Bisphosphonate Treatment Research Articles

THU432 Severe Osteoporosis Associated With A Novel Plastin 3 (PLS3) Mutation

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. S.M. Gandhi: None. E.S. Nylen: None. Early Onset Osteoporosis (EOOP) affects children and young adults and can be caused by endocrinopathies, chronic medical conditions, nutritional deficiencies, and/or genetic mutations. The most common inherited cause is osteogenesis imperfecta(OI), and a rare variant linked to OI includes a defect in the X chromosomal gene encoding Plastin 3 (PLS3). In our case, a 34-year-old male was referred for severe osteoporosis. He had been diagnosed with osteopenia at age 21. At age 24, imaging revealed multiple vertebral compression fractures and DXA scan confirmed severe osteoporosis. He required L3-L5 kyphoplasty and started on oral bisphosphonates for presumed OI despite negative gene mutation (i.e., COL1A1/COL1A2). He continued treatment for only 2 years. 8 years later, he had persistent osteoporosis (DXA L2-4 Z-score -3.6, LFN Z-score -3.2). He had no evidence of kyphosis or scoliosis and no extraskeletal manifestations such as blue-grey sclera or any dysmorphic features. The workup was negative for secondary causes of EOOP and he denied a family history of osteoporosis. Labs showed normal 24-hour urine calcium, bone markers, and bone Alkaline Phosphatase. Karyotyping showed normal XY and gene analysis was again negative for OI. He started treatment with intravenous Zoledronic acid, however, had a 2-year gap between doses initially causing BMD to drop by 6.5% in L2-L4 (Z -4.1) and by 5.7% in LFN (Z -3.1). Subsequently, he received a total of 5 doses of Zoledronic acid to date and had no further fractures. DXA significantly improved by 10.4% in L2-4 (Z -2.6), and 16.3% in LFN (Z -2.0). Repeated expanded gene testing showed a novel PLS3 hemizygous mutation (deletion at site C.234_237+10del of Exon 3). This case demonstrates a novel PLS3 mutation variant to be a plausible cause of adulthood EOOP which was responsive to bisphosphonate treatment. PLS3 is an F-actin binding and bundling protein involved in cytoskeletal remodeling and may have roles in calcium homeostasis, cell migration, endocytosis, DNA repair, and membrane trafficking. Currently, less than 30 loss of function variants of PLS3 have been identified and all lead to severe osteoporosis- particularly in children. However, our patient’s known onset of bone loss occurred much later- in his twenties and he had no evidence of extra-skeletal manifestations. The cause for such late presentation is unclear but may be attributed to this specific variant of PLS3. This case highlights that PLS3 mutation should be on the differential for EOOP even in early adulthood. Our patient’s BMD has markedly improved with bisphosphonates and he sustained no further fractures after starting therapy. Timely diagnosis and earlier detection will allow for appropriate genetic counseling, earlier screening, and treatment of affected family members. Presentation: Thursday, June 15, 2023

THU442 A Case Of Early Medication Related Osteonecrosis Of The Jaw In Patient Receiving Intravenous Zoledronate For Treatment Of Osteoporosis

Abstract Disclosure: V. Ekpe: None. X. Au: None. M. Golson: None. L.E. McGuire: None. L.E. Aguirre: None. Introduction: Medication related Osteonecrosis of the jaw (MRONJ) is a rare side effect in patients receiving nitrogen-containing bisphosphonates intravenously and other anti-bone resorptive agents such as denosumab . The incidence is 0.1% in patients with metabolic bone disease1. Annual infusions of zoledronic acid have been recommended in order to improve patient compliance, optimize therapeutic effects and to minimize side effects in selected patients. Risk factors include history of malignancy, smoking, poor dental health, prior oral surgery, high dose exposure to zoledronic acid and longer duration of treatment with anti-resorptive therapy. Increasing usage of bisphosphonates and other antiresorptive drugs, have led to an increased incidence of MRONJ. Clinical Case: We report the case of a 63-year-old Caucasian female suffering from osteoporosis who developed early stage MRONJ. She has a history of several years of oral bisphosphonate treatment and three annual administrations of zoledronic acid. Patient presented with a new complaint of gum pain and a sore above her tooth. Prior routine dental exams have all been unremarkable. She was promptly referred and evaluated by a dental provider. Dental photographs showed a resorptive defect at the gumline. Patient was diagnosed with medication related osteonecrosis of the jaw (MRONJ) in the gum area above tooth number 9. Our patient was treated with oral amoxicillin 500mg twice daily and chlorhexidine gluconate mouth rinse twice daily. The intravenous zoledronic acid was discontinued. Her gum infection resolved. Discussion: Early detection of MRONJ is possible in patients potentially at risk for this rare complication. Providers should be aware of MRONJ and refer those patients on antiresorptive drugs to the dentist for frequent evaluation and assessment for any drug-related jaw changes.

