Atypical Femoral Fractures Research Articles

Bisphosphonates and atypical femoral fractures: Is the location of the fracture associated with the time of consolidation?

IntroductionBisphosphonates are commonly prescribed to mitigate the effects of osteoporosis, a condition associated with an increased risk of fracture.However, despite their success, there has been growing concern regarding the long-term use of bisphosphonates because of the increased risk of atypical subtrochanteric fractures of the femur (AFFs).The objective of this study was to describe a cohort of patients with AFFs and evaluate the risk of evolving to non-union, the time of consolidation associated with the location of the fracture, the time of use of the drug, and the implant involved in its treatment. MethodsThis retrospective study recruited patients between June 2008 and May 2018. We identified patients with AFFs according to the task force criteria and a history of bisphosphonate use.We included all patients older than 65 years, with long-term use of bisphosphonates, AFF criteria according to the task force, and a follow-up of 12 months or longer.We studied the following variables: the time of use of bisphosphonates, localization of the fracture according to Hyodo et al., implant use, and fracture healing time, considering the presence of bone callus observed in two radiologic projections, which were measured in weeks. ResultsBetween June 2008 and May 2018, 72 patients met the task force criteria for AFFs.A total of 67 patients were included in this study. From this total, 37 were in the proximal region of the femur and 31 corresponded to the diaphyseal region.Univariate and multivariate analyses showed statistical significance in the time of bone healing compared with the different locations of the fracture along the femur. ConclusionAccording to our study, the localization of AFFs in patients with a history of bisphosphonate use influences the duration of bone healing.

Indication and adverse event profiles of denosumab and zoledronic acid: based on U.S. FDA adverse event reporting system (FAERS).

Objective: To investigate adverse events (AEs) associated with denosumab (Dmab) and zoledronic acid (ZA), compare their association strengths, and explore potential applications to provide clinical reference. Methods: We collected data from FAERS from January 2004 to November 2022 and mined AE signals for Dmab and ZA using ROR values. We compared signal intensity for same AEs and investigated off-label use. We also examined their AEs in adjuvant therapy for breast and prostate cancer. Results: 154,735 reports of primary suspect drugs were analyzed in the FAERS database (Dmab: 117,857; ZA: 36,878). Dmab and ZA had 333 and 1,379 AE signals, with 189 overlaps. The AEs of Dmab included death (ROR:3.478), osteonecrosis of jaw (ROR:53.025), back pain (ROR:2.432), tooth disorder (ROR:16.18), bone pain (ROR:6.523). For ZA, the AEs included osteonecrosis (ROR:104.866), death (ROR: 3.645), pain (ROR:3.963), osteonecrosis of jaw (ROR: 91.744), tooth extraction (ROR: 142.143). Among overlap signals, Dmab showed higher strength in exostosis of the jaw (ROR: 182.66 vs. 5.769), atypical fractures (ROR: 55.589 vs. 9.123), and atypical femur fractures (ROR:49.824 vs. 4.968). And ZA exhibited stronger associations in abscess jaw (ROR: 84.119 vs. 11.12), gingival ulceration (ROR: 74.125 vs. 4.827), increased bone formation (ROR: 69.344 vs. 3.218). Additionally, we identified 528 off-label uses for Dmab and 206 for ZA, with Dmab mainly used in prostate cancer (1.04%), breast cancer (1.03%), and arthritis (0.42%), while ZA in breast cancer (3.21%), prostate cancer (2.48%), and neoplasm malignant (0.52%). For Dmab in breast cancer treatment, AEs included death (11.6%), disease progression (3.3%), and neutropenia (2.7%), while for ZA included death (19.8%), emotional disorder (12.9%), osteomyelitis (11.7%). For prostate cancer treatment, Dmab`s AEs were death (8.9%), prostate cancer metastatic (1.6%), renal impairment (1.7%), while ZA`s included death (34.4%), general physical health deterioration (19.9%), and hemoglobin decreased (18.9%). Conclusion: Our analysis of FAERS database provided postmarketing surveillance data and revealed different strengths of reported AE signals between Dmab and ZA in some of their common AEs. It's also worth noting that both drugs have potential off-label applications, which could introduce new AEs. This highlights the necessity for safety monitoring when using Dmab and ZA off-label.

P63-5 Cases of atypical femur fractures; the rare adverse events requiring the multidisciplinary team decision-making

P63-5 Cases of atypical femur fractures; the rare adverse events requiring the multidisciplinary team decision-making

Frequency and pathogenesis of periprosthetic atypical femoral fractures associated with total knee arthroplasty: A multicenter prospective study with complementary histopathological and biomechanical analysis

