High FGF23 levels are associated with impaired trabecular bone microarchitecture in patients with osteoporosis.

This cross-sectional study examined the associations between c-terminal FGF23 levels, laboratory markers of bone metabolism and bone microarchitecture in 82 patients with osteoporosis. Higher FGF23 levels were associated with impaired trabecular but not cortical bone microarchitecture, and this was confirmed after adjusting for confounding variables such as age or BMI. INTRODUCTION: Fibroblast growth factor 23 (FGF23) is an endocrine hormone-regulating phosphate and vitamin D metabolism. While its mode of action is well understood in diseases such as hereditary forms of rickets or tumor-induced osteomalacia, the interpretation of FGF23 levels in patients with osteoporosis with regard to bone microarchitecture is less clear. METHODS: C-terminal FGF23 levels and bone turnover markers were assessed in 82 patients with osteoporosis (i.e., DXA T-score ≤ - 2.5 at the lumbar spine or total hip). Bone microarchitecture was measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia. Data were analyzed in a cross-sectional design using correlation and regression models. RESULTS: We found a significant negative logarithmic correlation between FGF23 levels and trabecular but not cortical bone microarchitecture at both skeletal sites. Furthermore, using a multiple linear regression model, we confirmed FGF23 as a predictor for reduced trabecular parameters even when adjusting for confounding factors such as age, BMI, phosphate, bone-specific alkaline phosphatase, vitamin D3, and PTH. CONCLUSIONS: Taken together, high FGF23 levels are associated with impaired trabecular bone microarchitecture in osteoporosis patients, and this association seems to occur after adjustment of confounding variables including phosphate and vitamin D. Future longitudinal studies are now needed to validate our findings and investigate FGF23 in relation to fracture risk.

Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2.

Pregnancy was found to be a skeletal risk factor promoting the initial onset of previously unrecognized monogenic bone disorders, thus explaining a proportion of cases with pregnancy-associated osteoporosis. Therapeutic measures should focus in particular on the normalization of the disturbed calcium homeostasis in order to enable the partial skeletal recovery. INTRODUCTION: Pregnancy-associated osteoporosis (PAO) is a rare skeletal condition, which is characterized by a reduction in bone mineral density (BMD) in the course of pregnancy and lactation. Typical symptoms include vertebral compression fractures and transient osteoporosis of the hip. Since the etiology is not well understood, this prospective study was conducted in order to elucidate the relevance of pathogenic gene variants for the development of PAO. METHODS: Seven consecutive cases with the diagnosis of PAO underwent a skeletal assessment (blood tests, DXA, HR-pQCT) and a comprehensive genetic analysis using a custom-designed gene panel. RESULTS: All cases showed a reduced BMD (DXA T-score, lumbar spine - 3.2 ± 1.0; left femur - 2.2 ± 0.5; right femur - 1.9 ± 0.5), while the spine was affected more severely (p < 0.05). The trabecular and cortical thickness was overall reduced in HR-pQCT, while the trabecular number showed no alterations in most cases. The genetic analysis revealed three novel mutations in LRP5, COL1A1, and COL1A2. CONCLUSION: Our data show that previously unrecognized monogenic bone disorders play an important role in PAO. Pregnancy should be considered a skeletal risk factor, which can promote the initial clinical onset of such skeletal disorders. The underlying increased calcium demand is essential in terms of prophylactic and therapeutic measures, which are especially required in individuals with a genetically determined low bone mass. The implementation of this knowledge in clinical practice can enable the partial recovery of the skeleton. Consistent genetic studies are needed to analyze the frequency of pathogenic variants in women with PAO.

Clinical, radiographic and biochemical characteristics of adult hypophosphatasia.

