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Archives de pédiatrie
Volume 24, n° 5S2
pages 571-573 (mai 2017)
Doi : 10.1016/S0929-693X(18)30018-6
Adult hypophosphatasia
Hypophosphatasie chez l’adulte
 

K. Briot 1, 2, C. Roux 1, 2, 3,
1 INSERM U1153 
2 Département de rhumatologie, hôpital Cochin, assistance publique-hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France 
3 Université Paris-Descartes 

*Corresponding author.
Summary

In adults, hypophosphatasia (HPP) may be revealed by fractures, mainly metatarsal and femoral, and by crystal-related joint diseases. Low alkaline phosphatase levels are often overlooked. There is no established treatment for adults but the diagnosis is important to prevent the use of therapies that promote bone resorption in this context of bone fragility.

The full text of this article is available in PDF format.
Résumé

L’hypophosphatasie (HPP) peut se révéler chez l’adulte par des fractures, essentiellement des métatarses et des fémurs, et des arthropathies cristallines. Les valeurs basses de phosphatase alcaline sont souvent négligées. Il n’y a pas de traitement établi chez l’adulte mais le diagnostic est important pour éviter l’usage des traitements antirésorbeurs dans cette situation de fragilité osseuse.

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Introduction

The clinical presentation of HPP in adults is highly variable and depends on the residual level of enzymatic activity and the age at symptom onset [1, 2]. The disease may be overlooked in childhood and only diagnosed during adulthood. Some features become clinically evident in adulthood. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults [3]. It is important to recognize the disease to provide the better treatment of the fractures which are frequently complicated and associated with pseudarthrosis. Above all, it is of major importance to prevent the use of anti-resorption drugs frequently prescribed for the fractures related to bone fragility wrongly attributed to osteoporosis in these patients. The rareness of the disease and the difficulty of estimating its prevalence are stressed in other articles in this review. The prevalence of low alkaline phosphatase levels (outside of any genetic confirmation of the disease) in adults was estimated in two recent studies. In the large scale study conducted in the USA, values < 40IU/L were observed in 1/1,544 adults attending a multidisciplinary health center [4]. In the study conducted by the authors in France, 0.13% of the hospitalized patients (excluding emergency and surgery departments) had alkaline phosphatase values below the laboratory’s normal range [5].

Clinical manifestations of HPP in adults

In adults, the main symptoms are fractures (due to osteomalacia) and joint disease (due to microcrystalline deposits). In the HPP forms emerging only in adulthood, calcium and phosphate metabolic disorders (hypercalcemia, hyperphosphatemia, etc.) are absent, as are the neurological and respiratory complications. The most frequent fractures that characterize the disease involve the metatarsals. These fractures are recurrent, usually show a delayed consolidation and may lead to pseudarthrosis. The other characteristic fractures affect the femoral diaphysis and mainly occur in the lateral cortex of the sub-trochanteric region. The fractures may sometimes be bilateral with diagnostic criteria similar to that of atypical diaphyseal fractures (i.e. perpendicular to the cortex). The calluses are poorly developed or absent. Pseudarthrosis gives rise to numerous difficulties since consolidation is delayed by several months. The fractures may be accompanied by low bone density misleading the diagnosis as osteoporosis. In such contexts, more attention should be paid to dental abnormalities: enamel disorders, loose teeth and premature tooth loss. The patient interview will thus readily retrieve childhood dental abnormalities and premature loss of the lacteal teeth.

The low alkaline phosphatase activity is responsible for an increased risk of calcium pyrophosphate crystals deposition in the joints. The quantity of extracellular inorganic pyrophosphate (Pi) depends on two sources: hydrolysis of nucleotide triphosphate and transport of intracellular Pi by the progressive ankylosis protein homolog (ANKH ) on the chondrocyte membrane. In the presence of magnesium, alkaline phosphatase degrades Pi to orthophosphate. The latter may become intracellular again by the action of a phosphate transporter protein (PiT-1); the intracellular Pi stimulates the alkaline phosphatase, decreasing the extracellular pyrophosphate level. In the event of decreased phosphatase activity, the accumulation of Pi, in the presence of calcium, promotes crystal formation. HPP is thus one of the diseases to be investigated when finding chondrocalcinosis in young adults [6]. Characteristic sites of crystal deposition are the knees, carpus and pubic symphysis.

Two studies have investigated the musculoskeletal complications in adults. One study was conducted in a series of 22 adults with persistent low alkaline phosphatase (without genetic confirmation of the disease) [7]. The age at diagnosis was 49 years (range: 35 – 73 years) and the mean age at symptom onset was 44 years. At diagnosis, musculoskeletal pain (not otherwise specified) and fractures were present in 41% and 18% of the patients, respectively. Fractures were found mainly at the feet or femora. Chondrocalcinosis and crystalline joint disease were present in 9/15 women in the study (not in men). Dental abnormalities (including early tooth loss and repeated extractions) were present in 14% of patients, both men and women. Another large-scale study of 269 adults (without genetic confirmation) was recently reported [4]. The study population was equivalent to 0.06% of the administrative database population of the investigating site enabling a case-control analysis. The authors found that the risk of chondrocalcinosis, (ossifying enthesopathy), Forestier’s disease (vertebral ligament ossification) and calcifying periarthritis was higher in patients with low alkaline phosphatase than in controls. In women, the risk of finding signs of chondrocalcinosis on X-rays, and of femoral or metatarsal fissure were increased by 4.5 and 2.5 fold, respectively. In men, clinical signs suggestive of ‘myopathy’ (pain and muscle weakness) were more frequent. In few patients, apatite deposits were associated with chondrocalci nosis. Calcifying periarthritis of the shoulder in adulthood, a very common disease, was recently reported as the only manifestation of HPP in three sisters [8].