IntroductionAlthough the diagnostic criteria for atypical femoral fracture (AFF) exclude periprosthetic fractures, reports of periprosthetic femoral fractures with characteristics of AFF are rapidly increasing. In this study, we investigated the frequency and pathogenesis of periprosthetic AFF associated with total knee arthroplasty (TKA) based on a theory of AFF subtypes that divides AFFs into two main types: fragility stress fractures of the bowed femoral shaft in the mid-shaft and “typical” subtrochanteric AFFs due to suppression of bone turnover (e.g., by bisphosphonates). Patients and MethodsThis multicenter prospective study of AFFs was conducted from 2015 through 2022. Clinical, pathological, and morphological characteristics were investigated in patients with periprosthetic AFFs associated only with non-stem TKA. Then, biomechanical investigation of the periprosthetic AFF was performed by computer tomography-based finite element analysis (CT/FEA) using two models with different load axes to examine how the correction of lower limb alignment by TKA influences the tensile stress distribution of the femur and the location of the AFF. ResultsFour of 61 AFFs (6.6%) were identified to be periprosthetic AFF (1 mid-shaft; 3 subtrochanteric). Periprosthetic AFFs had characteristics including mechanical stress due to bowing deformity and potentially suppressed bone turnover due to long-term exposure to specific drugs (e.g., bisphosphonates and glucocorticoids). Although 2 periprosthetic AFFs appeared to involve a bowed femur, one with both of the aforementioned characteristics occurred in the subtrochanteric region, which would be an unusual site for a bowed AFF, and it was demonstrated histologically to have biological activity at the fracture site, suggesting a stress fracture. Furthermore, CT/FEA revealed that tensile stress distribution changed proximally as load axis was shifted laterally according to correction of lower limb alignment by TKA. ConclusionOrthopedic surgeons should recognize the presence of TKA-associated periprosthetic AFF caused by various factors including specific drugs, bowing deformity, and lower limb alignment. X-rays of the full-length femurs should be checked regularly after TKA, especially in patients with bowed femurs or long-term exposure to specific drugs.

Bone alterations of pamidronate therapy in children with cerebral palsy complicating orthopedic management.

Cerebral palsy (CP) is a heterogeneous group of disorders with different clinical types and underlying genetic variants. Children with CP are at risk for fragility fractures secondary to low bone mineral density, and although bisphosphonates are prescribed for the treatment of children with bone fragility, there is limited information on long-term bone impact and safety. Children with CP usually present overtubulated bones, and the thickening of cortical bone by pamidronate treatment can potentially further narrow the medullary canal. Our purpose was to report bone alterations attributable to pamidronate therapy that impact orthopedic care in children with CP. The study consisted of 41 children with CP treated with pamidronate for low bone mineral density from 2006 to 2020. Six children presented unique bone deformities and unusual radiologic features attributed to pamidronate treatment, which affected their orthopedic care. The cases included narrowing of the medullary canal and sclerotic bone, atypical femoral fracture, and heterotopic ossification. Treatment with bisphosphonate reduced the number of fractures from 101 in the pretreatment period to seven in the post-treatment period ( P < 0.001). In conclusion, children with CP treated with bisphosphonate have a reduction in low-energy fractures; however, some fractures still happen, and pamidronate treatment can lead to bone alterations including medullary canal narrowing with sclerotic bone and atypical femoral fractures. In very young children, failure to remodel may lead to thin, large femoral shafts with cystic medullary canals. More widespread use of bisphosphonates in children with CP may make these bone alterations more frequent. Level of evidence: Level IV: Case series with post-test outcomes.

THU434 A Case Of An Atypical Femur Fracture Managed Medically With Teriparatide

Abstract Disclosure: S.V. Rupani: None. A. Kotwal: None. L. Graeff-Armas: None. Atypical femur fractures (AFFs) are atraumatic or low-trauma femur fractures located in the sub-trochanteric region or femoral shaft. AFFs represent around 0.5% of all femur fractures. The increased use of bisphosphonates has led to a rise in the incidence of AFFs as it has emerged as a potential complication. While the mechanism of bisphosphonate-related AFFs has yet to be elucidated, one proposed mechanism is that bisphosphonates can cause over-suppression of bone turnover. If over-suppression is a contributing factor, then hypothetically, anabolic therapy can help heal existing fractures and prevent impending fractures by reversing over-suppression. Numerous animal models have demonstrated that parathyroid hormone and teriparatide enhance fracture healing. However, clinical trials and meta-analyses on the effects of teriparatide in fracture healing have been equivocal. There have been both retrospective and prospective studies, along with anecdotal reports demonstrating the benefits of teriparatide in healing in AFFs. However, there have been no randomized controlled trials assessing the efficacy of teriparatide in AFFs. Based on this limited evidence, the American Society for Bone and Mineral Research recommends considering teriparatide in patients who have failed conservative therapy. We present a case of an incomplete AFF in the setting of short-term bisphosphonate use that was managed with teriparatide in addition to conservative measures. Our patient presented with a complete right AFF treated surgically and an incomplete left AFF that we managed medically with teriparatide. Repeat left femur imaging six months after starting teriparatide therapy showed interval callus formation consistent with a healed fracture. Right femur imaging also showed a healing proximal femoral shaft fracture status post intramedullary fixation. She completed twenty-five months of teriparatide therapy and did not sustain any interval fractures. Repeat imaging one year after completion of teriparatide therapy continued to show a stable healed left AFF, along with a healed right AFF. She is currently more than two years post-completion of teriparatide and has remained fracture free. This case highlights the role that teriparatide may have as an option for medical management in incomplete AFFs and to accelerate healing in complete AFFs that have been managed surgically. Furthermore, with therapeutic options for osteoporosis management limited in the post-AFF setting, teriparatide helps increase bone mineral density and reduce future fracture risk. Randomized controlled trials are needed to draw definite conclusions on the efficacy of teriparatide in managing AFFs. However, this is difficult given the rare occurrence of AFFs. Therefore, case reports like ours offer insight into when teriparatide may be helpful in managing AFFs. Presentation: Thursday, June 15, 2023

