Cost-utility analysis of denosumab and teriparatide in the treatment of postmenopausal osteoporosis in Chinese women / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of denosumab and teriparatide in the treatment of postmenopausal osteoporosis in Chinese women， and provide reference for relevant decision-making. METHODS From the perspective of health system in China， Excel 2003 was used to establish Markov model， and cost-utility analysis was used to evaluate the cost- effectiveness of denosumab or teriparatide combined with Calcium carbonate D3 tablets in the treatment of postmenopausal osteoporosis in Chinese women. Pharmacotherapy effects were obtained with network meta-analysis， and cost and health utility value data were obtained from published literature. The model cycle was 1 year， and the simulation time limit was the patient’s lifetime. Univariate sensitivity analysis and probabilistic sensitivity analysis were used to evaluate the effects of model parameter changes on the robustness of the results. Through scenario analysis， the cost-effectiveness of domestic drug cost used as drug cost of terlipatide group was discussed； the influence of residual effects of teriparatide on the results and the cost-effectiveness of sequential use of desumamab after terlipatide withdrawal were also discussed. RESULTS The effect of denosumab regimen was better than that of terlipatide regimen [13.24 quality-adjusted life years （QALYs） vs. 12.96 QALYs]， with lower cost （51 224.64 yuan vs. 167 102.67 yuan）， denosumab regimen was the absolutely superior regimen. The results of single factor sensitivity analysis showed that the cost and discount rate of Terlipatide injection had greater impact on the results. The results of probability sensitivity analysis showed that when three times of China’s per capita gross domestic product （GDP） in 2021 was used as the threshold of willingness to pay， the probability of cost-effectiveness of denosumab regimen was 93.5%. The results of scenario analysis showed that， whether the drug cost of terlipatide regimen which was replaced by domestic drugs， or the residual effect of terlipatide was considered， or desulmonab was used sequentially after two years of terlipide treatment， denosumab regimen was always the absolute advantage regimen. CONCLUSIONS Denosumab combined with Calcium carbonate D3 tablets is more cost-effective than teriparatide combined with Calcium carbonate D3 tablets in the treatment of postmenopausal osteoporosis in Chinese women.

Use of teriparatide in surgical planning for patients with osteoporosis / Uso de teriparatida no planejamento cirúrgico de paciente com osteoporose / Uso de teriparatida en la planificación quirúrgica en pacientes con osteoporosis

ABSTRACT: Currently, there are no guidelines for treating osteoporosis in spinal surgery. The rate of complications such as screw loosening, proximal junction kyphosis, cage subsidence, and loss of reduction in fractures is high. Objective: To evaluate the use of teriparatide and denosumab in planning spinal surgery in an osteoporotic patient with degenerative pathology, emphasizing the fusion rate, bone mineral density, and decreased complications. Method: A systematic search was performed in medical reference databases for comparative studies of teriparatide and denosumab in spinal surgery to evaluate fusion, screw loosening, bone mineral density, and decrease in the incidence of vertebral fractures. χ2 was implemented for the statistical analysis, according to PRISMA (2020). Result: Fusion rate with teriparatide was 79.28% in the first six months, 95% CI (OR 2.62) and decreased screw loosening rate 81.9% 95% CI (OR 0.6). Increase in bone mineral density 15.5% OR 1.49 (0.77 - 2.86) and decrease in vertebral fracture rate 85.4% OR 0.5. Conclusions: Teriparatide and denosumab should be considered in perioperative spinal planning due to their effectiveness, synergism, and low adverse effects; to improve bone mineral density and decrease the rate of complications. Clinical, comparative, and statistically significant studies are required to confirm this. Level of Evidence II; Systematic Review and Meta-analysis.

RESUMO: Atualmente não existem diretrizes para o tratamento da osteoporose em cirurgia da coluna vertebral. A taxa de complicações como afrouxamento de parafuso, cifose da junção proximal, subsidência da gaiola e perda de redução nas fraturas é alta. Objetivo: Avaliar o uso de teriparatida e/ou denosumabe no planejamento da cirurgia da coluna vertebral em pacientes osteoporóticos com patologia degenerativa, enfatizando a taxa de fusão, densidade mineral óssea e diminuição de complicações. Método: Foi realizada uma busca sistemática em bases de dados de referência médica para estudos comparativos de teriparatida e denosumabe em cirurgia da coluna vertebral, a fim de avaliar fusão, soltura de parafuso, densidade mineral óssea e diminuição da incidência de fraturas vertebrais. O χ2 foi implementado para a análise estatística, de acordo com PRISMA (2020). Resultado: A taxa de fusão com teriparatida foi de 79,28% nos primeiros 6 meses IC 95% (OR 2,62) e diminuiu a taxa de afrouxamento do parafuso 81,9% IC 95% (OR 0,6). O aumento da densidade mineral óssea foi de 15,5% OR 1,49 (0,77 - 2,86) e a diminuição da taxa de fratura vertebral atingiu 85,4% OR 0,5. Conclusões: A teriparatida e o denosumabe devem ser considerados no planejamento espinhal perioperatório devido à sua efetividade, sinergismo e baixos efeitos adversos, melhorando a densidade mineral óssea e diminuir a taxa de complicações. Estudos clínicos, comparativos e estatisticamente significativos são necessários para confirmar os achados. Nível de Evidência II; Revisão Sistemática e Meta-análise.

