Bone mineral density and fracture risk in adult patients with hypophosphatasia

Hypophosphatasia (HPP) is a rare genetic disorder caused by pathogenic variants in the ALPL gene entailing deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP) [1]. Clinical manifestation of the disorder comprises a wide spectrum of severity, ranging from life-threatening disease in infants to largely asymptomatic carriers [2‐4]. Particularly in adult patients, the phenotypic presentation is manifold, including bone issues with fractures, bone marrow lesions and musculoskeletal pain, and exhaustion and fatigue as well as supposed gastrointestinal and neuro-psychiatric symptoms [1, 5, 6]. While the underlying pathophysiologic mechanisms for many of these symptoms still have to be elucidated in detail, defective bone mineralization in HPP is well recognized [7]. Increased fracture rate and a high prevalence of insufficiency fractures and pseudofractures as well as recurrent bone marrow lesions are considered a hallmark of HPP in adult patients [4, 8‐10]. However, this does not apply to all patients and by now, there is no diagnostic marker or tool to anticipate what HPP patients are at risk for fractures. Furthermore, thanks to growing awareness for HPP among health care professionals, heterozygous ALPL variants are increasingly detected during routine diagnostic workup of osteoporosis and osteoporotic fractures, evoking the question if and how such an ALPL variant affects bone mineral density and appropriate clinical management [11, 12].

Assessing bone mineral density (BMD) by means of dual X-ray absorptiometry (DXA) is well established and standard of care for evaluating fracture risk in osteoporosis [13, 14] but only few studies with small case numbers provide data on BMD in adult patients with HPP [4, 6, 8, 15, 16]. Reported findings are heterogeneous and have not been associated with fracture pattern or prevalence, yet. Hence, it is unknown if BMD in adult patients with HPP is altered consistently and to what extent BMD measurement alone or in combination with other well-established parameters of the disease like ALP, pyridoxalphosphate (PLP), and phosphoethanolamine (PEA) can contribute to understanding and predicting fracture risk in HPP.

Considering differential localization and morphology of fractures observed in patients with adult HPP, there is a distinct type of fracture with supposedly different underlying pathophysiologic mechanisms that can readily be distinguished from, e.g., osteoporotic fractures. Pseudofractures (syn. Looser Zones), i.e., atraumatic radiolucencies, perpendicular to the cortex, incompletely spanning the diameter of the bone and affecting only one cortex on plain x-ray films as well as complete insufficiency fractures, i.e., atraumatic lucencies extending across both cortices, can be considered a hallmark of deficient mineralization and impaired remodeling. Owing to a supposedly insufficient healing response, these areas can exhibit cortical beaking or flaring. Depending on the individual situation, these lesions can finally heal, reoccur, or progress and eventually fracture completely upon minimal trauma. In HPP, pseudofractures most frequently occur along the diaphyseal axis of the weight-bearing lower extremities, specifically the femur [17, 18] and the metatarsal bones but can also be observed at other bones [1, 19, 20].

Despite continuously growing awareness for HPP both scientifically and in daily clinical routine, there are still no diagnostic landmarks helping to identify HPP patients at risk for developing any of these fractures, even though this surely is a key determinant to guide individual treatment strategies.

Combining BMD data and clinical information consistently obtained from a large cohort of adult HPP patients, this evaluation aims at elucidating a consistent pattern of BMD alterations in HPP patients and identifying to what extent and in combination with what other risk factors this may be helpful to anticipate the risk for specific fractures in HPP patients.

Out of 110 patients identified meeting the above selection criteria, 84 (76.4%) were female and 26 (23.6%) were male. All patients had genetically confirmed variants in the ALPL gene with 69 (62.7%) being heterozygously affected and 41 (37.3%) having two mutations (39 compound heterozygous, 2 homozygous). While both these groups were well balanced with regard to age and constitutional parameters, there were apparent differences regarding disease-specific laboratory parameters with significantly lower ALP activity and higher substrate levels for PLP and urinary PEA as well as higher serum-phosphorus in those subjects with two mutations. Baseline characteristics are detailed in Table 1.

The objective of this study was to evaluate BMD patterns detected with DXA in adult HPP patients in order to assess if DXA findings and other hallmarks of the disease are suitable to indicate the risk for HPP-related fractures. In order to have a consistent dataset, only patients with a documented genetic variant, low ALP, and both BMD assessments and laboratory workup performed with the same devices and tools at the same institution were included in this analysis.