In this study, we report on clinical, radiographic and biochemical characteristics of 38 patients with adult hypophosphatasia. High-resolution peripheral quantitative computed tomography showed alterations of bone microstructure in a subgroup of 14 patients. Pyridoxal-5-phosphate levels correlated with the occurrence of fractures and the number of symptoms. INTRODUCTION: Hypophosphatasia (HPP) is a rare disorder with a wide range of clinical manifestations. A reduced enzymatic activity of alkaline phosphatase (ALP) is the key marker of the disease, causing an accumulation of ALP substrates such as pyridoxal-5-phosphate (PLP). The purpose of this retrospective study was to further characterize adult onset HPP. METHODS: We assessed clinical, radiographic and laboratory characteristics of 38 adult patients with HPP. Diagnosis of HPP was established by the combination of low-serum ALP, raised PLP levels and typical symptoms and was genetically confirmed in 32 patients. Dual-energy X-ray absorptiometry (DXA) and laboratory data were available in most patients. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed in 14 patients. RESULTS: Clinical characteristics included a wide spectrum of symptoms. A history of fracture was present in 15 patients (39%). Twenty-one patients (55%) complained about recurring headaches, 23 patients (61%) had recurring muscle pain, 4 patients (11%) suffered from severe muscle weakness and 18 patients (47%) showed dental abnormalities. Z-scores assessed by DXA were only slightly reduced in most adult HPP patients. HR-pQCT of 14 patients showed microstructural changes of trabecular and cortical bone compared to reference values of healthy subjects. The occurrence of fractures and multiple symptoms (>2 typical HPP symptoms) were associated with significantly elevated levels of PLP. CONCLUSION: Adult HPP presents with a wide range of clinical symptoms and is not associated with low bone mass in general. PLP seems to be a good marker for disease severity in adult patients as its level is correlated with the occurrence of fractures and number of symptoms.

[Hypophosphatasia : What is currently available for treatment?] / Hypophosphatasie : Was ist gesichert in der Therapie?

This review presents the current knowledge on the diagnosis and treatment of hypophosphatasia, a rare genetic disease, caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene. The clinical spectrum of hypophosphatasia is highly variable ranging from lethal infantile forms to mild forms diagnosed in adults. Although the disease rarely occurs, correct diagnosis is important to provide appropriate treatment and to avoid worsening by use of harmful drugs such as bisphosphonates. Low serum values of alkaline phosphatase (ALP) is the main feature of HPP, but by itself not sufficient for diagnosis, as it can occur under different conditions. Diagnosis can be established by the combination of reduced levels of ALP, elevated ALP substrates (PLP, PEA, PPi) and typical symptoms and can be confirmed by genetic testing of ALPL mutations. Enzyme replacement therapy is now available for affected patients with onset of the disease during childhood and adolescence. Early results of enzyme replacement therapy are encouraging. However, a multidisciplinary approach remains the core of the treatment including nutritional support, monitoring of vitamin D, calcium and phosphate levels, physical therapy and regular dental care.

[Medication and bone metabolism: Clinical importance for fracture treatment]. / Medikamente und Knochenstoffwechsel : Klinische Bedeutung für die Frakturbehandlung.

INTRODUCTION: The improvement and acceleration of fracture healing has been a component of medical practice since fractures have been treated. The aim is not only to fulfill the basic principles of fracture healing, such as reduction, retention, soft tissue coverage and infection prevention but also to reduce negative influences on fracture healing and promote positive factors. Nicotine, alcohol, diabetes and malnutrition can negatively affect fracture healing and should be appropriately controlled during fracture treatment; however, it is far more difficult to develop medicinal treatment strategies that lead to improvement and acceleration of fracture healing. AIM: This article provides an overview of pharmacological factors influencing fracture healing. In addition, substances frequently used in clinical practice will be evaluated in terms of the effects on fracture healing processes. MATERIAL AND METHODS: An extensive literature search was conducted in PubMed based on thematic keywords. The selection of studies and scientific publications focused mainly on results from clinical trials in order to provide practically relevant information. RESULTS: In this context, preclinical studies have identified several drugs that lead to the acceleration of fracture healing; however, only a very limited number of clinical trials have confirmed this positive effect. Most of these studies dealt with drugs developed for the treatment of osteoporosis, as osteoporotic fractures are common and a positive or negative influence of such drugs are of particular interest in this field. In the field of osteoporosis medication a certain degree of positive effect of parathyroid hormone 1-34 (PTH) on fracture healing has been shown in clinical trials. For other osteoporosis medications no negative influence on fracture healing in clinical settings has been reported; however, there seems to be a positive effect in terms of better implant fixation for patients receiving oral bisphosphonate therapy. DISCUSSION: Systemic medication to improve fracture healing will not be part of the clinical routine in the foreseeable future as the available data for already approved drugs and drugs under development do not currently justify routine administration. However, the currently known data should encourage the potential of known medications to be completely exhausted in fracture healing studies as well as novel therapy options in the sense of positive effects on fracture healing in order to improve patient care.

[Vitamin D metabolism of the bone]. / Vitamin-D-Stoffwechsel des Knochens.