RESUMEN: Actualmente no existen pautas para el tratamiento de la osteoporosis en cirugía espinal. La tasa de complicaciones como el aflojamiento de los tornillos, la cifosis de la unión proximal, el hundimiento del aparato Ilizarov y la pérdida de reducción de las fracturas es alta. Objetivo: Evaluar el uso de teriparatida y/o denosumab en la planificación de la cirugía de columna en el paciente osteoporótico con patología degenerativa haciendo hincapié en la tasa de fusión, la densidad mineral ósea y la disminución de las complicaciones. Método: Se realizó una búsqueda sistemática en bases de datos de referencia médica para estudios comparativos de teriparatida y denosumab en cirugía espinal con el fin de evaluar la fusión, el aflojamiento de tornillos, la densidad mineral ósea y la disminución de la incidencia de fracturas vertebrales. χ2 se implementó para el análisis estadístico, según PRISMA (2020). Resultado: La tasa de fusión con teriparatida fue del 79,28% en los primeros 6 meses IC 95% (OR 2,62) y disminuyó la tasa de aflojamiento del tornillo 81,9% IC 95% (OR 0,6). Aumento de la densidad mineral ósea 15,5% O 1,49 (0,77 - 2,86) y disminución de la tasa de fractura vertebral 85,4% O 0,5. Conclusiones: La teriparatida y el denosumab deben ser considerados en la planificación espinal perioperatoria debido a su efectividad, sinergismo y bajos efectos adversos; con el fin de mejorar la densidad mineral ósea y disminuir la tasa de complicaciones. Se requieren estudios clínicos, comparativos y estadísticamente significativos para confirmarlo. Nivel de Evidencia II; Revisión sistemática y metaanálisis.

Teriparatide regulates osteoblast differentiation in high-glucose microenvironment through the cAMP/PKA/CREB signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of teriparatide on the differentiation of MC3T3-E1 cells in high-glucose microenvironment and explore the possible mechanism.@*METHODS@#MC3T3-E1 cells cultured in normal glucose or high-glucose (25 mmol/L) medium were treated with 10 nmol/L teriparatide with or without co-treatment with H-89 (a PKA inhibitor). CCK-8 assay was used to detect the changes in cell proliferation, and cAMP content in the cells was determined with ELISA. Alkaline phosphatase (ALP) activity and mineralized nodules in the cells were detected using ALP kit and Alizarin red staining, respectively. The changes in cell morphology were detected by cytoskeleton staining. Real-time PCR was used to detect the mRNA expressions of PKA, CREB, RUNX2 and Osx in the treated cells.@*RESULTS@#The treatments did not result in significant changes in proliferation of MC3T3-E1 cells (P > 0.05). Compared with the cells in routine culture, the cells treated with teriparatide showed significantly increased cAMP levels (P < 0.05) with enhanced ALP activity and increased area of mineralized nodules (P < 0.05). Teriparatide treatment also resulted in more distinct visualization of the cytoskeleton in the cells and obviously up-regulated the mRNA expressions of PKA, CREB, RUNX2 and Osx (P < 0.05). The opposite changes were observed in cells cultured in high glucose. In cells exposed to high glucose, treatment with teriparatide significantly increased cAMP levels (P < 0.05), ALP activity and the area of mineralized nodules (P < 0.05) and enhanced the clarity of the cytoskeleton and mRNA expressions of PKA, CREB, RUNX2 and Osx; the effects of teriparatide was strongly antagonized by co-treatment with H-89 (P < 0.05).@*CONCLUSION@#Teriparatide can promote osteoblast differentiation of MC3T3-E1 cells in high-glucose microenvironment possibly by activating the cAMP/PKA/CREB signaling pathway.

Anabolic therapy for osteoporosis: update on efficacy and safety

ABSTRACT Anabolic agents for the treatment of osteoporosis increase bone density, improve bone strength, and reduce fracture risk. They are distinguished from antiresorptive drugs by their property of increasing osteoblastic bone formation. Teriparatide and abaloparatide are parathyroid hormone receptor agonists that increase bone remodeling with bone formation increasing more than bone resorption. Romosozumab is a humanized monoclonal antibody to sclerostin that has a "dual effect" of increasing bone formation while decreasing bone resorption. The bone forming effects of anabolic therapy appear to be self-limited, making it imperative that it be followed by antiresorptive therapy to enhance or consolidate the beneficial effects achieved. Teriparatide, abaloparatide, and romosozumab each have unique pharmacological properties that must be appreciated when using them to treat patients at high risk for fracture. Clinical trials have shown a favorable balance of expected benefits and possible risks. Anabolic therapy is superior to bisphosphonates for high-risk patients, with greater benefit when initial treatment is with an anabolic agent followed by an antiresorptive drug, rather than the reverse sequence of therapy. Recent clinical practice guidelines have included recommendations with examples of patients who are candidates with anabolic therapy.

Definition and management of very high fracture risk in women with postmenopausal osteoporosis: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Association of Bone Assessment and Metabolism (ABRASSO)

ABSTRACT Several drugs are available for the treatment of osteoporosis in postmenopausal women. Over the last decades, most patients requiring pharmacological intervention were offered antiresorptive drugs as first-line therapy, while anabolic agents were considered a last resource for those with therapeutic failure. However, recent randomized trials in patients with severe osteoporosis have shown that anabolic agents reduce fractures to a greater extent than antiresorptive medications. Additionally, evidence indicates that increases in bone mineral density (BMD) are maximized when patients are treated with anabolic agents first, followed by antiresorptive therapy. This evidence is key, considering that greater increases in BMD during osteoporosis treatment are associated with a more pronounced reduction in fracture risk. Thus, international guidelines have recently proposed an individualized approach to osteoporosis treatment based on fracture risk stratification, in which the stratification risk has been refined to include a category of patients at very high risk of fracture who should be managed with anabolic agents as first-line therapy. In this document, the Brazilian Society of Endocrinology and Metabolism and the Brazilian Association of Bone Assessment and Metabolism propose the definition of very high risk of osteoporotic fracture in postmenopausal women, for whom anabolic agents should be considered as first-line therapy. This document also reviews the factors associated with increased fracture risk, trials comparing anabolic versus antiresorptive agents, efficacy of anabolic agents in patients who are treatment naïve versus those previously treated with antiresorptive agents, and safety of anabolic agents.