Overall, BMD was not generally decreased in these HPP patients and particularly lumbar spine T- and Z-Scores were rather increased. Specifically, patients with two mutations, lower ALP levels, and elevated levels for serum-phosphorus, PLP, and urinary PEA, i.e., most severely affected individuals, were showing significantly higher lumbar spine T- and Z-Scores. Moreover, lumbar spine BMD increased with progressive aging. A potential explanation for this finding of high lumbar spine BMD in more severely affected patients and with progressive aging could be compensatory appositional bone formation resembling a diffuse idiopathic skeletal hyperostosis and heterotopic calcification of neighboring soft tissue structures and ligaments as well as supposed osteoid overload potentially combined with structurally inappropriate mineralization [8, 23‐26]. The concept of such qualitative compromise of bone in the most severely affected patients is supported by the finding of these increased lumbar T- and Z-Scores being associated with HPP-related fractures. Even though the majority of HPP-related fractures were observed along the lower extremities, i.e., femur, metatarsal bones, and tibia, femoral BMD was not significantly altered and not a valid prognostic marker for this kind of fracture. This divergence is further substantiated by the finding that in those patients with HPP-related fractures, we could not confirm the generally well-established correlation of lumbar spine and total hip BMD values [27].

While accumulation of inorganic pyrophosphate (PPi) in HPP is considered to compromise proper bone mineralization, extracellular accumulation of PPi in soft tissues is supposed to trigger calcium pyrophosphate dihydrate (CPPD) deposition and crystal formation near joints and calcification of ligaments [24, 26, 28, 29]. Accordingly, inappropriately high lumbar spine DXA values due to, e.g., heterotopic soft tissue calcifications around the spine may thus be an indicator of particularly high PPi load which on the other hand is also associated with severely compromised bone mineralization, predisposing to pseudofractures. Since valid assays for direct measurement of PPi load are not available in clinical routine, yet, understanding this association appears even more important in order to determine an individual patient’s specific fracture risk. This actually corresponds to the finding of patients with lower ALP activity having significantly higher lumbar spine BMD (Fig. 2a).

Conversely, femoral BMD did not correlate with residual ALP activity, and femoral results did not significantly differ between patients with 1 vs. 2 mutations and patients with vs. those without HPP-related fractures suggesting that with regard to osteoporosis testing in patients with ALPL variants, specifically at higher age, this anatomic region may be more suitable and meaningful for assessing osteoporosis-related fracture risk.

It surely would have been appealing to make a direct comparison of HPP-related and osteoporotic fractures in HPP patients but at this point, the number of attributable osteoporotic fractures in this mixed cohort was too small to draw robust and clinically meaningful conclusion. Indeed a preliminary review of individual cases (data not shown) with osteoporotic fractures suggests less reduced ALP levels and less elevated serum-phosphorus, PLP, and urinary PEA levels along with reduced femoral BMD as indicators for osteoporotic fractures.

The findings of our study confirm and substantiate what has been expert-perceived knowledge before: Disease-related fracture risk in adult patients with HPP exhibits a distinctive pattern as compared with other conditions with increased risk for no/low-trauma fractures. Beyond a specific fracture type and morphology, this may also be reflected in characteristic DXA findings. Accordingly, this data provides first evidence that assessing BMD in HPP may have predictive value in terms of identifying patients with severely compromised mineralization mirrored in pathologically elevated lumbar spine BMD. While patients with pathologically elevated lumbar spine BMD appear to be prone to experience HPP-related fractures, DXA BMD at femoral sites appears to be largely unaffected by the underlying ALPL genotype, making this anatomical region suitable for assessing osteoporosis in patients harboring an ALPL variant, which is particularly important for further strategies in terms of identifying individually adjusted treatment strategies.

This study represents a first step towards discerning patients at risk for HPP-related fractures from patients with increased fracture risk for other reasons carrying an ALPL mutation and it also provides evidence that measuring BMD may be an informative tool for routinely assessing disease manifestation in adults with HPP and how to differently interpret associated findings. While patients prone to HPP-associated fractures (increased lumbar spine BMD, previous Pseudofractures, substantially elevated substrate levels, two mutations) may benefit from enhancing ALP enzyme activity in bone and should be spared from treatments binding hydroxyapatite and further reducing bone turnover [30], patients at risk for osteoporotic fractures (reduced femoral BMD, elevated bone turnover markers) without evidence for deficient bone mineralization, treatments aiming at improving BMD may be beneficial to reduce fracture risk. Osteoanabolic strategies that have been probed in that regard include sclerostin-inhibition [31] and solicited individual cases treated with PTH analogues [20, 32, 33] and even though systematic and long-term evidence for these strategies are lacking, available data and pathophysiologic considerations at least do not imply untoward effects regarding underlying HPP. If and how antiresorptive strategies can elicit a favorable benefit-risk ratio in these patients remains to be scrutinized, specifically when presuming that there may be some residual mineralization deficit and/or low remodeling activity even in the preferentially osteoporotic patients.

The limited number of cases and its retrospective nature can be considered major limitations of this study. Thus, further scientific effort is surely warranted to further refine criteria helping to assign individual patients to specific fracture risk categories and to generate evidence helping to advocate adjusted treatment strategies.

In adult HPP patients, elevated lumbar spine DXA values appear to be a hallmark of severe disease associated with an increased risk for HPP-related fractures while femoral BMD seems largely unaffected by disease severity. Distinctly analyzing lumbar spine and femoral BMD data may contribute to discriminating HPP-associated fracture risk from other causes of increased fracture risk due to low BMD which does not appear to be affected systematically in subjects with ALPL.