BACKGROUND: Bone health is a crucial requirement for individual mobility. Preventive, diagnostic, and therapeutic actions to preserve or restore bone health are major tasks for orthopedic surgeons and health practitioners in musculoskeletal medicine. RESULTS: In the context of the widespread vitamin D deficiency in Germany, it is relevant to keep in mind thatserum calcitriol levels above > 30 µg/l are necessary for optimal bone metabolism and bone health. In particular, because vitamin D deficiency not only increases the amount of non-mineralized bone matrix (osteoid), but it can also cause negative changes in the mineralized bone tissue. Widening of the osteons and osteocyte lacunae, together with increased bone aging under the osteoid layer, can lead to reduced fracture resistance. CONCLUSION: Integration of bone metabolism into the orthopedic strategy is an important concept for optimizing treatment in modern musculoskeletal medicine.

[Calcium and vitamin D in osteology]. / Kalzium und Vitamin D in der Osteologie.

Calcium homeostasis is of paramount physiological and pathophysiological importance in health and disease. This article focuses on the skeletal relevance of calcium and vitamin D in daily clinical practice. Against the background of an endemic vitamin D deficiency in Germany and the increasing number of patients with drug-induced (proton pump inhibitor) enteral calcium uptake problems, it is of critical importance to understand that a vitamin D level of > 30 µg/l (> 75 nmol/l) is required for intact skeletal mineralization and that furthermore, a physiological gastric acid production is essential for a normal enteral uptake of calcium from foodstuffs. Therefore, a guideline-conform handling of vitamin D and calcium substitution is required not only for patients with rheumatoid diseases but also for any osteological therapy.

Calcium gluconate supplementation is effective to balance calcium homeostasis in patients with gastrectomy.

UNLABELLED: We demonstrate histological evidence for hyperparathyroidism in patients with gastrectomy. This is, at least in part, explained by impaired calcium absorption, resulting in mineralization defects and secondary hyperparathyroidism. Additionally, we demonstrate improved bone mineralization in patients with gastrectomy after gluconate therapy and showed the effectiveness of calcium gluconate over carbonate to balance impaired calcium hemostasis in mice. INTRODUCTION: Gastrectomy and hypochlorhydria due to long-term proton pump inhibitor therapy are associated with increased fracture risk because of intestinal calcium malabsorption. Hence, our objectives were to histologically investigate bone metabolism in patients with gastrectomy and to analyze the impact of calcium gluconate supplementation on skeletal integrity in the setting of impaired gastric acidification. METHODS: Undecalcified bone biopsies of 26 gastrectomized individuals were histologically analyzed. In the clinical setting, we retrospectively identified 5 gastrectomized patients with sufficient vitamin D level, who were additionally supplemented with calcium gluconate and had a real bone mineral density (aBMD) follow-up assessments. A mouse model of achlorhydria (ATP4b-/-) was used to compare the effect of calcium gluconate and calcium carbonate supplementation on bone metabolism. RESULTS: Biopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (p < 0.05) as well as impaired calcium distribution in mineralized bone matrix compared to healthy controls. Five gastrectomized patients with sufficient vitamin D level demonstrated a significant increase in aBMD after a treatment with calcium gluconate alone for at least 6 months (p < 0.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria. CONCLUSION: Gastrectomy is associated with severe osteomalacia, marrow fibrosis, and impaired calcium distribution within the mineralized matrix. We show that calcium gluconate supplementation can increase bone mineral density in gastrectomized individuals and performs superior to calcium carbonate in restoring calcium/skeletal homoeostasis in a mouse model of achlorhydria.

Radiation-free spinometry adds to the predictive power of historical height loss in clinical vertebral fracture assessment.

