Atualmente é crescente o número de pacientes utilizando drogas que visam a alteração da remodelação óssea. Doenças como osteoporose e tumores ósseos têm possibilidade de tratamento com a utilização dos antirreabsortivos. Entretanto tais medicamentos apresentam, entre outros, um efeito colateral muito nocivo: a osteonecrose dos maxilares (ONM), que consiste em uma lesão rara, mas grave, da mandíbula ou maxila caracterizada por necrose óssea exposta. O denosumab é uma droga antirreabsortiva que possui um mecanismo de ação diferente do encontrado nos bisfosfonatos (BFs), medicação amplamente usada e anterior ao denosumab, entretanto já mostra efeitos colaterais similares aos BFs em relação à ONM e para ambos os medicamentos a fisiopatogenia da doença ainda não está esclarecida pela literatura Este trabalho teve como objetivo avaliar o efeito de diferentes concentrações do denosumab sobre a viabilidade, proliferação e migração de fibroblastos em cultura. Foram utilizados fibroblastos de mucosa bucal humana linhagem FMM1. Após serem submetidos aos testes de citotoxicidade com concentrações do denosumab variando de 10- 3?g a 10 - 7?g os fibroblastos não apresentaram quaisquer alterações quanto aos quesitos avaliados. Foi possível concluir que o denosumab não é citotóxico para fibroblastos em cultura. ecrose dos maxilares Fibroblastos / The number of patients using drugs that target the manipulation of bone remodeling is currently increasing. Bone volume diseases such as osteoporosis and tumors have the possibility of treatment with the use of antiresorptive medications. However, these drugs, among others, may present a very harmful side effect: osteonecrosis of the jaw (ONJ), which consists of a rare but severe injury characterized by exposed bone necrosis. The denosumab is an antiresorptive drug that presents a different mechanism of action found in bisphosphonates (BPs) and shows similar side effects to BPs regarding ONJ. BPs are a class of medication widely used and prior to denosumab. In both drugs the pathophysiology of the disease it is still not clear. This study aimed to evaluate the effect of denosumab in different concentrations on the viability, proliferation and migration of fibroblasts in culture. Were used human oral mucosa fibroblasts FMM1. After being subjected to denosumab concentrations ranging from 10-3?g to 10-7?g fibroblasts did not show any changes to the variables evaluated. It was possible to concluded that denosumab is not cytotoxic to fibroblasts in culture.

Atualmente é crescente o número de pacientes utilizando drogas que visam a alteração da remodelação óssea. Doenças como osteoporose e tumores ósseos têm possibilidade de tratamento com a utilização dos antirreabsortivos. Entretanto tais medicamentos apresentam, entre outros, um efeito colateral muito nocivo: a osteonecrose dos maxilares (ONM), que consiste em uma lesão rara, mas grave, da mandíbula ou maxila caracterizada por necrose óssea exposta. O denosumab é uma droga antirreabsortiva que possui um mecanismo de ação diferente do encontrado nos bisfosfonatos (BFs), medicação amplamente usada e anterior ao denosumab, entretanto já mostra efeitos colaterais similares aos BFs em relação à ONM e para ambos os medicamentos a fisiopatogenia da doença ainda não está esclarecida pela literatura Este trabalho teve como objetivo avaliar o efeito de diferentes concentrações do denosumab sobre a viabilidade, proliferação e migração de fibroblastos em cultura. Foram utilizados fibroblastos de mucosa bucal humana linhagem FMM1. Após serem submetidos aos testes de citotoxicidade com concentrações do denosumab variando de 10- 3?g a 10 - 7?g os fibroblastos não apresentaram quaisquer alterações quanto aos quesitos avaliados. Foi possível concluir que o denosumab não é citotóxico para fibroblastos em cultura. ecrose dos maxilares Fibroblastos / The number of patients using drugs that target the manipulation of bone remodeling is currently increasing. Bone volume diseases such as osteoporosis and tumors have the possibility of treatment with the use of antiresorptive medications. However, these drugs, among others, may present a very harmful side effect: osteonecrosis of the jaw (ONJ), which consists of a rare but severe injury characterized by exposed bone necrosis. The denosumab is an antiresorptive drug that presents a different mechanism of action found in bisphosphonates (BPs) and shows similar side effects to BPs regarding ONJ. BPs are a class of medication widely used and prior to denosumab. In both drugs the pathophysiology of the disease it is still not clear. This study aimed to evaluate the effect of denosumab in different concentrations on the viability, proliferation and migration of fibroblasts in culture. Were used human oral mucosa fibroblasts FMM1. After being subjected to denosumab concentrations ranging from 10-3?g to 10-7?g fibroblasts did not show any changes to the variables evaluated. It was possible to concluded that denosumab is not cytotoxic to fibroblasts in culture.