THU427 The Benefits Of Oral Bisphosphonates For Elderly Patients With A History Of Long Term Aromatase Inhibitor Use

Abstract Disclosure: L.D. Dominguez: None. S.E. Acosta: None. A.R. Alejandro: None. Aromatase Inhibitors (AI) are commonly used to treat estrogen receptor-positive breast cancer as they reduce the risk of recurrence and mortality. The AIs, however, can lead to a decrease in bone mineral density (BMD), resulting in fractures. According to the Journal of Bone Oncology (JBO), postmenopausal women on AIs with two or more risk factors for fractures should be placed on antiresorptive treatment (1). Our objective was to compare the BMD of at-risk patients that have been treated with antiresorptive treatment versus the BMD of patients not treated. An EMR chart review was conducted from 6/14/2022-8/20/2022, in which 295 patients were analyzed by the medications prescribed and their BMD. Our sample size was limited to 90 patients that had obtained DXA scores from the same GE Hologic densitometer. We hypothesized that patients on AIs and antiresorptive treatment would show more improvement in BMD than patients on AIs and not on treatment. Patients were analyzed in the comparison of their BMD. Of the 65 patients on AIs, only 17 were placed on antiresorptive treatment (26%). 94% of these patients showed improved BMD. The increase in BMD for the spine was significant (.030) as it exceeds the least significant change (LSC) of .027 g/cm^2. The improvement of .012 in the hip was not significant (.022 g/cm^2 LSC). 68.75% of patients on AI’s and not on treatment worsened by .025 in the hip (.022 g/cm^2 LSC) and by .017 in the spine (.027 g/cm^2 LSC). Alendronate (76%), Zoledronic acid (18%) and Ibandronate (6%) were commonly prescribed. The patients on Alendronate and Ibandronate, improved by .015 in the hip (.022 g/cm^2 LSC) and improved significantly by .028 in the spine (.027 g/cm^2 LSC). Patients on intravenous(IV) treatment improved significantly in the spine by .041(.027 g/cm^2 LSC) but only improved by .006 in the hip (.022 g/cm^2). Although IV administration of treatment is recommended for patients starting treatment (2), most patients showed a trend of improvement on oral bisphosphonates. Hence, to improve the care offered to at-risk patients who cannot obtain IV bisphosphonates, we can advocate for the use of oral bisphosphonate treatment.

Lesion Expansion in Gnathic Fibrous Dysplasia: Natural History, Indicators of Progression, and Response to Bisphosphonates.

Fibrous dysplasia (FD) is characterized by expansile fibro-osseous lesions that may occur in association with endocrinopathies as part of McCune-Albright syndrome (MAS). Craniofacial FD is a significant source of morbidity and most commonly involves the gnathic bones. There is a critical need to understand the natural history and risk factors for gnathic FD progression to develop preventative trials and identify candidates for intervention. The purpose of this study was to characterize gnathic FD lesion expansion and to identify risk factors associated with lesion growth. Patients with gnathic FD and serial CT imaging were evaluated. Volumetric analyses of CT scans were performed using MIM Encore software. Generalized mixed model analysis was used to account for intra-subject correlation, with FD lesion volume as the dependent variable. In addition to age, effects of MAS-associated endocrinopathies, sex, disease severity, and bisphosphonate treatment were evaluated. A total of 104 total lesions in 52 patients were characterized longitudinally. Median age at initial scan was 8.8 years (range 3.4-18.8), and median age at final scan was 16.8 years (range 6.9-33.4 years). The median number of scans per subject was 4 (range 2-14). FD lesion volume increased with age (2.50 cm3 /yr, 95% confidence interval [CI] 1.95-3.04, p < 0.001). However, lesion expansion rate decreased over time (-0.05 cm3 /yr, 95% CI -0.07 to 0.04, p < 0.001). Mandibular lesions tended to expand at a greater rate than maxillary lesions (p < 0.001). Growth hormone excess was associated with accelerated expansion rate (p = 0.002). Other MAS-associated endocrinopathies, pubertal status, sex, weight, lesion density, disease severity, and bisphosphonate treatment were not associated with lesion volume or expansion. Gnathic FD lesion expansion is most rapid in younger children and declines as patients approach adulthood. The availability of quantitative natural history data will guide clinicians in identifying patients who are candidates for medical and surgical interventions and clinical trials for preventative therapies. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