An inconvenient status in anti-osteoporotic treatment process: corticosteroid use

SUMMARY OBJECTIVE: There are limited studies investigating the comparison of the efficacy of anti-osteoporotic drugs in different conditions resulting in osteoporosis in older adults. This study aimed to compare the effectiveness of anti-osteoporotic agents in older adults with or without glucocorticoid-induced osteoporosis. METHODS: This retrospective study included 364 patients with osteoporosis, aged 65 years and older. Bone mineral density measurement was performed, and the percent change from baseline was calculated at month 24. RESULTS: Of the 364 patients, 80 were glucocorticoid users. Similar changes in the bone mineral density of the lumbar spine and femoral neck and fracture risk were found in patients with or without glucocorticoid-induced osteoporosis. There was no significant difference in bone mineral density changes between the groups in terms of anti-osteoporotic agents used. CONCLUSIONS: This study demonstrated that the response to anti-osteoporotic agents was similar in older adults with glucocorticoid-induced osteoporosis and those without glucocorticoid-induced osteoporosis. The results of our study may guide osteoporosis treatment in older individuals with glucocorticoid-induced osteoporosis.

Effects of teriparatide on bone formation in rats with experimentally induced premaxillary expansion

ABSTRACT Objective: This study aimed to evaluate the effects of systemic teriparatide on sutural bone formation after premaxillary suture expansion in rats. Material and Methods: Twenty Wistar male rats (8-10 weeks old) were randomly divided into two groups, namely, control (C, n=10) and teriparatide (T, n=10). An expansion force was applied to the maxillary incisors using helical spring for a seven-day expansion period, for both groups. On the eighth day, the rats were kept for a seven-day consolidation period, and then 60 µg/kg teriparatide (once a day) was administered to group T subcutaneously for seven days. Then, all the rats were sacrificed, and histological sections were stained with hemotoxylin-eosin for examination. Anti-osteonectin, anti-osteocalcin, anti-Vascular endothelial growth factor (VEGF) and anti-transforming growth factor beta (TGF-β) were evaluated by immunohistochemical analysis in the midpalatal suture area. Results: Histologically, the newly formed bone tissue was observed to be larger in group T than in group C. The number of immunoreactive osteoblasts for osteonectin, osteocalcin and VEGF antibodies was significantly higher in group T than in group C (p = 0.0001). The TGF-β antibody showed a mild reaction in group T, but did not reach significance in comparison with group C (p ˃ 0.05). Conclusion: Systemic teriparatide application following the premaxillary expansion of the suture area may stimulate bone formation and add to the consolidation of the expansion in rats by regulating osteonectin, osteocalcin and VEGF.

RESUMO Objetivo: O presente estudo teve como objetivo avaliar os efeitos do uso sistêmico da teriparatida na formação óssea sutural após a expansão da pré-maxila em ratos. Material e Métodos: Vinte ratos machos da raça Wistar (com oito a dez semanas de vida) foram divididos aleatoriamente em dois grupos: controle (C, n=10) e teriparatida (T, n=10). Uma força de expansão foi aplicada aos incisivos superiores, usando uma mola helicoidal, por um período de expansão de sete dias em ambos os grupos. No oitavo dia, os ratos iniciaram um período de sete dias de consolidação, nos quais 60 µg/kg de teriparatida foram administrados (uma vez ao dia), por via subcutânea, para o grupo T. Posteriormente, todos os ratos foram sacrificados e cortes histológicos corados com hemotolixina-eosina foram examinados. Por meio de análise imuno-histoquímica da região da sutura palatina mediana, avaliou-se a presença de anti-ostenectina, anti-osteocalcina, anti-fator de crescimento endotelial vascular (VEGF) e anti- fator transformador de crescimento (TGF-β). Resultados: Histologicamente, observou-se que o tecido ósseo recém-formado foi maior no grupo T do que no grupo C. O número de osteoblastos imunorreativos para anticorpos de osteonectina, osteocalcina e VEGF foi significativamente maior no grupo T do que no grupo C (p = 0,0001). O anticorpo TGF-β mostrou uma pequena reação no grupo T; porém, sem diferença significativa para o grupo C (p ˃ 0,05). Conclusão: O uso sistêmico de teriparatida após a expansão da sutura na região da pré-maxila pode estimular a formação óssea e melhorar a consolidação da expansão em ratos, por meio da regulação de osteonectina, osteocalcina e VEGF.