FRI680 Atypical Femoral Fracture In Patients With Hypophosphatasia: A Systematic Review

Abstract Disclosure: N. Charoenngam: None. J. Thongpiya: None. P. Yingchoncharoen: None. B. Ponvilawan: None. M.S. Marangoz: None. J. Chenbhanich: None. P. Ungprasert: None. A growing number of case reports and case series have demonstrated that atypical femoral fracture (AFF) can occur in patients with hypophosphatasia (HPP). Due to the lack of summary of the clinical manifestation, risk factors, associated ALPL variants and treatment, we conducted this systematic review with the goal to summarize the characteristics of all reported patients with HPP who sustained AFF. Additionally, we aimed to identify all available evidence to quantify the rate of co-existence between HPP and AFF. Potentially eligible articles were identified from MEDLINE and EMBASE databases from inception to September 2022 using search strategy consisting of terms related to “Hypophosphatasia” and “Atypical femoral fracture”. Eligible articles must report one of the following information: 1.) individual data of patient(s) diagnosed with HPP and AFF, 2.) prevalence of HPP among patients with AFF or 3.) prevalence of AFF among patients of HPP. Characteristics of patients reported in each study were extracted. A total of 148 potentially eligible articles were identified from the databases. After systematic review, 23 articles met the eligibility criteria. A total of 27 patients with AFF and HPP were identified. The mean ± SD age of the reported patients was 53.8 ± 12.7 years and 21 patients (77.8%) were female. Nine patients (33.3%) received antiresorptive medication (bisphosphonate and/or denosumab) and two patients (7.4%) received teriparatide prior to development of AFF. Seven (25.9%) and 17 (63.0%) patients sustained unilateral and bilateral AFF, respectively. Twelve patients (44.4%) had a history of fractures at other sites. Four (14.8%) and six (21.4%) patients received asfotase alfa and teriparatide after sustaining AFF. Two studies that reported the prevalence of AFF among patients with HPP of approximately 10%. One study reported one HPP patient in a cohort of 72 patients with AFF. In summary, based on the limited evidence, AFF occurred in up to 10% of patients with HPP. Based on the 27 case reports, almost two-thirds did not receive antiresorptive treatment, suggesting the HPP itself could potentially be a risk factor for AFF. Presentation: Friday, June 16, 2023

THU435 Atypical Femur Fractures In Antiresorptive- Therapy-naïve Patient Underscores Knowledge Gaps

Abstract Disclosure: T.L. Cater: None. M. Styner: None. Atypical femur fractures (AFF), so-named due to an unusual diaphyseal location, have been linked to antiresorptives (AR), though this remains unclear. AFF case reports are vital due to a lack of certainty about pathogenic mediators and management. Case: A 52-yr-old-female presented with symptomatic T6/T7/T8 compression sustained while raking acorns. Ten years prior, bilateral knee/thigh pain developed; X-ray showed mild arthritis; bone scan noted slight activity in lateral femoral cortices with later X-ray read as negative for fracture; DEXA indicated lowest T of −1.5 in the spine. She was managed with PT and bracing. Medical history included hip dysplasia s/p casting, endometriosis, infertility, hypothyroidism, and 2 full-term NSVD in her late 30s. She worked as an administrator before becoming a stay-at-home mom and denied alcohol or tobacco use. Family history was notable for hip fracture (mother) and hypermobility termed as Ehlers-Danlos (son). After thoracic healing, at 53, she was referred to endocrinology; exam showed Ht 69 in (175 cm), Wt 185 lb (83 kg), normal dentition, mild thoracic kyphosis without tenderness. Labs indicated normal Ca, Mg, PO4, Creat, 25(OH)D, Alk Phos, and SPEP. She was current on cancer screening including mammograms. She declined osteoporosis therapy, wishing to work on lifestyle, yet, when she returned to our clinic at 55, after new compression (T11/T12/L1), she was amenable to begin abaloparatide. Despite the anabolic, new L2/L3 fracture arose and thigh pain advanced. Genetic Invitae OI/bone fragility panel was negative for causal variants in 46 genes. DEXA showed 20% improved spine BMD: 5-15% in other sites. After 2 years of abaloparatide and 4 months after one-time dose of denosumab, a new L4 deformity arose, and thigh pain remained. She reported legs were giving way under her, prompting X-rays, which were concerning for bilateral AFF (confirmed with bone scan, MRI). In lieu of a 2nd dose of denosumab, romosozumab was started and she was promptly scheduled for prophylactic, orthopedic femoral nailing. Conclusions: This bisphosphonate-naïve-female began experiencing symptoms of AFF &amp;gt;5 years prior to presentation, concomitant with spine fragility. Skeletal deterioration occurred in absence of, as well as contemporaneous with, osteoporosis therapies, anabolic as well as one dose of AR despite improved BMD via DEXA. Her personal history of hip dysplasia might supply clues about geometry that favors AFF as her family history. Notably, long-standing discomfort in the thighs persisted and progressed during anabolic therapy. More research is needed to understand AFF pathogenesis, and this might also shed light on other severe forms of early bone fragility, as demonstrated herein. Our case also highlights a multi-year, sub-clinical period in which fragility progresses until a clinical diagnosis is reached, as well as the clinical conundrum of AFF management. Presentation: Thursday, June 15, 2023

