Fracture Liaison Service for Hip Fractures: Is It A Game Changer?

BACKGROUND: Osteoporosis is a common medical condition in older ages. A devastating result of osteoporosis may be a hip fracture with up to 30% mortality rate in one year. The compliance rate of osteoporotic medication following a hip fracture is 20% in the western world. OBJECTIVES: To evaluate the impact of the fracture liaison service (FLS) model in the orthopedic department on patient compliance following hip fracture. METHODS: We performed a retrospective review of all patients with hip fracture who were involved with FLS. We collected data regarding kidney function, calcium levels, parathyroid hormone levels, and vitamin D levels at admission. We educated the patient and family, started vitamin D and calcium supplementation and recommended osteoporotic medical treatment. We phoned the patient 6-12 weeks following the fracture to ensure treatment initiation. RESULTS: From June 2018 to June 2019 we identified 166 patients with hip fracture who completed at least one year of follow-up. Over 75% of the patients had low vitamin D levels and 22% had low calcium levels at admission. Nine patients (5%) died at median of 109 days. Following our intervention, 161 patients (96%) were discharged with a specific osteoporotic treatment recommendation; 121 (73%) received medication for osteoporosis on average of < 3 months after surgery. We recommended on injectable medications; however, 51 (42%) were treated with oral biphsophonate. CONCLUSIONS: FLS improved the compliance rate of osteoporotic medical treatment and should be a clinical routine in every medical center.

Evaluation of the first fracture liaison service in the Greek healthcare setting.

We evaluated the first implementation of FLS in the Greek healthcare setting, at the 251 Hellenic Air Force and VA General Hospital of Athens. Participation rate was moderate (54.5%) and needs improvement; osteoporosis medication was either suggested or reviewed in 74 out of the 116 patients recruited. PURPOSE: The purpose of this study was to evaluate the first implementation of a fracture liaison service (FLS) in Greece, at the 251 Hellenic Air Force and VA General Hospital, Athens. METHODS: Single-center, prospective study from May 1, 2013 to April 30, 2015 (first year-second year follow-up) was conducted. Patients of both genders aged 40-90 years old, with a history of a low trauma fracture and willing to participate, were included after identification by an FLS nurse. Following recruitment, osteoporosis risk factors were assessed, FRAX score was calculated for treatment-naïve patients, bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA), and osteoporosis treatment was suggested where applicable. The rate of participation, the indication of osteoporosis treatment, and the difficulties met were evaluated. RESULTS: Of the eligible 213 patients, 97 (45.5%) were reluctant to participate for personal reasons. From the 116 initially recruited patients (mean age 74.8 ± 12 years), 77 (66.4%) discontinued their participation at some point for various reasons and 39 patients concluded the study. All 116 patients were assessed for osteoporosis risk factors and given a tailor-made exercise and education program, while FRAX score was assessed in all treatment-naïve patients (74 patients, 63.8%). Osteoporosis medication was suggested or reviewed in 74 patients; however, an adherence rate of 100% is only available for the 24 who concluded the study. CONCLUSIONS: We report the first implementation of FLS in the Greek healthcare setting. The participation rate is moderate and definitely needs improvement.

Unmet needs and current and future approaches for osteoporotic patients at high risk of hip fracture.

This review provides a critical analysis of currently available approaches to increase bone mass, structure and strength through drug therapy and of possible direct intra-osseous interventions for the management of patients at imminent risk of hip fracture. PURPOSE: Osteoporotic hip fractures represent a particularly high burden in morbidity-, mortality- and health care-related costs. There are challenges and unmet needs in the early prevention of hip fractures, opening the perspective of new developments for the management of osteoporotic patients at imminent and/or at very high risk of hip fracture. Amongst them, preventive surgical intervention needs to be considered. METHODS: A European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)/International Osteoporosis Foundation (IOF) working group reviewed the presently available intervention modalities including preventive surgical options for hip fragility. This paper represents a summary of the discussions. RESULTS: Prevention of hip fracture is currently based on regular physical activity; prevention of falls; correction of nutritional deficiencies, including vitamin D repletion; and pharmacological intervention. However, efficacy of these various measures to reduce hip fractures is at most 50% and may need months or years before becoming effective. To face the challenges of early prevention of hip fractures for osteoporotic patients at imminent and/or at very high risk of hip fracture, preventive surgical intervention needs further investigation. CONCLUSION: Preventive surgical intervention needs to be appraised for osteoporotic patients at imminent and/or at very high risk of hip fracture.

