Efficacy and safety of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in osteoporosis not previously treated with bisphosphonates: a systematic review and meta-analysis of randomized controlled trials.

The study found that in osteoporosis patients who had not previously received bisphosphonate treatment and were in a treatment cycle of over 12 months, both teriparatide and denosumab significantly increased bone mineral density compared to bisphosphonates. Additionally, teriparatide was also shown to significantly decrease the risk of fractures. OBJECTIVE: The systematic review and meta-analysis aimed to assess and compare the safety and efficacy of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in patients with osteoporosis who had not previously received bisphosphonates. METHODS: We conducted a search of published literature from inception to May 31, 2023, including databases such as PubMed, Embase, Cochrane Library, CNKI, SinoMed, VIP, and WanFang. The study only included head-to-head randomized controlled trials (RCTs) that compared teriparatide and denosumab with bisphosphonates to treat patients with osteoporosis. Fixed-effect model and random-effect model were used due to clinical heterogeneity. Meta-analysis was performed via Stata 17.0. RESULTS: A total of 6680 patients were enrolled across 23 eligible trials. The results of the meta-analysis showed that teriparatide was superior to bisphosphonates in decreasing the risk of fracture (risk ratio (RR) = 0.61, 95% confidence interval (CI) (0.51, 0.74), P < 0.001). Denosumab showed no benefit compared to bisphosphonates in reducing the risk of fracture in treating osteoporosis (RR 0.99, 95% CI (0.62, 1.57), P = 0.96). Compared with bisphosphonates, teriparatide and denosumab could significantly improve femoral neck, total hip, and lumbar spine bone mineral density (BMD) (P < 0.05). Furthermore, teriparatide and denosumab did not increase the incidence of adverse events (teriparatide vs. bisphosphonates, RR 0.92, 95% CI (0.79, 1.08), P = 0.32; denosumab vs. bisphosphonates, RR 0.98, 95% CI (0.95, 1.02), P = 0.37). CONCLUSIONS: Teriparatide is superior to bisphosphonates in decreasing the risk of fracture in patients with osteoporosis. In addition, teriparatide and denosumab were more efficacious than bisphosphonates in increasing the percentage change in BMD at the femoral neck, total hip, and lumbar spine.

Efficacy and safety of denosumab and teriparatide versus oral bisphosphonates to treat postmenopausal osteoporosis: a systematic review and meta-analysis.

Study Design: A systematic review and Meta-analysis. Objective: To compare the efficacy and safety of denosumab and teriparatide versus oral bisphosphonates to treat postmenopausal osteoporosis. Summary of Background Data: While bisphosphonates have historically been the cornerstone of pharmacological management for bone protection in patients, emerging evidence suggests that teriparatide and denosumab warrant further investigation as potential first-line treatments. The optimal choice among denosumab, teriparatide, and oral bisphosphonates for the treatment of postmenopausal osteoporosis remains a subject of ongoing debate and controversy within the scientific community. Methods: This systematic review adhered meticulously to the rigorous standards outlined by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines as well as the Cochrane Collaboration recommendations. Additionally, it employed the AMSTAR (Assessing the methodological quality of systematic reviews) criteria to ensure methodological robustness and enhance the credibility of the findings. A systematic electronic search was conducted across Web of Science, PubMed, and the Cochrane Library databases from their inception dates up to February 2024. Results: In this meta-analysis of studies, our findings suggest that compared to bisphosphonates, both teriparatide and denosumab demonstrated notable increases in percentage changes in lumbar spine bone mineral density (BMD) among postmenopausal osteoporosis patients. Furthermore, denosumab exhibited superiority over teriparatide and oral bisphosphonates in enhancing percentage changes in both femoral neck and total hip BMD, indicating its potential as a more efficacious option. Regarding safety outcomes, no significant differences were observed in the incidence of serious adverse events among patients treated with teriparatide, denosumab, and bisphosphonates. However, teriparatide showed superiority over oral bisphosphonates in terms of a lower risk of general adverse events, suggesting a favorable safety profile. Conclusion: In conclusion, our study suggests that teriparatide and denosumab demonstrate comparable or potentially superior efficacy and safety profiles compared to oral bisphosphonates for the treatment of postmenopausal osteoporosis. Systematic Review Registration: PROSPERO, identifier CRD42024508382.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

Bioequivalence of Recombinant Human Teriparatide Injection in Healthy Adult Female Subjects in the Fasting State.

