Successful treatment using asfotase alfa for delayed healing of a metatarsal stress fracture in an adolescent girl with hypophosphatasia

Abstract

Background

Hypophosphatasia (HPP) is a rare metabolic bone disorder that can present with a wide spectrum of skeletal and extraskeletal signs and symptoms. Biochemically, HPP is characterized by a decreased activity of the tissue nonspecific alkaline phosphatase (TNSALP) and subsequent accumulation of inorganic pyrophosphate (PPi). Fractures in patients with HPP can show delayed healing or even progress to nonunion. In pediatric patients, fractures can be particularly debilitating, as children usually engage in high levels of physical activity.

Case presentation

The 16-year-old girl, carrying a pathogenic variant in the ALPL gene, presented 17 weeks (4 months) after the initial diagnosis of a fracture at the base of the fifth metatarsal (MT-V). The patient was still symptomatic, and magnetic resonance imaging and cone beam computed tomography (CBCT) showed no radiological signs of healing despite immobilization. Given the prolonged absence of fracture consolidation, TNSALP enzyme replacement therapy with asfotase alfa (AA) was initiated and dosed according to body weight, in line with approved pediatric regimens. Thirteen weeks after initiation of AA, CBCT demonstrated full radiological consolidation. Furthermore, bone mineral density (BMD) in the fracture gap increased by 36%, returning to the average BMD level of the MT-V.

Conclusion

Here we present, to the best of our knowledge, the first pediatric case in which treatment with AA supported healing of a delayed union stress fracture in the context of clinically diagnosed and genetically supported HPP. Our findings support considering AA initiation in pediatric patients diagnosed with HPP who present delayed fracture healing despite standard conservative management.

Introduction

Hypophosphatasia (HPP) is a rare metabolic disease that can cause a wide range of predominantly musculoskeletal symptoms due to (likely) pathogenic variants in the ALPL gene according to ACMG (American College of Medical Genetics and Genomics) classification [1]. These variants lead to reduced activity of tissue-nonspecific alkaline phosphatase (TNSALP), which consequently causes the accumulation of its substrates, predominantly inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP), and phosphoethanolamine (PEA) [2]. PPi is a potent inhibitor of hydroxyapatite formation and therefore disturbs bone mineralization [3], contributing to the dento-osseous manifestations of HPP, including rickets or osteomalacia, calcific arthropathies, and premature tooth loss [1, 4]. Furthermore, this inhibitory effect of PPi on mineralization can impair fracture healing, potentially leading to delayed union or even nonunion, which can also be present in pediatric and adolescent patients [3, 5–8]. These complications of fracture healing can severely affect the quality of life of the affected patients.

Several treatment options are available for treating delayed unions or nonunion including pharmacological, biophysical, and surgical interventions. Medications described in the context of impaired mineralization and delayed fracture healing in HPP include enzyme replacement therapy with asfotase alfa (AA), a modified recombinant variant of TNSALP, or a PTH analog, namely teriparatide [6, 9–11]. AA has been shown to significantly improve skeletal mineralization in pediatric patients and to promote fracture healing in adults with HPP [10, 12, 13]. While improved functional and radiographic skeletal outcomes in pediatric patients treated with AA have been well documented, reports specifically addressing delayed stress fracture healing in pediatric or adolescent patients remain limited, and monitoring of fracture healing in adolescents using cone beam computed tomography (CBCT) has not been described [14]. Here, we present the case of a 16-year-old girl with genetically supported diagnosed HPP who, despite adequate immobilization, showed no clinical or radiographic signs of fracture healing 17 weeks (4 months) after fracture of the fifth metatarsal (MT-V). Given the absence of fracture consolidation, AA was initiated. Treatment response was monitored through clinical and laboratory assessments, as well as CBCT, which was also applied to quantify local changes in bone mineral density (BMD).

Case information

A 16-year-old girl with previously diagnosed HPP and a heterozygous pathogenic ALPL variant (c.(−105 + 1_−104–1)_(61 + 1_62-1)del (ACMG class V)) presented 4 months after the initial diagnosis of a fracture at the base of the right MT-V following a supination injury during normal daily activity. The patient was still symptomatic and troubled by the persistent immobilization with a short walker ankle–foot orthosis and ambulation with crutches. Magnetic resonance imaging and CBCT showed no radiological signs of healing (Fig. 1A).

Fig. 1.