UNLABELLED: After introducing radiation-free spinometry as a diagnostic tool to predict prevalent vertebral fractures, its validity and comparison with established tools such as historical height loss (HHL) was missing. This study shows that radiation-free spinometry is valid and its application adds predictive power to the ability of HHL to assess presence of vertebral fractures. INTRODUCTION: Recently, radiation-free spinometry was introduced to identify patients with vertebral fractures (VFs). The goals of this study were to validate previous findings and to test the predictive accuracy of radiation-free spinometry compared to the assessment of historical height loss (HHL). METHODS: We analyzed 304 patients [258 (85%) females (age range, 42-90 years) and 46 males (50-84 years)], including 108 patients with VFs. We performed receiver operator characteristic and net reclassification improvement (NRI) analyses to quantify the predictive power and the added predictive ability of radiation-free spinometry and HHL for VFs. RESULTS: The estimated odds ratios in the thoracic and the lumbar spine showed no significant differences compared to the previously published, except for the effect of thoracic kyphosis in region "Th12 + L4-5." Radiation-free spinometry and HHL were both moderately accurate to raise suspicion for VFs. According to the NRI, which is defined as the net sum of the predicted risk increase in individuals who have VFs and the predicted net risk decrease for those who have not, we found significant improvements in all regions of interest when HHL and radiation-free spinometry were used in combination (area under the curve (AUC) 0.729-0.788). CONCLUSION: Our results based on a new data set suggest validity of the prognostic score published previously. In addition, although our findings did not confirm our initial hypothesis that radiation-free spinometry alone performs superior to the assessment of HHL to predict VFs, we showed that radiation-free spinometry still adds predictive power to the ability of HHL to discriminate patients with VFs.

A holistic hip fracture approach: individualized diagnosis and treatment after surgery.

Secondary fracture prevention is of paramount importance in the clinical management of patients with hip fractures. However, in contrast to the excellent surgical care provided to these patients in the Western hemisphere and despite good medical options, causative treatment of the underlying osteopathy causing skeletal fragility remains an unmet medical need that urgently needs to be improved. This calls for a concerted action between orthopedic/trauma surgeons and osteologists, as outstanding hospitals not only treat fragility fractures, but also prevent fractures from recurring. Aiming for a holistic hip fracture approach, in this work we highlight aspects of (a) improved risk assessment and differential diagnosis, (b) optimized basic medical care, and

Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis.

UNLABELLED: Indolent systemic mastocytosis (ISM) can trigger bone loss. However, the clinical relevance of different mast cell infiltration patterns for bone remains to be clarified. Here, we report increased bone turnover in individuals with ISM, and its extent is rather related to the type of mast cell distribution within the bone marrow than to the presence or absence of cutaneous manifestations. INTRODUCTION: It is well established that ISM can trigger osteopenia or osteoporosis. However, neither the clinical relevance of the infiltration pattern of mast cells within the bone marrow nor the impact of the presence or absence of cutaneous mast cell infiltration has been elucidated. METHODS: We retrospectively analysed 300 cases with histologically proven ISM of the bone marrow and performed quantitative histomorphometry for a subgroup of 159 patients that did not receive any treatment before the biopsies were taken. Most importantly, since 66 % of the patients displayed ISM without the characteristic skin lesions, we were able to compare ISM with or without cutaneous manifestation. RESULTS: We found that both forms of ISM were not only characterized by a decreased trabecular bone mass but also by an increased number of osteoclasts and osteoblasts. Interestingly, when we analysed these data in relation to mast cell distribution, we found that the bone cell numbers in cases with mast cell granulomas were significantly increased compared to cases with diffuse mast cell distribution. Moreover, evidence of increased bone turnover was also found in 16 patients displaying osteosclerosis. CONCLUSION: Based on the largest cohort of bone biopsies from patients with ISM analysed so far, we could demonstrate high bone turnover, more specifically increased osteoblast and osteoclast numbers and surface indices, as a cause of the skeletal changes. Moreover, the severity of the bone disease is presumably rather dependent on the amount of mast cells and their distribution within the bone marrow irrespective of the presence or absence of cutaneous involvement.

Osteocalcin is associated with testosterone in the general population and selected patients with bone disorders.

Research in the last decade has revealed that bone is not only a target tissue for numerous circulating hormones but functions as an endocrine organ itself. As a recent study demonstrated a stimulatory effect of the osteoblast-derived hormone osteocalcin (OCN) on testosterone production in mice, we investigated whether such an association can be replicated in humans. We used data from 1338 men (25-86 years) in the population-based epidemiological Study of Health in Pomerania and from 110 male outpatients with bone disorders (18-85 years) for the study. We analysed cross-sectional associations between OCN and total testosterone serum concentrations (TT), as well as associations between further markers of bone turnover [bone-specific alkaline phosphatase (BAP), serum C-terminal telopeptides of Type I collagen (CTX), urinary deoxypyridinoline] and TT using ordinary least square (OLS) regression models. Multivariable OLS models revealed a positive association between OCN and TT in the population-based (ß coefficients for a one standard deviation increase, 0.590; standard error (SE), 0.175; p-value, <0.01) and patient-based (ß coefficient, 0.575; SE, 0.132; p-value, <0.01) samples even after adjustment for age and body mass index (both samples), and time of blood sampling (population-based sample only). Furthermore, we observed positive associations between BAP and TT (ß coefficient, 0.403; SE, 0.170; p-value, 0.02) as well as between CTX and TT (ß coefficient, 0.733; SE, 0.172; p-value, <0.01) in men from the general population. The present investigation shows that OCN is associated with TT in the general population and in patients with bone disorders, and may thus indicate general male health status. Additional longitudinal observational studies are warranted to confirm our findings and future experimental research is necessary to elucidate potential mechanisms underlying the observed associations.