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.

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.

Novel pathogenic variants in SPARC as cause of osteogenesis imperfecta: Two case reports

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.

Retrospective evaluation of acute kidney injury in horses treated with nonnitrogenous bisphosphonates (2013-2020): 8 cases.

To describe a population of horses with acute kidney injury (AKI) following administration of bisphosphonates including clinical signs, clinicopathologic data, treatment, and outcome. Retrospective study from August 2013 to July 2020. Veterinary university teaching hospital. Eight adult horses with AKI following administration of nonnitrogenous bisphosphonates. None. Five horses received intramuscular clodronate (5/8; 62.5%) and 3 horses received intravenous tiludronate (3/8; 37.5%). Six horses (6/8; 75%) received concurrent nonsteroidal anti-inflammatory drugs. The most common initial presenting complaint was poor appetite (6/8; 75%), followed by abnormal urination (2/8; 25%). At the time of initial evaluation, the mean serum or plasma creatinine was 451.72±190.06μmol/L (5.11±2.15mg/dL) and BUN was 18.84±8.85mmol/L (52.75±24.77mg/dL). Five horses (5/6; 83.3%) had either an increased number of red blood cells (n=4) or hemoprotein (n=1) in the urine. All horses were treated with IV isotonic, balanced crystalloids either as a bolus, continuous rate infusion, or a combination of the 2. Seven horses (7/8; 87.5%) survived the initial episode of AKI and 1 horse (1/8; 12.5%) was euthanized. Of the 7 surviving horses, 2 horses (2/7; 28.5%) went on to develop chronic renal dysfunction. Warmblood breeds were overrepresented in the AKI group (P=0.008; odds ratio: 11.5, 95% confidence interval: 1.8-72.1), when compared to horses that received bisphosphonates during the study period and did not develop AKI. Bisphosphonate administration, with or without concurrent nonsteroidal anti-inflammatory drugs, can be associated with AKI in horses. Serum creatinine should be monitored prior to and following bisphosphonate treatment to minimize this risk. Further evaluation of renal function is warranted in horses that develop clinical signs of poor appetite, lethargy, or altered urination in the days following bisphosphonate treatment.

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.

891 A Systematic Review and Narrative Synthesis on the Efficacy of Bisphosphonate Therapy in the Management of Diffuse Sclerosing Osteomyelitis

Abstract Aim Diffuse Sclerosing Osteomyelitis (DSO) of the mandible is a rare condition, characterised by recurrent severe pain, and functional disturbances such as trismus. Management of DSO through antibiotics, steroids, and analgesia has been generally unsatisfactory. Several articles have suggested the use of bisphosphonate therapy as an alternative treatment option to achieve long-lasting symptom improvement. We aim to summarise all evidence relating to the efficacy of bisphosphonate therapy in DSO. Method A systematic review protocol was registered with PROSPERO and reported in accordance with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses. Comprehensive electronic search strategies of six databases were developed. Studies were screened according to the inclusion and exclusion criteria by two independent reviewers. Results Eight articles were eligible for inclusion. A total of 102 patients with a confirmed diagnosis of DSO received bisphosphonate treatment following a trial of conservative management. All studies reported significant reduction in levels of pain and swelling, and a reduction in cumulative doses of analgesics. Majority of patients reported that bisphosphonate therapy provided long-lasting symptom improvement. Three studies reported improvements in maximal mouth opening, with one study reporting a mean increase of 9.6mm. Improvements in panoramic radiographs and cone beam CT scans were also observed in five studies, with four patients demonstrating almost normal-to-normal bone architecture. Finally, all studies reported no long-term complications. Conclusions Bisphosphonate therapy does appear to be a promising treatment option for DSO. It has shown to improve symptoms and radiological features, providing long-term benefits. Further prospective studies are required to finetune treatment protocols.

