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

There is limited understanding of how asfotase alfa affects mineral metabolism and bone turnover in adults with pediatric-onset hypophosphatasia. This study showed that adults with hypophosphatasia treated with asfotase alfa experienced significant changes in biochemical markers of bone and mineral metabolism, possibly reflecting enhanced bone remodeling of previously osteomalacic bone. INTRODUCTION: Hypophosphatasia (HPP), due to a tissue nonspecific alkaline phosphatase (TNSALP) deficiency, can cause impaired bone mineralization and turnover. Although HPP may be treated with asfotase alfa, an enzyme replacement therapy, limited data are available on how treatment with asfotase alfa affects mineral metabolism and bone turnover in adults with HPP. METHODS: ALP substrates, bone turnover and mineral metabolism markers, and bone mineral density (BMD) data from EmPATHY, a single-center, observational study of adults (≥ 18 years) with pediatric-onset HPP treated with asfotase alfa (NCT03418389), were collected during routine clinical care and analyzed from baseline through 24 months of treatment. RESULTS: Data from 21 patients showed significantly increased ALP activity and reduced urine phosphoethanolamine (PEA)/creatinine (Cr) ratios after baseline through 24 months of asfotase alfa treatment. There were significant transient increases in parathyroid hormone 1-84 (PTH), osteocalcin, and procollagen type 1 N-propeptide (P1NP) levels at 3 and 6 months and in tartrate-resistant acid phosphatase 5b (TRAP5b) levels at 3 months, with a significant decrease in N-terminal telopeptide of type 1 collagen (NTX) levels at 24 months. Lumbar spine BMD T scores continuously increased during treatment. CONCLUSION: Significant changes in bone turnover and mineral metabolism markers after asfotase alfa treatment suggest that treatment-mediated mineralization may enable remodeling and bone turnover on previously unmineralized surfaces. Urine PEA/Cr ratios may be a useful parameter in monitoring treatment during routine care.

Bone mineral density and fracture risk in adult patients with hypophosphatasia.

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: 02/10/2018 - retrospectively registered.

Subtrochanteric and diaphyseal femoral fractures in hypophosphatasia-not atypical at all.

Risk for subtrochanteric and diaphyseal femoral fractures is considered increased in patients with hypophosphatasia (HPP). Evaluating a large cohort of HPP patients, we could for the first time quantify the prevalcence and identify both morphometric features as well as predisposing factors for this complication of severe HPP. INTRODUCTION: Subtrochanteric and diaphyseal femoral fractures have been associated with both, long-term antiresorptive treatment and metabolic bone disorders, specifically Hypophosphatasia (HPP). Building on a cross-sectional evaluation of real-world data, this study reports risk factors, prevalence, treatment outcome and morphometric particularities for such fractures in HPP as compared to Atypical Femoral Fractures (AFF) in long-term antiresorptive treatment. METHODS: For 15 out of 150 HPP patients identified with having experienced at least one such fracture, medical records were reviewed in detail, extracting medical history, genotype, lab assessments, bone mineral density (DXA), radiographic data on femoral geometry and clinical aspects of fracture etiology and healing. RESULTS: Bilateral fractures were documented in 10 of these 15 patients, yielding a total of 25 fractures for evaluation. Disease-inherent risk factors included autosomal-recessive, childhood onset HPP, apparently low alkaline phosphatase (ALP) ≤ 20 U/l and substantially elevated pyridoxal 5'-phosphate (PLP) > 3 times upper limit of normal as well as high lumbar spine BMD. Fracture morphology met definition criteria for AFF in 88% of cases. Femoral geometry revealed additional risk factors previously described for AFF, including decreased femoral neck-shaft angle and increased femoral offset. Extrinsic risk factors include Hypovitaminosis D (80%) and pre-treatment with bisphosphonates (46,7%) and Proton-Pump Inhibitors (40%). CONCLUSIONS: Increased risk for subtrochanteric and diaphyseal femoral fractures in HPP appears to result from both compromised bone metabolism as well as disease-associated bone deformities. In severe HPP, generous screening for such fractures seems advisable. Bisphosphonates and Hypovitaminosis D should be avoided. Healing is compromised and requires mindful consideration of both pharmacological and surgical options.

Efficacy and safety of whole body vibration in maintenance hemodialysis patients - A pilot study.

