Prolonged Use Of Bisphosphonates Research Articles

Effectiveness of acidified electrolyzed water in the prevention of bronj after exodonts: experimental study in wistars rats

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a complication associated with dental intervention and prolonged use of bisphosphonates (BF). Acidified Electrolyzed Water (AEA) is a substance that seems to improve tissue regeneration. To evaluate the effectiveness of (AEA) as an adjuvant in the treatment of BRONJ after lower molar extractions in Wistar rats. A split-mouth study was carried out in twelve Wistar rats (6 females and 6 males) received weekly intravenous injection of 0.3 mL of zoledronate (80 μg/kg in PBS) for 9 weeks and underwent tooth extraction. mandibular first and second molars in the eighth and ninth week, respectively. The Acidified Electrolyzed Water (AAG) group (right side of the mandible) was irrigated with AEA every three days while the control group (CG) (right side of the mandible) received no treatment after extractions. The animals were euthanized 6 weeks after the second extraction, the mandibles were dissected for clinical analysis with the data obtained submitted to statistical analysis with a significance level of 0.05. (Fischer's test). Two males were lost during AEA therapy, leaving 10 animals, 6 females and 4 males. Inflammation was absent in all alveoli; bone sequestration was noted in all alveoli; suppuration was present in 3 sites of the GC group, epithelialization present in 5 GAEA alveoli and 2 GC. Comparison of bone exposure did not show statistically significant results. The results obtained were slightly favorable to the use of AEA, however, without statistical significance.

Abstract #1408105: Treatment of Bisphosphonate Associated Atypical Femur Fracture with a Combination of Teriparatide and a Novel Surgical Technique

Atypical femur fractures (AFF) caused by long term Bisphosphonate use are associated with high rates of delayed healing and non-union, posing a significant challenge in the management of these patients. We describe the case of a 64-year-old female with osteopenia on Bisphosphonate therapy for 15 years who sustained a displaced left AFF following a fall from standing height. She reported a 6-month history of antecedent left groin pain. Radiographs of the left femur showed an acute displaced transverse diaphyseal fracture with lateral cortical thickening and beaking. The right femur radiograph showed features of abnormal cortical remodeling with thickened, irregular cortices. DEXA showed T-scores of -2.1 at the left femoral neck, -1.4 at the left total hip, and -1.4 at the lumbar spine. She underwent an open reduction and internal fixation with insertion of a cephalomedullary nail placed in compression mode. A novel technique of intraoperative removal of the endosteal hypertrophied cortical bone at the fracture with a Midas rex cutting burr was used and there was excellent cortical contact after reduction. She had immediate relief of her pain and was permitted to fully weight-bear postoperatively. Her bisphosphonate was stopped immediately and Teriparatide was initiated at 7 weeks post-operatively. Radiographs 8 weeks after initiation of Teriparatide showed evidence of normal fracture union with mature callus formation. AFF caused by prolonged Bisphosphonate use have a high rate of delayed healing and non-union due to abnormal bone remodeling. Use of Teriparatide post-operatively has been shown to reduce healing time in recent small studies in surgically treated patients. Our case demonstrates expedited healing time when Teriparatide was combined with a novel surgical technique involving removal of a portion of the abnormal fracture end and placement of an intramedullary nail in compression mode. Furthermore, the patient had radiographic evidence of cortical thickening on her right femur, increasing her risk for contralateral AFF. Prophylactic surgical stabilization was recommended but the patient has deferred this. She remains fracture-free and pain-free on the right side, suggesting a possible benefit of Teriparatide use in patients at risk for impending AFF. Our case demonstrates an expedited healing time (3.5 months) relative to previously reported average healing times for AFF (10.7 months), supporting the use of the combination of Teriparatide and a novel surgical technique.

