As fraturas femorais sÃo consideradas um problema de saÃde pÃblica e sÃo responsÃveis por um alto Ãndice de morbidade e mortalidade pela ocorrÃncia de possÃveis complicaÃÃes. Ocorrem nÃo somente em pacientes jovens expostos a grandes traumas como tambÃm na populaÃÃo idosa. A maioria dos pacientes idosos possui determinadas afecÃÃes como, por exemplo, a osteoporose, que aumenta ainda mais o risco dessas fraturas, jà que a tendÃncia à que a idade mÃdia da populaÃÃo aumente, as consequÃncias da osteoporose aumentarÃo na mesma proporÃÃo. Estudos clÃnicos demonstraram que o uso dos bifosfonatos reduzem o risco da ocorrÃncia dessa fraturas em pacientes osteoporÃticos. O Ãcido zoledrÃnico pertence à classe dos bifosfonatos, sendo considerado atualmente o mais potente. Como a dose que esses pacientes utilizam à anual, hà um aumento da aderÃncia e da persistÃncia dos pacientes no tratamento, diminuindo, assim, o risco de fraturas. Este trabalho teve, como objetivo, verificar os efeitos do Ãcido zoledrÃnico no processo de consolidaÃÃo Ãssea nos fÃmures de ratos reduzidos com fio de Kirshner. Foram utilizados 36 ratos machos, adultos, da linhagem Wistar, com peso que variou de 250 a 300g. Todos os animais foram submetidos à cirurgia em que era realizada a fratura da diÃfise femoral com uma guilhotina romba. Os animais foram divididos em dois grupos: o grupo do Ãcido zoledrÃnico, que recebeu, via intraperitoneal, 0,1 mg/Kg do Ãcido e o grupo controle. Os animais foram sacrificados com 7, 14 e 28 dias de pÃs-operatÃrio. Houve duas mortes por causas desconhecidas. Foram realizados estudos radiogrÃficos com filme de mamÃgrafo para analisar a densidade Ãptica e a Ãrea do calo Ãsseo, medida em mm e estudo histolÃgico, utilizando amostras coradas com picrosirius red sob a luz polarizada do microscÃpio, para quantificar a formaÃÃo de colÃgeno tipo I e tipo III na regiÃo cortical prÃxima a fratura e no calo Ãsseo. Em relaÃÃo à densidade Ãptica, nÃo se observou nenhum resultado estatisticamente relevante em relaÃÃo ao uso do Ãcido zoledrÃnico. Ao se realizar uma anÃlise intergrupos, em relaÃÃo à Ãrea do calo Ãsseo, nÃo houve diferenÃa significante (p<0,05) nos tempos de consolidaÃÃo utilizados nessa pesquisa. Apesar do grupo zoledronato no tempo de 28 dias ter um resultado muito prÃximo em relaÃÃo ao nÃvel de significÃncia (p=0,0532). Jà na anÃlise intragrupos, observa-se um aumento considerado natural na Ãrea do calo Ãsseo. A percentagem de colÃgeno tipo III no calo Ãsseo e nas corticais nÃo revelou diferenÃa significativa tanto na anÃlise intragrupos como na anÃlise intergrupos. Em contrapartida, esse trabalho teve resultados significantes em relaÃÃo ao colÃgeno tipo I, havendo um aumento da percentagem do colÃgeno tipo I no calo Ãsseo no tempo de consolidaÃÃo de 28 dias (p=0,0098). Nas corticais do fÃmur prÃximas à fratura, esse aumento foi verificado nos trÃs tempos de consolidaÃÃo considerados nesta pesquisa. Concluindo que o Ãcido zoledrÃnico promoveu uma maior deposiÃÃo de colÃgeno tipo I, sugerindo aceleraÃÃo no processo de consolidaÃÃo Ãssea, sobretudo na fase final da reparaÃÃo. Em relaÃÃo à percentagem de colÃgeno tipo III (no calo Ãsseo e nas corticais prÃximas ao calo), a Ãrea do calo Ãsseo e a densidade Ãptica do calo Ãsseo, nÃo houve resultados estatisticamente significantes. / Femoral fractures are considered a public health problem and account for a high rate of morbidity and mortality by the occurrence of complications. They occur not only in young patients exposed to major trauma but in the elderly population as well. Most elderly patients have certain conditions, eg, osteoporosis, which further increase the risk of such fractures. Since the trend is that the average age of population increase, the consequences of osteoporosis will increase proportionately. Clinical studies have demonstrated that the use of bisphosphonates reduces the risk of occurrence of fractures in osteoporotic patients. Zoledronic acid belongs to the class of bisphosphonates, currently