Bakgrund Osteoporos är den vanligaste skelettsjukdomen i Skandinavien. Ungefär varannan kvinna och var 4:e man kommer att drabbas av någon typ av fraktur under sin livstid. Med en åldrande befolkning kommer den medicinska och socioekonomiska effekten av osteoporos, särskilt postmenopausal osteoporos, att öka. Symtomen är smärta i benen men i vissa fall kan ryggkotorna pressas ihop vilket ger en måttlig ryggvärk. I Sverige inträffar årligen ca 70 000 osteoporosrelaterade frakturer. Uppskattad kostnad 3,5 miljarder kronor. Av de 70 000 frakturer årligen så är ca 17 000 höftledsfrakturer och 10 000 är kotfraktur. Läkemedel som används som förstahandsval är bisfosfonater som alendronat i behandling mot osteoporos. I andra hand används denosumab till patienter som inte tål bisfosfonater.  Syfte Syftet med studien var att jämföra effekten av alendronat och denosumab för att förebygga frakturer, samt att undersöka effekter på bentäthet (bone mineral density, BMD) av långtidsbehandling och korttidsbehandling av benskörhet/osteoporos hos postmenopausala kvinnor. Resultat Vid användning av alendronat under de första 3 åren jämfört med denosumab visar det sig att tillväxten på BMD i ländryggen är nästan densamma. Alendronat gav en ökning av BMD på 8,8% efter tre år i ländryggen och denosumab gav en BMD-ökning på 9,2% i ländryggen. Dock efter tre till fem års användning av alendronat börjar det att tappa sin effekt på ökning av BMD. Under de första tre årens använding av alendronat var NNT (numbers needed to treat) = 33 för förebyggande av vertebrala frakturer och för icke-vertebrala frakturer var NNT = 45. För denosumab var NNT = 20 för vertebrala frakturer och för icke-vertebrala frakturer var NNT = 50 under de första tre åren. Efter 10 års användning av alendronat ökade BMD i ländryggen 13,7%, medan för denosumab ökade BMD 18,4% efter 8 år användning. Slutsats Alendronat är ett bra val som läkemedel mot osteoporos de första tre till fem åren. Alendronat lagras i kroppen och fortsatt behandling har inte samma effekt på BMD-tillväxt som under de första åren. Däremot så är denosumab ett bättre alternativ som ger en fortsatt tillväxt av BMD under 8 års användning. Problemet är att denosumab är dyrt att ge till alla som har osteroporos. Förhoppningsvis blir biologiska läkemedel billigare i framtiden, så att fler människor kan behandlas med denosumab. / Background Osteoporosis is the most common skeletal disease in Scandinavia. About every other woman and every 4th man will suffer from some kind of fracture during their lifetime. With an aging population, the medical and socio-economic impact of osteoporosis, especially postmenopausal osteoporosis, will increase. The symptoms are pain in the legs, but in some cases the spine can be compressed, which causes a moderate backache. In Sweden, approximately 70,000 osteoporosis-related fractures occur annually. Estimated cost of SEK 3.5 billion. Of the 70,000 fractures annually, about 17,000 are hip fractures and 10,000 are vertebral fractures. Medicinal products used as first choice are bisphosphonates like alendronate in treatment for osteoporosis. Denosumab is used in patients who cannot take bisphosphonates. Aim The aim of the study was to compare the efficacies of alendronate and denosumab in preventing fractures and to examine the effects of long-term and short-term treatment of osteoporosis on bone mineral density (BMD) in post-menopausal women. Results When alendronate is used in the first 3 years compared with denosumab, BMD growth at the lumbar spine is almost the same. Alendronate gave a BMD increase of 8.8% after three years at the lumbar spine and denosumab a BMD increase of 9.2% at the lumbar spine. However, after three to five years of using alendronate, it begins to lose its effect on increasing BMD. In the first three years, the use of alendronate for preventing vertebral fractures gave a NNT (numbers needed to treat) = 33 and for nonvertebral fractures NNT = 45. For denosumab NNT = 20 for vertebral fractures and for nonvertebral fractures NNT = 50 in the first three years. After 10 years of use of alendronate, BMD increase at the lumbar spine was 13.7%, while denosumab resulted in a BMD growth of 18.4% after 8 years of use. Conclusion Alendronate is a good choice as a drug for the first three to five years. Alendronate is stored in the body and continued treatment does not have the same effect as the first few years. On the other hand, denosumab is a better alternative, as it results in continued BMD growth for up to 8 years of use. The problem is that denosumab is too expensive to give to everyone who has osteoporosis. Hopefully, in the future, biological medicines will become cheaper, so that more people can be treated with denosumab.