A single-center, randomized, open, 2-period, self-crossover, single-dose trial was conducted to evaluate the bioequivalence of the test (T) and reference (R) preparations in healthy adult female subjects under fasting conditions. Seventy-six subjects were enrolled in the study, and subjects were randomly divided into 2 groups at a 1:1 ratio and were administered once per period, with a 4-day washout period. In each period, plasma drug concentrations, blood calcium changes, and antibodies were determined for pharmacokinetics, pharmacodynamics, and immunogenicity analysis, respectively, and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity were within the predefined bioequivalence criterion of 80%-125%, indicating bioequivalence between the T and R preparations under fasting conditions. Comparable serum calcium levels demonstrated pharmacodynamics similarity, and no differences were found in immunogenicity profiles. Additionally, the incidence of adverse reactions to the T preparation was 18.4% lower than that of the R preparation (31.6%). This study confirmed the bioequivalence of the T and R preparations under fasting conditions, along with comparable immunogenicity profiles and good safety.

Systematical mutational analysis of teriparatide on anti-osteoporosis activity by alanine scanning.

Osteoporosis is a progressive systemic skeletal disease that decreases bone density and bone quality, making them fragile and easy to break. In spite of effective anti-osteoporosis potency, teriparatide, the first anabolic medications approved for the treatment of osteoporosis, was proven to exhibit various side effects. And the relevant structure-activity relationship (SAR) of teriparatide was in need. In this work, we performed a systematical alanine scanning against teriparatide and synthesized 34 teriparatide derivatives. Their biological activities were evaluated and the importance of each residue for anti-osteoporosis activity was also revealed. A remarkable decrease in activity was observed for alanine replacement of the residue Gly12, His14, Ser17, Arg20 and Leu24, showcasing the important role of these residues in teriparatide on anti-osteoporosis activity. On contrary, when Gly13 and Gln30 were mutated to Ala, the peptide derivatives exhibited the significantly increased activities, demonstrating that these two residues could be readily replaced. Our research expanded the peptide library of teriparatide analogues and presented a potential opportunity for designing the more powerful anti-osteoporosis peptide agents.

Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: To investigate the differences in the incidence rates of suspected stage 0/1 osteonecrosis of the jaw (ONJ) and incidence risk of relevant clinical findings of suspected stage 0 ONJ between patients treated with sequential therapy comprising weekly teriparatide for 72 weeks followed by alendronate for 48 weeks vs. those who received monotherapy with alendronate for 120 weeks. MATERIALS AND METHODS: Suspected stage 0/1 ONJ was defined by non-specific symptoms. Tooth mobility and periodontal symptoms (gingival bleeding, swelling, and/or pain) were selected as clinical findings of suspected stage 0 ONJ. Poisson regression models were applied to calculate the incidence rate ratios of suspected stage 0/1 between the teriparatide group (TG) and alendronate group (AG). Generalized linear models were used to calculate the risk ratios of clinical findings between groups. RESULTS: Two hundred and sixty-one participants in the TG and 344 in the AG answered a structured questionnaire on oral health and were included in this study. There were no significant differences between the groups in the incidence rate of suspected stage 0/1 ONJ at both 72 and 120 weeks. The risk ratio of the TG to AG for tooth mobility was 0.34 (95% confidence interval [CI] 0.13-0.88, p = 0.02) at 72 weeks and 0.90 (95% CI 0.40-2.03, p = 0.83) at 120 weeks. The incidence rate of tooth mobility related to periodontal symptoms decreased in the TG and increased in the AG during the study. CONCLUSION: Tooth mobility accompanied by clinical periodontal symptoms may be a useful early sign of stage 0 ONJ.

