Adult Hypophosphatasia Research Articles

Atypical femur fractures: a distinctive tract of adult hypophosphatasia.

Hypophosphatasia (HPP) is a congenital, rare and heterogeneous bone disorder, characterized by a deficit of calcified tissue mineralization, leading to skeletal deformities and osteomalacia in adults, rickets in infants and children, and fragility fractures and premature loss of dentition in children and adults. The disease is caused by a reduced or absent expression and activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, derived from inactivating mutations of the alkaline phosphatase (ALPL) gene. Six different clinical variants have been reported, defined by the onset age and characterized by different degrees of severity. The adult form of HPP presents a wide range of clinical manifestations, many of which are non-specific, mild, and often overlapping with other metabolic bone diseases. Consequently, many cases of adult HPP are, commonly, undiagnosed or misdiagnosed, and, subsequently, wrongly or non-treated with severe consequences for patients and a very negative impact on their quality of life and life expectancy, as well as with costs due to the administration of wrong therapies and treatments of their side effects. The occurrence of a fragility atypical femur fracture in the adulthood can be suspected as a clinical indication of an undiagnosed adult mild form of HPP; and the presence of at least one of this kind of fracture can help in the diagnosis of adult HPP, together with conventional HPP biochemical signs.

Recognizing the clinical triad and dural calcification in adult hypophosphatasia.

Recognizing the clinical triad and dural calcification in adult hypophosphatasia.

Hypophosphatasia: Review of Bone Mineral Metabolism, Pathophysiology, Clinical Presentation, Diagnosis, and Treatment

Hypophosphatasia (HPP) is a rare, inherited form of rickets or osteomalacia due to reduced activity of tissue non-specific alkaline phosphatase (TNSALP) caused by a loss of function mutation in the TNSALP gene marked by a low serum alkaline phosphatase. The ratio of PPi to Pi is crucial in the mineralization process. This process is regulated by the interaction of three phosphatases present in matrix vesicles: the mineralization promotors TNSALP and phosphatase orphan 1 (PHOSPHO1) and the mineralization inhibitor nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1). HPP is seen worldwide affecting all races. The broad-ranging clinical severity of HPP is correlated to the pattern of inheritance and degree of TNSALP activity, with lower levels of activity seen in the more severe autosomal recessive forms. HPP is marked by compromise of phase 2 hydroxyapatite crystal formation beyond the matrix vesicle resulting in skeletal hypomineralization, spontaneous fractures, tooth loss, and chondrocalcinosis. The major forms in declining order of severity include the following: perinatal, infantile, childhood, and adult HPP in addition to OdontoHPP and benign prenatal HPP. Biochemistry typically reveals a low serum alkaline phosphatase and elevated alkaline substrates such as pyridoxal-5′-phosphate (PLP) and phosphoethanolamine (PEA). Asfotase alfa, a recent novel enzyme replacement therapy for the treatment of HPP, has transformed this once lethal disease to one that is less severe.

Hypophosphatasia and the risk of atypical femur fractures: a case-control study.

BackgroundCase reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case–control study to assess the role of hypophosphatasia and atypical femur fracture.MethodsWe recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts.ResultsLow alkaline phosphatase levels (<55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis.ConclusionsWe found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use.Trial registrationClinicaltrials.gov number NCT01360099. Prospectively registered May 20, 2011. First patient enrolled June 14, 2011.

Adult Hypophosphatasia Treated with Teriparatide: Report of 2 Patients and Review of the Literature