Medication-induced osteonecrosis of the maxilla, potentiated by fungical infection: Case report

Osteonecrosis of the jaws induced using bisphosphonates refers to a condition characterized by the exposure of necrotic bone, usually in the face region and commonly originating from trauma. Osteonecrosis induced by bisphosphonates has its highest prevalence in the mandible and may be initially manifested by ulcerations in the oral mucosa, which expose the underlying bone due to its poor vascularization and the use of bisphosphonates. Bisphosphonates are indicated for the treatment of several comorbidities, such as malignant tumors, bone metastases, osteoporosis. Actinomycosis is rarely a pathological concern due to the low virulence of the organism, but it can manifest itself when associated with other pathologies such as osteonecrosis. The clinical case presents a patient who made prolonged use of bisphosphonates associated with low-intensity trauma evolving to maxillary osteonecrosis potentiated by actnomyses. This article aims to demonstrate the connection between actinomycosis and chronic osteonecrosis and the importance of correct diagnosis for correct treatment.

Beta tricalcium phosphate, either alone or in combination with antimicrobial photodynamic therapy or doxycycline, prevents medication-related osteonecrosis of the jaw

Surgical trauma in those under a prolonged use of bisphosphonates, can lead to mediation-related osteonecrosis of the jaw (MRONJ). This study aimed to evaluate the preventive therapies for MRONJ. Following four cycles of zoledronic acid administration, Wistar rats had their molar extracted, and were organized into nine treatment groups: negative control group (NCG), treated with saline solution and blood-clot in the alveolus; positive control group (PCG), with blood-clot in the alveolus; BG, β-tricalcium phosphate-based biomaterial; DG, 10% doxycycline gel; aG, antimicrobial photodynamic therapy; and DBG, aBG, aDG, and aDBG, using combination therapy. After 28 days, the lowest bone volume (BV/TV) was reported in PCG (42.17% ± 2.65), and the highest in aDBG (69.85% ± 6.25) (p < 0.05). The higher values of daily mineral apposition rate were recorded in aDBG (2.64 ± 0.48) and DBG (2.30 ± 0.37) (p < 0.001). Moreover, aDBG presented with the highest neoformed bone area (82.44% ± 2.69) (p < 0.05). Non-vital bone was reported only in the PCG (37.94 ± 18.70%). Owing to the key role of the biomaterial, the combination approach (aDBG) was the most effective in preventing MRONJ following tooth extraction.

ATYPICAL FEMORAL FRACTURES DUE TO THE USE OF BISPHOSPHONATES: EPIDEMIOLOGIC STUDY IN A TERTIARY HOSPITAL.

ABSTRACTObjective:Show the relationship between atypical femoral fractures and prolonged use of bisphosphonates and analyze the limit of its beneficial use.Methods:Retrospective cohort study (level of evidence 2B). From Atypical fracture cases, patients who used bisphosphonates were selected and the time period of their use was analyzed. Additionally, the variables sex, age, and the side most affected were studied.Results:Nine atypical femur fractures were found, all associated with the use of bisphosphonates. The average period of use of this medication was nine years (minimum of three years; maximum of 14 years). The patients’ mean age was of 78 years (69-88 years) and all were women, with the right member being the most affected.Conclusion:The use of bisphosphonates to prevent osteoporotic fractures has been increasingly frequent and, when used for a prolonged period, it has been related to atypical fractures. Further scientific studies on doses, maximum periods of treatment, and risk-benefit in the indication of these medications are needed to assist in therapeutic management for each case. Level of Evidence II, Retrospective Study.

Surgical and Pharmacological Management of Periprosthetic Atypical Femoral Fractures: A Narrative Literature Review.