FRI684 So Strong Yet So Fragile: Bilateral Periprosthetic Fractures On Denosumab

Abstract Disclosure: A. Syeda: None. F.S. Mirza: None. Background: Denosumab (DN) is a potent antiresorptive and has been associated rarely with atypical femoral fractures. We hereby report the first case of simultaneous bilateral femoral periprosthetic fractures (PPF) while on DN therapy (DNT). Clinical Case: A 78-year-old female with severe osteoporosis on DNT presented in January 2023 with bilateral femoral PPF after a mechanical fall whereby she tripped and landed on her knees. The patient had initially presented to us in late 2012. Treatment history included alendronate (ALN) for 5 years, on drug holiday since 2010. She underwent bilateral knee replacement surgeries in 2012 and DNT was started in 2013 after initial evaluation. She also had primary biliary cirrhosis, and although bone density (BD) improved on DNT, she exhibited escape from DN mediated suppression of bone resorption possibly related to the liver disease that was previously reported (1). DNT was stopped 5 years later when spine BD improved to osteopenic range and ALN 70 mg weekly was started. 1 year later, bone resorption markers were still elevated and zoledronic acid was substituted for ALN. She fell and had a pubic ramus fracture 11 months later. BD showed a 6% decrease for mean total hip and baseline forearm BD showed T-score of -3.7 on the right. DNT was restarted in December 2020 and continued every 6 months. Her health continued to deteriorate over next two years, with increase in LFTS, new anemia and thrombocytopenia due to a combination of myelodysplastic syndrome and splenomegaly. She also needed transcatheter aortic valve replacement for worsening CHF. She tripped and fell in January 2023. X-ray showed acute supracondylar bilateral PPF with comminution. She was high risk for anesthesia and anticoagulation was withheld due to a history of thrombocytopenia and gastrointestinal bleeding. Prior to the anticipated orthopaedic procedure, the patient developed severe hypotension and a rapid drop in hematocrit due to hemorrhagic shock. The family had requested DNR due to the multitude of medical issues. Conclusion: Occasional PPF have been reported in the setting of DNT, which may reflect the severity of osteoporosis. Altered stress distribution and decreased tensile strength of the bone secondary to screw/pin placement are thought to contribute to PPF, although the occurrence of PPF as an unusual presentation of an AFF cannot be excluded. Contribution of other comorbidities to poor bone quality may also have contributed to the bilateral PPF with poor outcome in our patient. 1. Vedere, T.R. and Mirza, F.S., 2017, April. Escape from Denosumab Mediated Suppression of Bone Resorption in Primary Biliary Cirrhosis. In 99th Annual Meeting of the Endocrine Society. Endocrine Society. Presentation: Friday, June 16, 2023

A population-based registry study of extended bisphosphonate use: minimal shift after landmark publications about shorter treatment duration.

Optimal duration of bisphosphonate therapy was unknown until the FLEX study was published in 2006 showing a 5-year course to be adequate for most women. In 2008 a link between long-term bisphosphonate and atypical femoral fractures was reported and confirmed in later studies. We hypothesized these landmark observations should have led to a decrease in use of bisphosphonates for >5 or 10 years, from 2010 onward. The Manitoba BMD registry with linkage to provincial pharmacy data was used to determine the percentage of long and very-long term bisphosphonate users from therapy start. The cohort comprised women age > 50 with BMD between 1995-2018 with oral bisphosphonate first prescribed for >90 days with adherence >75% in the first year. For each calendar year of continued therapy, the percentage of patients and medication possession rate was tabulated. The percentage of users beyond 5 years was compared between patients who started therapy in 1998-2004 (those taking 5 years of therapy still finish prior to 2010) versus 2005-2012 (all new therapy starts overlap 2010 in those taking ≥5 years treatment). The cohort included 2991 women with mean follow up 8.8(1.3) years, 64.9% of whom took continuous oral bisphosphonate for >5 years and 41.9% for >10 years. In the earlier vs later era, there were 74.4% vs 70.2% who completed 5 years. With respect to longer treatment, there were 68.0% and 60.5% of patients treated for 6 or more years (p < 0.0001) and 46.6% vs 33.5% treated for >10 years (p = 0.08). Medication possession rate was >79% in every year of therapy. Landmark studies leading to more limited bisphosphonate courses may have slightly reduced longer-term treatment, but up to one-third of adherent patients in the modern era still receive continuous bisphosphonate therapy for >10 years. This article is protected by copyright. All rights reserved.