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease from deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Reportedly, teriparatide (parathyroid hormone 1-34) can benefit the adult form of HPP, including fracture healing. We studied 2 women with adult HPP given teriparatide and reviewed the reports of 6 additional patients. A 68-year-old black woman (patient 1) described low-trauma fractures and had subnormal serum alkaline phosphatase (ALP) activity. Biochemical findings were consistent with HPP. Mutation analysis revealed a heterozygous defect in exon 10 of TNSALP (ALPL). Teriparatide was injected daily for 2 years. Four years later, she fractured her right hip. Treatment was resumed for 8 months without further fractures. A 53-year-old white woman (patient 2) reported low-trauma fractures and had subnormal serum ALP. Mutation analysis revealed a heterozygous defect in exon 8 of TNSALP. She injected teriparatide daily for 2 years. One year later, bone mineral density (BMD) declined and treatment was resumed for 3 months. When she sustained a sacral fracture, teriparatide was administered for a further 18 months. Patient 1's serum ALP increased while receiving teriparatide and returned to baseline after its discontinuation. BMD remained unchanged, but no fractures were sustained. Patient 2's serum ALP increased, but the improvement was not sustained. Femoral neck BMD increased significantly during the first cycle, declined significantly afterwards, and was regained during a second course of teriparatide. Teriparatide shows some benefit for adult HPP. ALP = alkaline phosphatase BMD = bone mineral density BSAP = bone-specific alkaline phosphatase CTX = C-telopeptide DXA = dual-energy X-ray absorptiometry FN = femoral neck HPP = hypophosphatasia LS = lumbar spine PEA = phosphoethanolamine PLP = pyridoxal 5'-phosphate PTH = parathyroid hormone SQ = subcutaneous TNSALP = tissue-nonspecific isoenzyme of alkaline phosphatase TPTD = teriparatide.

Adult hypophosphatasia.

Adult hypophosphatasia.

Abstract #508: Adult Hypophosphatasia Presenting with A low Bone Remodeling Rate

Abstract #508: Adult Hypophosphatasia Presenting with A low Bone Remodeling Rate

Genetically Modified Mice for Studying TNAP Function.

Genetically modified mice are powerful tools for understanding the functions of genes and proteins and often serve as models of human disease. Here, several knockout and transgenic mouse lines related to tissue-nonspecific alkaline phosphatase (TNAP) are described. Conventional TNAP knockout mice die before weaning and show vitamin B6 dependent epilepsy and impaired bone mineralization, mimicking infantile hypophosphatasia. Administration of recombinant human TNAP rescues the lethal phenotype and improves bone mineralization in the null knockout mice, and this enzyme replacement therapy has been successfully applied to the treatment of human patients. Transgenic expression of human TNAP also rescues the TNAP knockout mice. Studies of the TNAP knockout mice and their double knockouts with ectonucleotide pyrophosphatase/phosphodiesterase 1 or progressive ankylosis protein revealed that pyridoxal phosphate and inorganic pyrophosphate are natural substrates of TNAP. Bone osteopontin from TNAP knockout mice is highly phosphorylated, whereas osteopontin from TNAP knockout mice expressing human TNAP is de-phosphorylated, similar to that in wild type mice, indicating that osteopontin is also a natural substrate of TNAP and that phosphorylated osteopontin contributes the impaired bone mineralization in TNAP knockout mice. Conditional TNAP knockout mice and TNAP mutants produced by ENU (N-ethyl-N-nitrosourea) mutagenesis show milder hypophosphatasia and are expected to be useful models of adult hypophosphatasia.

Calcific Periarthritis as the Only Clinical Manifestation of Hypophosphatasia in Middle-Aged Sisters

Hypophosphatasia (HPP) is the inborn error of metabolism that features low serum alkaline phosphatase (ALP) activity caused by loss-of-function mutation(s) within the gene for the tissue nonspecific isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate (PPi), a TNSALP substrate and inhibitor of mineralization, leads frequently to premature tooth loss and often to rickets or osteomalacia. In affected adults, the excess PPi sometimes also causes calcium pyrophosphate dihydrate (CPPD) deposition, PPi arthropathy, or pseudogout, or seemingly paradoxical deposition of hydroxyapatite crystals in ligaments or around joints when the condition is called calcific periarthritis (CP). We report three middle-aged sisters with CP as the only clinical manifestation of HPP. Each presented during early adult life with recurrent episodes of pain principally around the shoulders, elbows, wrists, hips, or Achilles tendon. Otherwise, they were in good health, including no history of unusual dental disease, fractures, or pseudofractures. Calcific deposits were identified in symptomatic areas principally by ultrasonographic assessment but also confirmed radiographically. All three sisters had low serum levels of total and bone-specific ALP, hyperphosphatemia, and increased serum concentrations of the TNSALP substrate pyridoxal 5'-phosphate together characteristic of HPP. Mutation analysis revealed that each carried a single unique 18-bp duplication within TNSALP (c.188_205dup18, p.Gly63_Thr68dup) as did two of their healthy sons and their mother, who was without signs of CPPD deposition or CP but had knee osteoarthritis. We find that CP can be the only complication of HPP in adults. Thus, multiple juxta-articular deposits of hydroxyapatite causing CP may be a useful sign of HPP, especially when the CP is familial.

