[Recommendations for the healthcare of patients with FOP]. / Empfehlungen zur Versorgung von Patient:innen mit FOP.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible. AIM OF THE RECOMMENDATIONS: This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.

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.

Burden of disease associated with X-linked hypophosphataemia in adults: a systematic literature review.

This systematic review collated evidence on the burden of XLH in adults. Data captured highlight the substantial ongoing burden of XLH in adulthood and identified unmet needs. Greater awareness and understanding of the impact of XLH in adulthood are needed to improve care and outcomes in adults with XLH. INTRODUCTION: X-linked hypophosphataemia (XLH) is a rare metabolic bone disease characterized by renal phosphate wasting and musculoskeletal manifestations. Whilst the disease's impact in children is well documented, information on the effects of this progressive, debilitating condition on adults is lacking. This systematic review aimed to collate existing evidence on the burden of XLH in adulthood to identify unmet needs. METHODS: MEDLINE, Embase and Cochrane Library databases and recent congress reports were searched on 19 February 2019 for English-language publications describing the medical, humanistic and socio-economic impact of XLH in adults (≥ 18 years old). In addition, a structured Internet search was conducted. RESULTS: Of the 2351 articles identified, 91 met the selection criteria along with 44 congress abstracts. Data show that adults with XLH experience a range of clinical manifestations, particularly skeletal deformities and (pseudo)fractures, along with pain, dental abnormalities and impaired physical function and mobility. XLH in adulthood impacts on quality of life and places limitations on daily activities. The level of healthcare resource utilization among adults with XLH is indicative of substantial socio-economic burden; further research is needed to quantitate the economic impact on the healthcare system, society and patients. Adults with XLH may not receive appropriate care and treatment; a possible explanation for this is a lack of awareness among healthcare professionals. CONCLUSION: XLH in adults is associated with considerable disease burden and unmet needs. Forthcoming studies and increased awareness of the impact of XLH in adulthood should help to improve management of XLH in adulthood and patient outcomes.

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.

Asfotase alfa: enzyme replacement for the treatment of bone disease in hypophosphatasia.

Hypophosphatasia (HPP) is a rare disease caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNAP, TNSALP) gene. HPP causes a multisystemic syndrome with a predominant bone phenotype. The clinical spectrum ranges from high lethality in early onset (<6 months) HPP to mild late-onset syndromes. HPP management so far has been only supportive. Subcutaneous asfotase alfa, a first-in-class bone-targeted human TNAP enzyme replacement therapy, is the first compound to be approved for long-term treatment of bone manifestations in pediatric-onset HPP. In noncomparative clinical trials (treatment up to 7 years), this treatment was associated with skeletal, respiratory and functional improvement in perinatal, infantile and childhood-onset HPP. Compared with age-matched historical controls, patients with life-threatening perinatal and infantile HPP treated with asfotase alfa had substantially improved bone mineralization, survival and ventilation-free survival. In childhood HPP, asfotase alfa improved growth, gross motor function, strength and agility and decreased pain. The compound was well tolerated and most adverse events were of mild to moderate intensity. To date, data and experience concerning its efficacy and safety in long-term treatment are not yet available. Further studies to evaluate risks and benefits of enzyme replacement therapy with asfotase alfa in adults are in progress and are also strongly needed.

[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.

[Age and osteoporosis. Effects of aging on osteoporosis, the diagnostics and therapy]. / Alter und Osteoporose. Auswirkungen der Alterung auf die Osteoporose, deren Diagnostik und Therapie.

BACKGROUND: Osteoporosis is an age-associated disease, which is influenced by genetic, epigenetic and environmental factors. AIM: This article examines the evidence for specific aspects in osteoporosis diagnosis and management in higher age groups. MATERIAL AND METHODS: The study was based on extraction of data from literature databases and from the guidelines of the "Dachverband Osteologie" (DVO, Governing Body for Osteology). RESULTS: Age is a high risk factor for osteoporosis. Vitamin D insufficiency and reduced calcium absorption are common in the elderly. Loss of bone and muscle develop in a vicious circle of immobilization caused by underlying diseases. In addition deficits in cognition and coordination promote falls and fragility fractures. Clinical risk assessment including geriatric test batteries is recommended in all women > 70 and men > 80 years of age. Specific medication is indicated if the 10-year fracture risk exceeds 30 %, where in women > 75 and in men > 85 years of age bone density measurement can be relinquished. There is good evidence for the efficacy of antiosteoporotic medication even for the elderly. Prevention of falls requires multimodal management to enhance muscle power and coordination. It is essential to improve underlying cardiovascular, pulmonary and neurological diseases while critically evaluating the necessity of medication that boosts the risk of falls and fractures. There is good evidence for age and disease-adapted exercise programs such as Tai-Chi. Treating osteoporosis reduces the fracture risk, improves the quality of life, maintains independence and decreases mortality. CONCLUSION: Treating osteoporosis in the elderly is strongly recommended. Multimodal management and medication according to guidelines can be very successful, given that interdisciplinary and geriatric concepts consider the specific needs of the elderly population.