Spontaneous osteonecrosis of the knee (SONK).

PURPOSE: Spontaneous osteonecrosis of the knee (SONK/Morbus Ahlback) mainly affects the medial condyle of elderly women. It is assumed that localized vascular insufficiency leads to necrosis of the subchondral bone with subsequent disruption of the nutrition supply to the cartilage above. The aetiology remains unclear in detail. Operative treatment procedures compete against non-operative strategies, whereas the outcome is unpredictable in many cases. METHOD: A consecutive case series of five patients suffering from SONK was analysed. All patients underwent a clinical examination, magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry scan, as well as laboratory analyses and visual analogue scale (VAS) evaluation. Our treatment regime is based on high-dose vitamin D administered orally and intravenous application of 3 mg ibandronate two times within 8 weeks. Another 8 weeks later, all patients were followed up including a follow-up MRI. RESULTS: Within 4 weeks, all patients were free of symptoms. The MRI follow-up showed remission of the bone marrow oedema in every case studied. VAS decreased significantly from 7.4 ± 1.0 pre-interventional to 0.8 ± 1.0 post-interventional. No allergic reactions or other side effects were documented. CONCLUSION: We showed that our treatment regime not only eliminated the pathological findings in the MRI of all cases studied, but also decreased the pain level and functional limitations within a short-time period. LEVEL OF EVIDENCE: IV.

Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture.

SUMMARY: Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal bone mineral density (BMD) is rather low. Here, we have identified bone mineralization defects together with low serum 25-hydroxyvitamin D (25-(OH) D) levels as additional factors associated with femoral neck fractures. INTRODUCTION: Osteoporotic fractures of the femoral neck are associated with increased morbidity and mortality. Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal BMD is rather low. To identify possible additional factors influencing femur neck fragility, we analyzed patients with femoral neck fracture. METHODS: We performed a detailed clinical and histomorphometrical evaluation on 103 patients with femoral neck fracture including dual-energy X-ray absorptiometry, laboratory parameters, and histomorphometric and bone mineral density distribution (BMDD) analyses of undecalcified processed biopsies of the femoral head and set them in direct comparison to skeletal healthy control individuals. RESULTS: Patients with femoral neck fracture displayed significantly lower serum 25-(OH) D levels and increased serum parathyroid hormone (PTH) compared to controls. Histomorphometric analysis revealed not only a decreased bone volume and trabecular thickness in the biopsies of the patients, but also a significant increase of osteoid indices. BMDD analysis showed increased heterogeneity of mineralization in patients with femoral neck fracture. Moreover, patients with femoral neck fracture and serum 25-(OH) D levels below 12 µg/l displayed significantly thinner trabecular bone. CONCLUSION: Taken together, our data suggest that impaired bone mineralization accompanied by low serum 25-(OH) D levels is of major importance in the etiology of femoral neck fractures. Therefore, balancing serum 25-(OH) D levels and thereby normalizing PTH serum levels may counteract pronounced mineralization defects and might decrease the incidence of femoral neck fractures.

Increased expression of transthyretin in leptin-deficient ob/ob mice is not causative for their major phenotypic abnormalities.