Bakgrund: Osteoporos är en sjukdom som kännetecknas av minskad benmassa och försämrad benkvalitet vilket ökar risken för benbrott. Sjukdomen drabbar framför allt äldre kvinnor som passerat menopaus, men även män och yngre personer kan drabbas. Riskfaktorer inkluderar genetik, bristande fysisk aktivitet, rökning, alkoholkonsumtion och vissa sjukdomar och mediciner. Behandling av osteoporos fokuserar på att minska risken för frakturer genom att förbättra benhälsa och minska benförlust. Behandling kan ske med resorptionshämmande läkemedel som bisfosfonater eller denosumab som hämmar nedbrytningen av benmassa eller anabola läkemedel som teriparatid som stimulerar nybildning av benmassa.   Syfte: Syftet med detta litteraturarbete var att beskriva effekten av sekventiell behandling på bone mineral density (BMD) vid behandling med teriparatid följt av denosumab hos kvinnor med svår postmenopausal osteoporos utifrån tidigare studier.  Metod: De fem vetenskapliga artiklar som användes till litteraturstudien togs från databasen PubMed. Dessa analyserades med fokus på hur behandling med teriparatid följt av denosumab påverkar BMD hos kvinnor med svår postmenopausal osteoporos. Resultat: Resultatet visade en signifikant ökning av BMD på ryggraden i samtliga studier vid behandling med teriparatid följt av denosumab. En ökning av BMD kunde även ses på höft och lårbenshals dock var ökningen inte signifikant i alla studier. Frakturrisken studerades i tre av studierna. I en av studierna påvisades en signifikant minskning av frakturrisken vid behndling med teriparatid följt av denosumab, i en annan studie påvisades en minskning av frakturrisken dock var minskningen inte signifikant. I den tredje studien var det en mer fraktur i gruppen som fick teriparatid följt av denosumab.  Slutsats: Observerade data visar att behandling med teriparatid följt av denosumab har bättre effekt på BMD jämfört med monoterapi med denosumab eller teriparatid följt av bisfosfonater. Vidare studierna skulle dock behöva göras då det finns få randomiserade kontrollstudier och studierna som finns har relativt få antal deltagare. Dessutom skulle det behövas studier som pågår under längre perioder för att kunna påvisa eventuella långtidsbivekningar. / Background: Osteoporosis is a disease characterized by reduced bone mass and deteriorated bone quality, which increases the risk of bone fractures. The disease primarily affects older women who have gone through menopause, but men and younger individuals can also be affected. Risk factors include genetics. Lack of physical activity, smoking, alcohol consumtion and certain diseases and medications. Treatment of osteoporosis focuses on reducing the risk of fractures by improving bone health and reducing bone loss. Treatment may involve the use of resorption inhibitors such as bisphosphonates or denosumab, which inhibit the breakdown of bone mass, or anabolic drugs such as teriparatide, which stimulate the formation of new bone mass. Purpose: The purpose of this literature review was to describe the effect of sequential treatment on bone mineral density (BMD) in women with severe postmenopausal osteoporosis who were treated with teriparatide followed by denosumab. Method: The five scientific articles used for the literature review were retrieved from the PubMed database. These were analyzed with focus on how treatment with teriparatide followed by denosumab affects BMD in women with severe postmenopausal osteoporosis. Results: The results showed a significant increase in BMD in the spine in all studies when treated with teriparatid followed by denosumab. An increase in BMD could also be seen in the hip and femoral neck, although the increase was not significant in all studies. Fracture risk was studied in three of the studies. In one of the studies, a significant in fracture risk was demonstarted with treatment with teriparatid followed by denosumab. In another study, a decrease in fracture risk was observed, altough the decrease was not significant. In the third study, there were more fractures in the group that received teriparatid fallowed by denosumab. Conclusion: The observed data indicate that treatment with teriparatide followed by denosumab has a better effect on BMD compared to monotherapy with denosumab or teriparatide followed by bisphosphonates. However, further studies are needed as there are few randomized controll studies and the existing studies have a relatively small number of participants. In addition, studies conducted over longer periodes of time would be necessary to identify potential long-term side effects.

