we must emphasize the need for awareness of the possibility that long-term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage and adverse skeletal effects such as delayed fracture healing.
doi:10.3904/kjim.2012.27.1.98
PMCID: PMC3295996  PMID: 22403507
Bisphosphonates; Fractures, stress; Fracture healing
22.  Absence of femoral cortical thickening in long-term bisphosphonate users: Implications for atypical femur fractures 
Bone  2014;62:64-66.
The radiographs of patients on long term bisphosphonates with atypical femur fractures demonstrate markedly thick cortices at the site of the fracture. We conducted a prospective clinical study to determine if cortical thickening is increased in long term bisphosphonate users. We recruited 43 patients who had taken bisphosphonates for more than 5 years. A group of 45 healthy volunteers and 12 patients recently diagnosed with osteoporosis served as controls. We measured the cortical thickening as the ratio of femoral cortical thickness to diameter of the femur, and looked for cortical beaking.
No difference in the cortical thickness ratio was observed between long term bisphosphonate users and osteoporotic controls (0.53 vs. 0.54, p= 0.659). No cases of cortical beaking were seen and no increase in thigh pain was observed. The power of the study was 95% to detect a 10% difference in cortical thickness ratio. We conclude that long term bisphosphonate use does not produce a generalized increase in subtrochanteric femoral cortical thickening in the majority of patients.
doi:10.1016/j.bone.2014.01.011
PMCID: PMC4249765  PMID: 24468718
Atypical femur fracture; Osteoporosis
23.  Bilateral Atypical Femoral Fractures in a Patient with Multiple Myeloma Treated with Intravenous Bisphosphonate Therapy 
Case Reports in Orthopedics  2014;2014:452418.
Bisphosphonates are currently the standard approach to managing bone disease in multiple myeloma. Bisphosphonates have high bone affinity that inhibits osteoclastic activity and additionally reduces the growth factors released from malignant or osteoblastic cells, thereby impairing abnormal bone remodeling which leads to osteolysis. However, patients of multiple myeloma may be at a higher risk of atypical femoral fractures because the treatment for malignant myeloma requires notably higher cumulative doses of bisphosphonates. Here we present a patient with bilateral atypical femoral fractures and multiple myeloma treated with intravenous bisphosphonate therapy.
doi:10.1155/2014/452418
PMCID: PMC4129925  PMID: 25140264
24.  Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 2. The use of bone density measurement in the diagnosis and management of osteoporosis. 
OBJECTIVE: To determine the best method of diagnosing osteoporosis and determining fracture risk and to promote standards in the use of bone densitometry and the reporting of results. OPTIONS: Methods of bone mineral density measurement: dual-energy x-ray absorptiometry (DXA), radiographic absorptiometry, single-photon absorptiometry, dual-photon absorptiometry, quantitative computed tomography, quantitative ultrasound, neutron activation analysis. The options of using bone densitometry in individual patient management and as a mass screening tool are also considered. OUTCOMES: Appropriate use of densitometry to promote accurate diagnosis and assessment of fracture risk and timely, appropriate treatment. EVIDENCE: Relevant clinical studies and reports were examined. Clinical practice in Canada was also considered. VALUES: Accurate assessment of osteoporotic fracture risk and diagnosis of osteoporosis and assuring low exposure to medical radiation were given a high value. BENEFITS, HARMS AND COSTS: Early diagnosis through bone density measurement allows proper management of osteoporosis to minimize injury and disability, improve quality of life and reduce the personal and social costs associated with the condition. Potential harms include radiation exposure and cost. The harms and costs of appropriate use of DXA are minimal compared with the harms and costs associated with osteoporosis. RECOMMENDATIONS: Bone mineral density should be measured only to assist in making a clinical management choice. DXA is the best method of measuring bone density and, thus, the best available indicator of osteoporotic fracture risk. Plain radiographs may supplement DXA if there is a specific reason for their use. Measurement of the lumbar spine and femoral neck is standard, but a different site or a single measurement is recommended in specific cases. Unless accelerated bone loss is suspected, DXA should be repeated every 2 to 4 years for patients receiving ovarian hormone therapy and 1 to 2 years for patients undergoing bisphosphonate therapy. Measurements and reporting of results must be standardized. Reports should refer to the World Health Organization's recommended definitions of osteopenia and osteoporosis and provide actual measurement and its relation to peak bone mass.
PMCID: PMC1335455  PMID: 8837541
25.  Trends in Incidence of Subtrochanteric Fragility Fractures and Bisphosphonate Use Among the US Elderly, 1996–2007 
Increasing numbers of atypical hip fractures have been reported among patients with bisphosphonate use. However, the nature and extent of the problem are unknown despite recent investigations. To analyze national trends in hip fractures and medication use in the elderly US population, we respectively used the Nationwide Inpatient Sample (NIS) and the Medical Expenditure Panel Survey (MEPS) from 1996 to 2007. In NIS, subtrochanteric fragility fractures were compared with typical hip fractures in femoral neck and intertrochanteric regions. Between 1996 and 2007, age-adjusted rates for typical hip fractures decreased by 31.6% among women (from 1020.5 to 697.4 per 100,000 population) and 20.5% among men (from 424.9 to 337.6 per 100,000 population). In contrast, overall trends in age-adjusted rates for subtrochanteric fragility fractures remained unchanged among men (p = .34) but increased 20.4% among women from 28.4 (95% confidence interval [CI] 27.7–29.1) in 1999 to 34.2 (95% CI 33.4–34.9) per 100,000 population in 2007. The annual percentage increase was 2.1% (95% CI 1.3–2.8, p < .001) based on joinpoint regression analysis. In MEPS, bisphosphonate use increased predominantly in women (from 3.5% in 1996 to 16.6% in 2007) compared with men (2.3% in 2007). In the context of declining typical hip fractures among the US elderly, we observed small but significant increases in the incidence of subtrochanteric fragility fractures from 1999 among postmenopausal women. Using age-adjusted rates, we estimated that for every 100 or so reduction in typical femoral neck or intertrochanteric fractures, there was an increase of one subtrochanteric fragility fracture.
doi:10.1002/jbmr.233
PMCID: PMC3179297  PMID: 20814954
Aging; BonE; Population Studies; Osteoporosis; Bisphosphonates

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