Bone mineral density and fracture risk in adult patients with hypophosphatasia

Abstract

In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD. Introduction Hypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce. Methods Retrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history. Results Analysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was − 0.1 (SD 1.9), and mean total hip T-Score was − 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations. Conclusion BMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis. Trial registration number German register for clinical studies (DRKS00014022) Date of registration 02/10/2018retrospectively registered

Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa

“…In line with previous reports, lumbar spine BMD scores in this cohort of severely affected HPP patients were higher than femoral BMD scores and above average for the normal population [32,33]. A potential explanation for this finding was the accumulation of osteoid and inappropriately mineralized, mechanically inferior bone tissue, specifically in axially loaded vertebrae as a consequence of underlying osteomalacia with compromised bone quality and reduced turnover.…”

Hypophosphatasia: A Unique Disorder of Bone Mineralization

“…Patients with HPP have a generalized TNSALP deficiency that is associated with a rare form of rickets and osteomalacia, i.e., poorly mineralized cartilage or bone, respectively [ 8 , 16 , 39 ]. Although increased fragility fracture rates and recurrent bone marrow lesions are considered a hallmark of HPP due to defective bone mineralization in affected patients [ 40 , 41 , 42 ], this does not apply to all patients [ 43 ] due to the wide variety of genetic mutations. Thus, there are HPP-affected patients showing elevated lumbar spine values in dual X-ray absorptiometry (DXA) and an increased risk for HPP-related fractures [ 43 ].…”

“…Although increased fragility fracture rates and recurrent bone marrow lesions are considered a hallmark of HPP due to defective bone mineralization in affected patients [ 40 , 41 , 42 ], this does not apply to all patients [ 43 ] due to the wide variety of genetic mutations. Thus, there are HPP-affected patients showing elevated lumbar spine values in dual X-ray absorptiometry (DXA) and an increased risk for HPP-related fractures [ 43 ]. This could largely be explained by a compromised mineralization of the bone microarchitecture.…”

“…However, these are not pathognomonic findings for HPP [ 86 ]. The measurement of bone mineral density by Dual X Absorciometry (DXA) will support the diagnosis of HPP, but without being essential for it [ 85 ] since there are HPP-affected patients with a high risk of fragility fractures despite increased lumbar bone density determined by DXA [ 43 ]. In this context, it would be very useful to have studies evaluating bone architecture in patients with HPP to assess the contribution of trabecular and cortical bone to the risk of fractures in this population.…”

Evaluación de la densidad mineral ósea y de los parámetros de 3D-Shaper en la hipofosfatasia congénita del adulto

“…However, the limited evidence available in adults with HPP has shown a normal or slightly decreased BMD 7,[9][10][11][12] , from which it is deduced that bone densitometry may not adequately predict the risk of fracture 7 . Therefore, the objective of this study is to evaluate the BMD in the proximal femur (PF) and carry out a volumetric analysis of the cortical and trabecular bone of this region, as well as cortical thickness using 3D-Shaper in subjects with HPP, and compare these parameters between subjects with and without a history of fractures.…”