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.

Efficacy of switching from teriparatide to zoledronic acid or denosumab on bone mineral density and biochemical markers of bone turnover in older patients with severe osteoporosis: a real-life study.

PURPOSE: Osteoporosis is characterized by loss of bone mass and susceptibility to fracture. Skeletal effects of teriparatide (TPT) are not persistent after drug withdrawal and sequential therapy with bisphosphonates or denosumab (Dmab) after TPT discontinuation represents a valid option. Here, the two sequential strategies were evaluated in severe osteoporotic patients. METHODS: The study retrospectively enrolled 56 severe osteoporotic patients who received TPT for 24 months followed by 24 months of zoledronic acid (ZOL) (TPT + ZOL) or Dmab (TPT+Dmab). Clinical features, incident fractures, bone mineral density (BMD) measurements, and bone marker profiles were collected. One-way ANOVA analyzed the difference between mean T-scores at baseline, after 24 months of TPT, and after 2 doses of ZOL or after at least 3 doses of Dmab. RESULTS: Twenty-three patients received TPT + ZOL (19 females, 4 males; median [IR] age, 74.3 [66.9, 78.6] years) and 33 patients received TPT+Dmab (31 females, 2 males; mean [IR] age, 66.6 ± 11.3 years). Mean lumbar and hip T-scores were increased after both TPT + ZOL and TPT+Dmab (all p < 0.05 vs baseline). The size effects induced by TPT + ZOL on the lumbar and hip BMD T-scores were similar to those observed with TPT+Dmab with mean T-scores increases of about 1 and 0.4 SD, respectively. No significant between-group differences were identified. Incident fragility fractures occurred in 3 (13%) patients treated with TPT + ZOL and in 5 (15%) patients treated with TPT+Dmab. CONCLUSIONS: Sequential TPT + ZOL therapy is likely to increase bone mineralization at the lumbar level and to stabilize it at the femoral level, similarly to what obtained with the sequential TPT+Dmab. Both ZOL and Dmab are suggested to be effective sequential treatments after TPT.

[Side effects of osteoporosis treatments: how to explain them to patients?] / Effets indésirables des traitements contre l'ostéoporose : comment les expliquer aux patient-e-s ?

Despite the effectiveness of osteoporosis treatments, fear of side effects reduces both their prescription by doctors, and their acceptance by patients. The most common side effects are benign and transient, such as flu-like symptoms after zoledronate infusion, or nausea and dizziness after teriparatide introduction. On the other hand, the dreaded osteonecrosis of the jaw is very rare and associated with known risk factors. Only vertebral fractures after stopping denosumab make this treatment a matter for experienced practitioners. Therefore, knowing the side effects of prescribed treatments and explaining them to patients is essential to promote adherence.

Malgré l'efficacité des traitements contre l'ostéoporose, la crainte de leurs effets indésirables diminue tant leur prescription par les médecins que leur acceptation de la part des patients. Les plus fréquents de ces effets indésirables sont pourtant bénins et transitoires, comme l'état pseudo-grippal après perfusion de zolédronate ou les nausées et vertiges à l'introduction du tériparatide. De l'autre côté, l'ostéonécrose de la mâchoire tant redoutée est très rare et associée à des facteurs de risque connus. Seules les fractures vertébrales à l'arrêt du dénosumab font que ce traitement soit à réserver aux praticien-ne-s qui en ont l'habitude. C'est pourquoi connaître les effets indésirables des traitements prescrits et les expliquer aux patient-e-s est essentiel pour favoriser l'adhésion thérapeutique.

Treatment of Osteoporosis With Anabolic Agents and the Risk of Primary Bone Cancers: A Study of 44,728 Patients Treated With Teriparatide and Abaloparatide.