IntroductionAn increasing number of patients is annually undergoing total hip arthroplasty (THA), and a significant proportion of these patients are elderly and consequently at a higher risk of complications because of age, osteoporosis, and medical comorbidities. Periprosthetic femoral fractures (PFFs) are one of the worst complications of THA associated with high rates of unfavorable prognosis. Besides, in the last decade, a new independent disease entity called “atypical femoral fracture” (AFF) has been identified and defined by the American Society for Bone and Mineral Research (ASBMR) task force. Some PFFs present clinical history and radiographic aspect consistent with an AFF, meeting the ASBMR criteria for the diagnosis of AFF except that PFFs by themselves are an exclusion criterion for AFF. However, there is an increasing number of published studies suggesting that periprosthetic atypical femoral fractures (PAFFs) exist and should not be excluded by definition.SignificanceNowadays, although there is an increasing interest in PAFFs, there are still very few studies published on the topic and a lack of consensus regarding their treatment. This narrative literature review aims to introduce this new emerging topic to a wider readership describing the characteristics of PAFFs and the state-of-the-art in their management.ConclusionsMany authors agree that PAFFs should be considered as a subgroup of PFFs that have atypical characteristics; they also show a significant correlation with prolonged bisphosphonate use. A correct diagnosis is paramount for proper treatment of the disease that requires both surgical and medical actions to be taken.

Duration-Dependent Increase of Human Bone Matrix Mineralization in Long-Term Bisphosphonate Users with Atypical Femur Fracture.

Bisphosphonates (BPs) are the most widely used drugs for the treatment of osteoporosis but prolonged use of BPs might increase the risk of atypical femur fracture (AFF). There are only a few studies that address the bone material quality in patients on long-term BP treatment with or without AFFs. We analyzed 52 trans-iliac bone biopsies from patients on long-term BP therapy with (n=26) and without (n=26) AFF. At the microscopic level, the degree of mineralization of bone (DMB) was assessed on whole bone by X-ray digitized microradiography while microhardness by Vickers microindentation, and bone matrix characteristics by Fourier transform infrared microspectroscopy (FTIRM) (mineral/organic ratio, mineral maturity and crystallinity, and collagen maturity) were measured at random focal areas. The AFF patients were treated longer than non-AFF patients (9.7 ± 3.3 years versus 7.9 ± 2.7 years). As expected, bone remodeling was low in both groups, without difference between them. The AFF group had significantly higher DMB in cortical bone (+2.9%, p=.001), which remained so after adjusting for treatment duration (p=.007), and showed a trend in cancellous bone (+1.6%, p=.05). Consistent with higher DMB, heterogeneity index (HI) was lower in the AFF than in the non-AFF group, illustrating lower heterogeneity of mineralization in the AFF group. A significant positive correlation between the duration of treatment and DMB in cortical bone was found in AFF, and not in the non-AFF group. Microhardness and bone matrix characteristics were similar between groups. We conclude that the AFF group had a duration-dependent increase in DMB leading to a significantly higher DMB than the non-AFF. Because BPs have high affinity to bone mineral and lining the walls of the osteocyte lacunae, the accumulation of matrix-bound BPs in AFF could lead to inhibition of the osteocyte cytoskeleton blunting their response to mechanical strains, a hypothesis to be further investigated. © 2021 American Society for Bone and Mineral Research (ASBMR).

Controversies in the treatment of postmenopausal osteoporosis: How long to treat with bisphosphonates?

Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture leading to an increased risk of fractures. Fragility fractures, especially hip fractures, are associated with a significant reduction in the physical function and quality of life of affected patients, as well as increased mortality, leading to a major financial impact on health care. Many drugs have been registered for the treatment of osteoporosis and very recently, a new anabolic agent, romosozumab, has been approved in some countries. Despite the expansion of efficacious antiresorptive and anabolic therapies in recent years, a concomitant increase in concerns have been raised by physicians, patients and the lay press about the potential for adverse events, especially atypical femoral fractures (AFF) following prolonged use of bisphosphonates. Whatever the mechanism(s) may be, direct or indirect, linking prolonged bisphosphonate use to atypical femoral fractures, this adverse event is very rare in comparison to the magnitude of risk reduction of typical osteoporotic fractures. An estimated 162 osteoporosis-related fractures are prevented for each atypical femoral fracture associated with an anti-resorptive medication. Until a risk calculator for predicting risk of atypical fractures, becomes available in clinical practice, and we view this as an unlikely scenario, it is up to the physician to consider continuing or discontinuing bisphosphonate use after the critical 3-5 year period of treatment with zoledronic acid or alendronate, but close monitoring for the residual bone effects overtime should be planned. For other bisphosphonates, in which no residual effects are expected, drug holiday is usually not applied.