Treatment of primary osteoporosis in men.

With the aging of the population worldwide, osteoporosis and osteoporotic fractures are becoming a serious health care issue in the Western world. Although less frequent than in women, osteoporosis in men is a relatively common problem. Hip and vertebral fractures are particularly relevant, being associated with significant mortality and disability. Since bone loss and fragility fractures in men have been recognized as serious medical conditions, several randomized controlled trials (RCTs) have been undertaken in males with osteoporosis to investigate the anti-fracture efficacy of the pharmacological agents commonly used to treat postmenopausal osteoporosis. Overall, treatments for osteoporosis in men are less defined than in women, mainly due to the fact that there are fewer RCTs performed in male populations, to the relatively smaller sample sizes, and to the lack of long-term extension studies. However, the key question is whether men are expected to respond differently to osteoporosis therapies than women. The pharmacological properties of bisphosphonates, teriparatide, denosumab, and strontium ranelate make such differentiation unlikely, and available clinical data support their efficacy in men with primary osteoporosis as well as in women. In a series of well-designed RCTs, alendronate, risedronate, zoledronic acid, and teriparatide were demonstrated to reduce the risk of new vertebral fractures in men presenting with primary osteoporosis (including osteoporosis associated with low testosterone levels) and to improve the bone mineral density (BMD). In preliminary studies, ibandronate, denosumab, and strontium ranelate also showed their beneficial effects on surrogate outcomes (BMD and markers of bone turnover) in men with osteoporosis. Although direct evidence about their non-vertebral anti-fracture efficacy are lacking, the effects of bisphosphonates, denosumab, teriparatide, and strontium ranelate on surrogate outcomes (BMD and markers of bone turnover) were similar to those reported in pivotal RCTs undertaken in postmenopausal women, in which vertebral and non-vertebral anti-fracture efficacy have been clearly demonstrated. In conclusion, sufficient data exist to support the use of these pharmacological agents in men with primary osteoporosis. Further RCTs are warranted to establish their long-term efficacy and safety.

Sclerosis in bisphosphonate-related osteonecrosis of the jaws and its correlation with the clinical stages: study of 43 cases.

We analysed the degree of sclerosis in the different stages of bisphosphonate-related osteonecrosis of the jaws (BRONJ) and studied the relation between the grade of sclerosis, the clinical symptoms, and the depth of lucency. We compared 43 patients with mandibular BRONJ with a control group of 40 cases with no bony lesions. The presence of sclerotic bone, cortical irregularities, radiolucency, fragmentation or sequestration, periostitis, and narrowing of the mandibular canal were studied from computed tomographic (CT) scans using the program ImageJ 1.47v (National Institute of Health, Bethesda, USA) to measure the radiolucency, width of the cortices, and degree of sclerosis. Patients with BRONJ had more severe sclerosis than controls (p<0.01). There was also a significant difference among the different stages of BRONJ, with the highest values found in stage III (p=0.02). The degree of sclerosis differed according to sex, type of bisphosphonate, and the clinical characteristics such as pain, or suppuration, but not significantly so (p>0.05). We conclude that the degree of sclerosis increases with the clinical stage of BRONJ, and is correlated with the depth of lucency.

Bisphosphonate-related osteonecrosis of the jaw: what we have learned.

Bisphosphonate related osteonecrosis of the jaws (BRONJ) is an entity that has become prevalent upon the dental and medical community for more than 10 years. This entity is unfortunate because both oral and intravenous nitrogen containing bisphosphonates have beneficial effects for patients for certain conditions. The exact pathology of BRONJ has yet to be determined, although many hypotheses have been put forth. Since its prevalence, a clinical staging system has been developed and radiological findings have been described. BRONJ can be prevented if oral healthcare is undertaken before the start of bisphosphonate therapy or after a short time from the start of their use. However, after BRONJ has developed in patients, a myriad of treatments have been proposed that may help these patients.

Use of FRAX®-based fracture risk assessments to identify patients who will benefit from osteoporosis therapy.

