Abstract
Hypophosphatasia (HPP) is a rare inherited bone disorder with systemic symptoms, which vary depending on the time of onset and other factors. It may be fatal or cause severe clinical symptoms in infants and children. By comparison, adult HPP generally has a more favorable prognosis, and it is usually associated with chronic pain, recurrent fractures, and impaired quality of life. However, the diagnosis of adult HPP is often delayed or it may remain undiagnosed. Additionally, treatment options for adult HPP are not well established. We report a male patient in his 50s who experienced recurrent fractures in his 40s and 50s, together with chronic pain. He was diagnosed with HPP due to low serum alkaline phosphatase levels and a heterozygous missense variant of the ALPL gene (c.529G>A). He therefore started enzyme replacement therapy with asfotase alfa. After 12 months of treatment with asfotase alfa, his motor function showed marked improvement and he experienced fewer falls and no new fragility fractures, although his chronic pain remained.
Keywords: adult hypophosphatasia, alkaline phosphatase, asfotase alfa, recurrent fracture
Introduction
Hypophosphatasia (HPP) is a rare inherited bone disorder characterized by low serum alkaline phosphatase (ALP) levels and impaired bone mineralization due to loss-of-function variants in the ALPL gene, which encodes tissue-nonspecific ALP. The clinical presentation of HPP is highly variable. The perinatal and infant types are commonly associated with severe clinical symptoms and can be fatal, whereas adult HPP is generally milder with varying clinical presentations [1], often resulting in delayed diagnosis or even misdiagnosis [2, 3]. Common symptoms in adults include chronic pain, muscle weakness/pain, poor fracture healing, and recurrent fracture [4, 5], and these symptoms often develop and worsen with disease progression [6]. Long-term use of bisphosphates, especially among patients with atypical fractures, may also hide underlying HPP [7-9]. For these reasons, it is important to differentiate adult HPP from other bone metabolic diseases, especially osteoporosis [10]. The diagnostic criteria for adult HPP, which include several major and minor criteria, can facilitate its diagnosis [1].
We report a male patient in his 50s who was diagnosed with adult HPP following recurrent fractures and was subsequently treated with asfotase alfa. Our objective with this case report is to highlight the difficulty of diagnosing adult HPP. We also describe the clinical efficacy of asfotase alfa in a patient with adult HPP. Asfotase alfa has been reported to show good clinical efficacy in terms of quality of life (QOL), motor functions, and bone mineralization in adult HPP [11-13]. Asfotase alfa is approved for HPP regardless of age at first manifestation, including adults, in Japan [14], but it is only approved for pediatric-onset HPP in other countries. Consequently, there is limited experience of using asfotase alfa for treating adult HPP.
Case Presentation
This case was a male in his 50s with a body mass index of 32.0 kg/m2 who had been visiting our endocrinology clinic for the management of his type 2 diabetes from the age of 53 or 54 years. After about 1 year, he disclosed, for the first time, that he experienced a fracture of his left 7th rib at the age of 55 years. In a subsequent medical interview, he revealed that this was his fourth rib fracture and that he had experienced 3 previous rib fractures from the age of 45 years along with multiple falls and chronic pain (Table 1). He had experienced several prior fractures, which were treated at orthopedic surgery departments at other hospitals, but no clinical information was available.
Table 1.
Chronology of the patient
| Patient age (by decade) | Fracture sites | Causes | Pain | Other notes |
|---|---|---|---|---|
| 10–19 years | Left forearm Left elbow Left metatarsals Right metatarsals |
Judo practice Soccer practice Stress fracture Motorcycle fall |
− | No information |
| 20–29 years | Left clavicle | Traffic accident | − | No information |
| 30–39 years | None reported | None reported | − | Deafness |
| 40–49 years | Rib (#1) Rib (#2) |
Frequent falls | + | Diabetes |
| 50–59 yearsa | Left 7th rib (#3) Left 4th toe Left 12th rib (#4) & L1–L3 transverse processes |
Frequent falls | ++ | Suspicion of HPP |
Abbreviation: HPP, hypophosphatasia.
a The patient first attended our endocrinology department at 53–54 years old for the management of his diabetes. At the age of 55 years, we suspected HPP based on his medical history and clinical features. A more detailed timeline is shown in Fig. 1.