Atypical stress femoral shaft fracture secondary to alendronate therapy

Bisphosphonate (BP) therapy is widely used as it remains the first-line of treatment for osteoporosis. These antiresorptive drugs inhibit osteoclast function and promote apoptosis. However, atypical stress femoral fractures occurring in the diaphysis and subtrochanteric region are linked to prolonged BP use. The risk of fracture is directly proportional to the time exposed to the treatment. Ongoing BP exposure prevents bone resorption and replacement in areas with accumulated microdamage through targeted remodeling. Therefore, long-term BP use (more than 5 years) is an important risk factor. Atypical femoral fractures remain very rare, and the benefits of BP therapy for osteoporotic fracture prevention and treatment outweigh the risk. The present report consists of a rare case of a patient with an atypical diaphyseal femoral stress fracture secondary to prolonged alendronate use.

Surgical Fixation of Atypical Femur Fractures in Bisphosphonate-treated Patients.

ObjectiveTo evaluate the outcomes of the surgical fixation of atypical femoral fractures in bisphosphonate-treated patients with an intramedullary device.Materials and methodsThis multicentric study was carried out at the department of orthopedics, Dr. Ruth Phau Civil Hospital and Medicare Hospital, Karachi, Pakistan, between 2013 and 2018. In this retrospective observational study, we reviewed 10 bisphosphonate-treated patients, fixed surgically with an intramedullary nail after presenting with radiologically characteristic atypical femur fractures identified according to the American Society for Bone and Mineral Research criteria. We excluded patients with fractures sustained by high-energy trauma, road traffic accidents, fall from a height, and those associated with underlying malignancy.ResultsA total of 11 atypical femoral fractures in 10 patients were included, all of whom were females with a mean age of 68.6 (range 57-82) years. Out of 11 fractures, 81.8% (n=9) were located in the subtrochanteric region and two were located in the femoral shaft. The mean bisphosphonate use was 58.3 months. All patients were treated with intramedullary devices; an intramedullary interlocking nail in two cases and proximal femoral nail antirotation in nine cases. The mean follow-up duration was 12 months. All fractures were united in an average time of 9.9 months (range 6 - 16 months). Implant failure and/or nonunion were not observed, whereas delayed union was noted in five patients.ConclusionIntramedullary fixation is a reliable method for the treatment of atypical femur fractures in bisphosphonate-treated patients owing to its intramedullary placement. These devices act as an internal splint and can provide much more axial stability, reducing the risk of implant fatigue failure due to a delay in fracture healing from prolonged bisphosphonate use.

Successive ipsilateral atypical fractures of the left femoral neck andof the diaphysis. Case report and review of the literature

We present the case of an elderly osteoporotic woman who for the second time and successively has atypical ipsilateral fractures of the left femur, the first one of the diaphysis (AO32A3) and the second basicervical (AO31A1) intracapsular neck of the femur. It is thought that the cause of diaphyseal fracture is by osteoporosis therapy with alendronic acid for 10 years, but for the one of the femoral neck we have several theories: the prolonged use of bisphosphonates, abnormal gait in abduction becausethe intramedullary nail to treat the diaphyseal fracture with technical failures, very prominent in the trochanter and the proximal anti-rotating pin at the base of the femoral neck. We present anon-frequent case of an atypical fracture of the femoral neck,subsequent to a diaphyseal fracture of the same femurin an osteoporosis patient treated with bisphosphonates.