INTRODUCTION: Bone anabolic agents can benefit orthopaedic patients perioperatively and improve outcomes after fragility fractures. However, preliminary animal data raised concern for the potential development of primary bony malignancies after treatment with these medications. METHODS: This investigation examined 44,728 patients older than 50 years who were prescribed teriparatide or abaloparatide and compared them with a matched control group to evaluate risk of primary bone cancer development. Patients younger than 50 years with a history of cancer or other risk factors of bony malignancy were excluded. A separate cohort of 1,241 patients prescribed an anabolic agent with risk factors of primary bone malignancy, along with 6,199 matched control subjects, was created to evaluate the effect of anabolic agents. Cumulative incidence and incidence rate per 100,000 person-years were calculated as were risk ratios and incidence rate ratios. RESULTS: The overall risk of primary bone malignancy development for risk factor-excluded patients in the anabolic agent-exposed group was 0.02%, compared with 0.05% in the nonexposed group. The incidence rate per 100,000 person-years was calculated at 3.61 for the anabolic-exposed patients and 6.46 for control subjects. A risk ratio of 0.47 ( P = 0.03) and incidence rate ratio of 0.56 ( P = 0.052) were observed for the development of primary bone malignancies in patients undergoing treatment with bone anabolic agents. Among high-risk patients, 5.96% of the anabolic-exposed cohort developed primary bone malignancies and 8.13% of nonexposed patients developed primary bone malignancy. The risk ratio was 0.73 ( P = 0.01), and the incidence rate ratio was 0.95 ( P = 0.67). CONCLUSION: Teriparatide and abaloparatide can safely be used for osteoporosis and orthopaedic perioperative management without increased risk of development of primary bone malignancy.

Comparison of different parameters between daily and twice-weekly teriparatide in postmenopausal women with severe osteoporosis.

INTRODUCTION: Once-daily teriparatide (D-TPTD) and twice-weekly TPTD (W-TPTD), which are self-administered injections, are generally used in the treatment of severe osteoporosis. This study aimed to reveal the differences in the persistence, safety, and effectiveness of D-TPTD and W-TPTD. MATERIALS AND METHODS: A total of 102 patients received D-TPTD (n = 51) and W-TPTD (n = 51). The bone mineral densities (BMD) of the lumbar spine, total hip, and femoral neck were measured using dual energy X-ray absorptiometry. The persistence and effectiveness of the two treatments were compared at 12 months. RESULTS: The persistence in the D-TPTD and W-TPTD groups was 80.4% and 66.7% at 12 months, respectively (p = 0.178). The % changes (Δ) in BMD values from baseline for the lumbar spine in the D-TPTD were significantly higher than those in the W-TPTD (11.2% vs. 6.3%; p < 0.001) at 12 months. The ΔBMD values for the total hip (3.7% vs. 1.3%; p = 0.065) and femoral neck (2.2% vs. 1.6%; p = 0.489) did not differ significantly between the two groups at 12 months. The incidence of new morphological vertebral fractures in the D-TPTD and W-TPTD groups was 7.3% and 8.6%, respectively, at 12 months (p = 1.000). CONCLUSIONS: Lumbar spine BMD (LS-BMD) was significantly increased. Moreover, ΔLS-BMD in the D-TPTD group was higher than that in the W-TPTD group. This study showed that the persistence, ΔTH-BMD, ΔFN-BMD and incidence of vertebral fractures did not differ between the two groups.

Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.

BACKGROUND: The prevalence of osteoporosis is increasing in the United States. PURPOSE: To evaluate low bone mass and osteoporosis treatments to prevent fractures. DATA SOURCES: Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022. STUDY SELECTION: Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies (n ≥1000) for harms. DATA EXTRACTION: Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE). DATA SYNTHESIS: We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE). LIMITATION: Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years. CONCLUSION: Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42021236220).

Biosimilarity Assessment of the Biosimilar Teriparatide Candidate and the Reference Drug in Healthy Subjects.