Radiological follow-up and BMD quantification of a fifth metatarsal stress fracture in an adolescent girl with HPP under enzyme replacement therapy with asfotase alfa. A CBCT at week 17 (4 months) after fracture shows a persistent fracture gap without signs of callus formation or bridging, consistent with delayed union. B CBCT at week 30 (7 months), following 13 weeks of asfotase alfa therapy, shows complete consolidation of the fracture. C Quantitative measurement of BMD based on CBCT. BMD was measured within the fracture gap (brown) and in the adjacent intact region of the fifth metatarsal (beige). The precise regions are marked in the same colors on the 3D reconstruction image of MT-V. Duration of asfotase alfa treatment is indicated in green; the timepoint of fracture occurrence is marked by a dashed red line. Abbreviations: BMD, Bone mineral density; CBCT, cone beam computed tomography; HA, hydroxyapatite; HPP, hypophosphatasia; MT-V, fifth metatarsal

In addition to this delayed-healing fracture, her medical history included atraumatic skeletal lesions, comprising a stress fracture at the base of the left MT-III with delayed healing of 6 months, bone marrow edema at the left distal fibula, and bone marrow edema of the sesamoid bone of the right foot. Further findings comprised molar-incisor hypomineralization, slightly reduced grip force, and decreased bone mineral density (BMD) with a corresponding Z-score of − 2.2 at the lumbar spine, while height was normal for age at 167 cm, approximately the 75th percentile. Taken together, these manifestations are consistent with the musculoskeletal phenotype observed in HPP.

Given the persistently reduced alkaline phosphatase activity and persistently elevated pyridoxal 5′ phosphate levels (Fig. 2) together with the musculoskeletal phenotype and the absence of fracture consolidation over 4 months, TNSALP ERT with asfotase alfa was initiated and dosed according to body weight (1 mg/kg) and administered six times per week in line with approved pediatric regimens. The patient reported transient side effects of nausea and mild headache lasting about 30 min after the injection. At the patient’s request, therapy is currently being continued, however, if no further metatarsal stress fractures occur, treatment may be paused in the future.

Fig. 2 .

Biochemical response to enzyme replacement therapy in an adolescent girl with hypophosphatasia and delayed union after a fifth metatarsal stress fracture of the right foot. Fracture timepoint (red dashed line); individual measurements of laboratory parameters (blue); age- and sex-specific reference ranges (shaded grey areas); asfotase alfa treatment (green). Abbreviations: ALP, alkaline phosphatase; Bone ALP, bone-specific alkaline phosphatase; P1NP, procollagen type 1 N-terminal propeptide; PLP, pyridoxal-5′-phosphate; 25-OH-D, 25-hydroxyvitamin D; β-CTX, β-crosslaps

At the follow-up visit 30 weeks (7 months) after the initial diagnosis of the proximal MT-V fracture and 13 weeks after initiation of AA, CBCT demonstrated full radiological consolidation (Fig. 1B). Furthermore, we were able to show that BMD in the fracture gap increased by 36%, returning to the average BMD level of her MT-V (Fig. 1C). Notably, the patient experienced complete clinical resolution of symptoms, with no residual pain or functional limitation related to the MT-V fracture and discontinued concomitant conservative therapy once symptoms had significantly improved. In line with the administration of AA, laboratory parameters showed a marked increase in TNSALP and bone-specific ALP (Fig. 2). In parallel, levels of PLP decreased (Fig. 2), while other bone turnover markers remained essentially unchanged. As the determination of PPi levels is not available in the standard test panel of our hospital’s clinical chemistry department, where all serum parameters were determined, it was not assessed. Nevertheless, the reduction in the substrate PLP suggests a similar decrease in PPi levels, given the established correlation of both parameters [14–16].

Discussion

Increased fracture risk and prolonged bone healing are relatively common characteristics of HPP patients [4, 7, 8, 10, 18]. Therefore, effective treatment for delayed union and nonunion in patients diagnosed with HPP is essential. While the beneficial effects of AA on fracture healing have been reported in adult patients with delayed union and nonunion [10, 13], its impact specifically on delayed stress fracture healing in pediatric and adolescent patients has not yet been described.