Interaction of Microcracks and Tissue Compositional Heterogeneity in Determining Fracture Resistance of Human Cortical Bone.

Recent studies demonstrated an association between atypical femoral fracture (AFF) and long-term bisphosphonate (BP) use for osteoporosis treatment. Due to BP treatment, bone undergoes alterations including increased microcrack density and reduced tissue compositional heterogeneity. However, the effect of these changes on the fracture response of bone is not well understood. As a result, the goal of the current study is to evaluate the individual and combined effects of microcracks and tissue compositional heterogeneity on fracture resistance of cortical bone using finite element modeling (FEM) of compact tension (CT) specimen tests with varying microcrack density, location, and clustering, and material heterogeneity in three different bone samples. The simulation results showed that an increase in microcrack density improved the fracture resistance irrespective of the local material property heterogeneity and microcrack distribution. A reduction in material property heterogeneity adversely affected the fracture resistance in models both with and without microcracks. When the combined changes in microcrack density and tissue material property heterogeneity representing BP treatment were evaluated, the models corresponding to BP-treated bone demonstrated reduced fracture resistance. The simulation results also showed that although microcrack location and clustering, and microstructure significantly influenced fracture resistance, the trends observed on the effect of microcrack density and tissue material property heterogeneity did not change. In summary, these results provide new information on the interaction of microcracks, tissue material property heterogeneity, and fracture resistance and may improve the understanding of the influence of mechanical changes due to prolonged BP use on the fracture behavior of cortical bone.

Atypical fractures: An issue of concern or a myth?

Atypical Femoral Fractures (AFF) represent fractures located between the lesser trochanter and the supracondylar flare of a femur. An increasing pool of evidence supports their association with the prolonged use of bisphosphonates, even though a direct correlation is yet to be proved. The purpose of this review is to encapsulate the current evidence associating bisphosphonate use and the development of AFFs, the clinical features related to their presentation, as well as to report the armamentarium of strategies available in the prevention and treatment of AFFs. Based on these evidence, we propose a management algorithm for AFFs, that can serve as a guide for patients presenting with this condition.

Bilateral patellar fractures and increased cortical bone thickness associated with long-term oral alendronate treatment in a cat

Case summaryA 14-year-old cat presented with bilateral patellar fractures and radiographically thickened tibial cortices. This cat had been treated with alendronate for 8 years prior to presentation. To remove the subjectivity of the radiographic evaluation, tibial radiographs from 35 apparently healthy geriatric cats were used for comparison. Cortical and diaphyseal thickness were measured at the proximal and distal thirds of the tibia. Our cat had increased cortical bone thickness compared to that of the control cats.Relevance and novel informationTreatment with bisphosphonates can lead to brittle bones and fractures after prolonged use in humans. This is the first description of fractures and cortical bone changes that may have been associated with prolonged bisphosphonate use in a cat. Radiographic measurements of cortical bone thickness may identify cats that are at increased risk for bone pathology secondary to prolonged alendronate use.

Long-term use of bisphosphonates in osteoporosis.

Objectives:To report and describe the management and response to treatment of patients referred to the osteoporosis clinic after prolonged use of bisphosphonate BPs) (4 years and more) with and without new fracture (any site) or any other new skeletal symptoms.Methods:This is a single center observational retrospective cohort study conducted from January 2009 to May 2016 in a tertiary center. We describe cause of referral, X-rays findings, management, and response to treatment.Results:Thirty-four patients, aged 46-89 years, were collected. Reason for referral included review of therapy (11 patients), recent low trauma fracture (21 patients), or chronic severe thigh pain (2 patients) of unknown etiology. All patients with fracture or thigh pain (23/34 patients) were treated with teriparatide 20 mcg daily. Sixteen of them (16/23) completed teriparatide course (18-24 months), 11 patients had complete healing of fracture at the end of the course, and 5 remained with nonunion of fracture, the remaining 5 patients were lost to follow up.Conclusion:Prolonged use of bisphosphonates can lead to atypical femoral fracture that may involve sites other than femoral shaft or rarely chronic thigh pain without fracture. Teriparatide may facilitates fracture healing and improve thigh pain.

Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures

IntroductionPatients may be at an increased risk of atypical proximal femoral fractures with prolonged bisphosphonate use. Patients and methodsThis was a retrospective review of patients who sustained a subtrochanteric fracture of the femur in our department between April 2009 and March 2014. The radiographs were reviewed for features of atypical femoral fractures as described by the American Society of Bone Mineral Research. Results185 patients were coded according to the National Hip Fracture Database as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients had radiographic findings consistent with an atypical subtrochanteric fracture. 5 patients were excluded as their histology confirmed malignancy. 12 patients were taking bisphosphonates on admission. All 12 patients were females taking alendronic acid on admission, who sustained the fracture as the result of minimal or no trauma and underwent long gamma nail fixation. The mean age was 71.6 years (range 62–79 years). The mean length of time on bisphosphonates prior to admission was 8.33 years (range 3–25 years). 9/12 patients had pre-existing symptoms for between 5days and 2 years prior to admission. 1 patient sustained a broken gamma nail 14 weeks post-operatively requiring revision. The mean time to discharge from theatre was 16days (range 5–57days). The mean time to radiological union in the patients in whom there was evidence was 24 weeks. ConclusionsIn this small group of patients, management of this fracture pattern can be complex with the potential for delayed or non-union and prodromal symptoms are common.

Bisphosphonates Are Not Always Helpful: Commentary on an article by Hae-Seong Lim, MD, et al.: "Factors Associated with Increased Healing Time in Complete Femoral Fractures After Long-Term Bisphosphonate Therapy".

Somewhere between 20% and 33% of people will sustain an osteoporotic fracture during their lifetime1. Preventative treatment has mainly been antiresorptive therapy, such as bisphosphonates. These medications have reduced the risk of fractures in large clinical trials2,3. Unfortunately, prolonged use of bisphosphonates is associated with relatively rare but potentially troublesome atypical femur fractures (AFFs)4,5. We are just beginning to understand the clinical scenario of AFFs and develop patient treatment plans. The occurrence of AFFs is still relatively rare for bisphosphonate users6,7. Lim et al. have now evaluated 109 AFFs in 99 consecutive patients who had been operatively treated for complete AFFs. AFFs were defined by characteristic radiographic features, including a transverse or short oblique fracture line, medial spike, focal lateral cortical thickening, and no or minimal comminution, according …

Atypical Fractures Following Bisphosphonate Therapy.

Bisphosphonates have been widely used in the treatment of osteoporosis with well-documented long-term efficacy and safety, particularly in postmenopausal patients. But over the past decade, low-energy atypical subtrochanteric and proximal diaphyseal femoral fractures have emerged as an unexpected complication of prolonged bisphosphonate use. To the radiologist unfamiliar with this entity, the findings may be subtle and often missed, potentially evolving from an early incomplete fracture to a displaced complete fracture with a delay in diagnosis.In such instances where the radiographic findings are negative or equivocal and patients present with prodromal symptoms of aching or dull groin or thigh pain, additional work-up with advanced imaging techniques, such as magnetic resonance imaging, computed tomography, or bone scintigraphy, may prove diagnostic owing to their multiplanar capabilities and earlier detection of subtle periosteal changes. It is imperative that radiologists develop a search pattern to help identify such fractures and consider imaging evaluation of the contralateral extremity in suspected cases with prodromal symptoms to assess for an incomplete asymptomatic or minimally symptomatic fracture.

