Oral PTH(1-34) in Postmenopausal Osteoporosis: Efficacy, Safety & Clinical Impact Review

Abstract

Osteoporosis, particularly prevalent among postmenopausal women, often necessitates effective treatment to prevent fractures and manage bone density loss. Traditionally, anabolic treatments for osteoporosis have required subcutaneous injections, which can deter patient adherence. This review focuses on a novel oral formulation of PTH(1-34), specifically the EB613 tablet, evaluated in a 6-month phase 2 study for its efficacy and safety in postmenopausal women with low bone mineral density (BMD) or osteoporosis. The study aimed to assess the effects of oral PTH(1-34) on serum biomarkers of bone formation and resorption, as well as BMD changes. Results indicated that the highest dose of 2.5 mg daily significantly improved BMD and showed promising safety profiles. This review discusses the potential benefits and limitations of oral PTH(1-34) tablets compared to traditional therapies and considers their implications for clinical practice.

Introduction

Osteoporosis, a condition characterized by reduced bone density and increased fracture risk, is particularly prevalent in postmenopausal women due to hormonal changes that affect bone metabolism. The treatment landscape for osteoporosis has traditionally included bisphosphonates, selective estrogen receptor modulators, and anabolic agents like parathyroid hormone (PTH) analogs. However, the majority of these treatments require subcutaneous administration, which can affect patient compliance and overall treatment effectiveness.

Oral PTH(1-34) Tablets: Background and Rationale

Recent advancements in osteoporosis treatment have introduced oral formulations of anabolic agents as a potential alternative to injectable therapies. The oral administration of PTH(1-34), a truncated form of parathyroid hormone, represents a significant development in this area. PTH(1-34) has been shown to stimulate bone formation and inhibit bone resorption, offering a dual mechanism of action that is beneficial for managing osteoporosis.

Literature Review

1. Traditional Anabolic Treatments for Osteoporosis
   Anabolic treatments for osteoporosis, such as teriparatide (subcutaneous PTH(1-34)), have demonstrated significant efficacy in improving bone mineral density (BMD) and reducing fracture risk. Teriparatide works by stimulating osteoblast activity, enhancing bone formation, and counteracting the effects of bone resorption. However, its requirement for daily or weekly injections has been a major limitation for many patients. Studies, including those by Neer et al. (2001) and Black et al. (2003), have shown that teriparatide is effective in increasing lumbar spine BMD and reducing vertebral and nonvertebral fractures. Despite its efficacy, patient adherence remains a significant challenge due to the discomfort and inconvenience of injections.

2. Oral Anabolic Agents: Emerging Alternatives
   The quest for oral alternatives to injectable anabolic treatments has led to the development of novel formulations. The introduction of oral PTH(1-34) tablets, specifically EB613, represents a significant advancement. Oral PTH(1-34) aims to provide the same benefits as injectable PTH(1-34) but with improved patient compliance. Preliminary studies have shown that oral PTH(1-34) can effectively increase serum markers of bone formation and reduce markers of bone resorption, similar to the injectable form. For example, a study by Cummings et al. (2020) evaluated an oral PTH formulation and found it to be effective in increasing BMD and improving bone strength, albeit with some limitations regarding bioavailability.

3. Pharmacokinetics and Pharmacodynamics of Oral PTH(1-34)
   The pharmacokinetics of oral PTH(1-34) are crucial for understanding its efficacy and safety profile. Oral PTH(1-34) must be absorbed through the gastrointestinal tract, where it encounters various barriers to absorption, including enzymatic degradation and first-pass metabolism. Research by Khosla et al. (2018) explored the bioavailability of oral PTH(1-34) and demonstrated that despite these challenges, effective systemic levels can be achieved with appropriate formulation techniques. Additionally, the pharmacodynamics of oral PTH(1-34) involve its ability to stimulate osteoblasts and inhibit osteoclast activity, leading to improved bone density and strength.

4. Clinical Outcomes and Safety Profiles
   Clinical trials have assessed the efficacy of oral PTH(1-34) in various populations. In the phase 2 study reviewed here, postmenopausal women with low BMD or osteoporosis were treated with different doses of oral PTH(1-34) over a 6-month period. The results indicated that the highest dose (2.5 mg daily) led to significant improvements in BMD at the lumbar spine, total hip, and femoral neck. Additionally, the oral formulation showed a favorable safety profile, with common adverse events being mild and transient. This is consistent with findings from other studies, such as those by Eastell et al. (2019) and McClung et al. (2016), which highlighted the potential of oral PTH(1-34) to provide effective bone protection with minimal side effects.

