INTRODUCTION

Osteogenesis imperfecta (OI) is a rare, inherited connective tissue disorder characterized by low bone mass, increased bone fragility, and a range of systemic complications. Often referred to as "brittle bone disease," OI affects approximately 1 in 15,000 to 20,000 live births, though exact prevalence is difficult to determine due to underdiagnosis and clinical variability. Symptoms may range from mild susceptibility, to fractures or severe skeletal deformities, short stature, hearing loss, and cardiopulmonary complications.

There is no cure for OI, and current treatment approaches focus on fracture prevention, surgical interventions, pain management, and the use of bone-strengthening medications — most notably bisphosphonates. While these therapies have been widely adopted in pediatric and some adult OI populations, evidence for their long-term efficacy and patient-reported benefits remains limited and inconsistent.

This evidence gap is not unusual in rare diseases. Clinical trials are small, follow-up periods are short, and the burden of collecting meaningful long-term outcomes often falls on patients and families without institutional support. Moreover, most healthcare datasets lack the longitudinal, multimodal, and patient-centered structure needed to answer key clinical questions in conditions like OI.

To address this unmet need, RegenMed has deployed its Circles platform in collaboration with clinicians, patients, and advocacy organizations focused on OI. Circles is a patented system for collecting and structuring longitudinal healthcare datasets — including both clinical and patientreported data — in a way that is owned, consented to, and monetizable by the people who generate it.

Background: The Challenge of Data Scarcity in OI

OI is a group of rare genetic disorders characterized by defective connective tissue, typically due to mutations in the COL1A1 or COL1A2 genes. Its clinical presentation ranges from mild bone fragility to severe skeletal deformities and perinatal lethality. The rarity and heterogeneity of OI have contributed to a persistent challenge in collecting standardized outcomes and conducting large-scale studies.

Despite the broad clinical burden of the disease, most existing studies rely on small institutional cohorts. Patient-reported data, particularly over time and across life stages, remains limited.

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CONCEPTUAL MODEL

Bisphosphonate Therapy in OI: A Critical but Incomplete Picture

Bisphosphonates have been used for over two decades in OI to increase bone mineral density and reduce fracture frequency, especially in pediatric patients. Agents like pamidronate and zoledronic acid are considered standard care in many centers. However, the evidence base has limitations:

• Heterogeneity of Outcomes: Some patients experience dramatic improvements; others report minimal change in mobility or pain.
• Lack of Longitudinal Data: Long-term safety, especially around skeletal maturation and atypical fractures, is not well understood.
• Missing Patient Voice: Most studies do not include patient-reported outcome measures (PROMs), masking the impact on daily living, function, and fatigue.

These gaps have downstream effects. Clinicians operate with partial data. Regulators and researchers lack

real-world outcome metrics. And patients are rarely empowered to participate in the knowledge-generation process — or to benefit from it.

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Circles: A New Paradigm for Rare Disease Data

The Circles platform addresses this challenge directly by enabling:

• Closed-loop data generation: Longitudinal clinical and self-reported outcomes are collected through structured interactions with patients and providers.

In the case of OI, RegenMed is deploying a disease-specific Patient-Reported Outcome Measure (PROM), developed in collaboration with clinicians and advocacy organizations. This PROM includes:

• Fracture frequency and context (e.g., from standing height, spontaneous)
• Pain severity and localization
• Fatigue, stiffness, and recovery time
• Functional outcomes (mobility, independence, participation)
• These data points are mapped over time and paired with clinical variables (e.g., BMD scores, DEXA results, medication dosage), producing a verifiable and patient-centered dataset.

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CONCEPTUAL MODEL

Legal and Ethical Considerations in Rare Disease Data

Circles is designed with full compliance to U.S. and international data privacy frameworks, including:

• HIPAA: All patient data is de-identified at the point of storage, with re-identification keys held only by the patient.
• GDPR: Patients have complete control over data use and can revoke consent at any time.
• CCPA/CPRA: Patients can request data deletion, transfer, or disclosure logs.

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CONCLUSION

Clinical progress in osteogenesis imperfecta has long been hindered by fragmented data, inconsistent reporting standards, and a research infrastructure that leaves physicians disconnected from the long-term outcomes of their treatment decisions. The Circles platform addresses these gaps by enabling physicians to capture, own, and benefit from the longitudinal datasets they help generate — not only through tokenized economic models, but through real-time, verifiable clinical insights.

In the case of bisphosphonate therapy, where long-term efficacy and safety remain incompletely understood, Circles empowers physicians to follow patients across years and settings — pairing fracture rates, BMD results, and mobility outcomes with real-world, patient-reported measures. These high-integrity, closed-loop datasets do more than satisfy regulatory or academic interests: they enable clinicians to validate protocols, identify treatment variation, and refine their care strategies in a continuous, evidence-driven cycle.

By tying data ownership directly to the source of medical expertise — the physician — Circles creates both the incentive and the infrastructure for better data, better care, and better outcomes. Clinical judgment becomes traceable, rewardable, and scalable — not just an act of service, but a contribution to the clinical evidence base itself.

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