Long-term Bisphosphonate Therapy Research Articles

Differences in tissue-Level Properties as Assessed by Nano-Scratching in Patients With and Without Atypical Femur Fractures on Long-Term Bisphosphonate Therapy: A Proof-of-Concept Pilot Study

Differences in tissue-Level Properties as Assessed by Nano-Scratching in Patients With and Without Atypical Femur Fractures on Long-Term Bisphosphonate Therapy: A Proof-of-Concept Pilot Study

Severe atypical iliac wing fracture associated with long-term bisphosphonate use.

Bisphosphonate use is associated with atypical non-traumatic fractures, which are most commonly seen in the femur. We report a 63-year-old postmenopausal woman who presented acutely with progressively worsening lumbar pain radiating to her left hip for 10days. There was no antecedent trauma. On examination, the patient could not bear weight on her left leg due to the severity of the pain. Radiography and computed tomography of the pelvis demonstrated an iliac wing fracture which was treated conservatively. The patient had a significant past medical history of breast cancer and intense bisphosphonate use for several years which was discontinued 3years previously. No discrete bone lesion was seen at the fracture site on computed tomography, and there was no evidence of metastatic disease elsewhere. A dual-energy X-ray absorptiometry scan showed the lowest bone mineral density T-score of - 1.2. A diagnosis of an atypical fracture related to long-term bisphosphonate therapy was made. To the best of our knowledge, this is the first reported case of an isolated iliac wing fracture associated with long-term bisphosphonate therapy in the literature. Whilst the incidence of such fractures is exceedingly rare, it is an important differential in patients with atypical fractures on long-term bisphosphonates.

Review of recommendations for bisphosphonate treatment interruption-discontinuation

Bisphosphonates are the main medications in the treatment of osteoporosis, which are effective in reducing the risk of fractures in patients with osteoporosis. It is known that after treatment with bisphosphonates, bone mineral density remains quite stable for a certain time, as well as markers of bone metabolism remain reduced, which, along with the side effects of long-term bisphosphonate therapy, determines the possibility of “Drug holidays”. At the same time, during a break in bisphosphonate treatment, the risk of fractures begins to increase, which is a reason to resume therapy.Currently, there is no uniform worldwide data of starting a “drug holidays” on bisphosphonates. The duration of the “drug holidays” also differs in clinical recommendations from different countries. When to conduct a risk assessment of fractures during a “drug holidays”? To answer these questions, we assessed existing clinical recommendations for treatment interruption/discontinuation of bisphosphonates. A literature search was conducted using the following resources: PubMed®, the Cochrane Library, websites of major international osteoporosis associations, and other targeted Internet searches. The main search terms were “Clinical Guideline of Osteoporosis”, “Bisphosphonates”, “Drug holidays in osteoporosis”, “Discontinuation of bisphosphonates”. Тhe search was carried out using articles in Russian and English published between January 1, 2016 and September 15, 2023. 17 clinical guidelines from different countries (Russian, American, European, Asian and Australian) were found and analyzed in which was information about the break in the treatment and withdrawal of bisphosphonates.The majority of clinical recommendations have the same opinion on the issue of starting “drug holidays”: with a moderate risk of fractures, you can take a break from treatment with tableted bisphosphonates after 5 years, after zoledronic acid — after 3 years of therapy. At high and very high risk of fractures, the duration of treatment is 10 and 6 years, respectively. The duration of “drug holidays” vary in the recommendations, but in most cases the decision-making is based not on the duration, but on the assessment of the risk of fractures with their regular reassessment, which includes previous and new low-energy fractures, the emergence of new risk factors, a decrease in BMD, the dynamics of bone markers, re-evalua­tion of FRAX®.