OA07 A case of severe osteoporosis treated with teriparatide following the development of bilateral atypical femoral fractures due to IV zoledronic acid

Abstract Introduction Atypical femoral fractures (AFF) are a rare complication of long-term anti-resorptive therapy. A literature review of 310 cases of AFF did reveal a median duration of bisphosphonate therapy of 7 years. Additionally, simultaneous glucocorticoid use was seen in 34% of the cases and was reported to have a 5-fold increase in one case series. Around 70% of patients do describe a prodrome of thigh pain and around quarter of all cases will have bilateral involvement. Case description A 59-year-old lady with a background diagnosis of Behçet’s disease was referred for continuation of osteoporosis care. History of Fractures 2003- left-sided distal radial fracture; 2017 - refractured again after a fall; left 5th metatarsal fracture a few months later. 2019 - right navicular fracture, left pubic rami fracture and left iliac wing fracture, after a fall from the bus In 2023, she has tripped and fell from the standing height resulting in a left femoral shaft fracture, which had radiological features of an atypical femoral fracture. She denied any prodromal thigh pain. The orthopaedic team did an intramedullary nailing to the left femoral shaft. X-ray of the right femur shaft revealed cortical thickening of right mid femoral shaft. Treatment History In 2009, she was started on oral bisphosphonate therapy and from 2020 to 2022 received 3 doses of IV zoledronic acid at the national Behçet’s centre in Birmingham. She has been on long-term steroid therapy due to the underlying Behçet's disease and was on prednisolone 7mg daily when she was referred to us. Management of AFF The orthopaedic team initially recommended a watch and wait policy for the right side; however, following discussions with the patient and with us, prophylactic nailing of the right femoral shaft was done 2 months later. Investigations DXA scan in 2022: spine T-score of−3.3 (L2 −3.6, L3 −3.9, L4 −3.7); femoral neck T-score of −2.5. Despite treatment with oral and then parenteral bisphosphonates for the last 12 years, there is a significant reduction in BMD with 18.2% decrease in the spine and 7.1% decrease in the femoral neck compared to the last DEXA in 2019. Management plan The next step was to treat her with teriparatide, which she is currently having without any problems. We shall continue it for 24 months. Discussion Atypical femoral fractures are rare. Anti-resorptive medication including bisphosphonates and denosumab are known to cause atypical femoral fractures. Teriparatide, being anabolic agent, is not associated with the increased risk of atypical femoral fractures. While there are no randomised controlled studies about the use of teriparatide in healing atypical femoral fractures, there are some case reports where teriparatide had shown improved fracture healing in AFF. After the 24 months, to ‘lock in the effects’ of teriparatide, an anti-resorptive medication will be required. Because both femoral shafts have received intramedullary nailing, we would consider IV zoledronic acid after the 24 months of teriparatide. This is the approach supported by the European Calcified Tissue Society in their systemic review and recommendations on ‘Medical Management of Patients After Atypical Femur Fractures’ (https://doi.org/10.1210/clinem/dgz295). Key learning points Consider atypical femoral fracture in patients who are on anti-resorptive therapy and complain of thigh/groin pain. Atypical femoral fractures can be bilateral; therefore, evaluate both sides. Teriparatide can be used to treat osteoporosis in patients with atypical femoral fracture, but considerations will have to be made in relation to subsequent therapy.

P06 Think of hypophosphatasia if atypical fracture with persistent low ALP levels

