What is the optimal management plan for a patient with hypophosphatasia (HPP) and hypermobile Ehlers‑Danlos syndrome (hEDS), including enzyme replacement therapy, calcium and vitamin D supplementation, physiotherapy, pain control, dental care, and orthopedic considerations?

Management of Hypophosphatasia with Hypermobile Ehlers-Danlos Syndrome

For a patient with both hypophosphatasia (HPP) and hypermobile Ehlers-Danlos syndrome (hEDS), enzyme replacement therapy with asfotase alfa is the primary treatment for HPP, while avoiding bisphosphonates and vitamin D supplementation, combined with comprehensive physical therapy and pain management strategies tailored to the joint hypermobility and connective tissue fragility of hEDS. 1, 2

Critical Contraindications in HPP

Avoid the following treatments in HPP patients, as they are explicitly contraindicated:

• Bisphosphonates 1
• Denosumab 1
• Potent antiresorptive agents 1
• Vitamin D supplementation 1

These medications worsen bone mineralization in HPP and should never be used, even though they are standard treatments for osteoporosis. 1, 3

Enzyme Replacement Therapy for HPP

Asfotase alfa is the definitive treatment for HPP, approved by the FDA in 2015, and should be initiated in patients with significant symptoms including fractures, musculoskeletal pain, respiratory insufficiency, or dental complications. 2

• Asfotase alfa replaces the deficient tissue non-specific alkaline phosphatase (TNSALP) enzyme 2
• It improves bone mineralization, respiratory function, and long-term survival with an excellent safety profile 2
• Early treatment results in severe forms are extremely encouraging 3

Calcium and Phosphate Management in HPP

Do not supplement with phosphate or active vitamin D in HPP patients, as the pathophysiology differs fundamentally from X-linked hypophosphatemia. 1, 3

• Monitor and adjust calcium and phosphate intake through diet only 3
• Ensure adequate nutritional calcium without supplementation 3
• The low alkaline phosphatase in HPP causes accumulation of pyrophosphate (PPi) and phosphorylated osteopontin, which inhibit bone mineralization—this is opposite to phosphate-wasting disorders 1

Monitor vitamin D levels to ensure they are not deficient, but do not actively supplement unless there is documented severe deficiency requiring correction. 3

Physical Therapy Approach for Combined HPP and hEDS

Physical therapy must be carefully tailored to address both the bone fragility of HPP and the joint hypermobility/instability of hEDS. 4, 2, 3

For HPP-specific considerations:

• Implement careful and personalized physical therapy to avoid fractures 3
• Focus on gentle strengthening without high-impact activities 2
• Regular monitoring to prevent non-traumatic fractures 2

For hEDS-specific considerations:

• Prioritize joint stabilization exercises over stretching (avoid excessive flexibility training) 4
• Focus on proprioceptive training to prevent dislocations 4
• Include occupational therapy for activities of daily living 4
• Emphasize muscle strengthening around hypermobile joints 4

The combination requires a conservative approach: avoid high-impact activities that could cause fractures (HPP concern) while building protective muscle strength around unstable joints (hEDS concern). 4, 2, 3

Pain Management Strategy

Use a multimodal pain control approach that avoids NSAIDs when possible due to potential effects on bone healing in HPP. 5, 4

• Consider short-term NSAIDs only for acute flares of joint pain or enthesopathies 5
• Implement psychological support and cognitive-behavioral approaches for chronic pain management 4
• Consider intra-articular joint infiltrations for degenerative changes 5
• Address anxiety disorders commonly associated with hEDS, as they exacerbate pain perception 4

For hEDS-related chronic pain and fatigue, emphasize self-management strategies and pacing techniques. 4

Dental Care Protocol

Regular dental monitoring and preventive care are essential in HPP due to premature tooth loss and dental complications. 1, 6, 3

• Schedule frequent dental evaluations to monitor for premature exfoliation of fully rooted teeth 1, 3
• Implement preventive strategies to avoid dental abscesses 6
• Coordinate with dentists familiar with HPP, as dental manifestations may be the presenting feature (odontohypophosphatasia subtype) 1

Orthopedic Considerations

Fracture management in HPP requires specialized orthopedic care due to impaired bone mineralization and delayed/non-healing fractures. 1, 2

• Ensure accurate fracture treatment with orthopedic surgeons experienced in metabolic bone disease 2
• Anticipate prolonged healing times and potential for non-union 1
• Avoid elective orthopedic procedures until HPP is optimally treated with asfotase alfa 2

For hEDS, orthopedic management focuses on preventing and managing recurrent joint dislocations and subluxations. 4

• Consider bracing or taping for unstable joints 4
• Surgical intervention for joint stabilization should be approached cautiously due to tissue fragility and poor wound healing in hEDS 4

Additional Systemic Considerations for hEDS

Address extra-articular manifestations of hEDS that significantly impact quality of life: 5, 4

• Evaluate and treat orthostatic intolerance/POTS with increased fluid and salt intake, compression garments, and exercise training 5
• Consider cardiology referral for pharmacological management if conservative measures fail 5
• Screen for functional gastrointestinal disorders and mast cell activation syndrome (MCAS) 5
• If MCAS is suspected, trial histamine receptor antagonists and mast cell stabilizers 5
• Implement dietary modifications (gastroparesis diet, low-FODMAP) with nutritional counseling to avoid restrictive eating 5

Monitoring Protocol

Establish regular multidisciplinary follow-up to monitor both conditions: 6, 3

• Serial alkaline phosphatase levels to assess HPP disease activity 6
• Radiological monitoring for fractures and bone mineralization 6
• Functional assessments of joint stability and mobility 4
• Quality of life assessments given the high symptom burden of both conditions 5, 4

Common Pitfalls to Avoid

Do not treat HPP like osteoporosis—bisphosphonates and vitamin D are contraindicated and will worsen outcomes. 1

Do not encourage excessive stretching or flexibility exercises in hEDS—this worsens joint instability. 4

Do not dismiss chronic pain and fatigue as psychosomatic—these are legitimate manifestations of both conditions requiring comprehensive management. 4

Do not delay referral to specialists familiar with these rare conditions—both HPP and hEDS are frequently misdiagnosed or diagnosed late. 1, 6