being considered the most potent. Because the dose that these patients use is an annual basis, there is an increased adherence and persistence of patients in treatment, thereby decreasing the risk of fractures. This study aimed to evaluate the effects of zoledronic acid on bone healing in femurs of rats with reduced Kirshner wire. We used 36 adult male rats, Wistar, weights ranged from 250 to 300g. All animals underwent surgery that was performed on the fracture of the femoral shaft with a blunt guillotine. The animals were divided into two groups: the group of zoledronic acid, which received intraperitoneally 0.1 mg / kg of the acid and the control group. The animals were sacrificed 7, 14 and 28 days postoperatively. There were two deaths from unknown causes. We performed a radiographic study with film mammography to analyze the optical density and area of callus, measured in mm  and histological study, using samples stained with picrosirius red under dense microscopic light to quantify the formation of collagen type I and type III in the cortical region near the fracture and callus. No significant statistical results regarding the optical density were observed with the use of the zoledronic acid. When conducting a comparative inter-group analyses, the callus area showed no significant differences (p <0.05) in a time of consolidation (7, 14 and 28 days) used in this study. Despite the zoledronate group in 28 days time to have a result very close to the level of significance (p <0.05). In the intragroup analysis there is considerable increase in the natural area of the callus. The percentage of type III collagen in the cortical and callus did not possess significant differences in intragroup analysis and the analysis groups. By contrast this study had significant results in relation to collagen type I. Concluding that zoledronic acid significantly increased the percentage of type I collagen in the callus in healing time of 28 days. And in the cortical bone three times considered (7,14,28 days).

Background: Osteoporosis has become a major problem worldwide as the population ages. An osteoporotic fracture is associated with a high rate of morbidity and mortality. Data on the prevalence, risk factors and outcome of osteoporotic fractures in South Africa remains sparse. Method: A retrospective audit was undertaken in all patients attending the Endocrine Clinic at Groote Schuur Hospital between March 2019 and March 2020 for the treatment of osteoporosis. Patients folders were reviewed to obtain the following information: demographic data, risk factors, laboratory investigations, treatment, baseline and follow up DEXA scans. Results: 264 patients were evaluated, average age 65.7 ± 12.3 years, 92.8% (n=245) were female. Common risk factors included smoking (50.8%, n=134), vitamin D deficiency (29.2%, n=77), steroid use (21.6%, n=57) and primary hyperparathyroidism (15.2%, n=40). A fragility fracture was diagnosed in 68.6% (n=181) - vertebral only (54.7%, n=99), hip only (14.9%, n=27), vertebral and hip (10.5%, n=19), wrist (7.2%, n=13) and other (12.7%, n=23). Bisphosphonates were used by 75% (n=198) of patients at the time of enrolment. Of these, 80.8% (n=160) received intravenous zoledonic acid alone, 6.1% (n=12) received oral alendronate alone and 13.1% (n=26) initially received alendronate followed by intravenous zoledronic acid. Over 5.2 years there was an improvement in bone mineral density (BMD) of 4.4% at the lumbar spine, while there was slight worsening of BMD at the femoral neck (- 0.17%). A fracture whilst on treatment occurred in 10.6% (n=21) of patients. Conclusion: The majority of patients with osteoporosis at Groote Schuur Hospital had a fragility fracture at diagnosis with a vertebral fracture being most common. Bisphosphonate treatment showed a measurable improvement in BMD at the lumbar spine, however, there was no improvement at the femoral neck. Despite this, few patients had a symptomatic vertebral or hip fracture whilst on treatment.