Differences in bone histomorphometry between White postmenopausal women with and without atypical femoral fracture after long-term bisphosphonate therapy.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n= 20) and without (n= 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17yr. Despite the matched range of treatment duration (4-17yr), AFF patients received alendronate for significantly longer time (10.7yr) than non-AFF patients (8.0yr) (P= .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Bilateral Lumbar Pedicle Fracture in a Patient Receiving Long-Term Bisphosphonate Therapy: A Case Report

Bilateral Lumbar Pedicle Fracture in a Patient Receiving Long-Term Bisphosphonate Therapy: A Case Report

ID: 222892 Safety of Intermediate to Long-Term Intravenous Bisphosphonate Therapy in Complex Regional Pain Syndrome

Literature with respect to the role of intravenous bisphosphonates for managing pain in patients with Complex Regional Pain Syndrome (CRPS) is limited to small studies, reporting duration of therapy from few weeks to a year (1,2,3) We present a case of CRPS Type 1 managed with intravenous bisphosphonates for a duration of thirty months.

Use of Cone Beam Computed Tomography for identification and evaluation of medication-related osteonecrosis of the jaws: a dosimetric and multimodal imaging comparison

The aim of this study was to compare Orthopantomograms (OPT) and Computed Tomography (CT) with Cone Beam Computed Tomography (CBCT) in patients with Medication-Related OsteoNecrosis of the Jaws (MRONJ). The study included 25 patients (6 males and 19 females) with MRONJ who had a history of long-term bisphosphonate therapy or one of the recently re-entered MRONJ drugs and underwent OPT, CT and/or CBCT for determination of the extent of disease. We excluded patients with maxillary neoplasia. Considering the presence of early and late signs, OPT was diagnostic in 6 out of 17 cases (35%), while CT and CBCT were diagnostic in 25 out of 25 cases (100%). Analysing the different radiant doses delivered by the selected radiological methods on a phantom, it was found that a more significant effective dose was spread by CT (2.6 mSv) than CBCT (0.164 mSv) or OPT (0.02 mSv). CBCT, from our experience, is a candidate to replace OPT in the first diagnostic step in patients with suspected MRONJ, generating less effective doses and artefacts from metal components than CT.

Therapeutic strategy for atypical ulnar fracture in long use of bisphosphonate: A systematic review

BackgroundAtypical fractures are caused by the combined effects of severe suppression of bone metabolism (SSBT) due to long-term bisphosphonate therapy and chronic repetitive bone microdamage. Atypical ulnar fractures (AUFs) due to SSBT are rare, and there is no standard treatment strategy for such fractures. The relevant literature was reviewed, and the treatment strategy for AUF is discussed. MethodsA systematic review was conducted. All studies on ulnar fractures in individuals with a history of bisphosphonate use were included, and the data were extracted and analyzed from the perspective of the therapeutic strategy. ResultsForty limbs of 35 patients were included. As for the treatment of AUF, 31 limbs were treated surgically, and conservative treatment with casting was performed for 9 limbs. The bone fusion rate was 22/40 (55.0%), and non-union was seen in all patients treated conservatively. There was a significant difference in the bone fusion rate between patients with surgical treatment and those with conservative treatment. The bone fusion rate of patients with parathyroid hormone (PTH) and surgery was 82.3% (14/17 limbs); the bone fusion rate with PTH and bone graft was 69.2% (9/13 limbs). However, there were no significant differences in the fusion rate in the groups with or without PTH, with or without bone grafting, or the combination of the two treatments. There was also no significant difference in the bone fusion rate in the groups with or without low-intensity pulsed ultrasound (LIPUS) treatment. ConclusionsBased on the literature review, surgery is necessary to achieve bone union, but surgery alone is not adequate to achieve bony union. Bone grafting and the administration of PTH and LIPUS may promote early bone fusion, but the present study did not show significant advantages of these additional treatments for bone union.