The hormone leptin is a critical regulator of adipogenesis and energy metabolism. Similarly, leptin-deficient ob/ob mice display various metabolic abnormalities, including not only obesity and insulin resistance, but also hypogonadism and high bone mass. By genome-wide expression analysis using hypothalamus RNA from wild-type and ob/ob mice, we observed the increased expression of the gene for transthyretin (Ttr) in the latter, as confirmed by quantitative real-time-polymerase chain reaction. Because Ttr encodes a carrier protein for retinol transport, and because we further found increased retinol levels in the serum of ob/ob mice, we investigated whether the additional absence of Ttr would influence the ob/ob phenotype. It was found that Ttr-deficient ob/ob mice were indistinguishable from ob/ob littermates in terms of body weight, as well as serum glucose, insulin and cholesterol levels. Although all of these parameters were identical to wild-type controls in Ttr-deficient mice, we found that the sole deletion of Ttr caused a significant increase of trabecular bone mass, bone marrow adiposity and mean adipocyte area in white adipose tissue. Interestingly, all these latter parameters were highest in Ttr-deficient ob/ob mice, and only in these mice did we observe a full penetrance of liver steatosis at 24 weeks of age. Taken together, our data demonstrate that the increased expression of Ttr in ob/ob mice does not cause (but rather attenuates) their phenotypic abnormalities.

Influence of non-traumatic thoracic and lumbar vertebral fractures on sagittal spine alignment assessed by radiation-free spinometry.

UNLABELLED: Due to missing indications for specific diagnostics, the majority of non-symptomatic vertebral fractures are not diagnosed. This study shows the ability of radiation-free spinometry to assess sagittal spine parameters to raise suspicion for new non-traumatic thoracic and lumbar vertebral fractures and indicate specific diagnostics. INTRODUCTION: The primary aim of this study was to investigate the accuracy of radiation-free spinometry to predict new non-traumatic vertebral fractures (VF) by the assessment of thoracic kyphosis (TK), lumbar lordosis (LL), and trunk inclination. METHODS: Three hundred sixty-one patients (278 females and 83 males; age, 67.0 ± 8.6 years) were enrolled. In 86 women and 24 men, at least one non-traumatic VF was confirmed by radiography, MRI, and/or CT. Spinometry (video rasterstereography) was used to assess TK, LL, and trunk inclination. Receiver operating characteristic (ROC) and multivariate logistic regression analyses were performed to test the influence of age, sex, number, location, and grade of fractures on sagittal spine alignment. RESULTS: TK, LL, and trunk inclination were associated with advancing age (p < 0.05). Patients with prevalent thoracic and lumbar VFs showed increased TK (p < 0.001), decreased LL (p < 0.001), and increased trunk inclination (p < 0.001) in comparison to patients without VFs. ROC analysis revealed that the combination of TK and LL presented with the best predictive accuracy to raise suspicion for new grade 2 or grade 3 VFs in the thoracic and the lumbar spine (AUC, 0.752-0.771). Odds ratio (OR) showed an increased risk for VFs with increased TK (OR, 1.05-1.11; p < 0.001) and LL (1.05-1.07; p < 0.001) in specified regions of interest. A TK <50° (sensitivity, 88-100 %; specificity, 23-25 %) and LL (78-92 %; 24-27 %) were considered as appropriate cutoffs for future screening. CONCLUSION: Spinometry showed better predictive accuracy than historical height loss. Severe changes of TK and LL may help to raise suspicion of new VFs radiation-free and indicate proper diagnostics, such as radiographs, MRI, or CT.

Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene.

Hypophosphatasia (HPP) is a rare inborn disease caused by different mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Previous studies showed that gene mutations could exhibit a dominant negative effect leading to a mild HPP phenotype in heterozygous carriers. In the present report we describe the clinical and functional studies of a novel mutation localized in the start codon of transcript variant 1 of the ALPL gene from a female adult heterozygous carrier. The mutation results in translation of an N-terminally truncated protein, which might be identical to the deduced protein from ALPL transcript variant 2. When overexpressed in HEK-293 cells it does not exhibit any enzymatic activity and has no significant effect on the wild type ALPL protein. Furthermore it is not attached to the cell membrane. Due to the loss of the signal peptide an intracellular misrouting and a premature degradation is obvious. Hence the new isoform deposited in the database does not produce an active protein as it is the case in the natural mutation of our patient. Since the mutation does not produce a dominant negative protein in heterozygous carriers, the clinical phenotype in our patient and her relatives is very mild with only unspecific myalgia. However the patient developed bone marrow edema of both femoral heads during lactation after delivery of a healthy child, indicating a risk to develop alterations of bone metabolism in challenge situations. Her sister complains of identical symptoms, her father shows distinct symptoms of odonto-hypophosphatasia. The question if or if not carriers of ALPL mutations in general or only with distinct genotypes can be symptomatic in normal life or in challenge situations requires systematic clinical studies.

Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis.

UNLABELLED: 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. INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.