The availability of a once-a-year zoledronic acid infusion heralds a new era in the management of osteoporosis. It virtually eliminates the problem of poor compliance with orally administered bisphosphonates and, because it bypasses the gastrointestinal tract, it is not associated with gastrointestinal side effects. Zoledronic acid is effective for the treatment and prevention of postmenopausal osteoporosis, and for the treatment of osteoporosis in men, and glucocorticoid- induced osteoporosis. When administered within three months of a hip fracture, it reduces mortality and the risk of subsequent fractures. It is remarkably free of serious adverse effects. After administration of the intravenous infusion, about 18% of bisphosphonate-naïve patients experience an acute-phase reaction, including low-grade temperature, aches, and pains. This is reduced to about 9% in those who have been treated with oral bisphosphonates, and is further reduced by the concomitant and subsequent administration of acetaminophen. The likelihood and magnitude of the acute-phase reaction is less after the second infusion. Other adverse effects are similar to those encountered with other bisphosphonates. Because it is mostly excreted by the kidneys, zoledronic acid should not be administered to patients with a creatinine clearance less than 35 mL/min. It should not be administered to patients with hypocalcemia.

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) currently affects ~37 million Americans and causes substantially increased risk of skeletal fracture and fracture-related mortality. Current methods to treat CKD-related bone loss remain alarmingly ineffective. Skeletal fragility in CKD is predominately driven by deteriorations in cortical bone, highlighted by significant cortical porosity development. It is hypothesized that cortical porosity is largely driven by chronically high levels of parathyroid hormone (PTH), which alters the balance of bone remodeling in favor of rampant osteoclast activity and bone resorption. Restricting cortical bone deterioration and the development of cortical pores is likely essential to improve CKD patients’ bone health and reduce their fracture risk. The goal of this series of studies was to answer the following key questions: (1) to what degree do bisphosphonates, an approved pharmacological agent used in metabolic bone disease, accumulate in the skeleton of animals with CKD; (2) can smaller and more frequent doses of bisphosphonates alter skeletal accumulation and improve cortical architecture and the mechanical integrity of bone; (3) can non-bisphosphonate pharmacological interventions more specifically affect cortical bone deterioration. Utilizing epi-fluorescence and two-photon microscopy, our results show that bisphosphonates accumulate more in rats with renal impairment and fractionating bisphosphonates lowered skeletal accumulation irrespective of disease state. Further, studies in both rat and mouse models of CKD demonstrated different bisphosphonate treatments alone do not recover declines in cortical microarchitecture or mechanical properties in CKD. These findings demonstrate that a single intervention is not sufficient in managing CKD-induced bone alterations. Utilizing individual pore tracking analysis, we demonstrated cortical pores can be modulated with therapeutic interventions and can infill, despite the presence of CKD. Potent suppression of PTH led to significant pore infilling while more subtle reductions in PTH, via a calcimimetic, had less striking effects on bone. Calcimimetics mitigated cortical microarchitecture deterioration and reduced the rate of cortical pore expansion. Overall, these findings highlight the importance of PTH management for treating cortical deterioration in CKD. Although bisphosphonates can be utilized in ways that reduce skeletal accumulation, they appear to need co-therapies to reduce skeletal fragility associated with CKD.

Syfte: Att systematiskt sammanfatta litteraturen inom området för medicinska behandlingsalternativ för icke-infektiös, kronisk osteomyelit i käkarna, utvärderat genom utläkning i ben och smärtlindring. Metod: En systematisk litteraturöversikt gjordes i fyra databaser; PubMed, Cochrane Library, Web of Science och Scopus. Översikten utfördes enligt instruktioner från ”PRISMA checklist” och ”CRD’s guidance”. En kvalitetsbedömning gjordes av samtliga inkluderade publikationer.Resultat: Sökningen resulterade i 2 100 artiklar. Efter urvalsprocessen återstod tre artiklar som inkluderades i denna systematiska litteraturöversikt. Samtliga studier utvärderade olika typer av bisfosfonatbehandlingar – ibandronat, pamidronat och disodium clodronat. Den smärtlindrande effekten utvärderades i alla tre studierna och utläkningen av benet utvärderades i två av artiklarna. Konklusion: Behandling av icke-infektiös osteomyelit med bisfosfonater visar en reduktion av smärta. Dock är den smärtlindrande effekten beroende på typen av bisfosfonat. Resultaten gällande utläkningen av ben är tvetydiga och därför kan ingen konklusion gällande detta göras. Endast en artikel ansågs i kvalitetsgranskningen ha hög kvalitet. För att kunna ta fram tydliga, evidensbaserade riktlinjer