SAL001, a recombinant form of parathyroid hormone, is a biosimilar drug to teriparatide and is planned to be used in osteoporosis treatment. A single-dose, randomized, open-label, 2-way crossover trial was conducted in healthy subjects to compare the pharmacokinetics (PK) and safety between SAL001 and the reference drug. Sixty-four subjects were enrolled in the study, and 61 subjects completed the study. In each period, 20 µg of the test or reference formulation was administered subcutaneously. SAL001 was administered by autoinjector pen, whereas the reference drug was administered by a self-matched injection pen. Serial blood samples were obtained for the analyses of PK and serum calcium concentration. Geometric mean ratios with 90%CIs for the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were estimated. The safety of these 2 formulations was also evaluated. Overall, the 90%CIs for the geometric mean ratios of Cmax , AUC from time 0 to the last quantifiable time point, and AUC from time 0 extrapolated to infinity of the test or reference product were within 80.0%-125.0% of biosimilarity criteria. Other PK parameters, serum calcium concentration, and safety profiles had no significant differences between the 2 formulations. SAL001 demonstrated PK similarity to the reference drug, and the serum calcium concentration and safety profiles of SAL001 were also considered comparable to the reference drug.

A Bone Histomorphometric Analysis of Hypophosphatasia-related Osteoporosis after Teriparatide Treatment.

A 79-year-old man was admitted with a compression fracture of the first lumbar vertebra. His alkaline phosphatase (ALP) level was 35 IU/L, and his dual energy X-ray absorptiometry T score was -3.7 standard deviations, indicating osteoporosis. A genetic analysis showed a mutation of the alkaline phosphatase biomineralization-associated gene encoding tissue-nonspecific alkaline phosphatase. Hypophosphatasia-related osteoporosis was diagnosed. Alendronate, teriparatide, and minodronate were administered in that order. The ALP level increased during teriparatide use. A bone biopsy performed after three years of teriparatide treatment showed that cancellous bone was adynamic. In cortical bone, tetracycline double-labeling indicates enhanced bone formation. Teriparatide may thus be a viable treatment option even in patients with hypophosphatasia.

Sequential therapy with once-weekly teriparatide injection followed by alendronate versus monotherapy with alendronate alone in patients at high risk of osteoporotic fracture: final results of the Japanese Osteoporosis Intervention Trial-05.

In this randomized, controlled trial, sequential therapy with once-weekly subcutaneous injection of teriparatide for 72 weeks, followed by alendronate for 48 weeks resulted in a significantly lower incidence of morphometric vertebral fracture than monotherapy with alendronate for 120 weeks in women with osteoporosis at high risk of fracture. PURPOSE: To determine whether the anti-fracture efficacy of sequential therapy with teriparatide, followed by alendronate is superior to that of monotherapy with alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed. METHODS: Japanese women aged at least 75 years were eligible for the study, if they had primary osteoporosis and if they were at high risk of fracture. Patients were randomly assigned (1:1) to receive the sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 µg for 72 weeks, followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint in the final analysis was the incidence of morphometric vertebral fracture during the 120-week follow-up period. RESULTS: Between October 2014 and June 2020, 505 patients in the sequential therapy group and 506 in the monotherapy group were enrolled. Of these, 489 and 496, respectively, were included in the main analysis. The incidence of morphometric vertebral fracture during the 120-week follow-up period in the sequential therapy group (64 per 627.5 person-years, annual incidence rate 0.1020) was significantly lower than that in the monotherapy group (126 per 844.2 person-years, annual incidence rate 0.1492), with a rate ratio of 0.69 (95% confidence interval 0.54 to 0.88, P < 0.01). After 72 weeks, no patient had a severe adverse event that was considered related to the study drug. CONCLUSION: Once-weekly injection of teriparatide, followed by alendronate resulted in a significantly lower incidence of morphometric vertebral fracture than alendronate monotherapy in women with osteoporosis who were at high risk of fracture. TRIAL REGISTRATION NUMBER, DATE OF REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.

Comparison of pharmacokinetics, pharmacodynamics, safety, and immunogenicity of teriparatide biosimilar with EU- and US-approved teriparatide reference products in healthy men and postmenopausal women.

