Title

Breaking point: Unmasking Hypophosphatasia in a Patient with Recurrent Fractures Resistant to Therapy

Authors

Yesol Oh, MD., Jacob D. DeMott, MD., Sonia I. Bennett, MD, MPH.

Introduction

Hypophosphatasia (HPP) is a rare genetic disorder caused by mutations in the ALPL gene, leading to defective bone and teeth mineralization due to low levels of tissue nonspecific alkaline phosphatase (TNAP) [1]. HPP demonstrates a broad clinical spectrum, ranging from in utero death to asymptomatic presentations in adulthood. Infants and children typically present with skeletal, respiratory, and neurological complications associated with TNAP deficiency, whereas adults more commonly exhibit recurrent fractures, poor bone healing, and arthropathies [2]. Elevated vitamin B6 levels and low serum alkaline phosphatase (ALP) levels can assist in diagnosing HPP, and over 400 ALPL gene mutations have been identified [3]. Treatment strategies for HPP differ significantly from those for osteoporosis, as bisphosphonates, a standard therapy for osteoporosis, are not only ineffective in HPP but may also exacerbate the condition. In this case, we discuss a patient with history of multiple fractures and worsening BMD despite aggressive treatment with various medications. Genetic testing confirmed the diagnosis of HPP, enabling the patient to receive appropriate, targeted therapy.

Case Presentation

A 75-year-old female with a history of scoliosis and multiple fractures since childhood presented to the endocrinology clinic for management of her osteoporosis. Despite years of treatment with conventional osteoporosis therapies, including bisphosphonates, teriparatide, and denosumab, she continued to experience recurrent fractures and musculoskeletal pain. At the time of her clinic visit, the patient’s DEXA scan had shown worsening BMD in the right hip and lumbar spine. Interestingly, it was also noted that her alkaline phosphatase was low at 17, with previous levels as low as 11 (reference range 44 -147 IU/L). Her vitamin B6 level was elevated at 264 (reference range 3.4 – 65.2 µg/L). Given her history of limited clinical improvement despite multiple osteoporosis therapies, in combination with chronically low alkaline phosphatase levels, a diagnosis of hypophosphatasia secondary to enzyme deficiency was strongly suspected. Genetic testing confirmed the diagnosis, identifying a pathogenic variant in the ALPL gene associated with autosomal dominant and recessive hypophosphatasia (ALPL c.1240C>A, p.Leu414Met). The patient was initiated on asfotase alfa, an enzyme replacement therapy. She tolerated the treatment well, reporting improvements in muscle weakness and joint pain, and her DEXA results have remained stable without further fractures.

Discussion

This case emphasizes the importance of considering HPP in patients with unexplained fractures, especially when ALP levels are low and traditional osteoporosis therapies fail to provide benefit. Early identification of HPP is critical, as bisphosphonates, commonly used for osteoporosis, are not only ineffective but can further inhibit bone remodeling, leading to lower levels of ALP and worsening of the condition [4]. Given the ease of testing ALP levels and the critical importance of accurate diagnosis in guiding appropriate treatment, we recommend that ALP levels be included in the diagnostic work-up for osteoporosis or recurrent/pathologic fractures. In cases of persistently low ALP, genetic testing should be considered to confirm diagnosis. With increased awareness of this condition, we hope that future patients will receive timely intervention and improved clinical outcomes of HPP.

References

1. Rathbun, J. C. (1948). Hypophosphatasia: a new developmental anomaly. American journal of diseases of children, 75(6), 822-831. 2. Mornet, E., Yvard, A., Taillandier, A., Fauvert, D., & Simon-Bouy, B. (2011). A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Annals of human genetics, 75(3), 439-445. 3. Whyte, M. P. (2016). Hypophosphatasia—aetiology, nosology, pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology, 12(4), 233-246. 4. Rassie, K., Dray, M., Michigami, T., & Cundy, T. (2019). Bisphosphonate use and fractures in adults with hypophosphatasia. Journal of Bone and Mineral Research Plus, 3(10), e10223.