Hypophosphatasia

Hypophosphatasia (HPP) reveals a critical role for the “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP) in skeletal mineralization. Its biochemical hallmark, subnormal serum ALP activity, results from loss-of-function mutation(s) within TNSALP, the gene that encodes TNSALP. HPP spans an extraordinary range of severity partly explained by autosomal recessive versus autosomal dominant or recessive transmission causing severe and mild HPP, respectively. Perinatal HPP is usually fatal due to profound skeletal hypomineralization. Infantile HPP presents before the age of 6 months with rickets, failure-to-thrive, and sometimes hypercalcemia, craniosynostosis, or vitamin B6-responsive seizures. Respiratory failure and death often follow progressive chest deformity. Childhood HPP features loss of deciduous teeth from cementum hypoplasia, rickets, and weakness from static myopathy. Adult HPP causes osteomalacia with fractures and sometimes, inorganic pyrophosphate (PPi) deposition leading to arthropathy. Odonto-HPP refers to premature tooth loss alone. Discovery of phosphorethanolamine (PEA), PPi, and pyridoxal 5′-phosphate (PLP) accumulation in HPP demonstrated that TNSALP hydrolyzes several substrates of nanomolar or micromolar concentrations, and therefore is at much lower levels than the artificial substrates and pH of laboratory assays. Thus, “alkaline phosphatase” is a misnomer. Vitamin B6 disturbances in HPP reveal that TNSALP is a cell-surface enzyme. Membrane-impermeable PLP accumulates in plasma, but normal plasma concentrations of its hydrolysis product PL explain absence of symptoms of vitamin B6 deficiency or toxicity in all but the most severely affected HPP babies who can have vitamin B6-responsive seizures. PEA may derive from the GPI anchor for many cell-surface proteins. In HPP, hydroxyapatite (HA) crystals form normally in matrix vesicles (MVs) during “primary mineralization”, but excess PPi inhibits their growth after MVs rupture during “secondary mineralization” causing rickets or osteomalacia. Bone-targeted recombinant TNSALP therapy is emerging as an effective treatment.

Clinical spectrum of hypophosphatasia diagnosed in adults

The presentation of hypophosphatasia (HPP) diagnosed in adults demonstrates a wide range of clinical manifestations, many of which are nonspecific. We sought to assess clinical characteristics of adult HPP by evaluation of Mayo Clinic Rochester adults diagnosed with HPP from 1976 through 2008. Subjects were identified by diagnostic code or medical records. Inclusion criteria were age ≥18years at diagnosis; low serum alkaline phosphatase (AP) without bisphosphonate therapy; and one additional element: elevated pyridoxal 5′-phosphate (PLP) or urine phosphoethanolamine (PEA), evidence of osteomalacia, or family history. We were unable to distinguish manifesting carriers from silent unaffected carriers due to lack of a prospective standardized clinical evaluation and the absence of genetic testing. HPP was diagnosed in 22 unrelated adults (median age 49years; 68% women). Most patients (68%) were symptomatic at presentation with features including musculoskeletal pain (41%) or incident fracture (18%). A history of fracture was present in 54%: hip/femoral neck (23%), feet (23%, all women), wrist (18%), and spine (9%, all men). Nine patients (36%) had multiple fractures while 4 (all women) had subtrochanteric femur fractures. Radiographic chondrocalcinosis (27%) and documented pyrophosphate arthropathy (14%) were only observed in women. Median minimum serum AP was 43% below the lower normal limit. Urine PEA was elevated in 15/16 patients (94%). PLP median was 68μg/L (normal, 5–50μg/L) and all (n=8) were above normal. Symptomatic subjects had more fractures and chondrocalcinosis, lower median minimum AP and PLP and higher median PEA levels. Clinical features more common in fracture patients included symptoms at presentation, history of childhood rickets, dental abnormalities, lower median minimum AP and PLP, and higher median urine PEA. Four subjects had iliac crest bone biopsies, with 2/4 specimens consistent with osteomalacia.These results suggest that adult HPP demonstrates a wide spectrum of clinical manifestations including musculoskeletal pain, fractures, chondrocalcinosis and dental anomalies with some overlap in laboratory characteristics in relationship to disease severity. In addition to genetic and environmental factors, gender may influence the clinical expression of HPP.