gällande behandling av icke-infektiös osteomyelit behövs fler kliniska studier som håller hög kvalitet. Bisfosfonater verkar vara ett bra behandlingsalternativ av icke-infektiös osteomyelit. Ett alternativ till bisfosfonater, skulle kunna vara behandling med denosumab, som har liknande verkningsmekanism men kortare halveringstid. Dock krävs fortsatta studier inom detta område. / Aim: To systematically review the literature of medical treatment alternatives of non-infectious chronic osteomyelitis in the jaws regarding bone healing and pain relief. Methods: A systematic literature search has been made in four databases; PubMed, Cochrane Library, Web of Science and Scopus. The review was performed with directions from the PRISMA checklist and CRD’s guidance. A quality assessment was made of the included studies.Results: The search resulted in 2 100 articles and after the selection process, only three articles were included in this review. The studies evaluated different types of bisphosphonates - ibandronate, pamidronate and disodium clodronate. The reduction of pain was evaluated in all three articles and the bone healing was assessed in two of the articles. Conclusion: Treatment of non-infectious osteomyelitis with bisphosphonates shows a reduction in pain. However, the pain-relieving effect is most probably dependent on the type of bisphosphonates. The results of bone healing assessed from Tc-scans are ambiguous and therefore no conclusion can be made. Only one article in this review was considered to have high quality in the quality assessment. To enable clear guidelines regarding treatment of non-infectious osteomyelitis, more clinical trials with high quality is desirable. In summary, bisphosphonates seem to be a good alternative in treatment of non-infectious osteomyelitis. An alternative to bisphosphonates might be treatment with denosumab, which have a similar mechanism of action but shorter half-life. However, further research is needed.

Syfte: Att systematiskt sammanfatta litteraturen inom området för medicinska behandlingsalternativ för icke-infektiös, kronisk osteomyelit i käkarna, utvärderat genom utläkning i ben och smärtlindring. Metod: En systematisk litteraturöversikt gjordes i fyra databaser; PubMed, Cochrane Library, Web of Science och Scopus. Översikten utfördes enligt instruktioner från ”PRISMA checklist” och ”CRD’s guidance”. En kvalitetsbedömning gjordes av samtliga inkluderade publikationer.Resultat: Sökningen resulterade i 2 100 artiklar. Efter urvalsprocessen återstod tre artiklar som inkluderades i denna systematiska litteraturöversikt. Samtliga studier utvärderade olika typer av bisfosfonatbehandlingar – ibandronat, pamidronat och disodium clodronat. Den smärtlindrande effekten utvärderades i alla tre studierna och utläkningen av benet utvärderades i två av artiklarna. Konklusion: Behandling av icke-infektiös osteomyelit med bisfosfonater visar en reduktion av smärta. Dock är den smärtlindrande effekten beroende på typen av bisfosfonat. Resultaten gällande utläkningen av ben är tvetydiga och därför kan ingen konklusion gällande detta göras. Endast en artikel ansågs i kvalitetsgranskningen ha hög kvalitet. För att kunna ta fram tydliga, evidensbaserade riktlinjer gällande behandling av icke-infektiös osteomyelit behövs fler kliniska studier som håller hög kvalitet. Bisfosfonater verkar vara ett bra behandlingsalternativ av icke-infektiös osteomyelit. Ett alternativ till bisfosfonater, skulle kunna vara behandling med denosumab, som har liknande verkningsmekanism men kortare halveringstid. Dock krävs fortsatta studier inom detta område. / Aim: To systematically review the literature of medical treatment alternatives of non-infectious chronic osteomyelitis in the jaws regarding bone healing and pain relief. Methods: A systematic literature search has been made in four databases; PubMed, Cochrane Library, Web of Science and Scopus. The review was performed with directions from the PRISMA checklist and CRD’s guidance. A quality assessment was made of the included studies.Results: The search resulted in 2 100 articles and after the selection process, only three articles were included in this review. The studies evaluated different types of bisphosphonates - ibandronate, pamidronate and disodium clodronate. The reduction of pain was evaluated in all three articles and the bone healing was assessed in two of the articles. Conclusion: Treatment of non-infectious osteomyelitis with bisphosphonates shows a reduction in pain. However, the pain-relieving effect is most probably dependent on the type of bisphosphonates. The results of bone healing assessed from Tc-scans are ambiguous and therefore no conclusion can be made. Only one article in this review was considered to have high quality in the quality assessment. To enable clear guidelines regarding treatment of non-infectious osteomyelitis, more clinical trials with high quality is desirable. In summary, bisphosphonates seem to be a good alternative in treatment of non-infectious osteomyelitis. An alternative to bisphosphonates might be treatment with denosumab, which have a similar mechanism of action but shorter half-life. However, further research is needed.

