Drug efficacy and safety of denosumab, teriparatide, zoledronic acid, and ibandronic acid for the treatment of postmenopausal osteoporosis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study aims to compare the efficacy and safety of denosumab, teriparatide, zoledronic acid, and ibandronic acid for the treatment of women with postmenopausal osteoporosis. MATERIALS AND METHODS: Randomized controlled trials (RCTs) were searched in Medline, Embase, and Cochrane up to April 2022. Statistical analysis was performed using R 4.1.3 software, and quality evaluation was conducted using Review Manager 5.3. RESULTS: 51 RCTs containing 39,095 patients met our selection criteria. The efficacy results indicated that teriparatide was more effective than ibandronic acid in reducing vertebral fractures [relative risk (RR) = 0.536; 95% confidence interval (CI) (0.266, 0.998)]. Denosumab [mean difference (MD) = -4.19; 95% CI (-8.03, -0.355)] and teriparatide [MD = 4.64; 95% CI (1.60, 7.72)] showed better efficacy than ibandronic acid in improving spine bone mineral density (BMD). Denosumab showed better efficacy than teriparatide in improving radius BMD [MD = -4.14; 95% CI (-6.72, -1.54)], hip bone mineral density (BMD) [MD = -2.01; 95% CI (-3.80, -0.162)], and one-third radius BMD [MD = -3.63; 95% CI (-7.04, -0.151)]. Denosumab was associated with the greatest benefit in increasing radius BMD [the surface under the cumulative ranking curve area (SUCRA) = 0.999], hip BMD [surface under the cumulative ranking curve area (SUCRA) = 0.979], femoral neck BMD (SUCRA = 0.971), one-third radius BMD (SUCRA = 0.994) and preventing vertebral fractures (SUCRA = 0.806). Teriparatide was associated with the greatest benefit in preventing non-vertebral fractures (SUCRA = 0.927) and improving spine BMD (SUCRA = 0.899). The safety results indicated that teriparatide was safer than zoledronic acid regarding the risk of adverse events [RR = 0.958; 95% CI (0.919, 0.988)]. Teriparatide was associated with the greatest benefit in preventing adverse events (SUCRA = 0.908) and serious adverse events (SUCRA = 0.813). CONCLUSIONS: Our current results suggested that when considering both safety and efficacy, denosumab or teriparatide might be a better choice for women with postmenopausal osteoporosis.

The clinical effectiveness of denosumab (Prolia®) in patients with hormone-sensitive cancer receiving endocrine therapy, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis.

This systematic review (SR) assessed the use of denosumab (Prolia®) to treat osteoporosis in cancer patients receiving endocrine therapy. Denosumab was found to prevent vertebral fractures and improve bone mineral density in cancer patients with osteoporosis. This is the first SR to assess treating osteoporotic cancer patients with denosumab. PURPOSE: This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). METHODS: Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). RESULTS: A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. CONCLUSION: In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.

Los hallazgos oculares relacionados con el uso de bisfosfonatos orales / The ocular findings related to oral bisphosphonate use

Objetivo Nuestro objetivo fue investigar los hallazgos de afectación ocular en pacientes femeninas con osteoporosis que usaban bisfosfonato oral (BP). Métodos Se incluyó en el estudio a un total de 51 pacientes con osteoporosis, de 50 a 75 años, que utilizaron BP oral durante al menos un año para el grupo de estudio y a 64 pacientes sin osteoporosis de la misma edad para el grupo de control, todas del sexo femenino. Se anotaron el tipo de BP y el tiempo de exposición. Se evaluaron los resultados del examen oftálmico de las pacientes que recibieron BP oral por osteoporosis y de las controles. Resultados La duración media del uso de BP fue de 3,96 años. Se detectó que 4de 51 pacientes fueron diagnosticadas con disfunción de la glándula de Meibomio (7,8%), 7de 102 ojos tenían margen palpebral eritematoso, irregular, engrosado o telangiectasia alrededor de los orificios glandulares. No hubo hallazgos patológicos en el examen del fondo de ojo. El valor medio de las medidas del brote (ph/ms) fue de 7,90±7,96 en el grupo de estudio y de 5,02±0,81 en el grupo de control. Cuando se compararon los valores medios, hubo una diferencia significativa entre los 2grupos (p=0,001). Se encontró una diferencia significativa en el valor medio de las mediciones del flare entre las pacientes que usaban alendronato e ibandronato y las del grupo de control (p=0,001; p=0,005, respectivamente). Conclusión Nuestro estudio mostró que el flare de la cámara anterior asociado con la inflamación crónica del ojo se puede observar con mayor frecuencia en pacientes que usan alendronato e ibandronato por vía oral en comparación con aquellos que no lo hacen. Además, se puede decir que BP oral puede provocar efectos secundarios oculares similares a los de la BP intravascular (AU)