Acetabular and sacral insufficiency fractures in a patient with a long-term history of Alendronate consumption; a case report

BackgroundLong-term Bisphosphonate consumption has been reported to be associated with the incidence of atypical or insufficiency fracture, particularly in the proximal femur. We observed a case of acetabular and sacral insufficiency fractures in a patient with a long-term history of Alendronate consumption.Case presentationA 62-year-old woman was admitted with a complaint of pain in right lower limb following low-energy trauma. The patient had a history of Alendronate consumption for more than 10 years. The bone scan revealed increased radiotracer uptake in the right side of the pelvic, proximal right femur, and sacroiliac joint. The radiographs showed type 1 sacrum fracture, acetabulum fracture with femur head protrusion into the pelvis, quadrilateral surface fracture, fracture of the right anterior column, and right superior and inferior pubic fracture. The patient was treated with total hip arthroplasty.ConclusionThis case highlights the concerns regarding long-term bisphosphonate therapy and its potential complications.

Fractures atypiques de l’ulna: effet de la courbure de de l’ulna sur la localisation et ma survenue des fractures

IntroductionUlnar fractures associated with long-term bisphosphonate (BPs) therapy are rare, and the nature and extent of this potential risk remains unknown. Although ulna is generally considered a “straight bone”, it actually features a bow anatomically. For this reason, we speculated that ulnar bow may have a role in the development of atypical ulnar fractures (AUFs). Therefore, we compared the location and depth of ulnar bow between AUF patients and patients with atypical fractures other than the ulna. We aimed to answer: (1) whether a correlation exists between the location of the ulna bow and the location of AUFs, (2) whether the degree of ulnar bow affects the occurrence of AUFs. HypothesisUlnar bowing could play a critical role in the location and occurrence of AUFs. MethodsWe retrospectively reviewed the radiographs and medical records of 64 patients with atypical fractures admitted to our department between May 2010 to July 2020. The bow of the ulna was measured using anteroposterior (AP) and lateral radiographs. Bone angulation was described as apex of deformity, with apex lateral bow designated as AP plane bowing and apex posterior bow marked as lateral plane bowing. ResultsIn all patients with atypical fractures, bow locations were measured at the proximal third level to the index line in 68 % of AP plane and 72 % of lateral plane. In patients with AUFs, fracture sites occurred in the range of 20 % to<40 %, except in one patient. Fracture site versus apex lateral bow location and fracture site versus apex posterior bow location showed a statistically significant correlation coefficient of 0.81 (p<0.001) and 0.69 (p=0.003), respectively. In lateral plane, there was a significant difference between AUF patients and patients with atypical fractures other than the ulna in ulnar bow depth (p=0.014). However, no statistically significant differences were found in AP plane (p=0.110). DiscussionIn AUFs, fracture site was highly correlated with ulnar bowing location, and, as the degree of apex posterior bow increased, occurrence of AUFs increased. These findings are helpful in understanding the role of bowing as the ulnar geometry in the development of AUF and early identification of the location of suspicious AUF. Level of evidenceIV.

Untreated Atypical Left Femoral Shaft Fracture: A Case Report of Its Complication

Background: Bisphosphonate therapy is used to manage osteoporosis and decrease the risk of vertebral and hip fractures. These drugs act by suppressing osteoclast activity by inducing the inhibition of bone resorption and increasing bone mineral density. It has been shown that long-term use of bisphosphonate is correlated to a higher incidence of atypical femoral fractures. Case report: This is a case report of an 81-year-old female, on bisphosphonate therapy for 12 years and with chronic left thigh pain for two and a half years who developed an incomplete atypical left femur fracture. What’s special about this case is that the fracture was ignored and then progressed after three months into a complete displaced spiral fracture that required surgical fixation. Conclusion: The benefits of bisphosphonate treatment in preventing osteoporotic fractures outweigh the risk of the occurrence of these atypical fractures. Orthopedic surgeons as well as primary care physicians must keep atypical fractures in their differential diagnosis in patients presenting with prodromal symptoms and who are on long-term bisphosphonate therapy

Atypical femoral fracture mimicking lumbar radiculopathy in two patients taking bisphosphonate long-term: A case report