Hypophosphatasia — A clinical perspective

Atypical femoral fractures are defined as atraumatic fractures located in the subtrochanteric region or femoral shaft. They have been mainly reported in patients taking bisphosphonates. We report the case of a 67-year-old female with osteoporosis treated by alendronate during ten years. Radiographies showed atypical femoral fractures. Serum levels of total and bone-specific alkaline phosphatase were low. In order to accelerate bone healing, teriparatide was introduced. After one year of teriparatide treatment, pain and functional difficulty have decreased, and alkaline phosphatase levels were normalized. In view of this history of recurrent fractures, of atypical femoral fractures, of early spontaneous loss of teeth, and of low serum total and bone-specific alkaline phosphatase levels, the diagnosis of hypophosphatasia has been considered and confirmed by genetic research. Other conditions than exposure to anti-resorptive therapies may promote atypical femoral fractures, such as in conditions associated with abnormal bone structures, as hypophosphatasia, a rare inherited bone metabolism disorder. A few case reports have reported adult hypophosphatasia treated by teriparatide with a good efficacy on bone pain and consolidation but with mixed results on biological markers. Teriparatide may be therefore a treatment option in adult hypophosphatasia. ALP levels should be carefully checked among osteoporotic patients and specially before introducing a bone resorption inhibitor. Low alkaline phosphatase levels have to be taken into account and an evocative history of hypophosphatasia has to be sought because this condition may expose patients to develop atypical femoral fractures during bisphosphonate treatment.

Treatment with teriparatide in a patient with joint pain due to adult hypophosphatasia. A case report

Treatment with teriparatide in a patient with joint pain due to adult hypophosphatasia. A case report

“Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia

We report a 55-year-old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for "osteoporosis." Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the "tissue-nonspecific" isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn-error-of-metabolism.

Failure of Teriparatide in Treatment of Bone Complications of Adult Hypophosphatasia

To the Editor, Some authors have recently reported that teriparatide is effective in the treatment of the bone complications of hypophosphatasia [1, 2]. We report the case of a 43-yearold woman who was treated with teriparatide for 1 year but without effect. Since her childhood, the patient had presented numerous fractures (ribs, pelvis, both femurs) and had migratory arthritis. She was a heterozygous carrier of the N461L mutation in exon 12 of the TNSALP gene. She presented a nondisplaced fracture of the right humeral shaft that was painful and pseudarthrotic in spite of plaster immobilization for 3 months. Treatment was started with teriparatide, 20 lg/day. Fifteen days later, the patient required paracetamol for diffuse bone pain. Ten months after treatment was started, teriparatide was discontinued as bone pain had worsened, and in particular, the humeral pseudarthrosis remained unchanged on X-rays and CT scan. Before treatment, corrected serum calcium was 2.47 mmol/L, serum phosphorus 1.32 mmol/L, 24-hour urinary calcium 4.5 mmol/L, 25OHD 42 ng/mL, parathormone 24 pg/mL, alkaline phosphatase (ALP) 21 IU/L, bone ALP (bALP) \2 mg/L, osteocalcin 17 ng/mL, and serum CTX 178 pg/mL. At treatment discontinuation, serum calcium was 2.70 mmol/L, serum phosphorus 1.40 mmol/L, 24-hour urinary calcium 6.5 mmol/day, 25OHD 38 ng/mL, PTH 27 pg/mL, ALP 18 IU/L, bALP \2 mg/L, osteocalcin 43 ng/mL, and serum CTX 560 pg/mL. Spinal bone mineral density (BMD) was 1.05 g/cm (T score –1.1) and whole-body BMD 0.945 g/cm before treatment (femoral neck BMD could not be measured because of osteosynthesis), while spinal BMD was 1.04 and whole-body BMD was 0.920 after treatment. In the cases reported in the literature, teriparatide led to increased bALP levels and fracture healing [1–3]. However, although bone remodeling was stimulated in our patient, as shown by increased osteocalcin and CTX, teriparatide did not modify bALP levels or BMD and did not improve fracture healing. It caused marked bone pain and moderately elevated serum calcium. This is probably related to a different mechanism of decreased ALP activity, depending on the type of mutation: decrease in the quantity of the enzyme, its stability, or its catalytic power. In our patient, the N461L mutation led to complete disappearance of the bone isoenzyme, which was not modified by PTH treatment, whereas the level has been reported to increase in patients presenting the D378V [1] and the G339R, E191K, A176T, and V423A [2] mutations. The solution of the future could be treatment with recombinant ALP [3].