The skeletal system is the most common site of metastatic cancer spread. Bone metastases are often associated with severe morbidity, pain and functional impairment. Timely diagnosis and proper treatment may decrease morbidity, improve quality of life and in some cases even improve survival. External beam radiotherapy may effectively give pain relief in patients with painful bone metastases. In bone metastases from castration-resistant prostate cancer or urothelial bladder cancer, treatment with zoledronic acid or denosumab may reduce skeletal-related events. In contrast to castration-resistant prostate cancer, in patients with bone metastases from bladder cancer such treatment may even improve survival. On the other hand, the efficacy of these agents is questionable in patients with bone involvement from metastatic renal cell carcinoma or germ cell tumors. When bisphosphonates or denosumab are considered in such cases, the potential benefits of treatment should be critically weighed against the risk of side effects. In germ cell tumors, bone metastases may be cured by cisplatin-based chemotherapy, however, there are only limited data on the specific management of residual disease. Oligometastases may be treated by stereotactic radiotherapy or – especially in patients with renal cell carcinoma – by surgical resection and endoprosthetic replacement. Limited data are available on the management of bone involvement in germ cell tumors. Decisions on the resection or local radiotherapy of residual disease should be individualized considering the overall response and the feasibility and risks of resection.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13437号 / 論医博第2236号 / 新制||医||1054(附属図書館) / (主査)教授 松田 秀一, 教授 中山 健夫, 教授 森本 尚樹 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

The incidence of hypocalcemia and bone mineral density (BMD) changes in end-stage renal disease (ESRD) patients on denosumab remains unclear. We performed this meta-analysis to assess the incidence of denosumab-associated hypocalcemia and effects of denosumab on BMD in ESRD patients. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through November 2017 to identify studies evaluating incidence of denosumab-associated hypocalcemia and changes in serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and BMD from baseline to post-treatment course of denosumab in ESRD patients. Study results were pooled and analyzed using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017081074). Six observational studies with a total of 84 ESRD patients were enrolled. The pooled estimated incidence of hypocalcemia during denosumab treatment was 42% (95% CI 29–55%, I2 = 0%). Hypocalcemia occurred approximately 7 to 20 days after the first dose and reached nadir of low calcium levels in the first 2 weeks up to 2 months. However, there were no significant changes in serum calcium or phosphate from baseline to post-treatment course (≥ 3 months after treatment) with mean differences [MDs] of 0.20 mg/dL (95% CI, − 0.30 to 0.69 mg/dL) and − 0.10 mg/dL (95% CI, − 0.70 to 0.49 mg/dL). There were significant reductions in ALP and PTH levels with standardized mean differences (SMDs) of − 0.65 (95% CI − 1.13 to − 0.16) and − 1.89 (95% CI − 3.44 to − 0.34), respectively. There were significant increases in T-scores with MDs of 0.39 (95% CI 0.10 to 0.69) and 0.79 (95% CI 0.60 to 0.98) for lumbar spine and femoral neck, respectively. Our study demonstrates the estimated incidence of denosumab-associated hypocalcemia in dialysis patients of 42%. From baseline to post-treatment course, although there are no differences in serum calcium and phosphate, our findings suggest significant reductions in ALP and PTH and a significant increase in BMD. Currently, denosumab should not be considered as the treatment of choice in ESRD patients until more safety and efficacy data are available.