Abstract Introduction Hypophosphatasia (HPP), a rare, underdiagnosed metabolic genetic bone disease caused by diminished or absent expression of the tissue non-specific alkaline phosphatase (TNSALP) enzyme. The mutation of alkaline phosphatase (ALPL) gene leads to wide-ranging clinical manifestations, broadly classified into six different types based on age of onset and severity of the disease. Fragility fractures are predominant characteristics of adult onset HPP and are often misdiagnosed as osteoporosis, stipulating antiresorptive treatment. However, bisphosphonates (BP) make HPP more susceptible to atypical fractures and thus are contraindicated. A recent study shows 1:4 atypical femoral fracture cases are linked with monogenic bone diseases including HPP. Case description A 63-year-old Caucasian female was referred to our osteoporosis clinic, at the age of 57 following an atypical right femur fracture while on bisphosphonate and steroids. Her past medical history includes multiple right thigh sarcoma at the age of 39, 45 and 49 years requiring multiple surgeries and localised radiotherapy. She was also diagnosed with ocular myasthenia gravis two years before the atypical fracture, requiring long term high dose steroids. Her other co-morbidities include type 2 diabetes and hypertension. Due to long term steroids, her primary care physician initiated weekly 70 mg oral alendronic acid. However, three months later she had a spontaneous right mid shaft femur fracture. The patient experienced one year of right thigh pain prior to fracture which was not brought to medical attention. She underwent intramedullary nailing and successful rehabilitation. A thorough assessment in fracture liaison service spotted the history of primary tooth loss with roots intact in childhood, and chronic dental problems crowning in adult life requiring many caps and crowns. Her mother has a history of “childhood onset rickets”, bowing of legs and complete loss of all her permanent teeth at the age of 30 years. A review of blood tests revealed normal calcium, vitamin D and parathyroid levels, multiple low alkaline phosphatase levels between 16 – 23 U/L(normal range 30-130 U/L) prior to bisphosphonates, vitamin B6 fasting blood test had shown raised result at 140 (normal range 40-100). Xray of the left femur was normal. The dual energy X-ray absorptiometry (DEXA) scan yielded normal T score. The genetic test confirmed heterozygous gene mutation in ALPL gene, confirming a diagnosis of hypophosphatasia. She recovered well from her fracture and manages to walk more than one mile unaided. She is currently under regular follow-up in our hypophosphatasia clinic and has stopped bisphosphonates indefinitely. Discussion The underlying cause for atypical femoral fracture (AFF) in this case is multifactorial; long-term steroids, radiotherapy, HPP and bisphosphonate usage. Regardless, there is a relationship between hypophosphatasia and AFF. Some studies have proved that more than 90% of the patients with AFF used long term BPs. The defective ALPL gene in HPP affects bone mineralisation, resulting in accumulation of inorganic pyrophosphate (PPi), which impairs hydroxyapatite crystal formation causing recurrent fractures, osteopenia, delayed wound healing, dental problems, atypical and pseudo fractures. Bisphosphonates are chemical derivates of PPi, and thus inversely affect bone mineralisation especially in cases of TNSALP mutations and thus are contraindicated in HPP. The atypical fractures often may remain undiagnosed for a long time despite often prolonged prodromal pain occurring before the actual fracture. Careful clinical evaluation and plain X-ray will help to make the diagnosis. Hypophosphatasia related fractures mostly occur laterally in the subtrochanteric diaphysis. AFF cases often require surgical repair with intramedullary nailing. If an imminent atypical fracture is diagnosed early, prophylactic surgery is sometimes recommended. After three months of alendronic acid, bone turnover markers are usually suppressed, therefore despite the short time of alendronate exposure, this is likely to have contributed to the atypical femur fracture. Also, genetic test revealed inherited autosomal dominant trait of HPP in this case, enabled family screening and prevention of potential use of future bisphosphonates in affected family members. Key learning points HPP presenting in adulthood may be more common than previously though with a recent study estimating prevalence of the mild HPP genotype to be 1:508, although not all cases will be symptomatic. A persistent low alkaline phosphatase together with a fragility or atypical fracture raises suspicion of hypophosphatasia. A thorough clinical evaluation, fasting vitamin B6 levels, urine phosphoethanol amine levels and ALPL genetic test will aid the diagnosis. Severe cases of hypophosphatasia are treated with asfotase alfa, enzyme replacement therapy, to prevent debilitating complications, while most mild and moderate cases are offered supportive management. Bisphosphonate treatment is contraindicated in hypophosphatasia. It is worth reviewing ALP levels prior to antiresorptive therapy in suspected cases, as bisphosphonates often reduce ALP levels, masking the diagnosis. High risk Osteoporosis cases should be discussed in a multidisciplinary setting with careful risk-benefit evaluation. Cases like this highlight the importance of early HPP diagnosis to avoid contraindicating treatments and their consequences.

OA10 Pregnancy-associated osteoporosis - a rare subset of bone disease

OA10 Pregnancy-associated osteoporosis - a rare subset of bone disease

OA08 Atypical femoral fracture secondary to long term bisphosphonate use; are we doing enough to prevent it?