Objective We aimed to investigate ocular involvement findings in female osteoporosis patients using oral bisphosphonate (BP). Methods A total of 51 female osteoporosis patients aged 50-75 years using oral BP for at least one year for the study group and 64 age-matched non-osteoporosis female patients for the control group were included in the study. The BP type and exposure time were noted. The ophthalmic examination findings and measurements of the flare of the patients who received oral BP due to osteoporosis and the controls were evaluated. Results The mean duration of BP use was 3.96 years. In the study group, it was detected 4of 51 patients were diagnosed with meibomian gland dysfunction (MGD) (7.8%), 7of 102 eyes had erythematous, irregular, thickened lid margin or telangiectasia around the glandular orifices. There were no pathological findings on fondus examination. The mean value of measurements of the flare (ph/ms) was 7.90±7.96 in the study group, and 5.02±0.81 in the control group. When the mean values were compared, there was a significant difference between the 2groups (P=0.001). A significant difference was found in the mean value of measurements of the flare between the patients using alendronate, and ibandronate with the control group (P=0.001; P=0.005, respectively). Conclusion Our study showed that the flare in the anterior chamber associated with chronic ocular inflammation can be seen higher rate in patients using oral alendronate, and ibandronate compared to those who do not. Morever it can be said that oral BPs may cause similar ocular side effects like as intravascular BPs (AU)

Effects of bisphosphonates on appendicular fracture repair in rodents.

The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite their strength, bones do break and the main cause of fractures are trauma and decreased bone mineral density as a result of aging and/or pathology that weakens the bone's microarchitecture and subsequently, its material properties. Osteoporosis is a disease marked by increased osteoclast activity and decreased osteoblastic activity tipping the remodeling balance in favor of bone resorption and can be caused by aging, glucocorticoids, disuse and estrogen-deficiency. Ultimately, this leads to brittle and weaker bones which become more prone to trauma or stress-induced fractures. The current treatment for preventing and treating osteoporotic fractures is the use of antiresorptive drugs such as bisphosphonates (BPs) and denosumab, but unfortunately, their long-term use, especially with alendronate and ibandronate, has been associated with increased risk of atypical femoral fractures (AFFs); femoral diaphyseal fractures distal to the lesser trochanter but proximal to the supracondylar flare. The purpose of this review is to examine the information that exists in the literature examining the effects of BPs on fracture repair of long bones in rodent (rat and mouse) models. The focus on rodents stems from the scientific community's unresolved need to develop small animal models to examine the molecular, cellular, tissue and biomechanical mechanisms responsible for the development of AFFs and how best they can be treated.

Efficacy of bisphosphonate therapy on postmenopausal osteoporotic women with and without diabetes: a prospective trial.

BACKGROUND: The co-occurrence of diabetes and osteoporosis is common in postmenopausal women. For the treatment of postmenopausal osteoporosis, current guidelines recommend initial treatment with bisphosphonates, but it is unclear whether bisphosphonates provide a similar degree of therapeutic efficacy in patients with diabetes. This study sought to compare the efficacy of monthly oral ibandronate for retaining bone mineral density (BMD) in diabetic and non-diabetic postmenopausal women with osteoporosis. METHODS: Postmenopausal osteoporotic women with or without diabetes were enrolled in this study from three hospitals in an open-label approach from 2018 to 2020. Each group of patients received oral ibandronate 150 mg once monthly for 1 year. BMD, trabecular bone score (TBS), serum C-terminal telopeptide of type I collagen (CTx) and procollagen type 1 N-terminal propeptide (P1NP) were evaluated prospectively. Treatment-emergent adverse events and changes in glucose metabolism during drug use were also monitored. RESULTS: Among the 120 study participants, 104 (86.7%) completed the study. Following 1 year of treatment, BMD increased by 3.41% vs. 3.71% in the lumbar spine, 1.30% vs. 1.18% in the femur neck, and 1.51% vs. 1.58% in the total hip in the non-diabetes and diabetes groups, respectively. There were no significant differences in BMD changes between the groups, and the differences in CTx or P1NP changes between groups were not significant. We did not observe any significant differences in baseline TBS values or the degree of change between before and after 1 year of ibandronate treatment in either group in this study. A total of 11 adverse events (9.2%) that recovered without sequelae occurred among the 120 included patients, and there was no significant difference in the frequency of adverse events between the groups (p = 0.862). The changes in fasting glucose and glycated hemoglobin levels between before and after treatment were not significant in the diabetic group. CONCLUSIONS: Bisphosphonate therapy showed similar increases in BMD and decreases in CTx and P1NP of postmenopausal women with and without diabetes. Monthly oral ibandronate can be a safe and effective therapeutic option in postmenopausal osteoporosis patients with type 2 diabetes. TRIAL REGISTRATION: NCT number: NCT05266261, Date of registration: 04 March 2022.