The patient's medical history included clinical bilateral sensorineural hearing loss, which first developed in his 30s; chronic hepatitis C infection due to stimulant drug injections around 20 years of age, in sustained virological response with interferon and antiviral agents; coronary intervention for acute coronary syndrome at the age of 49 years; sleep apnea syndrome, dyslipidemia, and hypertension; and 4 or 5 episodes of bilateral ankle arthralgia and possible diagnosis of gout, which we suspected to be pseudogout. His dental history was normal, with no history of premature loss of deciduous teeth and no episodes of dental treatment.
Owing to a low 25-hydroxyvitamin D level of 52.17 nmol/L (20.9 ng/mL) (normal range 49.92–74.63 nmol/L [20.0–29.9 ng/mL]), our patient had been taking vitamin D3 (1000 units/day) for 1.5 years. Other medications included semaglutide (0.5 mg/week), metformin (2000 mg/day), empagliflozin (10 mg/day), aspirin (100 mg/day), vonoprazan (10 mg/day), atorvastatin (20 mg/day), ezetimibe (10 mg/day), pemafibrate (0.2 mg/day), azilsartan (40 mg/day), nifedipine (40 mg/day), allopurinol (200 mg/day), and ursodeoxycholic acid (300 mg/day).
The patient's lifestyle factors included a history of smoking (5 cigarettes/day; 8.75 pack-years from 20 to 55 years old) and alcohol consumption (3 times/week and 40 g/drink).
The family medical history consisted of diabetes and bile duct cancer in the patient's father. There was no family history of fracture.
Diagnostic Assessment
At the age of 55 years, approximately 10 years after his first fracture in adulthood, the patient was suspected of having HPP considering his fourth rib fracture and prolonged low ALP levels (Fig. 1). Since his first visit to the endocrinology department at our hospital, he experienced fragility fractures due to 3 falls. The left 7th rib fracture that initially raised our suspicion of HPP was followed by a left 4th toe fracture due to a fall, and L1–L3 transverse process fractures and a left 12th rib fracture due to another fall. His health was complicated by chronic pain. His recurrent fractures, particularly over the previous 2 years, led to a temporary decline in activities of daily living, absence from work, and frequent visits to orthopedic surgery departments, and had persistent effects on daily life.
Figure 1.
Evolution of ALP levels prior to and during treatment with asfotase alfa. Serum ALP levels are shown on a logarithmic-scale axis.
Abbreviations: ALP, alkaline phosphatase; HPP, hypophosphatasia.
The laboratory test results, including bone markers, were generally within normal ranges and his glycated hemoglobin (HbA1c) was well controlled (50 mmol/mol; 6.7%; normal range 27–44 mmol/mol [4.6%–6.2%]). The 25-hydroxyvitamin D level was elevated (79.62 nmol/L; 31.9 ng/mL; normal range 49.92–74.63 nmol/L [20.0–29.9 ng/mL]) due to vitamin D supplementation. However, his serum ALP was low (0.55 μkat/L [33 U/L]; normal range 0.63–1.89 μkat/L [38–113 U/L]) and his calcium level was elevated at 2.48 mmol/L (9.9 mg/dL; normal range 2.13–2.63 mmol/L [8.5–10.5 mg/dL]). Dual energy x-ray absorptiometry revealed bone mineral density T-scores of −1.4 for femoral neck, −0.9 for total hip, and −1.3 for lumber spine (L1–L4). 99mTechnetium bone scintigraphy (Fig. 2) revealed abnormal uptake in a left rib, which was considered to be a post-traumatic reaction. Hotspots were also visible on left margins of lumbar vertebrae L1, L4, and L5 (1 month after the fracture) that were indicative of increased uptake due to osteophytes, and in the bilateral ankle joints that were considered to be due to arthropathy. Magnetic resonance imaging revealed fractures of the left 12th rib and transverse process fractures of L1–L3, which were probably due to a fall. No evidence of renal calcification or urolithiasis was observed on computed tomography. Overall, the laboratory tests and imaging did not indicate any primary diseases that could cause secondary osteoporosis or conditions that could cause low ALP levels.
Figure 2.