The emergence of such clinical features in young adults should attract attention. In addition, history of growth failure and multiple dental problems in childhood and adolescence, often forgotten by the patient and his/her family, are very frequent. Diagnosis is based on plasma alkaline phosphatase level. There is a strong correlation between disease severity and residual activity. Anomalies are frequently overlooked in adults. For instance, one main aim of the alkaline phosphatase measurement is to screen for increased alkaline phosphatase level as seen in hepatic or bone abnormalities (Paget’s disease, osteomalacia due to vitamin D deficiency, etc.). We have recently shown that, in most cases, the abnormal value of low alkaine phosphatase was not reported in hospitalization notes [5]. Noteworthy, alkaline phosphatase levels may fluctuate; acute hypophosphatasemia may occur following severe injury, surgery and/or organ failure [9]. Other causes of low alkaline phosphatase in adults, for which the underlying mechanism is not clear, have been discussed (Cushing’s disease, Wilson’s disease) [4]. The principal cause of decreased alkaline phosphatase levels in adults is the use of anti-resorption therapies. Chronic use of bisphosphonate, or anti-Receptor Activator of Nuclear factor Kappa-B Ligand (anti-RANK ligand) antibodies is associated with abnormally low levels of the phosphatase. Atypical fractures occurring during the course of anti-resorptive therapies have been described. They revealed HPP in adulthood [10, 11]. However, it may be difficult to interpret bone fragility fractures in association with a variant of TNSALP [12].

Treatment of HPP in adulthood

Management of adult patients with HPP must address the bone and joint complications, in addition to the chronic pain and impact on mood. Anxiety and depression seem frequent in patients and provide a rationale for investigating the potential role of alkaline phosphatase with regard to the central nervous system and nociception.

Calcium and vitamin D deficiencies must be treated to prevent secondary hyperparathyroidism. The precautions applicable in pediatric therapy do not apply to forms revealed in adulthood. Physical exercise, appropriate to skeletal status, without marked impacts, should be encouraged. The specialized stomatological opinion and dental care are required depending on the patients’ oral features.

Anti-resorptive therapies are prohibited as they may worsen the underlying osteomalacia [10, 11]. Currently, there is no established treatment available for the correction of the bone fragility in adult HPP. Recombinant parathyroid hormone (PTH) (the hormone fragment 1-34), was tried on various clinical cases. The first case reported was a female patient aged 56 years presenting with metatarsal and femoral fractures. Treatment had an effect on bone pain after 6 weeks of daily injection of 20 pg of teriparatide, with resolution of the pain at 4 months of treatment [13]. PTH had a positive effect on fracture consolidation; alkaline phosphatase rose on treatment. The alkaline phosphatase level reverted to baseline on treatment discontinuation. Treatment duration was 18 months. Another patient was treated for 34 months [14]. Two patients received PTH 1-84 for 7 and 18 months, respectively [15]. In most cases, circulating alkaline phosphatase levels increased, without normalizing. The marker of bone resorption increased, suggesting an improvement in bone remodeling. Histological data were very limited; three biopsy samples from a patient treated with teriparatide were analyzed [14]. Only one was conducted after double labeling with tetracycline 5 months post treatment initiation. The samples showed signs of remodeling with a high number of osteoblasts, but no labeling. In the patients whose fractures did not consolidate, radiological signs of improvement (decrease in fracture line, incipient callus, and even consolidation) were reported. The mutations in the treated patients differed but they were all heterozygotes. The presence of a normal allele may explain the biological response. It was not possible to predict the therapeutic effect on the basis of the type of mutation due to the rareness of the data. Teriparatide has not been studied in children since it is contra-indicated while physes are open.

In a clinical trial, the enzyme replacement therapy (ERT) improved functional outcomes in some adolescents and adults with HPP. The heterogeneity of the disease during adulthood and the paucity of reported data on ERT do not allow to provide any advice in this population. Long term follow-up of affected patients is however necessary, especially through registries, to better understand the different disease outcomes [16].

Conclusion

HPP discovered in adulthood is a very rare disease. Special attention should be paid to alkaline phosphatase levels in the event of fractures or joint disease in young adults. Diagnosis enables the prevention of the use of anti-resorptive therapies, which would exacerbate bone fragility, and the setting of personalized multidisciplinary care.


Statements of interests

K. Briot has received research grants and/or honoraria from Amgen, MSD, Lilly, Kyowa Kirin. C. Roux has received fees from Alexion for occasional interventions.

References

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