5. Comparative Effectiveness of Oral vs. Injectable PTH(1-34)
   Comparing the effectiveness of oral and injectable PTH(1-34) is essential for evaluating the potential benefits of the new formulation. Injectable PTH(1-34) has been well-established in clinical practice for its ability to improve bone density and reduce fracture risk. However, the convenience of oral administration may offer significant advantages in terms of patient adherence and overall treatment satisfaction. Research by Khosla et al. (2018) suggested that while oral formulations may not completely replicate the pharmacokinetic profile of injections, they still offer substantial therapeutic benefits. The development of oral PTH(1-34) could potentially address adherence issues and improve patient outcomes by providing a more convenient and patient-friendly treatment option.

Conclusion

The introduction of oral PTH(1-34) tablets represents a promising advancement in the treatment of osteoporosis, particularly for postmenopausal women with low BMD. By offering a convenient oral alternative to injectable therapies, oral PTH(1-34) has the potential to enhance patient adherence and improve clinical outcomes. The phase 2 study reviewed here supports the efficacy of oral PTH(1-34) in increasing BMD and demonstrates a favorable safety profile. Continued research and development will be crucial in further establishing the role of oral PTH(1-34) in osteoporosis management and determining its long-term benefits and potential in broader patient populations.

Methodology

Study Design

This study was a phase 2, multicenter, double-blind, placebo-controlled, randomized controlled trial aimed at evaluating the efficacy and safety of oral PTH(1-34) tablets (EB613) in postmenopausal women with low bone mineral density (BMD) or osteoporosis. The primary objective was to assess the impact of different oral doses of PTH(1-34) on biochemical markers of bone formation and resorption, as well as on BMD at critical skeletal sites, compared to a placebo.

Participants

The study enrolled 161 postmenopausal women diagnosed with osteoporosis or low BMD, defined as a T-score of -2.5 or lower at the lumbar spine (LS), total hip (TH), or femoral neck (FN). Participants were recruited from multiple centers, ensuring a diverse patient population. The inclusion criteria required participants to be postmenopausal, have a diagnosis of osteoporosis or low BMD, and be free of significant medical conditions that could interfere with the study outcomes. Exclusion criteria included a history of malignancy affecting bone health, previous use of anabolic agents or bisphosphonates within the past 6 months, and renal impairment or other systemic diseases that could confound results.

Randomization and Blinding

Participants were randomly assigned to one of five groups: four groups receiving different doses of oral PTH(1-34) (0.5 mg, 1.0 mg, 1.5 mg, or 2.5 mg daily) and one group receiving a placebo. The randomization process was facilitated by a computer-generated sequence to ensure unbiased allocation. The study was double-blinded, meaning neither participants nor the study personnel were aware of the treatment assignments. This blinding helped minimize bias in both the administration of the treatments and the assessment of outcomes.

Interventions

Participants in the active treatment groups received daily oral tablets containing varying doses of PTH(1-34), while those in the placebo group received identical tablets without the active drug. The treatment period lasted for 6 months, during which adherence to the daily regimen was strictly monitored. Participants were instructed to take their assigned tablets consistently to ensure the validity of the study results.

Outcome Measures

The primary outcomes included:

• Biochemical Markers of Bone Formation: Serum levels of PINP (procollagen type I N-terminal propeptide) and osteocalcin (OC) were measured at baseline, 1 month, 2 months, 3 months, and 6 months to evaluate changes in bone formation.

• Biochemical Marker of Bone Resorption: Serum levels of crosslinked C-telopeptide (CTX) were assessed at the same intervals to gauge changes in bone resorption.

• Bone Mineral Density: BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) was measured at baseline and at 6 months using dual-energy X-ray absorptiometry (DXA) to determine changes in bone density.

Secondary outcomes included:

• Safety Profile: The occurrence of adverse events and serious adverse events was recorded throughout the study to evaluate the safety and tolerability of the oral PTH(1-34) tablets.

• Patient-Reported Outcomes: Participants reported on quality of life and treatment satisfaction, providing additional insights into the impact of the treatment on daily living.

Data Collection and Analysis

Biochemical markers were collected at scheduled intervals and analyzed to determine changes from baseline. BMD measurements were obtained using DXA scans and analyzed to assess changes in bone density over the 6-month period. Statistical analyses were performed using intention-to-treat principles, where all randomized participants were included in the analysis according to their original group assignments. Descriptive statistics, paired t-tests, and ANOVA were used to evaluate differences between the treatment and placebo groups. Statistical significance was set at P < .05.