Aim: The overall aim is to (i) analyze the prognosis of dental implant treatment concerning marginal bone loss (MBL) in patients undergoing or have undergone treatment with bone antiresorptive or antiangiogenic medication for osteoporosis (ii) and additional purpose to assess the available scientific literature in the first aim concerning the risk of getting medication-related osteonecrosis of the jaw (MRONJ) associated with dental implant installation.  Material and methods: A systematic literature search was conducted in October 2021 in the following three databases; MEDLINE/PubMed, Cochrane Library and Web of Science. PRISMA 2009 Flow Diagram were used for the selection process, whereas the included studies were evaluated for quality assessment using Newcastle Ottawa Scale (NOS).  Results: The search resulted in four included studies considering the eligibility criteria. The studies evaluated MBL in osteoporotic patients undergoing or have undergone oral bisphosphonate (BP) treatment before and/or during implant placement. MRONJ was also assessed in all four articles.  Conclusions: The results of this present study do not indicate that patients undergoing or have undergone antiresorptive or antiangiogenic medication for osteoporosis are at an increased risk of MBL in dental implants during follow-up periods. The present data assessing the risk for developing MRONJ remains low for osteoporotic patients. Therefore, dental implant surgery is considered possible with success in osteoporotic patients receiving earlier mentioned medications. However additional studies are required to evaluate the effects on this patient group concerning osseointegration of dental implant regarding MBL. / Syfte: Syftet med denna studie är att analysera prognosen för implantatbehandling avseende marginell benförlust (MBL) hos patienter som genomgår eller har genomgått behandling med benantiresorptiv eller antiangiogen medicin för osteoporos. Ytterligare utförs en bedömning av tillgänglig vetenskaplig litteratur gällande risken för läkemedelsrelaterad käkbensnekros (MRONJ) associerat med implantatinstallation hos patienter som genomgår eller har genomgått behandling med benantiresorptiv eller antiangiogen medicin. Material och metod: En systematisk elektronisk litteratursökning genomfördes i oktober 2021 i följande tre databaser; MEDLINE/PubMed, Cochrane Library och Web of Science. PRISMA 2009 Flow Diagram användes för urvalsprocessen, varav de inkluderande studierna kvalitetsgranskades enligt Newcastle Ottawa Scale (NOS). Resultat: Sökningen resulterade i fyra studier, enligt inklusions- och exklusionskriterier. Studierna utvärderade MBL hos osteoporospatienter som går eller har gått behandling med orala bisfosfonater före eller under implantatinstallationen. MRONJ fastställdes i alla fyra artiklar. Slutsats: Resultatet av denna studie indikerar inte att patienter som genomgår eller har genomgått behandling med benantiresorptiv eller antiangiogen medicin för osteoporos löper en ökad risk för MBL av dentala implantat under uppföljningsperioder. Nuvarande data bedömer att risken för att utveckla MRONJ är fortfarande låg för osteoporos patienter. Därför antas implantatkirurgi kunna utföras på osteoporos patienter som står på denna medicinering. Dock krävs ytterligare studier för att utvärdera effekterna av denna patientgrupp gällande osseointegration av dentala implantat avseende MBL.