Effect of teriparatide on residual back pain after percutaneous kyphoplasty for osteoporotic thoracolumbar compression fracture / 中华创伤杂志

Objective:To investigate the effect of teriparatide on residual back pain (RBP) after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture (OVCF).Methods:A retrospective cohort study was used to analyze the clinical data of 90 OVCF patients sustaining RBP after PKP admitted to Second Affiliated Hospital of Kunming Medical University from September 2015 to March 2019, including 18 males and 72 females, at age of 57-85 years［(68.0±5.9) years］. Teriparatide treatment was applied regularly in 32 patients (teriparatide group) and antiosteoporosis drug was administered routinely in 58 patients (routine treatment group). Visual analogue scale (VAS) and Oswestry disability index (ODI) were compared between the two groups before operation, at 24 hours, 1 month, 3 months, 6 months and 12 months after operation. Anterior vertebral body height (ABH), middle vertebral body height (MBH), kyphosis angle (KA), maintenance rate of anterior vertebral body height (MRABH), maintenance rate of middle vertebral body height (MRMBH) and difference of kyphosis angle (DKA) were measured at 24 hours and 12 months after operation to evaluate the maintenance of vertebral height and incidence of vertebral refracture. Levels of type I collagen carboxy-terminal peptide (β-CTX) and serum N-terminal osteocalcin (N-MID) were measured before operation and at 12 months after operation to evaluate the improvement of bone metabolism. The adverse reactions of teriparatide group were observed.Results:All patients were followed up for 12-36 months［(14.3±0.6)months］. VAS and ODI were decreased gradually with time in both groups (all P<0.01). There were no significant differences in VAS between the two groups before operation and at 24 hours after operation (all P>0.05). Teriparatide group showed VAS of (4.4±0.6)points, (3.2±0.5)points, (2.0±0.5)points, (1.1±0.1)points at 1, 3, 6 and 12 months after operation, significantly lower than those in routine treatment group［(4.9±0.6)points, (4.0±0.6)points, (3.2±0.7)points, (2.7±0.1)points, respectively］(all P<0.01). Teriparatide group showed ODI of 26.5±1.3 and 20.6±1.2 at 6 months and 12 months after operation, significantly lower than those in routine treatment group (28.2±1.6, 23.6±1.6) (all P<0.01). There were no significant differences in ODI between the two groups at other time points (all P>0.05). Both groups presented significantly lowered levels of ABH and MBH at 12 months after operation as compared with those at 24 hours after operation (all P<0.01). There were no significant differences in ABH or MBH between the two groups at 24 hours after operation (all P>0.05). ABH, MBH, MRABH and MRMBH in teriparatide group were (1.9±0.2)cm, (1.7±0.2)cm, 0.91±0.02 and 0.92±0.02 at 12 months after operation, significantly higher than those in routine treatment group［(1.7±0.2)cm, (1.6±0.2)cm, 0.86±0.02 and 0.87±0.02］(all P<0.01). KA in both groups showed significant increase at 12 months after operation as compared with that at 24 hours after operation (all P<0.01). There was no significant difference in KA between the two groups at 24 hours after operation ( P>0.05). KA in teriparatide group was (7.3±0.7)° at 12 months after operation, significantly lower than (9.5±0.5)° in routine treatment group ( P<0.01). DKA in teriparatide group was (5.3±1.3)° at 12 months after operation, significantly lower than (6.6±1.4)° in routine treatment group ( P<0.01). Incidence of vertebral refracture in teriparatide group was 7% (2/32), significantly lower than 35% (15/58) in routine treatment group ( P<0.05). Level of β-CTX was not significantly different between and within the two groups before operation and at 12 months after operation (all P>0.05). There was no significant difference in N-MID between the two groups before operation ( P>0.05). After treatment for 12 months, level of N-MID in teriparatide group was significantly increased［19.5 (17.6, 20.9)pg/ml］as compared with that before operation［18.2 (14.6, 21.0)pg/ml］( P<0.01), and was significantly higher than that in routine treatment group［17.6 (15.3, 19.9)pg/ml］( P<0.01). Routine treatment group showed no significant difference in level of N-MID before operation and at 12 months after operation ( P>0.05). Two patients in teriparatide group had orthostatic hypotension after treatment. Conclusion:For OVCF patients with RBP after PKP, teriparatide can effectively alleviate pain, improve motor dysfunction, maintain the height of bone cement vertebral body, reduce incidence of vertebral refracture and enhance the activity of osteoblasts, with less adverse reactions.

Which is the best antiresorptive treatment after finishing teriparatide? / ¿Cuál es el mejor tratamiento antirresortivo luego de terminar con teriparatide?

Abstract Anabolic drugs are the treatment of choice for osteoporotic patients with very high risk of fractures. Post anabolic treatment with an antiresorptive drug maintains the bone mineral density (BMD) gained. The recommendations regarding the ideal antiresorptive drug are not precise. The aim of this paper is to compare the usefulness of zoledronate and denosumab in a group of 28 women with very high risk of fractures. All of them completed at least one year of treatment with teripatide and latter 14 received zolendronate and 14 denosumab for another year. We retrospectively review their biochemical and densitometric changes. Both treat ment groups experienced a reduction in bone turnover markers of the same magnitude at the end of the second year. In Lumbar Spine BMD increase of 3.96 ± 8.56% Median (Me) 2.54 p = 0.21 in zolendronate group and 3.55 ± 5.36% (Me 5.14) p = 0.07 in denosumab group. Femoral Neck BMD changed -0.09 ± 6.50% (Me 0.29) p = 0.85 in zolendronate group, and - 3.41 ± 5.08% (Me 5.35) p = 0.59 in denosumab group, with no difference between both groups. In Total Hip BMD an increase of 0.55 ± 4.20% (Me 0.43) p = 0.70 in zoledronate group, and 4.53 ± 5.13% (Me 0.64) p = 0.04 with denosumab. We conclude that both antiresortive treatments have a similar effect in biochemical markers after one year of treatment. BMD increase significantly in total hip and changed with a trend toward in lumbar spine with denosumab, but without differences between both groups of treatment.