Several pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, and strontium ranelate have demonstrated efficacy in reducing the incidence of osteoporotic fractures, the most severe consequence of postmenopausal osteoporosis. Until recently, bone mineral density (BMD) was the primary factor used to determine which postmenopausal women may require osteoporosis treatment. However, clinical guidelines now recommend the use of the Fracture Risk Assessment Tool (FRAX(®)), a computer-based algorithm introduced by the World Health Organization, to help primary care physicians identify postmenopausal women who may be candidates for pharmacological osteoporosis therapy based on the level of fracture risk. Beyond its utility as a resource for determining whether or not to initiate osteoporosis treatment, clinical studies have begun to evaluate the correlation between FRAX(®)-based 10-year fracture probability and efficacy of different osteoporosis treatments. Bazedoxifene, clodronate, and denosumab have shown greater fracture risk reduction at higher FRAX(®)-based 10-year fracture probabilities, but the efficacy of raloxifene, alendronate, and strontium ranelate were relatively stable regardless of fracture probability. In summary, these data suggest that the relationship between FRAX(®)-based fracture probability and efficacy of different osteoporosis treatments varies depending upon the agent in question.

Adverse events across generations of bone-modifying agents in patients with solid tumor cancers reported in Phase III randomized trials.

AIMS: The objective of this study is to compare adverse events experienced among different bone-modifying agents. METHODS: A literature search was conducted to identify Phase III bisphosphonate and bone-modifying agent trials reporting adverse effects. Thirty-seven adverse events of interest were identified for six different treatment options. Weighted linear regression modeling was performed on the adverse event proportions with treatment groups, normalized through applying natural log transformations. RESULTS: There were significant differences in adverse events of vomiting (p = 0.045) and osteonecrosis of the jaw (p = 0.017), and combined item events of nausea/vomiting (p = 0.048), hematological and lymphatic system toxicities (p = 0.020), and any respiratory system problem (p = 0.023) between bone-modifying agent and placebo trials. The significant toxicities were observed even after adjusting for the two confounding factors of age and primary cancer site. CONCLUSION: While adverse effects are consistently experienced more frequently in patients receiving bone-modifying agents when compared with placebos, we find that the majority of individual side effects are not significantly more frequent in patients receiving bone-modifying agents compared with placebo.

Prediction of bioavailability of selected bisphosphonates using in silico methods towards categorization into a biopharmaceutical classification system.

The physicochemical properties relevant to biological activity of selected bisphosphonates such as clodronate disodium salt, etidronate disodium salt, pamidronate disodium salt, alendronate sodium salt, ibandronate sodium salt, risedronate sodium salt and zoledronate disodium salt were determined using in silico methods. The main aim of our research was to investigate and propose molecular determinants thataffect bioavailability of above mentioned compounds. These determinants are: stabilization energy (deltaE), free energy of solvation (deltaG(solv)), electrostatic potential, dipole moment, as well as partition and distribution coefficients estimated by the log P and log D values. Presented values indicate that selected bisphosphonates a recharacterized by high solubility and low permeability. The calculated parameters describing both solubility and permeability through biological membranes seem to be a good bioavailability indicators of bisphosphonates examined and can be a useful tool to include into Biopharmaceutical Classification System (BCS) development.

Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients.

INTRODUCTION: Bisphosphonates are used to reduce skeletal related events in patients with bone consuming diseases such as osteoporosis and bone metastases. However recently there has been an increased awareness of bisphosphonate-associated necrosis of the jaws (BP-ONJ). Many authors propose conservative management in these cases but invariably the problem is not treated successfully allowing the bone defect to worsen. Recently there has been a move to treat this problem surgically. The aim of this retrospective study was to provide a surgical solution for patients suffering from BP-ONJ. MATERIALS AND METHODS: All patients presenting with BP-ONJ were treated with bone debridement of the affected area and multilayer wound closure. The considered variables were: gender, age, underlying diagnosis, type of bisphosphonate (BP) used, duration of bisphosphonate use, route of administration, location of the osteonecrosis, clinical symptoms, association with dental treatment and surgical outcome. RESULTS: Nineteen cases of a total of 21 demonstrated no recurrence of osteonecrosis during follow up (Mean 16 months - Range 12-24 months). One patient with a bilateral defect showed a dehiscence on one side and a small fistula on the contralateral side 6 weeks post-operatively and required revision surgery. Another patient developed a fistula after 4 weeks that was treated successfully with antibiotics and curettage. No patients had evidence of exposed bone, bland mucosa nor pain at the surgical site. CONCLUSION: The technique described can be recommended for patients with BP-ONJ if a conservative treatment fails.

