Welcome to the Part 2 of the 2022 HPP Case Discussion.
In October 2021- January 2022, insights on current perceptions and practice patterns were collected from specialists across Canada via a needs assessment questionnaire.
Key learning from the assessment relevant to this issue
- There is agreement that HPP symptoms can have a significant impact on QoL (84%)
To what extent do you agree with the following statements on disease burden and support:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]
- There is not a consistent/defined approach for evaluating burden of disease at most centres (69%)
Is there is a consistent/defined approach for evaluating burden of disease within your centre?
See the Appendix for more data gathered from the assessment on assessing burden of disease and treatment!
The intent of this 2-part series is to shed light on the education gaps identified through the assessment. Each issue includes a case study and provides additional information on best practices.
Part 1 explored the benefits and challenges with implementing family mapping in Canadian HPP practice.
Part 2 focuses on appropriate initiation of treatment based on clinical symptoms and consistent burden assessment.
Issue 1 can be accessed here: Click Here
We are pleased to have Dr. Aliya Khan (McMaster University) leading this initiative, with support from Dr. Sarah Khan, MD FRPC (Bone Research and Education Clinic (BREC) and Credit Valley Hospital).
What we learned in Part-1:
- HPP is a rare, potentially life-threatening inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene.
- Key diagnostic indicators include genetic variants of the ALPL gene, low age-specific serum ALP and increased levels of substrates (PPi, PLP, PEA) as well as the clinical features of HPP.
- Use of family mapping can improve identification of HPP and reduce delays in diagnosis and management.
- HPP has a heterogeneous presentation with wide-ranging severity.
HPP is a Multisystem Disease
HPP is a multisystem disease with deleterious effects that can appear at different ages and progress over time. Key features that can be present in children and adults are outlined in Table 1. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults.
Table. Key Features of HPP¹
The symptoms of HPP may not be recognized as being part of a constellation of features of a multisystem disease leading to delays in diagnosis and inappropriate treatment which may be harmful, such as bisphosphonate therapy. Bisphosphonate therapy in HPP can further lead to impairments in bone mineralization making the underlying osteomalacia worse.
Assessing Burden of Disease- Best Practices
Limited data on the disease burden on physical function and quality of life are available. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy.
Pharmacologic therapy is based on the severity of the HPP. The following case study, and subsequent discussion outlines appropriate initiation of treatment based on clinical symptoms and consistent burden assessment.
¹ Table adapted from Khan, Aliya & Josse, R. & Kannu, Peter & Villeneuve, J. & Paul, T. & van uum, Stan & Greenberg, C.R.. (2019). Hypophosphatasia: Canadian update on diagnosis and management. Osteoporosis International. 30. 10.1007/s00198-019-04921-y.
ID: 37-year-old female with hypophosphatasia
Past Medical History:
- Hypophosphatasia diagnosed at the age of 2 based on early tooth loss and delayed gross motor development and low ALP levels. She did not have any skeletal deformities or respiratory issues in infancy. DNA analysis confirmed HPP with heterozygous mutation in N400S in ALPL gene. No further treatment was provided, and patient was recently referred to endocrinology for evaluation.
Medications: escitalopram, iron, Vit D
Family History: Father has hypophosphatasia
Social History: Non-smoker, occasionally drinks alcohol, currently unemployed due to debilitating pain
Case: Her active symptoms included significant muscle weakness, gait instability and joint pains. Patient has been unable to stay employed due to ongoing fatigue and generalized pain. She had no history of fractures. Further clinical assessment revealed her quality of life to be significantly impacted as assessed in clinic by the SF-36 scoring system. She was only able to walk 450 m during the 6-minute walk test (for her age, weight, and height the expected walk should be at least 675 m). She rated her pain between 8-10 on the Wong-Baker FACES scale.
Her baseline labs were as follows:
Baseline bone density was normal. Skeletal X-rays did not show evidence of chondrocalcinosis but did reveal moderate mid-lower cervical kyphosis. No nephrocalcinosis noted on kidney ultrasound.
Given her significant MSK pain, poor mobility, and decreased quality of life she was started on asfotase alpha treatment.
Following initiation of enzyme replacement therapy, a significant improvement was noted in her mobility as well as a reduction in her chronic MSK pain. She was able to begin employment and reduce the dose of the SSRI that she was using for anxiety and depression. Her SF-36 scoring shows that she noticed a significant improvement in physical, emotional, social functioning as well as an improvement in her energy levels. Her Wong-Baker faces pain rating scale post-treatment was between 0-2 which was a significant improvement compared to her pre-treatment scores which were between 6-8.
Considerations for treatment initiation
The primary treatment for hypophosphatasia is enzyme replacement therapy (ERT) with asfotase alfa, a recombinant ALP enzyme replacement drug.
In 2015 the enzyme replacement therapy (ERT), asfotase alfa, was approved by Health Canada for use in patients of any age with pediatric-onset HPP. Access to asfotase alfa is determined by clinical criteria and varies from province to province.
Canadian recommendations advise that adults with HPP be considered for treatment with ERT in the presence of the following criteria¹:
- Osteomalacia and complications of osteomalacia
- Intractable musculoskeletal pain requiring or unresponsive to opioids.
- Presence of chondrocalcinosis with intractable pain
- Major osteoporotic fractures
- Delayed or incomplete fracture healing
- Individuals with significant impairment in function with impaired gait and mobility
Prior to initiation of treatment with ERT a confirmed diagnosis of HPP is required.
Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving treatment.
Considerations for assessing burden of disease
Limited evidence on the patient-reported burden of HPP and its impact on an individual’s HRQoL exists in the literature.