Resumen Los anabólicos son el tratamiento de elección en la osteoporosis con muy alto riesgo de fracturas. Después del tratamiento anabólico un fármaco antirresortivo mantiene la densidad mineral ósea (DMO) ganada. Las reco mendaciones sobre el fármaco antirresortivo ideal no son precisas. El objetivo de este trabajo es comparar la utilidad de zoledronato y denosumab en un grupo de 28 mujeres con muy alto riesgo de fracturas. Todas ellas completaron al menos un año de tratamiento con teripatide y luego 14 recibieron zolendronato y 14 denosumab durante un año. Revisamos retrospectivamente sus cambios bioquímicos y densitométricos. Ambos grupos de tratamiento experimentaron una reducción de los marcadores de recambio óseo de la misma magnitud al final del segundo año. En columna lumbar la DMO aumentó 3.96 ± 8.56% Mediana (Me) 2.54, p = 0.21 en el grupo zolendronato y 3.55 ± 5.36% (Me 5.14) p = 0.07 en el grupo denosumab. La DMO del cuello femoral cambió -0.09 ± 6.50% (Me 0.29) p = 0.85 en el grupo zolendronato y - 3.41 ± 5.08% (Me 5.35) p = 0.59 en el grupo de denosumab, sin diferencias entre ambos grupos. En la Cadera Total la DMO aumentó 0.55 ± 4.20% (Me 0.43) p = 0.70 con zoledronato y 4.53 ± 5.13% (Me 0.64) p = 0.04 con denosumab. Concluimos que ambos tratamien tos antiresortivos tuvieron un efecto similar en los marcadores bioquímicos después de un año de tratamiento. La DMO aumentó significativamente en la cadera total y mostró una tendencia similar en columna lumbar con denosumab, sin diferencias entre ambos tratamientos.

Avaliação do reparo ósseo após a instalação de implantes funcionalizados com medicação anabólica associada à administração sistêmica de antireabsortivo em ratas com deficiência de estrógeno e síndrome metabólica / Evaluation of bone repair after installation of implants functionalized with anabolic medication associated with systemic administration of antiresorptive in rats with estrogen deficiency and metabolic syndrome

O objetivo do presente estudo foi investigar a ação da associação de medicação sistêmica (bifosfonato oral) e teriparatida como medicação local funcionalizando as superfícies dos implantes. Para a realização deste projeto, o mesmo foi divido em 2 etapas. A primeira etapa consistiu na determinação do melhor protocolo para a funcionalização de implantes com teriparatida, a partir da técnica layer by layer. Ainda nesta etapa, foram realizados testes físicos e in vitro (culturas de células) a fim de avaliar as propriedades da superfície funcionalizada, quanto à melhora nas respostas osteogênicas. A segunda etapa consistiu na realização de experimentos in vivo para avaliar o efeito desta superfície funcionalizada durante o reparo periimplantar. Para isso, 96 ratas Wistar, adultas jovens foram divididas em seis grandes grupos: 1. Grupo SHAM (n=16), no qual os animais foram submetidos à ovariectomia fictícia e dieta balanceada. 2. Grupo SHAM/SM (n=16), no qual os animais receberam dieta de cafeteria. 3. Grupo OVX (n=16), no qual os animais foram submetidos a cirurgia de ovariectomia e não receberam tratamento medicamentoso. 4. Grupo OVX/SM (n=16), no qual os animais foram submetidos à cirurgia ovariectomia e receberam dieta de cafeteria. 5. Grupo OVX/RIS (n=16), no qual os animais foram submetidos à cirurgia de ovariectomia e tratados com risedronato de sódio. 6. Grupo OVX/SM/RIS (n=16), no qual os animais foram submetidos à cirurgia de ovariectomia e à dieta de cafeteria associada ao tratamento medicamentoso com risedronato de sódio. Em cada grande grupo há dois subgrupos: A- implantes convencionais e B- implantes funcionalizados com teriparatida. No dia 0 foi realizada a ovariectomia ou cirurgia fictícia. Passados 30 dias foi iniciado o tratamento medicamentoso com risedronato de sódio. Após 30 dias do início do tratamento medicamentoso, os animais foram submetidos à exodontia do primeiro molar superior direito, em seguida receberam os implantes na região onde foi realizada a exodontia. Aos 28 dias após a instalação dos implantes, os animais foram submetidos à eutanásia para mensuração do torque de remoção. Os dados foram submetidos ao teste de homocedasticidade (Shapiro Wilk). Houve a confirmação de distribuição normal dos dados amostrais e na sequência, foi realizado o teste paramétrico ANOVA One Way, seguido do pós teste de Tukey, com o nível de significância de 5% (p< 0,05). Os implantes funcionalizados apresentaram os maiores valores de torque de remoção em todos os grupos experimentais. A associação sistêmica entre o risedronato de sódio e teriparatida de forma tópica fez com que o grupo OVX/SM/RIS teriparatida obtivesse o maior torque de remoção quando comparado aos demais grupos. Com isso, conclui-se que o desempenho clínico dos implantes funcionalizados com teriparatida foi favorável, no entanto, quando associado à administração sistêmica de risedronato de sódio, os resultados se tornam mais promissores(AU)