Here, a 16-year-old patient with a genetically supported HPP diagnosis exhibited a delayed union of an MT-V fracture with no signs of consolidation after 4 months of immobilization. Exact numbers for delayed union or non-union of fractures are hard to find in the literature, but it seems to be a relevant problem as “recurrent and poorly healing fractures” were documented in 36.5% of HPP patients in the global HPP registry [19]. So, probably, recurrent metatarsal stress fractures that eventually fail to heal may not be a rare finding in patients with HPP [7]. This may indicate that certain skeletal sites, such as the metatarsals, may be predilected for fractures in HPP. Therefore, therapies targeting the underlying biochemical alterations may be beneficial for treating such fractures. Following initiation of AA, BMD within the fracture gap increased to levels close to the surrounding intact bone (MT-V), indicating complete fracture consolidation. In addition, clinical recovery to the patient’s previous level of activity further supports the functional relevance of this BMD increase. Considering the preceding prolonged period without signs of fracture healing, this suggests a significant treatment-associated effect. During the therapy with AA, the laboratory parameters changed as expected, with large increases in ALP and bone-specific ALP due to the exogenous supplementation and consequently a reduction of one of the substrates, PLP. PLP is a sensitive and specific biochemical marker for hypophosphatasia and generally reflects the severity of the disease [15–17]. It can therefore be assumed that levels of PPi, another substrate of TNSALP and a potent inhibitor of mineralization, also decreased [15–17]. The accumulation of PPi likely played a role in the disturbed fracture healing, as it impairs hydroxyapatite formation, which is essential for the mineralization of newly formed osteoid within the fracture gap. Therefore, it is highly likely that the enzymatic activity of TNSALP reestablished by AA was essential for successful fracture healing and preventing nonunion. This is further supported by the rapid mineralization observed in the fracture region, suggesting that previously unmineralized osteoid was able to mineralize once the inhibitory effect of excess circulating PPi was diminished [3, 7, 10].

From a clinical perspective, in pediatric HPP with a fracture that shows little radiographic progression at 6 to 8 weeks, particularly if the patient presents a medical history of recurrent stress fractures, initiation of AA can be carefully considered if all regulatory prescription criteria are fully met. However, not every patient with HPP and a fracture necessarily requires treatment with AA. The presence of additional HPP-related symptoms and the overall severity of the disease should also be taken into account. A targeted, highly individualized approach could be considered for patients with HPP who have a history of delayed union or recurrent (metatarsal) stress fractures. Normally, AA treatment is lifelong, but the optimal treatment duration for fracture consolidation remains unknown, and decisions should be individualized, as the risk of recurrent stress fractures after discontinuation is also unclear [20].

In conclusion, this case highlights the potential positive effects of AA on fracture healing in a pediatric patient with HPP and delayed union. Our findings support considering the initiation of AA in pediatric patients diagnosed with HPP who present delayed union despite standard conservative management. Given the underlying biochemical alterations caused by TNSALP deficiency, AA may be essential to restore physiological bone healing and prevent progression to nonunion. Nevertheless, additional studies are needed to clarify the process of fracture healing in HPP, particularly under treatment with AA.

Author contribution

Oskar Windels: data curation; formal analysis; investigation; writing-original draft; writing—review and editing. Alexander Simon: data curation; formal analysis; investigation; writing-original draft; writing—review and editing. Nicole Muschol: writing—review and editing. Timur Yorgan: conceptualization; investigation; project administration; supervision; writing-original draft; writing—review and editing. Florian Barvencik: conceptualization; investigation; project administration; supervision; writing-original draft; writing—review and editing.

Funding

Open Access funding enabled and organized by Projekt DEAL. This project has received funding from the Deutsche Forschungsgemeinschaft (DFG), Clinical Research Unit CFU 5029, Precision Medicine for Early-Onset Low Bone Mineral Density Disorders (517063424).

Data availability

The datasets analyzed and presented in this study are available from the corresponding author upon reasonable request. Restrictions may apply due to data privacy of patient data.

Declarations

Ethics approval

This study has been performed in accordance with the 1964 Declaration of Helsinki and its later amendments, and approval for this project was obtained from the local ethics committee (Ethikkomission der Ärztekammer Hamburg, PV5364).

Patient consent

Written informed consent was obtained from the patient.

Conflict of interest

AS and TY state that they have no conflict of interest. NM has received travel support, consulting fees and/or honoraria from Amicus, BioMarin Pharmaceutical, Chiesi, GC Biopharma, JCR Pharmaceuticals, Sanofi Genzyme, Takeda, Ultragenyx, and Regenxbio. OW has received a travel grant from Inozyme, FB has received honoraria, served as a speaker, and acted as a consultant for Alexion, Diasorin, Blueprint Medicines (Germany) GmbH, UCB, and FOMF GmbH Forum für medizinische Fortbildung, and has received institutional research grants from Alexion and UCB.