Bone scintigraphy at 3 hours after administration of 99mTc-hydroxymethylene diphosphonate (830 MBq). The radiology report indicated a hotspot on the lateral side of the left 7th rib, indicative of a post-traumatic reaction (arrow on anterior view); and hotspots on the left margins of the first, fourth, and fifth lumbar vertebrae (arrows on posterior view) indicative of increased uptake due to osteophytes. Other hotspots included bilateral ankle joints that were consistent with arthropathy (arrows on both views), and in the jaw that were consistent with tooth decay or periodontitis (arrow on anterior view).
Abbreviations: L, left; R, right.
Because the ALP level was decreased but the levels of ALP substrates (blood pyridoxal 5′-phosphate [PLP], blood pyridoxal [PL], and urine phosphoethanolamine [PEA]) were within normal ranges, we decided to perform genetic testing of the ALPL gene. This revealed a heterozygous missense variant in ALPL, c.529G>A p.Ala177Thr, which was previously reported to be pathogenic in the ALPL Gene Variant Database [15] (https://alplmutationdatabase.jku.at/). The patient satisfied the diagnostic criteria proposed by the HPP International Working Group [1] with 2 major criteria (ALPL gene variant and recurrent metatarsal fractures) and 1 minor criterion (chronic musculoskeletal pain).
Treatment
Following diagnosis of HPP, subcutaneous injection of asfotase alfa was started at a dose of 80 mg (1.0 mg/kg), 6 times/week. The administration of vitamin D3 was continued during asfotase alfa treatment.
Outcome and Follow-Up
At the most recent follow-up, the patient had been continuing treatment with asfotase alfa for 12 months and reported no adverse events. During this time, there were marked increases in his ALP levels, as an expected effect of asfotase alfa, demonstrating success of self-injection and good adherence (Fig. 1). PEA slightly decreased, and both PLP and the PLP/PL ratio, which were initially within the reference ranges, also decreased (Table 2). After starting treatment with asfotase alfa, he experienced one fall without a resulting fracture (Table 2). His motor function also improved. He was able to walk 70 m further in the 6-minute walk test (6MWT) compared with the distance before starting asfotase alfa. There was also an improvement in the 36-item Short Form Health Survey (SF-36) scores for physical functioning. There were no notable changes in bone mineral density or trabecular bone score during this time. He also reported that his chronic pain, which mainly involved the trunk, had improved slightly. The visual analog scale score for pain improved, although the SF-36 item for bodily pain deteriorated (Table 2).
Table 2.
Changes in blood biochemistry, motor function, bone mineral density, pain, and SF-36 scores during 12 months of treatment with asfotase alfa
| Outcome | Before treatment | After 3 months of treatment | After 6 months of treatment | After 12 months of treatment | Reference range |
|---|---|---|---|---|---|
| Serum ALPa | 0.55 μkat/L (33 U/L) |
126.92 μkat/L (7600 U/L) |
103.44 μkat/L (6194 U/L) |
78.49 μkat/L (4700 U/L) |
0.63–1.89 μkat/L (38–113 U/L) |
| BAP | 7.9 μg/L | ND | ND | 773 μg/L | 3.7–20.9 μg/L |
| Urine PEA (inpatient department)b | 72.0 μmol/day | ND | ND | ND | 31.0–110.0 µmol/day |
| Urine PEA (outpatient department)c | ND | ND | ND | 55.8 μmol/gCr | N/Ad |
| Blood PLP | 35.9 nmol/L | ND | ND | 10.6 nmol/L | 20.5–151 nmol/L |
| Blood PL | 14 nmol/L | ND | ND | 18.1 nmol/L | 8.8–58.7 nmol/L |
| PLP/PL ratio | 2.6 | ND | ND | 0.6 | N/Ad |
| Number of falls over previous 3 months | One fall (vertebral fracture) |
None | One fall (no fracture) |
None | N/Ad |
| 6-minute walk test | 473 m | 513 m | 533 m | 543 m | N/Ad |