Abstract Introduction Atypical femoral fractures (AFF) are low energy subtrochanteric or femoral shaft fracture associated with long term use of bisphosphonates (BP). Although the absolute risk of AFF is low and ranges between 3.2-50 cases/100,000 person-years, this risk is said to double with prolonged use (&amp;gt;5 years). ROS and American Society for Bone and Mineral Research (ASBMR) recommends regular review of patient at 5 years for oral BP and 3 years for intravenous BP. We would like to share our experience with two AFF which was seen in our bone clinic over the last one year resulting from prolonged bisphosphonates use. Case description Case 1 A 76-year-old Caucasian lady was reviewed for follow-up appointment in bone clinic for the management of steroid induced osteoporosis. She was on AA for 13 years for primary prophylaxis. It was noted that she was experiencing discomfort in her right thigh for the last 8 months. Her initial femoral X-ray showed incomplete AFF of the right femur and she was referred to orthopaedics who suggested conservative management. 6 months later, she unfortunately had a fall resulting in right femur fracture which required intramedullary nailing. X-ray of the contralateral side shows periosteal thickening and she is waiting for prophylactic nailing. Case 2 79 year old white Caucasian presented to the hospital with a fall. She has been on long term steroids for PMR and was on alendronate for 20 years for primary prophylaxis. X-ray showed complete AFF of proximal right femur shaft which required intramedullary nailing, subsequently developed pain in left hip during physiotherapy and X-ray showed incomplete AFF of mid left femur which needed prophylactic nailing. She was then referred to our clinic for further risk stratification. Both the patients had their bisphosphonates stopped and was advised reduced weight bearing along with calcium and vitamin D supplementation. The table summarises the background history and investigations post presentation with AFF: Discussion Bisphosphonates are one of the mainstays for managing steroid induced osteoporosis and for patients with high risk fragility fractures. Despite the increasing awareness of long term complication, we still see patients with AFF who have missed the opportunity for review in primary and secondary care particularly among patients with primary prophylaxis with satisfactory DEXA scan. ROS and ASBMR recommends review of patients who are on oral bisphosphonates at 5 years and for patients on intravenous bisphosphonates at 3 years for further risk stratification to reduce the incidence of AFFs. It also recommends close monitoring in patients with prodromal pain in the hip, groin or thigh especially in those who have high risk factors such as long term glucocorticoid use, Asian race and femoral bowing. Cessation of bisphosphonates can result in 70% reduction of developing AFF. Hence a break in the treatment for approximately 18-24 months needs to be considered for patients who are at lower levels of risk for fragility fracture such as age &amp;lt;75years, no previous history of fragility fracture, DEXA T score more than −2.5 and low FRAX score. Yet, this is not happening in routine clinical practice both in primary and secondary care and patients fall out of safety netting resulting in AFF. We need robust pathway and safety netting for patients who are on long term treatment. This situation could have also been exacerbated by the COVID pandemic which has increased the waiting lists and cancelled appointments. Resulting in many elderly patients having no follow ups and DEXA assessments for risk stratification. Key learning points Following the COVID pandemic there has been a huge impact on the waiting list, which has further pushed follow-up review for patients on long term bisphosphonates. This has resulted in a missed opportunity to identify patients with low risk to have a break in the BPs treatment. We feel that with appropriate treatment pathways needs to be set at primary care and secondary care level to capture these patients on long bisphosphonates after 3 to 5 years of BP use; especially patients who are at higher AFF risk, including patients on glucocorticoids and patients of Asian ancestry. Steps must be put in place to ensure counselling and education is given to patients about risk of AFF and prodromal symptoms such as thigh or groin pain which are initial symptoms, so that they can seek appropriate review at primary care level. ROS and ASBMR Task Force 2013 need to be implemented locally to capture patients with long term BPs treatment. Also, if patients has AFF fracture, imaging of the other leg has to be considered for further evaluation as more than one fourth of the cases have contralateral lesion.

Atypical Femoral Fracture in Hypophosphatasia: A Systematic Review.

To summarize the characteristics of all reported patients with hypophosphatasia (HPP) who sustained atypical femoral fracture (AFF) and identify all available evidence to quantify the rate of coexistence between HPP and AFF. Potentially eligible articles were identified from the MEDLINE and EMBASE databases from its inception to September 2022, using a search strategy consisting of terms related to "Hypophosphatasia" and "Atypical femoral fracture." Eligible articles must report one of the following information: (1) individual data of patients diagnosed with HPP and AFF, (2) prevalence of HPP among patients with AFF, or (3) prevalence of AFF among patients of HPP. Characteristics of patients reported in each study were extracted. A total of 148 articles were identified. After the systematic review, 24 articles met the eligibility criteria. A total of 28 patients with AFF and HPP were identified. The mean ± SD age of the reported patients was 53.8 ± 12.5 years, and 22 patients (78.6%) were female. Nine patients (32.1%) received antiresorptive medication (bisphosphonate and/or denosumab), and two patients (7.1%) received teriparatide prior to the development of AFF. Seven (25.0%) and eighteen (64.3%) patients sustained unilateral and bilateral AFF, respectively (laterality not reported in three cases). Thirteen patients (46.4%) had a history of fractures at other sites. Four (14.3%) and seven (25.0%) patients received asfotase alfa and teriparatide after sustaining AFF. Two studies reported the prevalence of AFF among patients with HPP of approximately 10%. One study reported one HPP patient in a cohort of 72 patients with AFF. Based on the limited evidence, AFF occurred in up to 10% of patients with HPP. Based on the 28 case reports, about two-thirds did not receive antiresorptive treatment, suggesting that the HPP itself could potentially be a risk factor for AFF.

Prevalence of monogenic bone disorders in a Dutch cohort of atypical femur fracture patients

Prevalence of monogenic bone disorders in a Dutch cohort of atypical femur fracture patients

A Case Report of Oral Bisphosphonate Treatment for Osteoporosis Leading to Atypical Femoral Fracture and Pathologic Mandibular Fracture.