Data from the Global HPP Registry suggest that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset (i.e. pediatric vs. adult-onset) highlighting limitations of categorizing HPP by age of onset.²
The efficacy of ERT for HPP is assessed primarily based on improvements in clinical symptoms and manifestations of HPP.
The goals of therapy vary on the severity of the condition as well as the patients age. In perinatal and infantile patients the goal is to optimize respiratory status and control seizures. In children the goal is to improve growth and mobility and ensure that developmental milestones are being met. Oral health also must be evaluated and optimized. In adults the goal is to optimize bone mineralization and bone strength and prevent fractures as well as improve muscle function and mobility and control MSK pain.
Monitoring recommendations for patients with HPP vary by age.
It is recommended to evaluate the laboratory profile measuring calcium corrected for albumin, phosphate, 25OH vitamin D, PTH , CBC, ALT, ALP , creatinine, and 24-hour urine for calcium and creatinine at baseline. Following initiation of therapy the lab profile can be repeated at 2 weeks and then every 3 months for the 1st year.³
The substrates of TNSALP can be measured by evaluating vitamin B6 levels which reflect pyridoxal 5’phosphate (PLP) Urinary PEA can be measured commercially. Inorganic pyrophosphate PPi is not available commercially. The substrates of TNSALP are elevated prior to starting therapy with asfotase alfa. Following asfotase alfa therapy dramatic rises in ALP levels are seen up to several thousand units per liter. The substrates of TNSALP may not be detectable on asfotase alfa as the substrates are hydrolyzed in the test tubes on therapy.
Physical examination can be completed every 3 – 6 months evaluating muscle mass and muscle function as well as gait speed, timed up and go test, 6-minute walk test as well as growth velocity with monitoring of height, weight, BMI in children and head circumference and shape in infants.
Quality of life can be evaluated by the SF 36 scale at baseline and then again at 6-12 months after starting enzyme replacement therapy.
Skeletal x-rays are advised at baseline with repeat imaging at 3, 6, and 12 months in children. BMD is recommended by DXA assessment at baseline and then annually thereafter. Eye examination for ectopic calcification is recommended at baseline and this can be followed every 2 yrs. A renal US can be completed at baseline and can be repeated in 2-3 years evaluating nephrocalcinosis or occult nephrolithiasis.
Baseline and routine dental visits are recommended to assess for premature tooth loss, dental caries or abnormal dentition.
Treatment with asfotase alfa therapy in adults and adolescents with HPP showed reduction in the substrates of TNALP (PLP and PPi). Previous studies have shown that treatment improved walking ability, muscle strength and running speed in patients who received treatment compared to the control group. Adverse reactions to monitor for on treatment include injection site reactions, lipodystrophy, local skin discoloration, ophthalmic and renal ectopic calcifications.⁴
Upon treatment initiation patients should be monitored at each visit to assess for potential adverse events to treatment which include an accurate history that evaluates hypersensitivity reactions, signs, and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function and lipodystrophy.
For children <5 years of age periodic evaluations for craniosynostosis (including fundoscopy) are also recommended.
Additional recommended patient assessments are based on patient age and include monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life.³
Appendix: Needs Assessment Feedback – Burden of disease and treatment
The HPP needs assessment survey developed in collaboration with Dr. Aliya Khan was distributed to Canadian specialists with an interest/focus in the category.
Have you maintained management/treatment with any patients transitioning from pediatric over to adult?
If yes, on a scale of 1-5 how easy was this process?
[1 being difficult, 3 being neutral, 5 being easy]
Further explanation on barrier that exists with transition included:
- Identifying consistent primary care MDs for overall health
- lack of adult carers
Have you treated any HPP patients with STRENSIQ® (asfotase alfa)?
If yes, the percent that were pediatric vs. adult is as follows:
- All/100% pediatric (60% of responders to this question)
- 70% pediatric (20% of responders to this question)
- 20% pediatric (20% of responders to this question)
What do you perceive as the largest barriers/challenges with use of STRENSIQ® (asfotase alfa)?
- Cost/Access due to cost and coverage constraints/Funding (64%)
- Haven’t needed to access it yet. The issue with it will be that I deal with several provinces that have different mechanisms [for approval] (9%)
- Lack of clear guideline regarding use (9%)
- Approval for adult populations (9%)
- Lack of additional well controlled clinical trials (9%)
(Click on Images to Enlarge)
¹ Khan, Aliya & Josse, R. & Kannu, Peter & Villeneuve, J. & Paul, T. & van uum, Stan & Greenberg, C.R.. (2019). Hypophosphatasia: Canadian update on diagnosis and management. Osteoporosis International. 30. 10.1007/s00198-019-04921-y.
² Seefried, L., Dahir, K., Petryk, A., Högler, W., Linglart, A., Martos-Moreno, G.Á., Ozono, K., Fang, S., Rockman-Greenberg, C. and Kishnani, P.S. (2020), Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry. J Bone Miner Res, 35: 2171-2178. https://doi.org/10.1002/jbmr.4130
³ Kishnani PS, Rush ET, Arundel P, Bishop N, Dahir K, Fraser W, Harmatz P, Linglart A, Munns CF, Nunes ME, Saal HM, Seefried L, Ozono K. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017 Sep;122(1-2):4-17. doi: 10.1016/j.ymgme.2017.07.010. Epub 2017 Jul 25. PMID: 28888853.
⁴ Kishnani PS, Rockman-Greenberg C, Rauch F, Bhatti MT, Moseley S, Denker AE, Watsky E, Whyte MP (2019) Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 121:149–162
Support for this case series is provided by Alexion, AstraZeneca Rare Disease.