| Timed Up and Go test | 5.00 seconds | 6.45 seconds | 5.03 seconds | 6.03 seconds | N/Ad |
| Grip strength (R/L) | 32.5/31.5 kg | 37/29 kg | 32.5/32.5 kg | 34.5/31.5 kg | N/Ad |
| BMD | |||||
| Lumbar spine | 0.843 g/m2 | 0.814 g/m2 | 0.848 g/m2 | 0.825 g/m2 | N/Ad |
| Femoral neck | 0.686 g/m2 | 0.699 g/m2 | 0.705 g/m2 | 0.694 g/m2 | N/Ad |
| Total hip | 0.782 g/m2 | 0.760 g/m2 | 0.806 g/m2 | 0.784 g/m2 | N/Ad |
| TBS | 1.169 | 1.163 | 1.118 | 1.124 | N/Ad |
| VAS for paine | 42 mm | 32 mm | 30 mm | 30 mm | N/Ad |
| SF-36 scores | |||||
| Physical functioning f | 85 | ND | ND | 95 | N/Ad |
| Role physical f | 87.5 | ND | ND | 100 | N/Ad |
| Bodily pain f | 62 | ND | ND | 51 | N/Ad |
| General health f | 35 | ND | ND | 35 | N/Ad |
| Vitality f | 62.5 | ND | ND | 56.3 | N/Ad |
| Social function f | 100 | ND | ND | 75 | N/Ad |
| Role emotional f | 100 | ND | ND | 100 | N/Ad |
| Mental health f | 70 | ND | ND | 65 | N/Ad |
| PCSg | 38.5 | ND | ND | 46.2 | N/Ad |
| MCSg | 46.7 | ND | ND | 39.9 | N/Ad |
Abbreviations: ALP, alkaline phosphatase; BAP, bone alkaline phosphatase; BMD, bone mineral density; L, left; MCS, mental component summary; N/A, not applicable; ND, no data (not measured); PCS, physical component summary; PEA, phosphoethanolamine; PL, pyridoxal; PLP, pyridoxal 5′-phosphate; R, right; SF-36, 36-item Short Form Health Survey; TBS, trabecular bone score; VAS, visual analog scale.
a Serum ALP was recorded in conventional units and converted to International System (SI) units using the online calculator at: https://academic.oup.com/amamanualofstyle/si-conversion-calculator.
b Measured at an inpatient department.
c Measured at an outpatient department.
d A normal/reference range has not been established.
e Measured using a 100 mm scale, where 100 mm represents the maximum level of pain.
f The score range is 0–100 points, where higher scores indicate better health status.
g The average score for the Japanese population is 50 points.
Discussion
This patient had a history of fractures in his teens and early 20s related to trauma/sports injuries, but no obvious symptoms of HPP in adolescence. However, during and after middle age, he experienced recurrent falls and fragility fractures, a sign of HPP. The disease activity in adult HPP patients is known to fluctuate over time, and early diagnosis and regular follow-up, even in asymptomatic patients, are needed to reach a diagnosis of HPP. Recently, the HPP International Working Group proposed diagnostic criteria for HPP in adults [1], and a major criterion is elevated levels of tissue-nonspecific ALP substrates. However, elevated levels of ALP substrates were not evident in our case, and he did not experience premature loss of deciduous teeth. Upon reviewing his medical records, we found he had persistently low serum ALP levels, recurrent fractures, chronic pain, sensorineural hearing loss, and pseudogout, which are common symptoms and highly indicative of HPP. The high frequency of falls was also unusual for the patient's age.
Genetic testing revealed a heterozygous missense variant of the ALPL gene, c.529G>A [15]. Although this variant was classified as pathogenic, the Nagahama study (a Japanese cohort study) detected c.529G>A in 1.07% of subjects and the ALP activity was significantly lower in subjects with the heterozygous variant than in those with wild-type ALPL [16]. In several prior cases of suspected HPP, c.529G>A was detected as a compound heterozygote variant [17, 18]. Considering the existing evidence, reduced ALP activity may not be fully explained by the heterozygous variation, c.529G>A. Accordingly, another modifier might contribute to the decrease in ALP activity in our case. Additionally, the clinical phenotype may not be fully predictable by the genotype.