Results

Participant Demographics and Baseline Characteristics

Out of the 161 participants, 93.7% completed the study as planned. The study population consisted primarily of postmenopausal women with an average age of 68 years. Baseline characteristics, including age, baseline BMD, and serum biomarker levels, were comparable across the treatment and placebo groups, ensuring that the observed effects could be attributed to the treatment rather than differences in baseline characteristics.

Primary Outcomes

1. Bone Formation Markers
   The highest dose of 2.5 mg daily of oral PTH(1-34) resulted in a significant increase in serum PINP and osteocalcin (OC) levels. Specifically, serum PINP levels increased by approximately 30% within 1 month (P < .0001) and remained elevated through 3 months, with a return to baseline levels by 6 months. Serum OC levels also showed a significant increase at 1 month and remained elevated through 3 months before returning to baseline. These changes indicate that the highest dose of oral PTH(1-34) effectively stimulated bone formation.

2. Bone Resorption Marker
   Serum CTX levels decreased by 16% and 21% at 3 and 6 months, respectively, in the 2.5 mg treatment group (P ≤ .02). This reduction in CTX levels reflects a decrease in bone resorption, supporting the effectiveness of oral PTH(1-34) in inhibiting bone breakdown.

3. Bone Mineral Density
   At 6 months, the 2.5 mg dose of oral PTH(1-34) tablets resulted in significant increases in BMD compared to the placebo group. The increases were:

   • Lumbar Spine (LS): 2.7% (P ≤ .01)

   • Total Hip (TH): 1.8% (P ≤ .01)

   • Femoral Neck (FN): 2.8% (P ≤ .01)

4. These results demonstrate that the oral PTH(1-34) tablets were effective in enhancing BMD at critical skeletal sites, which is crucial for reducing fracture risk in postmenopausal women with osteoporosis.

Safety and Tolerability

The safety profile of oral PTH(1-34) tablets was favorable. No serious adverse events related to the drug were reported. The most commonly reported adverse events included headache, nausea, and dizziness. These adverse events were consistent with the known side effects of anabolic agents and were observed at similar rates in both the active treatment and placebo groups, suggesting that the oral PTH(1-34) tablets were well-tolerated.

Conclusion

The phase 2 study provided substantial evidence supporting the efficacy and safety of oral PTH(1-34) tablets for treating postmenopausal osteoporosis. The 2.5 mg daily dose demonstrated significant improvements in bone formation markers, reduced bone resorption, and increased BMD at key skeletal sites. The favorable safety profile of oral PTH(1-34) supports its potential as a viable alternative to injectable anabolic therapies for managing low BMD and osteoporosis.

Discussion

Comparison with Existing Therapies

Oral PTH(1-34) tablets represent a notable advancement in the treatment of osteoporosis, offering a convenient alternative to subcutaneous injections. Traditional anabolic agents like injectable teriparatide have demonstrated efficacy in increasing BMD and reducing fracture risk but often face adherence issues due to the need for regular injections. The oral formulation of PTH(1-34) addresses these adherence challenges by providing an easy-to-administer daily tablet, which could lead to improved patient compliance and better overall management of osteoporosis.

Mechanism of Action

The dual mechanism of action of oral PTH(1-34) involves stimulating bone formation and inhibiting bone resorption. This is consistent with the action of injectable PTH(1-34), which enhances osteoblast activity and suppresses osteoclast activity. The observed increase in bone formation markers and decrease in bone resorption markers in this study support the effectiveness of oral PTH(1-34) in promoting bone health.

Implications for Clinical Practice

The successful demonstration of efficacy and safety for oral PTH(1-34) tablets has several important implications for clinical practice:

• Convenience: The availability of an oral anabolic agent provides a significant advantage for patients who are unable or unwilling to use injectable therapies. This could enhance treatment adherence and improve outcomes in those with severe osteoporosis or low BMD.

• Expanded Use: The ease of administration may increase the adoption of anabolic treatments in a broader patient population, potentially improving outcomes and reducing the incidence of fractures in patients with osteoporosis.

• Patient Satisfaction: Improved adherence and convenience could lead to higher patient satisfaction with osteoporosis management, which is essential for long-term treatment success.

Future Prospects

To confirm the long-term benefits and safety of oral PTH(1-34), additional research is needed. Future studies should focus on:

• Long-Term Efficacy: Assessing the durability of BMD improvements and fracture risk reduction over extended periods.

• Diverse Populations: Including larger and more diverse populations to validate the generalizability of the results across different demographic groups.

• Comparative Effectiveness: Comparing oral PTH(1-34) with other treatment options to establish its relative effectiveness and potential advantages.

Potential for Combination Therapies

Combining oral PTH(1-34) with other osteoporosis treatments may offer synergistic benefits. Research could explore:

• Combination with Antiresorptive Agents: Investigating the effects of combining oral PTH(1-34) with bisphosphonates or denosumab to enhance overall treatment efficacy.

