Abstract
Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP), its manifestations may include atypical femoral fractures (AFF). However, the prevalence of low serum ALP and HPP in patients with AFF remains unknown. We retrospectively analyzed ALP levels and clinical manifestations compatible with HPP in 72 adult patients with confirmed AFF by chart review. ALP values were compared with those of a control group of patients with prior proximal femoral fracture during antiresorptive treatment (n = 20). Among the AFF patients, 18 (25%) had at least one serum ALP value ≤ 40 IU/L, although in all but one case, at least one ALP value > 40 IU/L was also detected at another time point. Most low ALP values were associated with antiresorptive treatment (P = 0.049) and lowest levels of ALP did not differ between the AFF and the control groups (P = 0.129). However, low ALP values among AFF patients were associated with a higher rate of bilateral AFF (50% vs 22%, P = 0.025), metatarsal fracture (33% vs 7%, P = 0.006), and with trends for more frequent use of glucocorticoid (22% vs 8%, P = 0.089) and proton pump inhibitor (61% vs 44%, P = 0.220). In one AFF patient with low ALP and clinical suspicion of HPP, a rare pathogenic heterozygous variant of the ALPL gene was identified. In conclusion, low ALP values are common among subjects with AFF and mainly related to concomitant antiresorptive medication. Hence, low serum ALP has low specificity for HPP among AFF patients.
Highlights
Atypical femoral fractures (AFFs) are uncommon and have been associated mainly with prolonged use of bisphosphonates and denosumab, about 10% occur in the absence of exposure to antiresorptive treatment [1–4]
Compared with the AFF group treated with antiresorptive treatment (AR), patients in the control group, i.e., with hip fractures on BPs therapy, were slightly older (P = 0.026), had lower body mass index (BMI) (P = 0.011), a trend for shorter AR duration (P = 0.071), and higher CTX levels (P = 0.002)
Our results show that low alkaline phosphatase (ALP) values are a common finding in patients with AFF and that these values are mainly associated with concurrent antiresorptive medication, similar to BPs-treated subjects with typical hip fractures
Summary
Atypical femoral fractures (AFFs) are uncommon and have been associated mainly with prolonged use of bisphosphonates and denosumab, about 10% occur in the absence of exposure to antiresorptive treatment [1–4]. Recent studies report an increased risk for subtrochanteric and diaphyseal femoral fractures in patients with hypophosphatasia (HPP) [1, 6]. HPP is an inborn error of metabolism characterized by a quantitative deficit of alkaline phosphatase (ALP), due to a loss‐of‐function mutation in the ALPL gene ( known as TNSALP gene) that encodes the tissue non-specific ALP [7]. The adult form of HPP presents with a wide range of clinical manifestations, including skeletal alterations due to defective bone mineralization such as osteopenia, premature tooth loss, rickets, osteomalacia, delayed fracture healing, stress fractures of metatarsal bones, AFF, or cortical stress fractures (pseudo-fractures) which can resemble bisphosphonate‐associated incomplete AFF when localized to the lateral side of the femoral shaft [8]. HPP manifests with clinical signs and non-specific and mild extra-skeletal symptoms such as seizures, nephrocalcinosis, kidney stones,
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