Effects of low dose bisphosphonates treatment on the mandibular bone in rats with and without mini-implants application: an experimental model

Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a pathological condition observed in patients underwent oral surgical procedures during bisphosphonates treatment. Although several studies have focused on the BRONJ, the exact pathophysiological pathways remain still unclear. In this study we aimed to observe the effects of the low-dose bisphosphonates administration on mandibular bone of rats with and without mini-implants application. For this study we used 28 male Wistar rats, divided in in two groups: 1) control group, treated with saline solution (n = 14 rats); 2) ZA group, treated with low dose zoledronic acid (n=14 rats). After 6 weeks of treatment, the half of each group underwent mini-implant application. All rats were sacrificed and their mandibles were analyzed by light microscopy and scanning electron microscopy (SEM). Our data have shown a healthy bone tissue of control group both with and without mini-implant application. In the treated group empty osteocyte lacunae have been observed and they slightly increase in rats with mini-implant application. Although that, no bone exposition has been observed. By that, during low dose zoledronic acid treatment we can observe the presence of empty osteocytes lacunae, also called “primary lesion”, that not seem to be sufficient alone to determine osteonecrosis of the jaw spontaneously or even after mini-implant application.

Women's perspectives regarding osteoporosis, fracture risk, and pharmacologic treatment: a cross-sectional study.

Bisphosphonate medications can prevent the substantial bone loss that occurs during early menopause, but little is known about whether women would accept bisphosphonate treatment at this time in their life, when imminent fracture risk is low. We assessed women's perspectives regarding bone loss, fracture risk, and preventative pharmacotherapy in early menopause. In this cross-sectional study, Canadian women aged ≥ 45years were recruited via Facebook advertisement to complete an electronic survey. Primary outcome was the proportion of early menopausal respondents (≤ 5years since final menstrual period) who were worried about bone loss and fractures. Secondary outcomes were the proportionof early menopausal women willing to accept pharmacologic intervention aimed at preventingeither bone loss or future fractures. We compared responses between early menopausal women and older women (> 5years since final menstrual period). 2033 women responded to the Facebook advertisement, 1195 eligible women (aged: 45 to 89years) started the survey, and 966 completed it. Among early menopausal respondents (N = 98), 38 (42%) were worried about future fractures and 9 of 25 (36%) who had a prior bone mineral density scan were worried about their results. A total of 42 (47%) were willing to start medication to prevent fractures, and 48 (54%) would start medication to prevent bone loss. Responses were comparable between early menopausal women and older women. Menopausal women are concerned about bone loss and fractures. Many women would consider early menopausal pharmacotherapy, with the goals of preserving bone health and lowering their risk of fractures.

Long-term effectiveness and predictors of bisphosphonate treatment in type I complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a painful disease that leads to chronic pain and disability. Bisphosphonates are largely used in the real-life for the treatment of CRPS, but data on long-term effectiveness and its predictors are lacking. We conducted a longitudinal observational study on patients with type I CRPS treated with IV neridronate (100 mg on 4 occasions). Clinical and demographic characteristics were collected at baseline, after 3 months (M3) and after 12 months (M12). Multivariable logistic regression was employed to determine the factors associated with long-term response to treatment. 103 patients with type I CRPS treated with IV neridronate were included in the study. Mean VAS pain at baseline was 79.1 mm and decreased significantly at M3 (-45.9 mm, 95% CI 40.1 to 51.8) and M12 (-61.6 mm, 95% CI 55.3 to 67.9). Hyperalgesia and allodynia resolved in 84.3% and 88.1% of patients at M12. Loss of motion resolved in 53.5% of patients. The predictors of excellent response were gender (male better), predisposing event to CRPS (no event being better than any predisposing event), site of CRPS (lower limb being better), and early response at M3 on VAS pain (2.5 times the chance of being excellent responder every 10 mm decrease). In this real-life study neridronate was associated with rapid and progressive improvement of symptoms of CRPS which was maintained up to 3 years of follow-up. The predictors of excellent response were early response, lower limb localisation, absence of predisposing events and male gender.