OBJECTIVES: The aim of this study was to assess safety and effectiveness of Whole Body Vibration exercise (WBV) to improve physical performance and parameters of inflammation in patients on maintenance hemodialysis (MHD). METHODS: Prospective, open-label trial in n=14 patients on maintenance hemodialysis. Participants performed WBV twice weekly for 12 weeks before (n=8) or after (n=6) hemodialysis sessions. The primary endpoint was physical performance assessed by the Short-Physical-Performance-Battery (SPPB). Secondary endpoints included established parameters of musculoskeletal assessment and blood chemistry. RESULTS: As compared to baseline, physical performance (SPPB) improved significantly (p=0.035). Moderate advances were also seen for 6-Minute-Walking test, Timed-up-and-go test, jumping height and handgrip strength. Improvements were particularly pronounced in subjects with seriously impaired baseline performance. Skeletal muscle index showed a tendency to better values. Laboratory data exhibited a significant reduction of white blood cell count and a trend to lower levels of hsCRP. WBV was generally well tolerated. Two events of clinically significant blood pressure decline occurred in patients exercising after dialysis sessions. CONCLUSIONS: Results of this pilot study suggest effectiveness and safety of WBV in hemodialysis patients. Beneficial effects may affect both, parameters of physical performance and systemic inflammatory activity, which should be verified in larger scale clinical trials.

[Diagnostics in osteology]. / Diagnostik in der Osteologie.

Clinical diagnostics in metabolic bone diseases cover a broad spectrum of conventional and state of the art methods ranging from the medical history and clinical examination to molecular imaging. Patient treatment is carried out in an interdisciplinary team due to the multiple interactions of bone with other organ systems. Diagnosis of osteoporosis is supported by high level national guidelines. A paradigm shift concerning the clinical relevance of bone mineral density measurement renders this now to be a strong risk factor rather than a diagnostic parameter, while strengthening the value of other clinical factors for risk assessment. The impact of parameters for muscle mass, structure and function is steadily increasing in all age groups. In order to identify underlying diseases that influence bone metabolism a panel of general laboratory diagnostic parameters is recommended. Markers for bone formation and resorption and specific parameters for the regulation of calcium and phosphate metabolism should be evaluated by specialists because they require diligence in preanalytics and experience in interpretation. Genetic diagnosis is well established for rare bone diseases while diagnostic panels are not yet available for routine diagnostics in polygenetic diseases such as osteoporosis. Conventional radiology is still very important to identify, e. g. fractures, osteolytic and osteoblastic lesions and extraosseous calcifications; however tomography-based methods which combine, e. g. scintigraphy or positron emission technologies with anatomical imaging are of increasing significance. Clinical diagnostics in osteology require profound knowledge and are subject to a dynamic evolution.

[Regulation of bone metabolism in osteoporosis : novel drugs for osteoporosis in development]. / Regulation des Knochenstoffwechsels bei Osteoporose : Neuartige Osteoporosemedikamente in der Entwicklung.

Bone is continuously regenerated and remodeled as an adaptation to mechanical load. Bone mass and fracture resistance are maintained by a balanced equilibrium between bone formation and bone resorption. Regeneration and response to mechanical load are, however, impaired in osteoporosis and during aging. Bone resorption is enhanced by chronic inflammation while bone formation is altered by rising levels of inhibitors in the aging organism. Core molecular principles of the regulation of bone metabolism in health and disease have been characterized and developed as therapeutic targets. The receptor activator of nuclear factor kappaB ligand (RANKL) and osteoclast-derived protease cathepsin K are important regulators and effectors of osteoclast differentiation and bone resorption. Bone formation is stimulated by bone morphogenetic proteins (BMP) and via the parathyroid hormone receptor and the Wnt signaling pathway. The principles of osteoclast inhibition using bisphosphonates have now been known for almost three decades. Based on more recent knowledge RANKL and cathepsin K have been developed as new therapeutic targets to inhibit bone resorption. While denosumab, a RANKL antibody, has already been introduced into routine treatment strategies, the cathepsin K antagonist odanacatib is currently in the licensing process. Bone formation can also be stimulated by local administration of BMPs, by systemic treatment with the parathyroid hormone fragment teriparatide and by using antibodies targeting the Wnt inhibitor sclerostin. The latter are presently being tested in phase III clinical studies. In the near future a panel of traditional and novel treatment strategies will be available that will enable us to meet the individual clinical needs during aging and for the treatment of osteoporosis.

Respiration of amniotic fluid in near-term foetal rabbit.