Biosimilar teriparatide (INTG-8) was tested in a healthy population of males and postmenopausal females to assess pharmacokinetic bioequivalence to originator teriparatide comparator products. Primary pharmacokinetic comparison confirmed bioequivalence. Pharmacodynamics, safety, and tolerability were comparable to the originator products. INTG-8 was therefore confirmed to be biosimilar to originator products. INTRODUCTION: The purpose of this present study was to demonstrate pharmacokinetic (PK) equivalence of a biosimilar teriparatide (INTG8) to EU- and US-approved teriparatide reference products in healthy men and postmenopausal women. Secondary objectives included comparison of the pharmacodynamics (PD), safety, and tolerability. METHODS: One hundred and five subjects randomly (1:1:1) received single subcutaneous 20 µg injection of teriparatide biosimilar, EU- and US-teriparatide on 3 consecutive days in this assessor-blind, three-period, single-dose, crossover study. Maximum serum concentration (Cmax), area under the curve (AUC) from time zero to t (AUC0-t), and AUC from time zero extrapolated to infinity (AUC0-∞) were primary PK parameters, analyzed by non-compartmental methods. The secondary PD endpoints were maximum observed effect (Emax), area under the effect curve (AUE) from time zero to the last measurable concentration (AUE0-t), and time to maximum observed effect (Tmax) for total serum calcium levels. Safety, tolerability, and immunogenicity were also evaluated. This study was registered with ctri.nic.in/ (CTRI/2020/10/028627) on 26 October 2020. RESULTS: Baseline demographics were similar across the three-treatment sequence groups. The 90% confidence intervals (CI) for the geometric mean ratios (test:reference) of Cmax, AUC0-t, and AUC0-∞ were within the predefined bioequivalence criterion of 80.00% to 125.00%, which demonstrated PK equivalence of teriparatide biosimilar to EU- and US-teriparatide for all primary endpoints. The PD comparability was demonstrated by similar serum calcium levels. Study treatments were generally well tolerated and showed no meaningful differences in safety or immunogenicity profiles. There were no deaths, or serious AEs were reported during this study. CONCLUSION: The study demonstrated PK bioequivalence of teriparatide biosimilar to the EU- and US-teriparatide reference products with comparable PD, safety, and immunogenicity profiles.

Cardiac adverse events in bisphosphonate and teriparatide users: An international pharmacovigilance study.

BACKGROUND: Cardiovascular effects of osteoporosis medications have recently been highlighted. Although oral and intravenous bisphosphonates are assumed to have similar cardiovascular safety, few head-to-head comparisons exist. The cardiovascular safety of teriparatide is unknown. Aim We conducted a pharmacovigilance safety study of cardiac events using real-life adverse event reports from alendronate, zoledronic acid and teriparatide users. METHODS: Adverse drug reactions were obtained from Vigibase, a WHO database of individual case safety reports (ICSRs) from 130 countries (1967-2020). ISCRs for atrial fibrillation (AF), angina pectoris, arteriosclerosis coronary artery (ACA), cardiac arrhythmias, coronary artery disease (CAD), thromboembolic events (TE), ischaemic heart disease (IHD), torsade de pointes/QT prolongation (TDP) associated with alendronate, zoledronic acid and teriparatide use were extracted. Data were included in a disproportionality analysis where the lower end of the 95 % credibility interval for the information component (IC025), showing a statistical association when >0. Head-to-head comparisons of ISCRs were estimated by age-adjusted odds ratios and 95 % confidence intervals. RESULTS: 465 episodes of angina, 287 ACA, 13,385 arrhythmias, 792 CAD, 6743 TE, 3264 IHD, 1037 myocardial infarcts, and 3714 TDP events were recorded across 50,365 alendronate, 52,436 zoledronic acid and 137,629 teriparatide users. There was a significant association between alendronate and zoledronate with all outcomes except MI. Teriparatide use was associated with AF, arrythmias and angina only. In head-to-head comparisons, teriparatide use was associated with fewer ACA and CAD events than alendronate and fewer ACA than zoledronic acid. DISCUSSION: Osteoporosis medication use is associated with adverse cardiac events, except for MI, and these appear to be more common with oral and intravenous bisphosphonates than teriparatide. Our data do not support differential effects of oral and intravenous bisphosphonates on cardiac events. Mechanisms whereby teriparatide may be cardio-protective warrant further investigation.