Bisphosphonate Use May be Associated With an Increased Risk of Periprosthetic Hip Fracture

BackgroundOsteoporosis is common among patients undergoing primary total hip arthroplasty (THA). This study aimed to evaluate the effect of bisphosphonate treatment on osteoporotic patients undergoing primary THA. MethodsUsing a national database, 30,137 patients who had osteoporosis before primary elective THA were identified during 2010 to 2020. Patients undergoing nonelective THA and those using corticosteroids or other medications for osteoporosis were excluded. Bisphosphonate users and bisphosphonate naïve patients were matched 1:1 based on age, sex, Elixhauser comorbidity index, and a history of obesity, rheumatoid arthritis, tobacco use, and alcohol abuse. Kaplan–Meier and multivariate analyses were used to compare 2-year outcomes between groups. ResultsAmong matched cohorts of 9,844 patients undergoing primary THA, bisphosphonate use was associated with a significantly higher 2-year rate of periprosthetic fracture (odds ratio 1.29, 95% confidence interval 1.04 to 1.61, P = .022). There was a trend toward increased risk of any revision with bisphosphonate use (odds ratio 1.19, confidence interval 1.00 to 1.41, P = .056). Rates of infection, aseptic loosening, dislocation, and mortality were not statistically different between bisphosphonate users and bisphosphonate-naïve patients. ConclusionIn osteoporotic patients, bisphosphonate use before primary THA is an independent risk factor for periprosthetic fracture. Additional longer-term data are needed to determine the underlying mechanism for this association and identify preventative measures.

Osteoporosis and Fracture Risk among Older US Asian Adults.

This review summarizes the current knowledge regarding osteoporosis and fracture among older US Asian adults. Asian adults have lower (areal) bone density than non-Hispanic White adults and thus are more likely to be diagnosed and treated for osteoporosis, despite their lower risk of hip fracture. The latter may relate to favorable characteristics in hip geometry, volumetric bone density, and bone microarchitecture; lower risk of falls; and other clinical factors. The fracture risk calculator FRAX accounts for the lower risk of hip fracture among US Asian adults. However, data on major osteoporotic fracture risk remain limited. Fracture rates also vary by Asian subgroup, which may have implications for fracture risk assessment. Furthermore, among women receiving bisphosphonate drugs, Asian race is a risk factor for atypical femur fracture, an uncommon complication associated with treatment duration. Recent clinical trial efficacy data pertaining to lower bisphosphonate doses and longer dosing intervals may be relevant for Asian adults. More research is needed to inform osteoporosis care of US Asian adults, including risk-benefit considerations and the optimal duration of bisphosphonate treatment. Greater evidence-based guidance for primary fracture prevention among US Asian adults will ensure health equity in the prevention of osteoporotic fractures.

Interactive Associations between PPARγ and PPARGC1A and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case-control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01-9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69-0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.

How the COVID-19 pandemic affected bone health: a retrospective, longitudinal study on denosumab persistence from the epicentre of European spreading.

This study aimed to evaluate persistence on denosumab (Dmab) treatment during the COVID-19 pandemic and the clinical effects of possible discontinuation. We retrospectively assessed patients affected by osteoporosis and treated with Dmab, scheduled to have the yearly renewal of prescription between March 9, 2020, and May 9, 2021, 2months after the second pandemic wave. In June 2022, a telephone survey started, by calling all patients who missed the yearly renewal of Dmab. Predictors of missed renewal and fragility fracture occurrence were assessed by logistic analyses. Patients scheduled to have a renewal of Dmab prescription during the observational period were 538 (age 75.5 ± 9.3years, female 511). A total of 152 (28.2%) patients did not have the renewal. Patients not renewing Dmab prescription were significantly older (p = 0.01) and more frequently affected by pulmonary (p = 0.04) and cardiovascular comorbidity (p = 0.01). Telephone survey on non-persistent patients showed that 44 had died, 28 patients were missing, 23 shifted to bisphosphonate treatment, and 22 patients suspended Dmab. Following discontinuation, 12/22 patients (54.5%) reported fragility fractures; 5/22 had multiple fractures, for a total number of 18 fractures, mainly vertebral. Logistic analyses showed that the odds of Dmab withdrawal increased in older patients with pulmonary comorbidity and treated for a shorter time. Dmab discontinuation was the only variable that increased the risk of fracture. This study provided real-world data about an impaired persistence of Dmab treatment resulting in an increased number of fragility fractures in a geographic area heavily affected by the outbreak of COVID-19.