BackgroundAtypical femoral fracture (AFF) is a rare complication in patients with osteoporosis undergoing long-term bisphosphonate therapy. The most common symptom of incomplete AFF is nonspecific thigh pain, which is often difficult to distinguish from other causes.Case presentationWe present two cases of AFF misdiagnosed as lumbar radiculopathy. Both patients visited our hospital for thigh pain, and in both cases the findings of lumbar spine magnetic resonance imaging showed substantial nerve compression. These patients had been treated for lumbar radiculopathy, but localized symptoms became conspicuous and femoral radiographs revealed complete AFF. The initial radiographs were reviewed retrospectively and revealed slight lateral cortical thickening in the affected femur, denoting a missed incomplete AFF. Internal fixation with intramedullary nails was performed.ConclusionsAFF may mimic lumbar radiculopathy. Therefore, clinicians should consider AFF as a differential diagnosis in older patients with lumbar canal stenosis who are undergoing long-term bisphosphonate therapy and present with thigh pain.

Atypical fractures of the ulna: Effect of bowing of the ulna on fracture location and occurrence

IntroductionUlnar fractures associated with long-term bisphosphonate (BPs) therapy are rare, and the nature and extent of this potential risk remains unknown. Although ulna is generally considered a “straight bone”, it actually features a bow anatomically. For this reason, we speculated that ulnar bow may have a role in the development of atypical ulnar fractures (AUFs). Therefore, we compared the location and depth of ulnar bow between AUF patients and patients with atypical fractures other than the ulna. We aimed to answer: (1) whether a correlation exists between the location of the ulna bow and the location of AUFs, (2) whether the degree of ulnar bow affects the occurrence of AUFs. HypothesisUlnar bowing could play a critical role in the location and occurrence of AUFs. MethodsWe retrospectively reviewed the radiographs and medical records of 64 patients with atypical fractures admitted to our department between May 2010 to July 2020. The bow of the ulna was measured using anteroposterior (AP) and lateral radiographs. Bone angulation was described as apex of deformity, with apex lateral bow designated as AP plane bowing and apex posterior bow marked as lateral plane bowing. ResultsIn all patients with atypical fractures, bow locations were measured at the proximal third level to the index line in 68% of AP plane and 72% of lateral plane. In patients with AUFs, fracture sites occurred in the range of 20% to<40%, except in one patient. Fracture site versus apex lateral bow location and fracture site versus apex posterior bow location showed a statistically significant correlation coefficient of 0.81 (p<0.001) and 0.69 (p=0.003), respectively. In lateral plane, there was a significant difference between AUF patients and patients with atypical fractures other than the ulna in ulnar bow depth (p=0.014). However, no statistically significant differences were found in AP plane (p=0.110). DiscussionIn AUFs, fracture site was highly correlated with ulnar bowing location, and, as the degree of apex posterior bow increased, occurrence of AUFs increased. These findings are helpful in understanding the role of bowing as the ulnar geometry in the development of AUF and early identification of the location of suspicious AUF. Level of evidenceIV.

Bisphosphonate-induced atypical femoral fracture in tandem: long-term follow-up is warranted.

SummaryAlthough bisphosphonates (BPs) are mainly used for the treatment of osteoporosis and are generally safe, long-term use and more dosage as utilised in malignant conditions may be associated with the rare adverse event of an atypical femoral fracture (AFF). Occasionally, the risk of developing an AFF persists long after BPs are withdrawn. A 39-year-old woman who underwent chemotherapy and an autologous stem cell transplantation for multiple myeloma presented to us with history of pain in the left thigh. She had received multiple doses of oral and parenteral BPs for about 10 years in view of the underlying myeloma with osteoporosis. Her investigations showed a suppressed CTX of 192 pg/mL, and radiograph of pelvis displayed thickened cortices with beaking of the left femoral shaft, which was suggestive of an AFF. Following discontinuation of BPs, she underwent prophylactic intra-medullary nailing with which her symptoms improved. Five years later, she presented with similar complaints on the right side. Investigations showed that her bone turnover continued to be suppressed with Cross linked C- Telopeptide of type 1 collagen (CTX) of 165 pg/mL and an X-ray done showed AFF on the right side despite being off BPs. A second intra-medullary nailing was done and on follow-up, she has been symptom-free and independent in her daily activities. Discontinuation of BPs may not prevent the incident second AFF and, therefore, thus warranting long-term follow-up.Learning pointsRegular screening and follow-up of patients who receive long-term bisphosphonate (BP) therapy should be done.Discontinuation of BPs does not preclude the possibility of repeated occurrence of a second AFF.Long-term BP therapy warrants regular monitoring and follow-up should an AFF occur