An effect comparison of alendronate and teriparatide in patients with glucocorticoid-induced osteoporosis: A protocol for systematic review and meta-analysis.

BACKGROUND: Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis and the resulting fractures cause significant morbidity. Oral bisphosphonates are currently regarded as first line options on the grounds of their low cost. However, teriparatide has been shown to be superior in its effects on bone mineral density and vertebral fracture risk in glucocorticoid-treated individuals with osteoporosis. We conducted a protocol for systematic review and meta-analysis to assess the effectiveness of alendronate and teriparatide in patients with glucocorticoid-induced osteoporosis. METHODS: The study protocol has been registered on international prospective register of systematic review (PROSPERO registration number: CRD42022371561). The procedure of this protocol will be conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis Protocols guidance. PubMed, EMBASE, MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, ClinicalTrials.gov trials registry, and Chinese Clinical Trial Registry will be searched from January 1980 to November 2022. Two authors will assess methodological quality of included studies separately by the Cochrane collaboration's risk of bias tool. We will apply RevMan 5.4 software for statistical analysis. RESULTS: This study will provide a high-quality comprehensive evaluation of the efficacy and safety of alendronate and teriparatide for treating patients with glucocorticoid-induced osteoporosis. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether teriparatide is an effective intervention for patients with glucocorticoid-induced osteoporosis.

Romosozumabe para mulheres com osteoporose na pós menopausa, a partir de 70 anos, que apresentam risco muito alto de fratura por fragilidade e que falharam (apresentaram duas ou mais fraturas) com o padrão de tratamento medicamentoso / Romosozumab for postmenopausal women with osteoporosis, aged 70 years and older, who are at very high risk of a fragility fracture and who have failed (have had two or more fractures) with their standard of care

INTRODUÇÃO: A osteoporose é uma doença caracterizada pela baixa massa óssea acompanhada de deterioração da arquitetura óssea, o que aumenta o risco de fratura. Segundo a Organização Mundial de Saúde, a osteoporose é definida como DMO ≤ -2,5 desvios padrão abaixo do pico de massa óssea encontrada no adulto jovem. É uma doença geralmente é silenciosa até a ocorrência de fratura, que caracteriza seu principal desfecho clínico. O tratamento envolve abordagem não farmacológica e farmacológica. Na última modalidade, os Protocolos Clínicos e Diretrizes Terapêuticas (PCDT) da Osteoporose do Ministério da Saúde (2014) recomendam em primeira linha a utilização de bisfosfonatos (alendronato, risedronato ou pamidronato) e, em segunda linha, raloxifeno, calcitonina ou estrógenos conjugados. Contudo, o PCDT não apresenta informações sobre o tratamento subsequente em caso de falha, de modo que o paciente não teria opção terapêutica em terceira linha, justificando-se, assim, a avaliação do romosozumabe para esta população. PERGUNTA DE P

[Experience in using teriparatide for the treatment of postoperative hypoparathyroidism in hemodialysis patients].

The frequency of chronic postoperative hypoparathyroidism after total parathyroidectomy for secondary and tertiary hyperparathyroidism in patients with end-stage renal failure, according to various authors, can reach 20% or more. Prescribing active metabolites of vitamin D and calcium it is not always sufficient for achievement of target goals. This dictates the need for replacement therapy with recombinant parathyroid hormone. Teriparatide is the only drug of this series approved by the American Food and Drug Administration (FDA) and registered in the Russian Federation. However, it is registered as an anabolic anti-osteoporotic drug and is not indicated for the treatment of chronic hypoparathyroidism. The use of teriparatide in postoperative hypoparathyroidism in patients receiving renal replacement therapy with programmed hemodialysis in the Russian Federation has not been previously studied. Data on this issue is also limited in foreign literature. However, it is a potential treatment option for hemodialysis patients with chronic hypoparathyroidism and severe bone disorders. In this article, we present 2 clinical cases of substitution and anabolic therapy with teriparatide in this cohort of patients.