Efectos adversos de los bisfosfonatos / Adverse effects of bisphosphonates

Los aminobisfosfonatos son fármacos que han sido utilizados con éxito en el tratamiento de la osteoporosis desde hace más de 20 años. Aunque en los estudios principales realizados para obtener la aprobación de su comercialización no se registraron efectos adversos relevantes, en los últimos años, y como resultado de la farmacovigilancia, se ha comunicado de manera irregular una serie de complicaciones, algunas potencialmente graves, que han puesto en duda la seguridad de estos fármacos, sobre todo en dosis elevadas como las que se utilizan en oncología y en tratamientos de larga duración, como los que se emplean en la osteoporosis. En la presente revisión, basada en el análisis de las pruebas científicas más relevantes procedentes de los ensayos clínicos, series de casos, estudios de cohortes y bases de datos publicados hasta el momento, se resumen las características clínicas y epidemiológicas de los efectos adversos de los bisfosfonatos (AU)

Aminobisphosphonates are drugs that have been used successfully in the treatment of osteoporosis for more than 20 years. Although main registry studies found a scarcity of relevant adverse events, in recent years and as a result of pharmacovigilance, different complications have been reported, some potentially serious. This has raised questions on the safety of these drugs, especially in high doses, like those used in oncology and long-term treatment, as needed in patients with osteoporosis. In this review, based on the analysis of relevant scientific evidence from clinical trials, case series, cohort studies and databases published to date, we summarize the clinical and epidemiological characteristics of the adverse effects of these drugs (AU)

Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

PURPOSE: Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. MATERIALS AND METHODS: The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. RESULTS: Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates. CONCLUSIONS: Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate.

Bisphosphonate-related osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle?

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate therapy, primarily diagnosed in patients with cancer and metastatic bone disease and receiving intravenous administrations of nitrogen-containing bisphosphonates. If diagnosis or treatment is delayed, BRONJ can develop to a severe and devastating disease. Numerous studies have focused on BRONJ, with possible pathomechanisms identified to be oversuppression of bone turnover, ischemia due to antiangiogenetic effects, local infections, or soft tissue toxicity. However, the precise pathogenesis largely remains elusive and questions of paramount importance await to be answered, namely 1) Why is only the jaw bone affected? 2) Why and how do the derivatives differ in their potency to induce a BRONJ? and 3) Why and when is BRONJ manifested? The present perspective reflects on existing theories and introduces the hypothesis that local tissue acidosis in the jaw bone offers a conclusive pathogenesis model and may prove to be the missing link in BRONJ.

Treatment options for osteoporosis and decision making criteria: 2009.

Osteoporosis is recognized worldwide as a major public health problem since many decades ago, mainly due to the cost of treatment for related fragility fractures. Fortunately, WHO has provided new strategies for identifying populations with a high ten-year fracture risk, which together with increasingly sensitive diagnostic methods make it feasible for decision makers in this field to design cost effective fracture prevention strategies. These strategies are aimed at preventing falls and improving bone strength and therefore diminishing the prevalence and incidence of new or recurrent osteoporosis related fractures. Herein we review the content of these new strategies, and the medical treatments available, as well as their efficacy in the Mexican context. Several countries are now reporting a decreasing incidence and prevalence of osteoporosis related fractures, after 30 years of clinical and population-based interventions. Mexico has several effective anti-fracture drug treatments available. Such drugs can be classified according to the mechanism that makes them effective as: 1) antidestructive or anticatabolic, 2) bone forming or anabolic, and 3) those with both actions or mixed drugs. The authors argue that treatment strategies that use drugs to strengthen bone tissue must assure normal mineralization of the already formed, remnant bone tissue and/or the newly formed bone tissue in order to encourage biochemical outcomes like formation of mature hydroxyapatite crystals with complete biomechanical and biochemical properties and therefore long term benefits. The present review includes some perspectives that will surely enhance osteoporosis management in the near future and which will bring about a decrease in the impact of the problems in Mexico.