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

Un 1er travail a étudié les effets osseux mandibulaires de l’injection unilatérale dans les muscles masticateurs de toxine botulique (BTX) chez le rat adulte. Ceci entraine une perte osseuse mandibulaire condylienne et alvéolaire homolatérale importante. Une hypertrophie osseuse de l’enthèse d’insertion mandibulaire du muscle digastrique a été observée et pourrait correspondre à une étiologie pour les tori. Les effets de la BTX sur le cartilage articulaire condylien mandibulaire dans le même modèle animal ont été recherchés par analyse microtomographique du cartilage articulaire après augmentation de contraste à l’acétate d’uranyle. Aucune différence d’épaisseur cartilagineuse n’a été mise en évidence entre les groupes contrôles et BTX.Le 3ème travail a consisté en l’étude histologique et microtomographique des tori mandibulaires chez l’homme.Les tori sont différents des exostoses des os longs par plusieurs caractéristiques (dont l’absence de Fe et Al dans la matrice osseuse) et une asymétrie du remodelage osseux a été mise en évidence.La 4ème partie a consisté en l’étude de la qualité osseuse et de la microvascularisation alvéolaire dans un modèle animal d’ostéonécrose mandibulaire (ONM) aux bisphosphonates (BP). Des signes cliniques et microtomographiques d’ONM ont été observés dans la majorité des cas. La minéralisation osseuse était plus élevée après imprégnation en BP. La microvascularisation osseuse alvéolaire apparaissait augmentée après avulsion dentaire chez les animaux contrôles mais pas chez les animaux ayant reçu des BP témoignant ainsi d’un effet anti angiogénique in vivo des BP qui pourrait jouer un rôle dans la physiopathologie de l’ONM. / First, bone changes at the mandible were studied after a unilateral botulinum toxin (BTX) injection in masticatory muscles in adult rats. A major alveolar and condylar bone loss was evidenced. The occurrence of a hypertrophic bone metaplasia at the digastric muscle enthesis was evidenced as well. This could constitute an etiological factor for tori. Then, condylar articular cartilage changes at the mandible were studied in the same BTX animal model, using microtomography after contrast enhancement of cartilage with uranyl acetate. Cartilage thickness measurement showed no difference when comparing control and BTX groups.A third work studied mandibular tori in human using histologic and microtomographic techniques. Tori appeared different from long bone exostoses by several characteristics (absence of Fe and Al in the bone matrix) and a specific asymmetric bone remodeling was evidenced.The fourth part consisted in the study of alveolar mandibular vascularization and quality of the bonematrix in an animal model of osteonecrosis of the jaws(ONJ) after bisphosphonates (BP) injections. Clinical and microtomographic signs of ONJ were found in mostof the cases. An increased mineralization of the alveolar bone was observed after BP impregnation. Microvascularization was increased after tooth extraction in the alveolar bone of control animals but it was impaired in ZA treated rats. Such an in vivo antiangiogenic effect of BPs could play a role in the pathophysiology of ONJ.

QUALITATIVE ASPECTS OF ADHERENCE TO ANTIRESORPTIVE TREATMENT IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS Author: Aneta Ravingerová Supervisor: Magda Vytřísalová Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Social and Clinical Pharmacy INTRODUCTION: Compliance is using of medication in accordance with a prescription drug regimen. Qualitative aspect of compliance represents use of drugs in correct way. significantly affects treatment outcomes.Suboptimal compliance The study aim was to assess qualitative compliance with bisphosphonates (BIS)AIMS: among Czech women with osteoporosis in common clinical practice. METHODS: Data collection was performed using anonymous questionnaire in five outpatient Compliance with fivecentres in the Czech Republic from November 2012 to March 2013. dosing instructions for safe use and adequate absorption of BIS was evaluated. : A total of 363 patients were involved in the analysisRESULTS (mean age 68.9 years). once a week dosing forms ofPatients were treated with BIS - alendronate, alendronate + once a month dosing formvitamine D in a fixed combination, risedronate (N = 36.6 %) or - Only 46.6 % of respondents from weekly subgroup were compliantibandronate (N = 63.4 %). with all five dosing recommendations in monthly subgroup....