Genetic Hypophosphatasia as a Cause of Recurrent Stress Fractures in a Female Runner

Introduction Recurrent stress fractures in endurance weight-bearing athletes are common. However, evaluation for secondary causes is not always performed, leading to missed diagnoses. Hypophosphatasia is a rare genetic disorder caused by a genetic abnormality on the alkaline phosphatase, biomineralization associated gene, leading to a deficiency of the enzyme tissue-nonspecific alkaline phosphatase (TNAP), leading to bone loss, dental issues, and disordered calcium homeostasis. The key to diagnosis is recognizing the decreased value of alkaline phosphatase (ALP) and subsequent testing to confirm the diagnosis. Newer treatments, including bone-specific recombinant ALP, allow a better quality of life for those affected. This case illustrates the diagnosis and treatment options for this rare genetic condition. Case Presentation A 38-year-old female runner presented with right leg pain for 2 months. Eight weeks prior, she sought care and a magnetic resonance imaging showed a grade 3 stress reaction with marrow edema. X-rays at that time were read as normal. She has been non-weight-bearing since with little improvement. Medical history showed multiple stress reactions in the tibia and feet, gluten intolerance without a formal biopsy performed, a couple of low ALP readings, and severe iron deficiency. Patient denied any vitamin supplementation. There is no family history of endocrine, autoimmune, or neuromuscular diseases. The general exam was normal, notably with intact dentition. Cardiovascular, neurological, and skin exams were normal. The musculoskeletal exam showed tenderness to palpation at the right mid-anterior fibula, pain with hopping on her right leg, and bilaterally there was functional valgus with one-legged squat. Physical therapy was prescribed. Initial labs showed that vitamin B12, vitamin D, parathyroid hormone, calcium, thyroid-stimulating hormone, folate, and prealbumin levels were all normal. Complete blood count was unremarkable. A comprehensive metabolic panel was unremarkable except for low ALP at 28 U/L (NL: 44–147 U/L), which was repeatedly low. Due to the decreased ALP levels, follow-up labs were ordered. Osteocalcin and bone-specific ALP were normal. Dual-energy X-ray absorptiometry scan revealed lumbar spine and hip areas with Z-scores all above −1.0. Vitamin B6 was elevated at 186.6 nmol/L (NL: 20–125 nmol/L). The patient was referred to a hypophosphatasia specialist and a genetic counselor, where hypophosphatasia was confirmed with the pathogenic alkaline phosphatase, biomineralization associated variant being present. She was started on Strensiq ERT (Alexion, Boston, MA), generic asfotase alfa, and within a few months was able to return to activities, running 5Ks and pursuing moderately strenuous hikes. The patient is now three years past this diagnosis and has had no further stress fractures. Discussion Recurrent stress fractures are common in endurance weight-bearing athletes with a history of stress fracture and female sex being among the greatest risk factors (1). An evaluation should be done to rule out causes other than relative energy deficiency in sport, which was lower on the differential for this patient due to regular menstrual cycles, successful pregnancies, good nutrition, and a healthy body image. Broad differential diagnoses for recurrent stress fractures include thyroid disease, parathyroid disease, vitamin D deficiency, relative energy deficiency in sport, iron deficiency anemia, neoplasm, genetic abnormalities, malabsorptive conditions (inflammatory bowel disease or celiac), and hypogonadism (2). Differential diagnoses based on low ALP levels also are variable (Table). Table. - This is a general list of etiologies that present with lower than normal alkaline phosphatase, but is not exhaustive (3). Differential Diagnoses for Low Alkaline Phosphatase Hypophosphatasia Hypothyroidism Malnutrition or protein-calorie deficiency Vitamin B12 deficiency Celiac disease or other malabsorptive syndromes Trace element deficiency (zinc and magnesium) Wilson’s disease Postmenopausal women on estrogen therapy Men with recent heart surgery Severe anemia Children with achondroplasia or cretinism Aplastic anemia Chronic myelogenous leukemia ALP plays a role as an enzyme that breaks down phosphates at high pH levels. Zinc and magnesium are cofactors. Types of ALP include tissue-specific ALP and TNAP. The TNAP is present in the liver, bone, and kidney. Serum ALP is composed of more than 80% liver and bone sources. Elevated