[Pathophysiology of bone metabolism]. / Pathophysiologie des Knochenstoffwechsels.

Osteoporosis is a multifactorial disease entailing a high risk to sustain fragility fractures. Its susceptibility is determined by genetic and environmental factors and underlying diseases. Bone is rebuilt and regenerated by osteoclasts, osteoblasts and osteocytes. Local and systemic growth and differentiation factors such as Insulin-like growth factors, bone morphogenetic proteins and wnt-proteins confer anabolic signals, while the RANK/RANK-Ligand and Osteoprotegerin (OPG) system regulates bone resorption. The ratio of osteoclast stimulating RANKL and its soluble decoy receptor OPG is modulated by sex hormones, vitamin D, parathyroid hormone, local growth factors and mechanical loading. Osteocytes regulate bone mass via the bone formation inhibitor sclerostin. Bone is tightly interconnected with and regulated by the calcium/phosphate/vitamin D system via the parathyroid gland, the gut, liver and kidneys. Sex hormones are important for bone formation during adolescence and their loss in menopause/andropause exaggerates bone resorption. Basically over-activity of osteoclasts and/or functional deficits of osteoblasts can cause negative bone balance and favor osteoporosis.

Serum CA 125 levels in early pregnancy and subsequent spontaneous abortion.

CA 125 has been found in high concentrations in human amniotic fluid throughout gestation, with significant quantities seen in the decidua and chorion. Because disruption of the epithelial basement membrane of the fetal membrane or the decidua could theoretically lead to a rise in maternal CA 125 levels, this increase may be a predictor of subsequent spontaneous abortion of the fetus. A study was initiated to investigate whether a sudden rise in the serum CA 125 level might predict spontaneous first-trimester abortions. CA 125 levels of 101 pregnant women were evaluated 18-22 days from conception and 6 weeks from conception (a frequent time for spontaneous abortion) to determine whether there is a sudden increase (from baseline or early trimester levels) during the middle or late first trimester immediately before or at the time of abortion. The results indicated that although there was a definite correlation found between elevation of CA 125 and spontaneous abortion, the higher levels occurred early in the first trimester whereas the majority of abortions did not occur until much later, after fetal viability was established. Six of ten women with CA 125 levels of 150 U/mL or greater aborted, compared with four of 92 women with CA 125 levels less than 150 U/mL. One of 11 women pregnant after in vitro fertilization had a CA 125 level above 150 U/mL, and she aborted.

Very high CA 125 levels during early first trimester in three cases of spontaneous abortion with chromosomal abnormalities.

Three women with very elevated, early-first-trimester CA 125 levels spontaneously aborted but not until later in the first trimester or early in the second trimester. All three products of conception showed chromosomal abnormalities. Further investigation is warranted to see if high CA 125 levels might be predictive of abnormal karyotypes.

Aldo Castellani--an appraisal of his life and oeuvre.

Aldo Castellani was one of those pioneers who initiated breath-taking discoveries and progress in medical sciences during the early years of this century with great personal engagement and courage. His striking findings, such as the so-called Absorption-Test, the introduction of multiple vaccination, or the exploration of sleeping sickness and the discovery of Trichophyton rubrum, were achieved before he was even 35 years old. He received acknowledgement as a physician and lecturer. Many of his disciples and coworkers became first rate scientists, owing a lot to his encouraging personality. Castellani's straight forward character endeared him to many famous contemporaries. His uncompromising nationalism for Italy on the other hand arouse astonishment and aversion. His involvement in three wars again and again, rendered scientific researches and work difficult.