Made available in DSpace on 2011-05-04T12:36:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 / As atividades de rastreamento do horizonte tecnológico, uma forma de avaliação de tecnologia em saúde realizada no início do ciclo de vida das tecnologias, vêm sendo difundidas em países desenvolvidos desde a década de 90, visando tornar mais eficientes os processos de tomada de decisão relativos à incorporação de novas tecnologias. Trata-se de uma abordagem sistemática para a identificação e avaliação de tecnologias novas / emergentes, com o objetivo de alertar os tomadores de decisão quanto à sua existência e potenciais conseqüências de sua incorporação para o sistemade saúde, antes da difusão do seu uso. Considerando a relevância de operacionalizar as atividades de rastreamento do horizonte tecnológico para a atenção à saúde no Brasil, apresente dissertação teve o objetivo de produzir subsídios para a elaboração de diretrizes de um sistema de rastreamento do horizonte a ser criado no País. Para auxiliar o processo de elaboração, foi realizado um exercício de rastreamento do horizonte, no qual foi utilizado o caso das tecnologias envolvidas no manejo da osteoporose em mulheres na pós-menopausa, um problema de saúde considerado relevante, para o qual não existe solução razoável. Inicialmente, procedemos a uma revisão do conceito e das experiências internacionais com sistemas de rastreamento do horizonte tecnológico (SRH) em saúde. As fontes consultadas e os trabalhos analisados indicam um consenso de que um SRH deve sempre basear seu trabalho na melhor evidência preliminar disponível sobre o efeito das tecnologias, na saúde das pessoas e sobre o sistema de saúde, e atuar de maneira transparente, explicitando ao máximo a metodologia adotada no processo de trabalho. A revisão também permitiu a identificação de muitos desafios e pontos críticos para o desenvolvimento e operacionalização de tal sistema. O exercício de rastreamento realizado possibilitou a identificação de uma nova tecnologia medicamentosa, o denosumab, para o tratamentoda osteoporose, cujos ensaios clínicos de fase II e III, recentemente publicados, foram analisados. As limitações enfrentadas na realização do exercício permitiram reconhecer algumas dificuldades básicas específicas da avaliação tecnológica no início do ciclo devida. A avaliação das experiências internacionais e o exercício acima referido indicam que, para o desenvolvimento e operacionalização de um SRH no Brasil, o intercâmbio e a colaboração institucional com as unidades governamentais de monitoramento do horizonte de países desenvolvidos será fundamental, tendo em vista o corpo qualificado e a longa experiência daquelas unidades nessas atividades e, ainda, a quantidade de trabalho e de tempo envolvidos na análise de cada tecnologia e a urgência inerente a essas atividades. Além disso, deverá haver uma articulação entre os atores-chave, especialmente os do âmbito governamental, com o objetivo de discutir e estabelecer as diretrizes para a criação do sistema. Com isso, espera-se que as informações produzidas pelo SRH brasileiro sejam adequadamente utilizadas no processo de tomada de decisão do sistema de saúde. / Activities related to horizon scanning of technologies for health care, a form of health technology assessment carried out at the beginning of the life cycle of those technologies, have been adopted in several developed countries since the 90s, with the purpose of improving the efficiency of decision making related to the incorporation of new technologies. Horizon scanning consists of a systematic approach to identify and assess new and emerging technologies in order to warn health care decision makers about the existence and potential consequences of their incorporation to individuals and to the health system, before the diffusion stage. Given the importance of developing horizon scanning activities for health care technologies in Brazil, the present work had the objective of producing subsidies for the elaboration of guidelines to develop a horizon scanning system in Brazil. To aid that elaboration process, the case of technologies designed for the secondary prevention of osteoporotic fractures after menopause, a relevant public health problem far from being solved, was analyzed. Initially, a review of the concept of horizon scanning in health care and of the related international governmental experiences was carried out. The available sources and studies indicate a consensus on that: a) recommendations made by a horizon scanning 8 system must be supported by the best available early scientific evidence of the consequences on the health of the individuals and on the health system of the adoption of new/emerging technologies; b) the horizon scanning system must act in a transparent way, making explicit the criteria and methodology it uses. The review also showed that there remain several challenges to be dealt with in order to further develop such monitoring system. The horizon scanning exercise related to the secondary prevention of osteoporotic fractures enabled the identification of a new drug, called denosumab; phase II and phase III trials of that technology have been recently published and were analyzed. Limitations faced in such exercise made it possible the identification of some specific difficulties associated to technology assessment at the beginning of the life cycle. The review of the international experiences with horizon scanning of health care technologies, at central government level, along with the mentioned exercise, indicate that, for developing a horizon scanning system in Brazil, collaboration with developed countries’ units is essential, taking into account the qualified and experienced staff of such units as well as the amount of work and time involved in the analysis of each technology and the inherent urgency of such activities. Finally, key actors, specially those at central government level, must be articulated for the discussion and elaboration of the guidelines towards the creation of such system. In this way, the chances of a successful effort, with an adequate utilization of produced information in the process of decision-making, are increased.