The objective of this study was to investigate the action of the association of systemic medication (oral biphosphonate) and teriparatide as local medication functionalized to the surfaces of implants. For the execution of this project, it was divided in 2 stages. The first stage consisted in determining the best protocol for the functionalization of implants with teriparatide, based on the layer by layer technique. Still in this stage, physical and in vitro tests (cell cultures) were performed in order to evaluate the properties of the functionalized surface, regarding the improvement in osteogenic responses. The second stage consisted in conducting in vivo experiments to evaluate the effect of this surface functionalized during the peri-implant repair. For this, 96 Wistar rats, young adults were divided into six large groups: 1. SHAM Group (n=16), where the animals underwent sham surgery and balanced diet. 2. SHAM/SM Group (n=16), in which the animals received a cafeteria diet. 3) Group OVX (n=16), in which the animals underwent ovariectomy without drug treatment. 4. Group OVX/SM (n=16), in which the animals underwent ovariectomy and received a cafeteria diet. 5. Group OVX/SM/RIS (n=16), in which the animals underwent ovariectomy surgery and cafeteria diet associated with drug treatment with sodium risedronate. 6. Group OVX/RIS (n=16), in which the animals underwent ovariectomy and were treated with sodium risedronate. In each large group there are two subgroups: A- conventional implants and B- implants functionalized with teriparatide. After 30 days of beginning the drug treatment, the animals were submitted to bilateral first molar exodontia, then received the implants in the region where the exodontia was performed. At 28 days after installation of the implants, the animals were euthanized to measure the removal torque. The data were submitted to the homoscedasticity test (Shapiro Wilk). There was confirmation of normal distribution of the sample data and in the sequence, the parametric test ANOVA One Way was performed, followed by Tukey's post-test, with the significance level of 5% (p< 0.05). The functionalized implants had the highest removal torque values in all experimental groups. The systemic association between sodium risedronate and teriparatide topically resulted in the OVX/SM/RIS teriparatide group obtaining the highest removal torque when compared to the other groups. Thus, it is concluded that the clinical performance of implants functionalized with teriparatida was favorable, however, when associated with systemic administration of sodium risedronate, the results become more promising(AU)

Recombinant human parathyroid hormone (1-34): Pro-osteogenic action and application in oral field / 中国组织工程研究

BACKGROUND: Recombinant human parathyroid hormone 1-34 (rhPTH 1-34), also known as teriparatide, is the amino terminal fragment of parathyroid hormone. Teriparatide, as a bone anabolic drug, has become a research hotspot because it can directly stimulate new bone formation and increase bone mass. It also attracts attention and application in the oral field due to its strong osteogenesis effect. OBJECTIVE: To review the osteogenic mechanisms, efficacy and safety of teriparatide and its research progress in the oral field. METHODS: The first author searched the PubMed and WanFang databases for relevant literature published over the past two decades. The keywords were “rhPTH(1-34); teriparatide; osteoporosis; stomatology; Jaw; implant-osseointegration; periodontal” in English and Chinese, respectively. Fifty-six eligible articles were finally reviewed. RESULTS AND CONCLUSION: Teriparatide can directly stimulate the formation of osteoblasts in new bone and achieve effective anabolic metabolism. Studies of teriparatide in the oral field have shown good results in promoting implant-osseointegration, periodontal regeneration, bone defect healing and the stability of orthodontics, but increasing high-quality animal experiments and clinical studies are still needed. Future use of parathyroid hormone drugs and their analogues can be combined with bone tissue engineering technology to provide favorable effects in bone repair as well as in oral and maxillofacial repair.

Effect of Osteoporosis Medication on Fracture Healing: An Evidence Based Review

A systematic search was conducted and relevant studies that evaluated the influence of osteoporosis medications (bisphosphonates [BPs], denosumab, selective estrogen receptor modulators [SERMs], recombinant human parathyroid hormone teriparatide [TPTD], and strontium ranelate [SrR]) on wrist, hip, and spine fracture healing, were selected. BPs administration did not influence fracture healing and clinical outcomes after distal radius fracture (DRF). Similar results were observed in hip fracture, but evidence is lacking for spine fracture. Denosumab did not delay the non-vertebral fractures healing in one well-designed study. No studies evaluated the effect of SERMs on fracture healing in humans. One study reported shorter fracture healing times in TPTD treated DRF patients, which was not clinically meaningful. In hip fracture, recent studies reported better pain and functional outcomes in TPTD treated patients. However, in spine fracture, recent studies found no significant differences in fracture stability between TPTD treated patients and controls. Evidence is lacking for SrR, but it did not influence wrist fracture healing in one study. In comparisons between TPTD and BPs, fracture healing and physical scores were not significantly different in hip fracture by 1 study. In spine fracture, controversy exists for the role of each medication to the fracture stability, but several studies reported that fracture site pain was better in TPTD treated patients than BPs treated patients. Considering no clinical data of negative fracture healing of the antiresorptive medication and the danger of subsequent fracture after initial osteoporotic fracture, there is no evidence to delay initiation of osteoporosis medications after fracture.

Role of Teriparatide Vs Zoledronic Acid in Osteoporosis as well as in Pathological Fractures due to Osteoporosis

Background-Present prospective study is intended to compare role of Teriparatide and Zoledronic acid in osteoporosis as well as in pathological fracture due to osteoporosis so as to help elderly postmenopausal women to combat with osteoporosis & complications arising due to it. Material & Methods-This study is carried out in Pacific Medical College & Hospital,Udaipur in the department of orthopedics from Dec. 2107 to June 2019.Total of 100 women were included at the time of beginning but 20 women were lost in the follow up due to various reasons.51 patients of group 1 were given Zoledronic acid & 29 patients were given Teriparatide.Patients were evaluated upto 12 months at regular intervals. Serial DEXA scans were done,assessment & comparison were done accordingly. Conclusion-Treatment of osteoporosis is multimodal with no definitive single molecule available.This study compared Zoledronic acid & Teriparatide.Although T-score has nearly the same value but our study resulted in increase BMD score & fewer side effects by the use of Teriparatide so it is concluded that patient with very low BMD requires treatment with Teriparatide.