BACKGROUND Bisphosphonates inhibit bone resorption in patients with postmenopausal osteoporosis and reduce osteoporotic fracture incidence. Medication-related osteonecrosis of the jaws (MRONJ) and atypical femoral fractures (AFF) are both rare but serious adverse effects of anti-resorptive drugs (ARD) such as bisphosphonates. The most advanced form of MRONJ is termed stage 3 and can lead to severe local sequelae like pathologic mandibular fractures (PMF). This study reports a case of MRONJ-related PMF and AFF with osteomyelitis secondary to bisphosphonate treatment for osteoporosis. CASE REPORT A 63-year-old white woman was diagnosed with PMF related to MRONJ stage 3 during treatment of an AFF with osteomyelitis. She had been treated for postmenopausal osteoporosis with 70 mg of alendronate weekly for 2 years. The PMF was treated by stable internal fixation combined with debridement and sequestrectomy, but further debridement was required and 2 mandibular implants were then removed. Postoperative recovery was uneventful and the mandibular infection was controlled after the second surgery. Three weeks later, she was discharged from the hospital, instructed to discontinue the use of alendronate, and referred for 30 sessions of hyperbaric oxygen therapy. At the 3-year follow-up, the PMF was completely healed without signs of mandibular infection or bone exposure. CONCLUSIONS This report raises awareness of both MRONJ and AFF as possible adverse effects of short-term bisphosphonate therapy for postmenopausal osteoporosis, and highlights the importance of dental and orthopedic follow-ups. It is crucial to emphasize the need for early diagnosis and treatment to prevent MRONJ progression to PMF.

Could Some Patients With Fibromyalgia Potentially Have Hypophosphatasia? A Retrospective Single-Center Study.

Hypophosphatasia (HPP) is a rare disease characterized by incomplete or defective bone mineralization due to a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP. Disease presentation is heterogeneous and can present as a chronic pain syndrome like fibromyalgia (FM). Our objective was to determine if there are any potential patients with HPP in the group of patients who were diagnosed with FM. Antiresorptive therapy use can trigger atypical femur fractures in patients with HPP. We performed a retrospective chart review of all patients 18 years or older at a single academic center who were diagnosed with FM and had either a low or a normal ALP level. The following characteristics were reviewed: biological sex; age; history of fractures; diagnosis of osteoporosis, osteopenia, osteoarthritis, and chondrocalcinosis; genetic testing; vitamin B6 level testing; and medications. Six hundred eleven patients with FM were identified. Two hundred had at least one low ALP level, and 57 had at least three consecutively low measurements of ALP, 44% of which had a history of fractures. No patients had vitamin B6 levels checked. None of the patients had previous genetic testing for HPP or underwent testing for zinc or magnesium levels. The percentage of patients with FM who were found to have consistently low ALP levels was 9.3%. None had vitamin B6 level or genetic testing, suggesting that the diagnosis was not suspected. It is important to diagnose HPP given the availability of enzyme replacement therapy to prevent complications from HPP such as fractures. Our data support screening for this condition as a part of the initial workup of FM.

Position Statement: Atypical Femoral Fracture from the Korean Society for Bone and Mineral Research in 2023.

As the aging population increases, the number of patients with osteoporosis is gradually rising. Osteoporosis is a metabolic bone disease characterized by low bone mass and the microarchitectural deterioration of bone tissue, resulting in reduced bone strength and an increased risk of low-energy or fragility fractures. Thus, the use of anti-resorptive agents, such as bisphosphonates (BPs), to prevent osteoporotic fractures is growing annually. BPs are effective in reducing hip and other fractures. However, the longer a patient takes BPs, the higher the risk of an atypical femoral fracture (AFF). The exact mechanism by which long-term BP use affects the development of AFFs has not yet been clarified. However, several theories have been suggested to explain the pathogenesis of AFFs, such as suppressed bone remodeling, impaired bone healing, altered bone quality, and femoral morphology. The management of AFFs requires both medical and surgical approaches. BPs therapy should be discontinued immediately, and calcium and vitamin D levels should be evaluated and supplemented if insufficient. Teriparatide can be used for AFFs. Intramedullary nailing is the primary treatment for complete AFFs, and prophylactic femoral nailing is recommended if signs of an impending fracture are detected.

Adjuvant pharmacological strategies for the musculoskeletal system during long-term space missions.

Despite two hours of daily exercise training, muscle wasting and bone loss are still present after 6-month missions to the international space station. Some crew members lose bone much faster than others. In preparation for Moon and Mars, space agencies are therefore reviewing their countermeasure portfolios. Here, we discuss the potential of current pharmacological strategies. Bone loss in space is fueled by bone resorption. Alendronate, an oral bisphosphonate, reduced bone losses in experimental bed rest and space. However, gastrointestinal side effects precluded its further utilization in space. Zoledronate (a potent bisphosphonate), denosumab (RANKL antagonist) and romosozumab (sclerostin antagonist) are all administered via injection. They effectively suppress bone resorption and are routinely prescribed against osteoporosis. Their serious adverse effects, namely osteonecrosis of the jaw and atypical femur fractures occur very rarely when the usage is limited to one or two years. Hence, utilization of one of these compounds may outweigh the bone risks of space travelling, in particular in those with high bone resorption rates. Muscle wasting in space is likely due to hampered muscle protein synthesis. Even though this might theoretically be countered by the synthesis-boosting effects of anabolic steroids, the practical grounds for such recommendation are currently weak. Moreover, they reveal their full potential only when combined with an anabolic exercise stimulus, e.g. via strength training. It therefore seems that a combination of exercise and pharmacological countermeasures should be considered for musculoskeletal health on the way to Moon and Mars and back.