OBJECTIVE: To examine the existence of amniotic fluid inhalation in foetal rabbit near term. STUDY DESIGN: Rabbit red cells labelled with 51 radio-chromium (Cr51-S1: Injectable solution sodium chromate, volumic activity: 74 MBq/ml; Cis-BioInternational, France) were injected into the amniotic sac of 24 New Zealand White foetal rabbits (mean gestation: 31 days) at day 25 per-laparotomy. At day 26, just prior to caesarean section, human serum albumin labelled with 125 radio-active iode (125I-HSA) (SERALB-125: human serum albumin labelled with radioactive Iode 125, volumic activity: 185 kBq/ml, Cis-BioInternational, France) was injected into each amniotic sac. The lungs, digestive tracts, kidneys and liver were excised separately and radioactivity counted in each organ. RESULTS: On day 26 of gestation, the 51Cr-RC radioactivity rate per gram of tissue in lungs, digestive tract amniotic fluid, liver and kidneys were respectively 1.66 +/- 2.8%, 1.15 +/- 1.6%, 0.015 +/- 0.02% and 0.04 +/- 0.07% of the total amount of radioactivity injected into the amniotic sac at day 25. The lungs' radioactivity was significantly higher than liver (t = 2.94, P < 0.01) or kidneys radioactivity (t = 2.38, P < 0.05). The 125I-HSA injected just prior to caesarean section at day 26 was not found in any foetal organ. CONCLUSIONS: Lung radioactivity is not related to gasps induced by caesarean section, or to a vascular diffusion since lung radioactivity was significantly higher than liver or kidneys' radioactivity. The results of these series of experiments demonstrate that amniotic fluid inhalation does exist in foetal rabbit near term.

Effects of chronic organic dust exposure on respiratory function and airway responsiveness in peat moss factory workers.

Fifty-two males and 1 female, who were 19 to 62 y of age (median = 26), were employed at an eastern Quebec peat moss plant and were included in this study. Of these 53 workers, 29 were smokers, 5 were ex-smokers, and 19 had never smoked. The workers were divided by level of exposure into 4 groups: (1) group 1--minimal exposure (N = 7); (2) group 2--light exposure (N = 7); (3) group 3--moderate exposure (N = 17); and (4) group 4--heavy exposure (N = 22). Chest radiographs and physical examinations were normal for all subjects. Only 1 subject had precipitins to Penicillium and Monocillium species isolated from the peat moss plant. Pulmonary function tests were normal and similar in all groups. Thirty-three subjects (20 smokers, 4 ex-smokers, and 9 nonsmokers) had chronic bronchitis; these symptoms were related to work exposure for 28 subjects. Bronchial responsiveness to methacholine was measured in 14 subjects who had persistent cough and sputum. No subject had evidence of airway hyper-responsiveness, i.e., PC20 metacholine less than 8 mg/ml. We concluded that the peat moss workers in our study showed no evidence of extrinsic allergic alveolitis; however, chronic exposure to organic dust leads to chronic cough and sputum production, which is not associated with significant lung impairment nor increase in nonspecific airway responsiveness.

Sequential bronchoalveolar lavage in experimental extrinsic allergic alveolitis. The influence of cigarette smoking.

We studied the alterations induced by acute experimental extrinsic allergic alveolitis (EAA) on bronchoalveolar cell population in smoking and nonsmoking guinea pigs. Sixty-two animals divided into 3 groups were studied: Group 1 (17 animals), controls; Group 2 (21 animals), extrinsic alveolitis; Group 3 (24 animals), cigarette smoking and alveolitis. Bronchoalveolar lavages (BAL) were performed on Days 1, 19, and 44 for all animals. Group 3 animals had a fourth lavage before starting cigarette smoking, that is, 28 days before the beginning of the antigen injections. The other lavages were as for the other groups. BAL results on Day 1 were similar for each group. Cigarette smoking per se did not modify BAL in Group 3. EAA induction resulted in a large increase in all BAL cells, especially neutrophils of recovered fluid, which increased from 38 x 10(3) to 1,474 x 10(3) ml-1 (p less than 0.01) in Group 2 and from 58 x 10(3) to 740 x 10(3) in Group 3 (p less than 0.01). After maintenance, BAL neutrophils.ml-1 decreased to 444 x 10(3) in Group 2 (p less than 0.01), but stayed the same in Group 3: 973 x 10(3). After EAA induction, BAL neutrophils.ml-1 were higher in Group 2 than in Group 3 (p = 0.039); however, Group 2 had less neutrophils.ml-1 than Group 3 (p = 0.035) after EAA maintenance. We conclude that EAA results in a neutrophilic alveolitis and which can be evaluated by sequential BAL, and that cigarette smoking decreases the initial neutrophilic response and retards the eventual recovery during maintenance injections.

The preferential location of the human Y chromosome in somatic metaphase. I. Influence of Y polymorphism.