Adult hypophosphatasia with painful periarticular calcification treated with surgical resection

Hypophosphatasia is a rare inherited disorder characterized by a low serum alkaline phosphatase (ALP) activity and defective bone mineralization. Adult hypophosphatasia typically manifests in middle-age as a result of osteomalacia with recurrent stress fractures of the lower limb. However, considerable variation occurs in the clinical expression of hypophosphatasia, and no curative treatment has yet been established. We herein report a case of adult hypophosphatasia with painful calcific periarthritis, which showed improvement after surgical resection. A 32-year-old male was referred to our clinic complaining of pain in his elbows and knees. A painful subcutaneous mass was palpable on his right lateral epicondyle, where periarticular calcification was detected by plain radiography. The laboratory data showed a slight decrease in serum ALP activity and bone mineral density, and an elevation in the urinary phosphoethanolamine. Genomic DNA sequencing revealed an F310L mutation and a Y246H polymorphism in the tissue-nonspecific alkaline phosphatase gene, confirming the diagnosis of hypophosphatasia. The pain in the patient's right elbow was not responsive to nonsteroidal anti-inflammatory drugs, and triamcinolone diacetate was locally injected for treatment. His symptoms were ameliorated after the injection; however, they recurred in 3months, and he became refractory to additional steroid injection. Surgical debridement of the calcified lesion was performed, and his symptoms were successfully ameliorated after the surgery.

Hypophosphatasie : diagnostic et conduite à tenir

Hypophosphatasia is a rare inborn metabolic disorder, characterized by a genetic defect in the gene (ALPL) coding the tissue-nonspecific alkaline phosphatase (TNSALP). Defective bone mineralization and dental anomalies are the main features of the disease. The clinical expression is highly variable, ranging from lethal type to less severe bone and joint disorders. According to age, different forms have been described: perinatal (respiratory complications, in most case very severe and lethal), infantile (rickets, vitamin-B6 dependant seizures), juvenile (dental lesions, short stature, bone deformations, waddling gait), adult hypophosphatasia (history of rickets, pseudo-fractures, delayed consolidation of fractures, pyrophosphate arthropathy) as well as odonto-hypophosphatasia. Different radiographic anomalies may be observed at different stages of the diseases; rachitic changes, bone deformations, functional cranisosynostosis in children; in adults radiographs may show stress fractures, sometimes complete fractures with poor healing, chondrocalcinosis with calcium pyrophosphate crystal deposition. The diagnosis is based on laboratory findings: marked reduction of serum alkaline phosphatase activity, increased urinary excretion of phosphoethanolamine and inorganic pyrophosphates, increased serum pyridoxal-5’-phosphate. Histologically, mineralization of osteoid bone tissue is defective. Genomic DNA sequencing can detect mutations of ALPL gene in 95% of cases; more than 200 mutations have been described (http://www.sesep.uvsq.fr/03_hypo_mutations.php). The mode of inheritance is variable and it complicates the genetic counselling; hypophosphatasia may be inherited in an autosomal dominant or autosomal recessive manner. There is no established treatment of hypophosphatasia. Vitamin D supplementation may induce hypercalcemia and hypercalciuria. Vitamin B6 supplementation is given in children suffering from epilepsy and NSAID may be useful to treat bone inflammatory lesions. Encouraging results have been observed in patients given daily subcutaneous parathyroid hormone or teriparatide. Very promising results have recently been obtained by enzyme replacement therapy for severe infantile forms of the disease.

Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis

Histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia not only confirmed the expected enrichment of non-mineralized osteoid, but also demonstrated an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix. Adult hypophosphatasia is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase. While it is commonly accepted that the increased fracture risk of the patients is the consequence of osteomalacia, there are only few studies describing a complete histomorphometric analysis of bone biopsies from affected individuals. Therefore, we analyzed iliac crest biopsies from eight patients and set them in direct comparison to biopsies from healthy donors or from individuals with other types of osteomalacia. Histomorphometric analysis was performed on non-decalcified sections stained either after von Kossa/van Gieson or with toluidine blue. Bone mineral density distribution was quantified by backscattered electron microscopy. Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult hypophosphatasia, our histomorphometric analysis revealed alterations of the trabecular microarchitecture and an increased number of osteoblasts compared to healthy controls or to individuals with other types of osteomalacia. Moreover, the analysis of the mineralized bone matrix revealed significantly decreased calcium content in patients with adult hypophosphatasia. Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals.

Clinical, pathological and genetic evaluations of Chinese patients with autosomal-dominant hypophosphatasia

Objectives Hypophosphatasia (HPP) is an inherited disorder characterised by defective bone and tooth mineralisation and deficient serum and bone alkaline phosphatase activity, and it results from mutations in alkaline phosphatase ( ALPL) encoding tissue-nonspecific alkaline phosphatase (TNAP). The objective of the present work was to explore the correlations between genotype and phenotype in a Chinese family affected by autosomal-dominant HPP. Design We examined all individuals of a HPP family by clinical and radiographic examinations as well as laboratory assays. Furthermore, a prematurely exfoliated tooth was observed histopathologically. Based on the clinical and pathological manifestations, the causative gene ALPL was selected for further analysis and screened for mutations. Results The proband presented the characteristic clinical features of childhood HPP such as rachitic skeletal changes, early loss of primary teeth, and short root anomalies of the permanent teeth. Histopathological evaluation of a tooth revealed a “shell” structure, severe mineralisation defects of dentin, and an absence of cementum. The patient's mother and grandfather were clinically diagnosed with adult HPP. The family showed autosomal-dominant moderate hypophosphatasia. DNA sequencing and analysis revealed a novel missense mutation (c.251A>T) in exon4 of ALPL. This mutation (p.E84V) is located in the secondary structure of TNAP's homodimer interface, and it was predicted to have a dominant negative effect. Conclusion Our findings suggest the missense transversion (c.251A>T, p.E84V) should be responsible for the HPP phenotype in this Chinese family.

Parathyroid Hormone Treatment Improves Pain and Fracture Healing in Adult Hypophosphatasia

Adult hypophosphatasia (HPP) is characterized by low serum alkaline phosphatase (S-ALP) and poorly healing fractures due to ALPL gene mutations. Increased S-ALP and fracture repair were reported in two patients treated with teriparatide, PTH 1-34. The effects of full-length PTH 1-84 have not been studied. Two 56- and 64-yr-old sisters (patients 1 and 2) with HPP and with long-standing, painful femur fractures received PTH 1-84 (Preotact, 100 μg/d sc) for 7 and 18 months, respectively. Patient 1 had another treatment 8 months later because of new femur fractures. We characterized the underlying mutation(s) and treatment effects according to S-ALP, bone markers, serum ionized calcium, plasma phosphate (P-Pi), pain, mobility, and fracture healing. Both patients were compound heterozygotes for a p.G339R and p.E191K ALPL mutation. S-ALP increased significantly, 4.9- and 6.8-fold in patient 1 and 2.7-fold in patient 2. Responses decreased at 6 months but remained higher than basal activity. Serum N-terminal propeptide of type I procollagen and urinary N-telopeptide of type I collagen increased 14- to 19-fold and 9-5-fold in patient 1, respectively, and 9- and 3-fold in patient 2. P-Pi fluctuated in patient 1 and increased in patient 2. Pain and mobility improved promptly. Fractures healed after 7-8 months of treatment in patient 1 and at 15 months in patient 2. PTH 1-84 improves pain, mobility, and fracture repair in adult HPP, even after repeat treatment. Residual activity of the p.E191K ALPL gene mutation could explain why PTH can stimulate S-ALP. P-Pi concentrations may modulate the response.