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Sequence HPP is a physician-designed clinical program for the systematic identification, diagnosis, and longitudinal management of adults with known and suspected hypophosphatasia — grounded in international consensus frameworks and structured around validated clinical endpoints.
Hypophosphatasia in adults presents with a heterogeneous, multisystem phenotype that is routinely mistaken for osteoporosis, fibromyalgia, chronic fatigue syndrome, or non-specific musculoskeletal pain. The diagnostic signal — persistently low alkaline phosphatase — is paradoxically ignored by most laboratory workflows that flag only elevated values.
A 2023 study found that 9% of patients in osteoporosis clinics had at least one low ALP value, with confirmed HPP identified in a subset. Most were never evaluated because standard lab panels do not flag low-normal or low ALP. These patients are actively receiving care for the wrong diagnosis.
Bisphosphonates and denosumab are contraindicated in HPP — they further suppress already-deficient TNSALP activity. Case reports document bilateral atypical femoral fractures in undiagnosed HPP patients on antiresorptives. Pre-treatment ALP screening is not current standard of care.
Adult HPP patients experience a diagnostic odyssey averaging years to decades, cycling through multiple specialists without identification. The systemic nature of the disease — bone pain, fatigue, muscle weakness, dental disease, neuropsychiatric symptoms — leads to fragmented, organ-by-organ evaluation that misses the unifying diagnosis.
All patients initiating bisphosphonate or denosumab therapy should have alkaline phosphatase checked. Persistently low values warrant ALPL gene testing and referral to metabolic bone disease or genetics before continuing antiresorptive treatment.
Our structured clinical pathway maps each phase to specific evidence citations from international consensus guidelines (Seefried 2025, Brandi 2024, Dahir & Dunbar 2025) and landmark clinical trials with 5+ years of follow-up data.
Comprehensive genetics evaluation using the HPP International Working Group major/minor criteria framework. Baseline labs (ALP, PLP, Ca, PO4, PTH, 25OH-D), ALPL gene sequencing, baseline functional assessments (6MWT, TUG, grip strength), full PROM battery (14 instruments), skeletal survey, DXA, and dental evaluation. Differential diagnosis excludes secondary causes of low ALP.
Pain and fracture management, bone-safe physical therapy initiation, metabolic monitoring every 6 weeks. The critical treatment decision — whether to initiate enzyme replacement therapy — follows a structured 26-criteria framework evaluating 9 positive indicators, 4 negative indicators, and individualized gray-zone assessment.
Treatment response tracking using validated endpoints: 6MWT improvement (MCID ≥30m), BPI pain reduction (MCID ≥2 NRS points), PLP normalization. Progressive strengthening programs, metabolic labs every 12 weeks, follow-up imaging for pseudofracture healing. Phase gate review confirms sustained improvement before transition to maintenance.
Long-term monitoring per amended 2025 guidelines: biannual physician visits, annual metabolic panels, annual DXA and dental assessment, biannual PROM collection, injection site rotation monitoring (5-site protocol), and anti-drug antibody testing if loss of response suspected (60-89% develop antibodies).
Diagnosis follows the HPP International Working Group framework (Brandi et al., 2024), requiring ≥2 major criteria or 1 major + 2 minor criteria for clinical diagnosis, with ALPL sequencing for genetic confirmation.
Not all patients with HPP require enzyme replacement therapy. Our treatment decision framework follows the 26-criteria assessment from Dahir & Dunbar (2025), balancing disease severity against treatment burden.
6 mg/kg/week total subcutaneous dose (typically 2 mg/kg 3×/week or 1 mg/kg 6×/week). Clinical trials demonstrate sustained improvement in 6-minute walk distance (355→450m), pain reduction, and biochemical normalization through 5+ years of treatment. Real-world data shows 70% muscle strength improvement and 100% walking distance improvement in treated cohorts.