Outcomes between older adults with atypical and typical femoral fractures are comparable

IntroductionAtypical femoral fractures (AFFs) are rare but a serious complication associated with prolonged use of bisphosphonates. However little is known about clinical outcomes of AFFs. The aim of this study is to compare the characteristics and postoperative outcomes between older patients with AFFs and typical femoral fractures (TFFs). MethodsA retrospective matched cohort study (each AFF was age- and sex-matched with three TFFs) of patients aged 65 years or older who were admitted to The Queen Elizabeth Hospital, South Australia between January 2011 and December 2013 was undertaken. Baseline characteristics of both groups were compared. The primary outcomes evaluated were level of independence in mobility at discharge and 3 months after surgery. Secondary outcomes included length of hospital stay, post-operative complications, rate of surgical revision, discharge destination (after acute hospital stay or rehabilitation), 28-day hospital readmission and 12-month mortality. ResultsTen patients (mean age: 78.1 years) with AFFs were compared with 30 matched TFFs. Patients with AFFs were predominantly female (90%) and 80% had been taking oral bisphosphonate. Nine of the AFFs had their fractures fixed with an intramedullary (IM) nail. The level of independent mobility at discharge (OR 0.31; 95%CI: 0.06–1.71; p=0.26) and at 3 months (OR 0.51; 95%CI: 0.10–2.53; p=0.47) were comparable between the two groups. Only one AFF patient treated with plate and screws required surgical revision, compared with none in the TFF group. Secondary outcomes were not significantly different between the two groups. ConclusionRecovery of mobility and reoperation rates after surgery of patients with AFFs were favourable and did not differ significantly from TFFs. Further consideration should be given to using IM fixation in the management of AFFs in older people.

Assessment of the effect of reduced compositional heterogeneity on fracture resistance of human cortical bone using finite element modeling

The recent reports of atypical femoral fracture (AFF) and its possible association with prolonged bisphosphonate (BP) use highlighted the importance of a thorough understanding of mechanical modifications in bone due to bisphosphonate treatment. The reduced compositional heterogeneity is one of the modifications in bone due to extensive suppression of bone turnover. Although experimental evaluations suggested that compositional changes lead to a reduction in the heterogeneity of elastic properties, there is limited information on the extent of influence of reduced heterogeneity on fracture resistance of cortical bone. As a result, the goal of the current study is to evaluate the influence of varying the number of unique elastic and fracture properties for osteons, interstitial bone, and cement lines on fracture resistance across seven different human cortical bone specimens using finite element modeling. Fracture resistance of seven human cortical bone samples under homogeneous and three different heterogeneous material levels was evaluated using a compact tension test setup. The simulation results predicted that the crack volume was the highest for the models with homogeneous material properties. Increasing heterogeneity resulted in a lower amount of crack volume indicating an increase in fracture resistance of cortical bone. This reduction was observed up to a certain level of heterogeneity after which further beneficial effects of heterogeneity diminished suggesting a possible optimum level of heterogeneity for the bone tissue. The homogeneous models demonstrated limited areas of damage with extensive crack formation. On the other hand, the heterogeneity in the material properties led to increased damage volume and a more variable distribution of damage compared to the homogeneous models. This resulted in uncracked regions which tended to have less damage accumulation preventing extensive crack propagation. The results also showed that the percent osteonal area was inversely correlated with crack volume and more evenly distributed osteons led to a lower amount of crack growth for all levels of material heterogeneity. In summary, this study developed a new computational modeling approach that directly evaluated the influence of heterogeneity in elastic and fracture material properties on fracture resistance of cortical bone. The results established new information that showed the adverse effects of reduced heterogeneity on fracture resistance in cortical bone and demonstrated the nonlinear relationship between heterogeneity and fracture resistance. This new computational modeling approach provides a tool that can be used to improve the understanding of the effects of material level changes due to prolonged BP use on the overall bone fracture behavior. It may also bring additional insight into the causes of unusual fractures, such as AFF and their possible association with long term BP use.