Atypical femoral fracture, case report and literature review / Fractura atípica del fémur, reporte de caso y revisión de la literatura

Abstract: Introduction: Bisphosphonates have been the gold standard in the management of osteoporosis. Its antiresorptive effect has reduced the incidence of fractures due to bone fragility, as well as its impact on public health. We present the clinical case of a patient in prolonged treatment with bisphosphonates and atypical bilateral femur fracture. Case report: A 65-year-old female who presented a fall from her own height, on treatment with risedronate for seven years, and a history of systemic arterial hypertension and hypercholesterolemia, both with medical treatment. Diagnosed with bilateral atypical femoral fracture, treated with closed reduction internal fixation (CRIF) with intramedullary nailing, application of calcium citrate and teriparatide. Discussion: Multiple studies indicate that the benefit of using bisphosphonates for osteoporosis is higher than the risk of presenting atypical fractures.

Resumen: Introducción: Los bifosfonatos han sido de gran utilidad en el manejo de la osteoporosis. Su efecto antirresortivo ha disminuido la incidencia de fracturas por fragilidad ósea, así como, su impacto en salud pública. Presentamos el caso clínico de una usuaria en tratamiento prolongado con bifosfonatos y fractura atípica de fémur bilateral. Caso clínico: Femenino de 65 años, presenta caía de su plano de sustentación, en tratamiento con risedronato desde hace siete años y antecedente de hipertensión arterial sistémica e hipercolesterolemia, ambas con manejo médico. Diagnosticada con fractura bilateral de fémur, tratada con enclavado centro-medular, citrato de calcio y teriparatida. Discusión: Múltiples estudios refieren que el beneficio del uso de bifosfonatos en la prevención del riesgo de fracturas es mayor, aunque exista la posibilidad de presentar fracturas atípicas.

Comparision of Effect of Teriparatide and Alendronate Sodium on the Bone Mineral Density in Post-Menopausal Women

Aim: Purpose of this study was to know which one is better modality of treatment for osteoporosis in postmenopausal women – enhancing bone formation or reducing bone resorption. Methods: Total 120 patients were included in this study and randomly divided in two groups. Group A patients were given teriparatide injection and Group B patients were given alendronate sodium tablet. Both groups were given Calcium supplement, and vitamin D supplement along with therapy. Bone mineral density (BMD) at the spine and hip was assessed by dual-energy x-ray absorptiometry (DEXA) scan before and after the therapy. Results: Average Bone mineral density (BMD) in teriparatide group was - 2.77 in pretreatment and – 1.8767 after one year follow up. Average BMD in alendronate sodium group was -2.78 in pretreatment and – 2.00 after one year follow up. Avearage gain in BMD in Group A was – 0.8933 and in group B was –0.78. Conclusion: Teriparatide seems to be better treatment for oeteoporosis as compared to alendronate therapy.

The effectiveness and safety of parathyroid hormone in fracture healing: A meta-analysis

The very large economic and social burdens of fracture-related complications make rapid fracture healing a major public health goal. The role of parathyroid hormone (PTH) in treating osteoporosis is generally accepted, but the effect of PTH on fracture healing is controversial. This meta-analysis was designed to investigate the efficacy and safety of PTH in fracture healing. The EMBASE, PubMed, and Cochrane Library databases were systematically searched from the inception dates to April 26, 2018. The primary randomized clinical trials comparing PTH treatment for fracture healing with placebo or no treatment were identified. We did not gain additional information by contacting the authors of the primary studies. Two reviewers independently extracted the data and evaluated study quality. This meta-analysis was executed to determine the odds ratio, mean difference, standardized mean difference, and 95% confidence intervals with random-effects models. In total, 8 randomized trials including 524 patients met the inclusion criteria. There were significant differences in fracture healing time, pain relief and function improvement. There were no significant differences in the fracture healing rate or adverse events, including light-headedness, hypercalcemia, nausea, sweating and headache, except for slight bruising at the injection site. We determined that the effectiveness and safety of PTH in fracture healing is reasonably well established and credible.

The efficacy of sustained-release chitosan microspheres containing recombinant human parathyroid hormone on MRONJ

Abstract Treatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration. In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control. In this study, we aimed to investigate a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ). This treatment protocol consisted of administering human parathyroid hormone (hPTH) loaded chitosan microspheres which were prepared by ionotropic gelation method or/and the prepared microspheres were suspended in a poloxamer gel. After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies. Zoledronic acid was administered daily to forty-eight adult female Sprague-Dawley rats, divided into four experimental groups, at a daily concentration of 0.11 mg/kg over three weeks to induce the MRONJ model. At the end of this period, maxillary left molar teeth were extracted. In the first group, the subjects received no treatment. In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket. The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH. The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres. Both treatment groups received a total of 7 µg of hPTH at the end of the treatment protocol. Our study demonstrates successful attenuation of MRONJ through a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.