Orthognathic surgery in patients treated with bisphosphonates: A case series

The aim of this case series was to complete the literature with six other cases of orthognathic surgery in patients treated with bisphosphonate (BP). The majority of studies concerning oral and maxillofacial surgery focus on dental extractions and implant placement in patients treated with BP. Only 5 cases of orthognathic surgery in patients treated with BP have been reported: four cases for osteogenesis imperfecta and one case for osteoporosis. Six patients were included in the study from January 2009 to December 2020: 3 treated for fibrous dysplasia and 3 treated for osteoporosis. BP treatment was stopped for 2 cases because it was the scheduled end of their treatment for fibrous dyplasia. The other four cases didn’t stop taking BP for surgery. No precautions for the prevention of MRONJ were taken. The operative follow-up was uneventful. Mucosal healing was satisfactory for all patients at D15. No material exposure were observed. Bone consolidation appears complete on X-rays and on CT-scans at D45 with disappearance and bone filling of the fracture line associated with the absence of painful mobility of the maxilla and mandible on clinical examination. Until now, all the patients have a stable class I occlusion, no signs of osteonecrosis on X-rays (no signs of bone demineralization, no hypermineralized bone sequestration, no signs of osteolysis) or periodontal disease and healed osteotomies of the jaw without radiological features. No relapse were observed. The management of patients treated with bisphosphonate should be done carefully but orthognathic surgery is no longer a contraindication.

Pengetahuan dokter gigi mengenai pencabutan gigi pada pasien terapi bisfosfonat

Background: Appropriate dental extraction management with osteoporosis patient that consume bisphosphonate is the best way to prevent bisphosphonate related osteonecrosis of the jaw Objective: evaluate the dentist knowledge and awareness in West Jakarta about dental extraction management in patient with osteoporosis that consume bisphosphonate Methods: This research method is a descriptive observational study with a cross-sectional design with 97 respondents. The data was collected through a questionnaire addressed to West Jakarta-based dentists, and the data was then displayed in the form of a graphic and percentage. The data obtained was then categorized into 3 level which are high if the respondents have ≥80 score, average if the respondents have 60-70 score and low if the respondents have score ≤50 Result: there are 85,54% respondents with a low level of knowledge, 10,31% who have average level of knowledge and 5,15% who have low level of knowledge. Conclusion: Dentists level of knowledge in West Jakarta about dental extraction with osteoporosis patients under bisphosphonate treatment is categorized low.

Role of Bisphosphonates in Periodontal Diseases: Systematic Review.

The chief aim in managing periodontal diseases is the elimination of causative factors that may vary from pathogens to physical parameters. In the current systematic review, the effectiveness of "Bisphosphonate Therapy" as a supplement to "Scaling and Root Planing (SRP)" in the management of periodontitis is calibrated from the previous studies. An extensive online search in the various databanks of EMBASE, Medline, Pubmed, and Scopus was conducted. The keywords searched were "Probing depth (PD)" which was the main endpoint, and variations in "Clinical Attachment Level (CAL)" and/or "Bone Defect (BD) fill" were the secondary variants that were searched for in the current study. The data collected were tabulated and compared using the means and the standard deviations. Using the random effect method the mean variations and the confidence intervals (95%) of the parameters were assessed. Eight studies were finalized. Alendronate was utilized as a supplement to SRP in seven studies, four of which employed topical administration and three of which used oral alendronate. A substantial grade of heterogeneity for Probing depth (P < 0.0001), Clinical Attachment Level (P = 0.007), and Bone Defect fill (P < 0.0001) was observed amongst groups when comparing the properties of adjunctive BT to SRP alone. In comparison to SRP alone, SRP with bisphosphonate treatment significantly reduced PD (P = 0.002), increased CAL (P = 0.008), and filled BD (P < 0.001). Although BT as an adjunct appears to be successful in treating periodontitis, its practical applicability is questionable due to the possibility of developing jaw osteonecrosis and the short-range follow-up of the research.