Risk factors for development of Atypical Femoral Fractures in patients on long-term oral Bisphosphonate therapy

Risk factors for development of Atypical Femoral Fractures in patients on long-term oral Bisphosphonate therapy

Atypical Femoral Shaft Fractures secondary to long-term Bisphosphonate therapy

Atypical Femoral Shaft Fractures secondary to long-term Bisphosphonate therapy

Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis.

Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. We analyzed the trabecular microarchitecture, bone metabolism, and material strength of iliac crest bone biopsy samples from 10 female patients with rheumatoid arthritis who received an average of 6.7years of BP therapy for GIO (GIOBP group), compared with those of 10 age- and bone mineral density (BMD)-matched non-rheumatoid arthritis postmenopausal women (reference group). Patients in the GIOBP group had a significantly greater fracture severity index, as calculated from the number and the extent of vertebral fractures compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. Our findings indicate that patients receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

Atypical Femur Fracture in the Setting of Long-Term Bisphosphonate use for Osteogenesis Imperfecta: A Case Report

Bisphosphonate (BP) therapy for moderate to severe osteogenesis imperfecta (OI) has become a mainstay of treatment in the last three decades. Given the significant improvements in bone mineral density and theoretical reductions in fracture risk, many patients are treated with bisphosphonates for prolonged periods of time. There currently lacks consensus in the optimal duration of BP therapy for patients with OI, and patients are often treated on a case-by-case basis. Long-term BP therapy has been associated with atypical femur fractures in adult patients treated for osteoporosis. The American Society for Bone and Mineral Research concluded that the median duration of BP therapy in patients with atypical femur fractures was 7 years. The role of long-term BP therapy in OI patients with atypical femur fractures remains unclear. Here, a case report is presented of an adolescent patient with type V OI that sustained a subtrochanteric femur fracture with features of an atypical pattern following treatment with intravenous pamidronate for 10.5 years. At the time of injury, the contralateral femur was also found to have atypical features suggestive of an impending fracture. The completed fracture was treated with closed reduction and cephalomedullary nail fixation. The impending fracture was prophylactically stabilized using the same technique. Prior to the injury, limb-length radiographs obtained to evaluate lower extremity alignment demonstrated features of an impending fracture but went unnoticed. Further studies are needed to clarify the role of long-term BP therapy in patients with OI suffering from atypical femur fractures.

Atypical fixation failure after the internal fixation of a peri-implant subtrochanteric fracture in a patient on long-term bisphosphonate therapy and its management: An interesting case report

Atypical fixation failure after the internal fixation of a peri-implant subtrochanteric fracture in a patient on long-term bisphosphonate therapy and its management: An interesting case report

Long-term bisphosphonate therapy and atypical femoral fracture: Can you have too much of a good thing?

The long-term, continuous use of bisphosphonates (beyond 5 years) is not wholly without risk. Atypical femoral fracture is an uncommon but potentially very serious adverse event associated with the long-term use of bisphosphonates. Here we consider the complexities of long-term bisphosphonate prescribing, particularly in those that are low risk of osteoporotic fracture, wherein the duration of therapy should be reviewed regularly with individualised risk assessment to ensure the duration of treatment is appropriate.