Untreated adult HPP is associated with marked worsening of QOL, regardless of the timing of onset [19], and treatment with asfotase alfa was reported to improve QOL and motor functions [11, 20]. Asfotase alfa is also associated with improved bone mineralization and healing of fractures [12, 13], which is related to increased bone density [12], improved structural bone quality [21], and histological bone mineralization [22]. Over 12 months of treatment with asfotase alfa, our patient showed an improvement in motor function with fewer falls and no additional fractures, although his pain persisted. Notably, he could walk 70 m further during the 6MWT, exceeding the minimum clinically important difference of 31 m per year for adults and adolescents [23]. This is similar to an earlier study of adults in which the median 6MWT distance increased significantly from 267 to 320 m (P = .023) [20]. An improvement in the Timed Up and Go test, as an indicator of the risk of falls, was reported in younger patients, but the mechanisms remain unknown [19, 20]. Improvements in symptoms and mobility were also reported in a female in her 50s who was diagnosed with adult-onset HPP and started treatment with asfotase alfa [24]. Overall, these findings suggest that the improvement in motor function in our patient was clinically relevant.
In conclusion, adult HPP is difficult to diagnose, and treatment options are not well established. Here, we have described a patient who was diagnosed with adult HPP following recurrent falls and fractures during and after middle age, low serum ALP levels, and presence of a heterozygous missense variant of the ALPL gene (c.529G>A). The patient commenced treatment with asfotase alfa, leading to an increase in ALP together with an improvement in motor function with fewer falls and no new fractures, although his pain persisted. Low serum ALP levels and unexpected fragility fractures are potential signs of adult HPP, and clinicians should suspect HPP in adults with history of repeated minor fractures. Asfotase alfa is an important treatment for adult HPP, although the cost is substantially high. The potential candidates for asfotase alfa, optimal duration of treatment, and treatment goals in patients with adult HPP have not yet been defined and need to be investigated in the future.
Learning Points
It is challenging to diagnose HPP in adults. Recurrent fracture and low ALP levels are common features and included in the diagnostic criteria.
Genetic testing of the ALPL gene plays an important role in confirming diagnosis of HPP in suspected cases.
Enzyme replacement therapy with asfotase alfa is effective in patients with adult HPP, although further evidence needs to be accumulated.
Acknowledgments
The authors wish to thank the patient for agreeing to publication of this case report, and the healthcare team who supported this patient. The authors are grateful to Mitsuko Kudo for her technical support. The authors would like to thank Nicholas D. Smith of EMC K.K. for providing medical writing assistance, funded by Alexion Pharma GK. Alexion provided scientific accuracy review of their data; however, authors retain control and final authority of publication content and decisions, including the choice of journal.
Abbreviations
- 6MWT
6-minute walk test
- ALP
alkaline phosphatase
- HPP
hypophosphatasia
- PEA
phosphoethanolamine
- PL
pyridoxal
- PLP
pyridoxal 5′-phosphate
- QOL
quality of life
- SF-36
36-item Short Form Health Survey
Contributor Information
Reiko Inoue, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara-shi, Chiba 299-0111, Japan.
Kota Ishizawa, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara-shi, Chiba 299-0111, Japan.
Yuria Takamura, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara-shi, Chiba 299-0111, Japan.
Fukuo Kosokabe, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara-shi, Chiba 299-0111, Japan.
Koji Takeuchi, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara-shi, Chiba 299-0111, Japan.
Daisuke Inoue, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara-shi, Chiba 299-0111, Japan.
Contributors
All authors made individual contributions to authorship. R.I., K.I., F.K., K.T., and D.I. were involved in the diagnosis and management of the patient. R.I., Y.T., and D.I. were involved in the treatment of the patient. R.I. and D.I. were involved in the manuscript submission. All authors reviewed and approved the final draft.
Funding
No public or commercial funding.
Disclosures
D.I. has received honoraria from Daiichi Sankyo, Teijin Pharma, and Amgen. D.I. is an Editorial Board Member for JCEM Case Reports and played no role in the Journal's evaluation of the manuscript. R.I., K.I., Y.T., F.K., and K.T. have no conflicts of interest to be disclosed. Alexion Pharma GK provided scientific accuracy review of the data; however, authors retain control and final authority of publication content and decisions, including the choice of journal.
Informed Patient Consent for Publication
Signed informed consent was obtained directly from the patient.
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.