Baseline characteristics of postmenopausal women with osteoporosis treated with teriparatide in a real-world setting in Latin America: a subregional analysis from the Asia and Latin America Fracture Observational Study (ALAFOS)

Abstract Background: Osteoporosis is a major healthcare concern in Latin America. Factors such as changing demographics, fragmented healthcare systems, and financial considerations may result in a huge increase in the burden of osteoporosis in this region. The aim of this article is to describe the baseline clinical characteristics and fracture history of patients who are prescribed teriparatide in normal clinical practice in Latin America. Methods: We conducted a prospective, multinational, observational study (the Asia and Latin America Fracture Observational Study [ALAFOS]) in 20 countries worldwide to assess the incidence of fractures in postmenopausal women with osteoporosis receiving teriparatide as a part of routine clinical practice in a real-world setting. In this subregional analysis of the ALAFOS study, we report the clinical characteristics, fracture history, risk factors for osteoporosis, comorbidities, previous osteoporosis therapies and health-related quality of life measures at baseline for patients from the four participant Latin American countries: Argentina, Brazil, Colombia, and Mexico. Results: The Latin America subregional cohort included 546 postmenopausal women (mean [SD] age: 71.0 [10.1] years; range: 40-94 years), constituting 18% of the ALAFOS total population. The baseline mean (SD) bone mineral density T-scores were - 3.02 (1.23) at the lumbar spine and - 2.31 (0.96) at the femoral neck; 62.8% of patients had a history of low trauma fracture after the age of 40 years and 39.7% of patients had experienced ≥1 fall in the past year. Osteoporosis medications were used by 70.9% of patients before initiating teriparatide. The median (Q1, Q3) EQ-5D-5 L Visual Analog Scale (VAS) scores for perceived health status at baseline was 70 (50, 80). The mean (SD) worst back pain numeric rating scale score for the overall Latin American cohort was 4.3 (3.4) at baseline. Conclusions: This baseline analysis of the Latin America subregion of the ALAFOS study indicates that patients who are prescribed teriparatide in the four participant countries had severe osteoporosis and high prevalence of fractures. They also had back pain and poor health-related quality of life. The proportions of patients with severe or extreme problems on the EQ-5D-5 L individual domains were lower than those in the overall ALAFOS study population.

Effects of Weekly Teriparatide Administration for Vertebral Stability and Bony Union in Patients with Acute Osteoporotic Vertebral Fractures

STUDY DESIGN: An open-label, non-randomized prospective study. PURPOSE: Teriparatide (TPTD) is known to be an antiosteoporotic agent that may accelerate the healing of fractures. This study was designed to investigate the effect of once-weekly TPTD administration on vertebral stability and bony union after acute osteoporotic vertebral fracture (OVF). OVERVIEW OF LITERATURE: Once-weekly TPTD administration can lead to early vertebral stability and promote bony union of fractured vertebrae in patients with severe osteoporosis. METHODS: Forty-eight subjects with acute OVF were assigned to receive activated vitamin D3 and calcium supplementation or onceweekly subcutaneous injection of TPTD (56.5 μg) in combination with activated vitamin D3 and calcium supplementation for 12 weeks. Vertebral stability was assessed using lateral plain radiography. Vertebral height at the anterior location (VHa) and the difference in VHa {ΔVHa=VHa (supine position)−VHa (weight-bearing position)} were measured at baseline and 12 weeks after starting treatment. Bony union was defined as the absence of a vertebral cleft or abnormal motion (ΔVHa >2 mm). RESULTS: Although not significant, ΔVHa, indicating vertebral stability, tended to be lower in the TPTD group at 12 weeks (p=0.17). As for subjects with severe osteoporosis, ΔVHa at 12 weeks was significantly lower in the TPTD group than in the control group (mean ΔVHa: control group, 3.1 mm (n=15); TPTD group, 1.4 mm (n=16); p=0.02). The rate of bony union was significantly higher in the TPTD group than in the control group (control group, 40%; TPTD group, 81%; p=0.03). CONCLUSIONS: Once-weekly TPTD administration may facilitate early bony union after acute OVF accompanied by severe osteoporosis.

Effect of Teriparatide on Subsequent Vertebral Fractures after Instrumented Fusion Surgery for Osteoporotic Vertebral Fractures with Neurological Deficits

STUDY DESIGN: Retrospective case review. PURPOSE: To assess the incidence and effect of teriparatide (TP) on subsequent vertebral fractures following a long-instrumented fusion surgery for osteoporotic vertebral fractures (OVFs). OVERVIEW OF LITERATURE: TP treatment may be a useful strategy for patients with OVFs treated with a long-instrumented surgery. METHODS: Overall, 47 patients who underwent long-instrumented fusion surgery (≥3 levels) for OVFs with neurological deficits between 2010 and 2013 were enrolled. The mean age of the subjects was 76 years; the study population comprised 20 males and 27 females. The mean follow-up duration was 23 months. The average of fused vertebrae was 4.9. TP was used for 19 patients who comprised the TP group. The incidence of subsequent VFs was estimated with Kaplan–Meier analyses and compared between the TP and non-TP groups using the log-rank test. Risk factors were evaluated using a Cox proportional hazards model. RESULTS: A total of 38% (18/47 cases) of the subjects were identified with subsequent VFs. There were no significant differences in the age, sex, fused levels, presence of prevalent fractures, and correction loss of the two groups. The occurrence of subsequent VFs was lower in the TP group than in the non-TP group (16% vs. 54%, p=0.014). The log-rank test revealed that the TP treatment significantly reduced the risk of subsequent VFs (p=0.048). A Cox proportional hazards model revealed that preoperative TP treatment is only a protective factor of subsequent VFs after instrumented fusion surgery for OVFs (hazard ratio, 0.281; p=0.047). CONCLUSIONS: In this retrospective study, pre- and postoperative TP treatment significantly reduced the incidence of subsequent VFs after instrumented fusion surgery for OVFs. A prospective randomized study is warranted to determine the efficacy of TP treatments.