Treatment options for osteoporosis and decision making criteria: 2009 / Alternativas de tratamiento para osteoporosis y criterios de decisión: 2009

Osteoporosis is recognized worldwide as a major public health problem since many decades ago, mainly due to the cost of treatment for related fragility fractures. Fortunately, WHO has provided new strategies for identifying populations with a high ten-year fracture risk, which together with increasingly sensitive diagnostic methods make it feasible for decision makers in this field to design cost effective fracture prevention strategies. These strategies are aimed at preventing falls and improving bone strength and therefore diminishing the prevalence and incidence of new or recurrent osteoporosis related fractures. Herein we review the content of these new strategies, and the medical treatments available, as well as their efficacy in the Mexican context. Several countries are now reporting a decreasing incidence and prevalence of osteoporosis related fractures, after 30 years of clinical and population-based interventions. Mexico has several effective anti-fracture drug treatments available. Such drugs can be classified according to the mechanism that makes them effective as: 1) antidestuctive or anticatabolic, 2) bone forming or anabolic, and 3) those with both actions or mixed drugs. The authors argue that treatment strategies that use drugs to strengthen bone tissue must assure normal mineralization of the already formed, remnant bone tissue and/or the newly formed bone tissue in order to encourage biochemical outcomes like formation of mature hydroxyapatite crystals with complete biomechanical and biochemical properties and therefore long term benefits. The present review includes some perspectives that will surely enhance osteoporosis management in the near future and which will bring about a decrease in the impact of the problems in Mexico.

La osteoporosis se reconoce mundialmente como un problema de salud pública desde hace muchas décadas, principalmente por el impacto global implícito en la atención de las fracturas que ocasiona. Afortunadamente, cada vez contamos con más y mejores estrategias desarrolladas por la OMS para identificar oportunamente a las personas en riesgo de sufrir una fractura; actualmente es posible definir este riesgo para los siguientes diez años. Lo cual, aunado a métodos cada vez más sensibles para establecer diagnósticos definitivos y opciones de tratamiento costo-eficaces para evitar caídas y disminuir significativamente la presentación de fracturas, permite a quien toma decisiones en este problema diseñar y poner en práctica planes de atención sustentados en la mejor evidencia científica, que son motivo de esta revisión. Varios países empiezan a informar un abatimiento del número de fracturas, después de haber establecido programas dirigidos a este fin desde hace 30 años. Contamos con medicamentos que han demostrado su eficacia para abatir la presentación de la primera fractura o de fracturas recurrentes de manera costo-eficiente, estos se pueden dividir para su estudio de acuerdo al mecanismo de acción que los vuelve eficaces. Así, aquellos que frenan la destrucción del tejido óseo se clasifican como anti-catabólicos, los que estimulan la formación de tejido óseo nuevo son anabólicos, los que tienen ambas acciones se conocen como de acción mixta. En todos los casos, el tejido remanente, previamente formado o en vías de destrucción, que se fortalecerá o el tejido de nueva formación, requieren medidas para garantizar que el proceso de mineralización suceda normalmente y se genere hidroxiapatita o un compuesto con características similares para que la eficiencia biomecánica del tejido realmente mejore a largo plazo. Esta revisión incluye algunas perspectivas que seguramente mejorarán nuestro manejo de la osteoporosis en el futuro inmediato y que...

Therapies for treatment of osteoporosis in US women: cost-effectiveness and budget impact considerations.

OBJECTIVE: To evaluate the cost-effectiveness of osteoporosis treatments for women at high fracture risk and estimate the population-level impact of providing bisphosphonate therapy to all eligible high-risk US women. STUDY DESIGN: Fractures, healthcare costs, and quality-adjusted life-years (QALYs) were estimated over 10 years using a Markov model. METHODS: No therapy, risedronate, alendronate, ibandronate, and teriperatide (PTH) were compared among 4 risk groups. Sensitivity analyses examined the robustness of model results for 65-year-old women with low bone density and previous vertebral fracture. RESULTS: Women treated with a bisphosphonate experienced fewer fractures and more QALYs compared with no therapy or PTH. Total costs were lowest for the untreated cohort, followed by risedronate, alendronate, ibandronate, and PTH in all risk groups except women aged 75 years with previous fracture. The incremental cost-effectiveness of risedronate compared with no therapy ranged from cost saving for the base case to $66,722 per QALY for women aged 65 years with no previous fracture. Ibandronate and PTH were dominated in all risk groups. (A dominated treatment has a higher cost and poorer outcome.) Treating all eligible women with a bisphosphonate would cost an estimated additional $5563 million (21% total increase) and would result in 390,049 fewer fractures (35% decrease). In the highest risk group, the additional cost of therapy was offset by other healthcare cost savings. CONCLUSIONS: Osteoporosis treatment of high-risk women is cost-effective, with bisphosphonates providing the most benefit at lowest cost. For highest risk women, costs are offset by savings from fracture prevention.