Incidence of giant cell arteritis after bisphosphonate exposure: A retrospective cohort study.

OBJECTIVES: Bisphosphonates may cause autoimmune reactions via a cytokine-mediated acute phase response. A case of giant cell arteritis (GCA) after zoledronate injection was recently reported. We aimed to evaluate this association by reviewing the incidence of GCA after bisphosphonate administration. METHODS: This was a retrospective study using the medical claims data of elderly patients in the 20% Medicare random sample from 2008-2014 who had received zoledronate or ibandronate. Patients who had a diagnosis claim of GCA within the past year before receiving either bisphosphonate were excluded. The development of GCA was assessed in 2 ways: GCA diagnosis claim within 28 days of bisphosphonate injection and another claim within 90 days of initial claim; and temporal artery biopsy claim within 28 days of bisphosphonate injection and GCA diagnosis claim within 90 days of biopsy. Due to the Centers for Medicare & Medicaid Services reporting requirements we excluded numbers less than 11 from analysis. RESULTS: The incidence of GCA was 0.010% and 0.013% after zoledronate and ibandronate injection respectively. In the zoledronate group incidence was highest in patients aged 75-85 years (0.011%), in Whites (0.011%), in the northeast census region (0.013%) and higher in females (0.011% vs 0.009%). All GCA cases noted in the ibandronate group involved White females. We are unable to report incidences by age and region due to the paucity of data. CONCLUSION: The incidence of GCA after bisphosphonate injection was not increased compared to the generally reported incidence in the USA.

Phase III Randomized Trial of Bisphosphonates as Adjuvant Therapy in Breast Cancer: S0307.

BACKGROUND: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

Effectiveness of monthly intravenous ibandronate on the low responders to oral bisphosphonate: the MOVEMENT study.

The MOVEMENT study was designed to assess the effectiveness of monthly intravenous ibandronate on bone mineral density (BMD) in daily clinical practice in Japanese patients with primary osteoporosis whose lumbar spine BMD did not increase despite oral bisphosphonate therapy. This study was a multicenter, prospective, interventional study (52 sites; August 2015 to March 2018). Patients aged ≥ 50 years with primary osteoporosis, evaluated as low responders to oral bisphosphonate treatment for 1-3 years, continued on their existing oral bisphosphonate or switched to monthly intravenous ibandronate (1 mg) for 12 months. The primary endpoint was change in lumbar spine BMD from baseline to 12 months in the intravenous ibandronate group (IV IBN). A total of 240 and 141 patients were enrolled in the IV IBN and oral bisphosphonate groups (OBP), respectively. At 12 months, a significant increase in mean percent change from baseline in lumbar spine BMD was observed in the IV IBN (2.70%). This change was also significant at 6 months (1.92%). Similarly, the change in total hip BMD showed a significant increase at 12 months (0.78%). In the IV IBN, the responder rate, percentage of patient whose change from baseline of lumbar spine BMD has greater than 0%, for lumbar spine BMD was high at both 6 (72.3%, 141/195 patients) and 12 (78.0%, 145/186 patients) months. No new safety concerns were observed in either treatment group. Treatment with intravenous ibandronate significantly increased lumbar spine BMD without any new safety concerns in Japanese patients with osteoporosis who showed low response to existing oral bisphosphonates.

Comparison of clinical effect in treatment of bone tumor between zoledronic acid needle and ibandronate needle.

To observe and analyze the clinical effect of zoledronic acid needle and ibandronate needle in treatment of bone tumor. 100 patients who have been treated in our hospital for bone tumor were selected as research objects. They were randomly divided into research group and control group, each containing 50 patients. The research group was applied with ibandronate needle therapy, while the control group was given with zeledronic acid needle therapy. After treatment, the clinical effects of the two groups were observed and analyzed. Through comparing the pain relief rate after treatment between the two groups, it can be known that the pain relief rate of research group was relatively higher, P<0.05; the rate of adverse effect in research group was relatively lower, P<0.05; the quality of life score (QLS) of research group was significantly superior to that of control group, P<0.05. theibandronate needle therapy is a more reliable and superior method in treatment of bone tumor compared with zoledronic acid needle therapy, which should be promoted in clinical treatment.