The location of the Y chromosome in metaphase figures was studied, with respect to its polymorphism, on 700 micrographs from blood lymphocyte cultures from 70 normal male members of seven Canadian family lines whose polymorphic Y chromosomes were inherited in a patrilinear fashion from seventeenth-century French ancestors. Three of these family lines were carriers of a long Y chromosome, two a small one, one had an average length Y and a seventh one had a satellited Y marker. The Y chromosome was peripheral in 75 to 90 per cent of the metaphase plates from each individual investigated. The long Y markers were more peripheral than the small ones while the average length Y chromosome had an intermediate position, whereas the satellited Y chromosome was located within the small group. The difference between the location of the long and the small Y chromosomes was highly significant. It is hypothesised that a heteromorphic Y might affect the nonrandom orientation of metaphasic chromosomes and favour meiotic nondisjunction and aneuploidy.

The influence of the length of the human Y chromosome on spontaneous abortions. A prospective study in family lines with inherited polymorphic Y chromosomes.

Following reports indicating a close association between the presence of a long Y chromosome in males and the risk of spontaneous abortion in their female partners, the incidence of spontaneous fetal loss was investigated in four family lines whose patrilineary ancestors emigrated from France to Canada during the second half of the seventeenth century. In two of the lines the males were carriers of a Yq+, in the other two the males had a Yq- or a normal Y chromosome. Results showed that in one of family lines with a Yq+, 17/26 (65.4%) wives had 33 (2.8%) spontaneous abortions in 151 pregnancies, whereas in each of the three other family lines 7/30 (23.3%) wives aborted 8 (4.9%), 15 (7.5%) and 10 (5.7%) times in 165, 200 and 175 pregnancies respectively. The high incidence of fetal loss found in one of the family lines whose males have a long Y chromosome correlates with previous observations on the influence of Yq+ on spontaneous abortions, and draws attention to the inheritable nature of this peculiarity. However, the low incidence of miscarriages observed in the other family line carrying a Yq+ seems to indicate that long Y chromosomes are of various types and could be produced by several mechanisms. Yq- does not seem to represent an increased risk of pregnancy loss. Results also demonstrated that while a long Y chromosome may affect the viability of the zygote, it does not affect the fertility of its carrier.

[Unusual chromosomal rearrangement. An autosomal telomeric translocation on a multicentury satellited Y (Yqs) chromosome]. / Un remaniement chromosomique inhabituel. Une translocation télomérique autosomique sur un Y à satellites (Yqs) multicentenaire.

A new born male infant with craniostenosis and minor phenotypic malformations was found to have a satellited Yq chromosome with, translocated on its satellite, a segment from the terminal part of the long arm of a presumed autosome 14. The rearrangement is de novo since the propositus' father has a non-rearranged satellited Y chromosome and he is, furthermore, a member of a family line in which a Yqs is transmitted in patrilineary fashion since 1668. Such and autosomal translocation on a satellited Y chromosome is a very rare event, because the abnormality makes up a double rearrangement on the same arm of a chromosome, with a three-century interval between the two phenomenons. A presumed partial trisomy 14q is associated with the clinical picture of the case.

[Absence of the palmar c triradius. Dermatoglyphic and geneologic study of a genetic character transmitted since the 17th century in a Quebec family]. / L'absence du triradius C palmaire. Etude dermatoglyphique et généalogique d'un caractère génétique, transmis depuis le dix-septième siècle, dans une lignée familiale québécoise.

A dermatoglyphic research on the absence of the palmar c-triradius was carried out in a Canadian family line originating from a French married couple who settled in the Quebec City area in 1649. Of the 51 individuals examined, 34 showed that c-triradius was missing on one or both palms. The study of the family tree and of the data confirms the hypothesis that an absent palmar c-triradius is an autosomal dominant trait transmitted by an heterozygous genotype with, in the present observation, an incidence of 66,6% and an estimated penetrance of 44,1%.

The chromosomes of the Canadian Beaver Castor canadensis.

A chromosome analysis of 24 Canadian beavers, Castor canadensis Kuhl (12 males and 12 females), captured in Laurentides Park, Qébec, has been performed from preparations of blood lymphocyte and skin cultures. The chromosome number was found to be 2n = 40. Measurements were made to determine relative lengths and arm ratios of chromosomes, which are metacentric or submetacentric. Results are in agreement with those already published regarding the chromosome number, but differ in the identification of the X chromosome, and in the morphology of the Y and some autosomes. C- ad G-banding techniques allowed the precise identification of individual chromosome pairs. A detailed idiogram of G-bands is presented.