serum levels can identify liver or bone pathology. Decreased levels may be seen in Wilson’s disease, zinc deficiency, hypothyroidism, pernicious anemia, and hypophosphatasia (3–5). ALP levels are high during childhood and puberty due to bone growth/development. ALP is also higher during pregnancy due to placenta-specific ALP (3). There can be a rise in the elderly, as well (3). Temporary serum ALP levels can increase after a fatty meal in people with blood type O or B due to increased intestinal-specific ALP. Therefore, fasting labs are recommended (3). Medications that are hepatotoxic or induce cholestasis can also elevate ALP, while other medications, such as azathioprine and clofibrate, can decrease serum ALP (3). Estrogen has a suppressive effect on total and bone-specific ALP levels, likely through reduction in bone turnover (3). Adult hypophosphatasia is a rare genetic disease caused by a mutation of the gene encoding TNAP. A lack of the enzyme prevents degradation of inorganic pyrophosphate, phosphoethanolamine, and pyridoxal 5’-phosphate (the active form of vitamin B6 measured in the serum). These accumulate and may lead to pathologic bone mineralization (3,5,6). An international working group has proposed diagnostic criteria for hypophosphatasia in children and adults (7). There are several variants that can be autosomal dominant or recessive and have a range of severity, with the worst cases being lethal in the perinatal period (4). The adult form usually manifests with stress fractures, pseudofractures, and dental issues (4–6). Treatment of hypophosphatasia depends on the type and severity. Targeted therapy consists of enzyme replacement therapy of bone-targeting recombinant ALP, asfotase alfa (8,9). There is growing evidence to support this therapy improving pulmonary function, calcium homeostasis, and survival in newborns (5,6). There is some controversy around treatment in patients without evidence of bone abnormalities; however, patients have still seen improvement of symptoms on asfotase alfa (10). Withdrawal of asfotase alfa therapy after initiation in young patients has shown clinical deterioration, though evidence is limited and further studies are needed to determine if lifelong treatment is indicated in adults (11,12). At least one clinical practice guideline has been released, which details clinical manifestations, diagnosis, management, and treatment of hypophosphatasia, which focuses on ALP enzyme replacement therapy (12). Other therapies include teriparatide (9,13), zinc supplementation (14), calcium and vitamin D supplementation, vitamin B6 supplementation, in at least one case Romosozumab (15), and Efzimfotase alfa (16). Notably, bisphosphonates are not a recommended therapy due to a risk of atypical femur fractures (12). It may seem paradoxical to supplement vitamin B6 in patients who have a high serum level. However, the inactive form of vitamin B6 (pyridoxine) induces cell death in a concentration-dependent fashion and inhibits the path of active vitamin B6-dependent enzymes (Fig.). Patients experiencing seizures from their pathology may respond well to vitamin B6 supplementation (17).Figure:: The role of vitamin B6 in the synthesis of hydroxyapatite via tissue-nonspecific alkaline phosphatase (TNAP) and its cofactors calcium (Ca), magnesium (Mg), and zinc (Zn) (18).Labs need to be monitored frequently including calcium, thyroid levels, liver function tests, and parathyroid levels. Patients may need physical or occupational therapy (5). In addition, neurology, endocrinology, or other specialists may be consulted depending on the patient’s needs. Patients should be diligent about dental appointments biannually (5). Conclusion Recurrent stress fractures are commonly seen in sports medicine, though causes are varied and they can occasionally be manifestations of lesser known etiologies. In this patient’s presentation of hypophosphatasia, the decreased ALP was key to guiding further evaluation. Once the diagnosis was made, enzyme replacement, physical therapy, patient education, and referrals were initiated. These steps allowed for the resolution of symptoms and return to activity with the understanding that this rare disease is lifelong and continued treatment and surveillance would be required. Specifically, this patient had labs checked at 3 months and is followed by endocrinology at regular intervals. She has had no further stress fractures, takes her asfotase alpha as prescribed, and maintains physical therapy. The authors declare no conflict of interest and do not have any financial disclosures.