Efzimfotase alfa (next-generation ERT) achieved 21-fold higher exposure in Phase 1, with Phase 3 trials enrolling. Gene therapy (AAV-ALPL vectors), mRNA approaches, and engineered cell-based therapies are in preclinical development. Teriparatide remains an off-label alternative for select cases when first-line therapy is ineffective or contraindicated.
Our outcomes framework is designed around the instruments validated in HPP clinical trials (NCT01163149, NCT04195763) and recommended by 2025 consensus monitoring guidelines. Every patient encounter generates structured, analyzable endpoint data.
| Instrument | Domain | Clinical Endpoint | Schedule |
|---|---|---|---|
| 6MWT | Functional capacity | Primary endpoint in Phase 2/3 trials; MCID ≥30m | q6m |
| TUG | Mobility / Balance | Added per amended 2025 monitoring guidelines | q6m |
| 5TSTS | Lower extremity strength | Lower administrative burden alternative to 6MWT | q6m |
| BPI | Pain characterization | Bone pain severity and interference; MCID ≥2 NRS | q6m |
| HAQ-DI | Functional disability | ADL limitation across 8 categories | q6m |
| FACIT-Fatigue | Fatigue severity | Key non-skeletal HPP burden; red flag <20 | q6m |
| FES-I | Fear of falling | Fracture anxiety; high-risk threshold ≥44 | q12m |
| OHIP-14 | Oral health QoL | Dental manifestation impact; 62% prevalence in adults | q12m |
| PHQ-9 | Depression screening | Specifically recommended by 2025 guidelines | q6m |
| GAD-7 | Anxiety screening | Emotional burden documented in Global HPP Registry | q6m |
| EQ-5D-5L | Quality of life | Utility measure for health economics | q12m |
| PROMIS-29 | Global function | Physical, mental, social health — multidomain | q6m |
| Pain NRS | Pain intensity | Quick serial tracking; treatment response measure | q3m |
| Grip Strength | Upper extremity | Objective muscle weakness assessment | q6m |
All PROM data, functional assessments, biochemical results, and treatment milestones are captured in a structured longitudinal database with automated red-flag detection, MCID tracking, and population-level analytics. This infrastructure enables real-world evidence generation, treatment response monitoring, and natural history characterization across the patient cohort.
Per Seefried et al. (2025), comprehensive HPP management requires coordinated expertise across 9 specialties. Our program provides the organizational infrastructure for this multidisciplinary model.
Disease state management, ALPL variant interpretation, treatment decision-making, and longitudinal care coordination. The clinical geneticist serves as the program anchor.
Pre- and post-test ALPL counseling, family cascade testing coordination, variant classification review, psychosocial support, and inheritance pattern education.
Bone-safe progressive strengthening, functional assessments (6MWT, TUG, grip), exercise prescription avoiding high-impact loading on compromised bone.
Metabolic bone disease co-management, DXA interpretation, calcium/vitamin D optimization, differentiation from osteoporosis and other metabolic bone diseases.
Chronic musculoskeletal pain is the most prevalent adult HPP symptom. Multimodal pain management integrated with disease-modifying therapy.
Annual dental surveillance (62% prevalence), fracture management and surgical planning, neuropsychiatric symptom monitoring and treatment.
Sequence HPP was designed for patients and families living with hypophosphatasia — providing the structured, evidence-based clinical framework that adult HPP care has been missing.
Adult HPP care today is fragmented across endocrinology, rheumatology, orthopedics, and primary care — none of whom own the diagnosis. This program provides the missing organizational layer: a single clinical home where identification, diagnosis, treatment decision-making, and longitudinal monitoring follow a structured, evidence-based protocol.
Rather than ad hoc management, Sequence HPP builds the clinical infrastructure for systematic HPP care: standardized diagnostic workflows, structured treatment decision frameworks, validated outcomes collection at every encounter, multidisciplinary coordination protocols, and a longitudinal data architecture designed for real-world evidence generation.
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