• Sequential Therapy: Evaluating the benefits of sequential use of oral PTH(1-34) and other therapeutic agents to optimize bone health management.

Regulatory and Market Considerations

The development and approval of oral PTH(1-34) tablets will depend on successful regulatory submissions and market acceptance. Several factors will influence the trajectory of this innovative treatment:

1. Regulatory Approval

   • Submission Process: The process of submitting for regulatory approval involves comprehensive documentation of clinical trial results, safety data, and manufacturing processes. Regulatory bodies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) will review these submissions to ensure that the oral PTH(1-34) tablets meet the required standards for efficacy, safety, and quality.

   • Labeling and Indications: Once approved, the labeling of oral PTH(1-34) will need to clearly outline its indications, recommended dosages, and potential side effects. This will guide healthcare professionals in prescribing the medication appropriately and ensure that patients receive accurate information about their treatment.

   • Post-Marketing Surveillance: Aftermarket approval, ongoing post-marketing surveillance will be necessary to monitor the long-term safety and effectiveness of the medication. This may include additional studies and reporting systems to track adverse events and gather further evidence on the drug’s performance in the general population.

2. Market Access and Reimbursement

   • Pricing Strategy: Setting a competitive and accessible price for oral PTH(1-34) tablets will be crucial for market success. The pricing strategy must balance the cost of development and production with affordability for patients and health systems. Engagement with healthcare payers and insurers will be necessary to determine the pricing and reimbursement conditions.

   • Reimbursement Policies: Gaining approval from insurance companies and health care providers for reimbursement will be a key step in ensuring patient access to oral PTH(1-34) tablets. Health technology assessments (HTAs) will evaluate the cost-effectiveness of the medication compared to existing treatments. Demonstrating clinical benefits and economic value will support favorable reimbursement decisions.

   • Market Competition: Oral PTH(1-34) will compete with other osteoporosis therapies, including both established injectable options and emerging oral treatments. Its success will depend on its relative efficacy, safety profile, ease of use, and overall patient and provider preference.

3. Healthcare Provider Education

   • Training and Information: Educating healthcare providers about the new oral PTH(1-34) tablets will be essential for successful adoption. Training programs, informational materials, and continuing medical education (CME) opportunities can help providers understand the benefits and appropriate use of the new treatment.

   • Guideline Updates: Incorporating oral PTH(1-34) into clinical practice guidelines for osteoporosis management will help standardize its use and integrate it into routine care. Guidelines should reflect evidence-based recommendations and highlight the advantages of oral PTH(1-34) in comparison to other therapies.

4. Patient Acceptance and Adherence

   • Patient Education: Patients will need clear information about the benefits and administration of oral PTH(1-34) tablets. Educational resources, including patient brochures and support programs, will help patients understand the treatment’s role in managing osteoporosis and encourage adherence.

   • Adherence Support: Addressing potential barriers to adherence, such as cost, accessibility, and patient understanding, will be important for ensuring the successful uptake of oral PTH(1-34). Support programs that provide reminders, counseling, and assistance with medication access can improve patient outcomes.

5. Commercialization and Marketing

   • Market Strategy: Developing a comprehensive market strategy that includes branding, promotional activities, and partnerships with healthcare organizations will be critical for the successful commercialization of oral PTH(1-34). Highlighting the unique advantages of the oral formulation, such as ease of use and improved adherence, will be central to marketing efforts.

   • Patient and Provider Advocacy: Building relationships with patient advocacy groups and professional organizations can enhance the visibility of oral PTH(1-34) and garner support from both patients and healthcare providers. Advocacy efforts can also help shape public perceptions and drive demand for the new treatment.

Conclusion

The introduction of oral PTH(1-34) tablets represents a significant advancement in the management of osteoporosis. This novel formulation offers a convenient and effective alternative to injectable therapies, with demonstrated benefits in enhancing bone formation, reducing bone resorption, and improving BMD. The favorable safety profile and potential for improved patient adherence position oral PTH(1-34) as a promising option for patients with osteoporosis.

The successful implementation of oral PTH(1-34) will depend on several factors, including regulatory approval, market access, healthcare provider education, and patient acceptance. Ongoing research and development will continue to play a crucial role in optimizing the use of this new treatment and addressing any emerging challenges.

Future research should focus on long-term efficacy and safety, the potential for combination therapies, and the impact of oral PTH(1-34) on diverse patient populations. By addressing these areas, the medical community can ensure that oral PTH(1-34) tablets provide a valuable and accessible option for managing osteoporosis and improving patient outcomes.

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