Influence of denosumab on bone mineral density in a severe case of pregnancy-associated osteoporosis.

Pregnancy and lactation-associated osteoporosis (PLO) with predominantly subsequent vertebral fracture is a rare but severe disease with an estimated incidence of 0.4 in 100,000. In the past, patients with PLO have been predominantly treated with oral and i.v. bisphosphonates to reduce subsequent fracture risk. Hereby, the use of bisphosphonates in premenopausal women is controversial, as bisphosphonates know to persist in bone for many years and can be exposed and circulate in maternal serum and subsequently pass the placenta barrier and may have a detrimental effect on fetal bone health. Here we report the effects of denosumab on the bone mineral density (BMD) and subsequent fracture risk in PLO. In this case presentation, denosumab was administered postpartum with 3000 IE vitamin D and 1000 mg of calcium daily in a patient with PLO and vertebral fracture of L1 and L4. After 18 months of treatment with denosumab, we could demonstrate a clinical significant increase of BMD at the lumbar spine, femoral neck, and total hip of 32.2%, 13.0%, and 11.5% respectively with no further subsequent fractures. As the patient had regular menstrual cycles and considered a further pregnancy, denosumab treatment was terminated and soon a second pregnancy occurred. After the second pregnancy, BMD decreased at the lumbar spine, femur neck, and total hip by -8.8%, -6.9%, and -7.0% respectively compared to the maximum values during treatment with denosumab, but was still significantly higher compared to baseline levels with no further fractures.

Effect of progestogen-only contraception on premenopausal fracture risk: a case-control study.

Our study demonstrated that progestogen-only oral and intrauterine contraceptives are not associated with fracture risk independent from age. PURPOSE: The use of progestogen-only contraception, resulting in a hypoestrogenic state, has been associated with impaired bone acquisition and increased fracture risk. The aim of this large population-based study was to assess the fracture risk in association with the use of progestogen-only contraceptives (progestogen-only pills (POPs) and progestogen-containing IUDs (LNG-IUD)). METHODS: We identified 14,421 women between 16 and 55 years of age with a first-time diagnosis of fracture and matched them with 14,421 random controls using the Disease Analyzer Database. RESULTS: The results of the first adjusted logistic regression model (ever use vs. never use of progestogen-only contraceptives) revealed that there was no significant association between the use of POPs (OR = 0.98, 95% CI 0.90-1.07, p = 0.657) or LNG-IUDs (OR = 0.99, 95% CI 0.81-1.21, p = 0.945) and fracture incidence. Also, in the second regression model, we observed no effect of duration of use of POPs (OR = 1.01, 95% CI 0.98-1.03, p = 0.672) or LNG-IUDs (OR = 0.94, 95% CI 0.87-1.02, p = 0.177) on fracture occurrence. We also observed no effect in different age groups. CONCLUSION: Our study results indicate that progestogen-only contraception (either POPs or LNG-IUPs) is not associated with fracture risk and may be considered a bone-safe option for adults and adolescents.

Incidence of fractures in patients with type 1 diabetes mellitus-a retrospective study with 4420 patients.

This retrospective study investigated the incidence of fracture in 4420 type 1 diabetes (T1DM) patients. Our findings indicate that patients with T1DM have an increased incidence of fractures. Further studies and preventive measures are urgently needed. INTRODUCTION: The aim of this study was to investigate the incidence of fracture in patients with type 1 diabetes mellitus (T1DM). METHODS: This study is based on the German Disease Analyzer database and included 4258 adult individuals with a T1DM diagnosis documented between January 2000 and December 2015 in 1203 general practices in Germany. Individual matching of T1DM and non-diabetic patients was performed. The cumulative incidence of new fractures was shown for up to 10 years after the index date using Kaplan-Meier curves. Cox proportional hazard models (dependent variable: incident fracture) were used to estimate the effect of T1DM on fracture incidence, as well as the effect of predefined variables on fracture incidence. RESULTS: After 10 years of follow-up, the cumulative fracture incidence was 18.4% for T1DM patients and 9.9% for non-diabetic patients (p < 0.001). A strong association between T1DM and fractures was found (HR, 2.01 (95% CI, 1.70-2.38) p < 0.001) in both female and male patients. Significant differences between T1DM and non-diabetes patients were found in lower leg/ankle, foot and toe, shoulder/upper arm, and rib(s), sternum and thoracic spine fractures. A significant association between higher age and fracture incidence was observed in T1DM patients. CONCLUSIONS: In summary, we found that patients with T1DM have a twofold increased fracture rate compared with healthy controls. Furthermore, fractures were associated with increased age and high HbA1c values.

[Differential diagnoses of osteoporosis]. / Differenzialdiagnosen der Osteoporose.

The differential diagnoses of osteoporosis in geriatric and trauma patients are very important as they may induce different therapies. On average approximately 20% of women and 50% of men have secondary causes of osteoporosis. The foundation of the diagnostics is a basic osteological laboratory investigation with which the most important secondary causes can be identified. From a geriatric and traumatological point of view vitamin D deficiency with secondary hyperparathyroidism, primary hyperparathyroidism, male hypogonadism, multiple myeloma and monoclonal gammopathy of unclear significance (MGUS) are of particular importance.

[Management of osteoporosis after fragility fractures]. / Management der Osteoporose nach Fragilitätsfrakturen.

Osteoporosis is defined as a systemic bone disease with decreased bone strength and an increased susceptibility for fractures. Older people in particular face an increased risk of fractures. These kind of fractures are usually caused by an inadequate trauma and are the so-called fragility fractures. In older adults immediate fracture stabilization and early mobilization have become the standard procedure after a fragility fracture. Treatment of the underlying osteoporosis often plays a minor role in clinical practice. Only a small group of patients are already under osteoporosis medication and even after a fracture occurs only few patients receive osteoporosis drug treatment with the aim to reduce the progression of osteoporosis and to reduce subsequent fractures. In the literature this has been described as the osteoporosis care gap. The following article presents an overview of treatment options and answers many different questions from the clinical routine.

[Identification, diagnostics and guideline conform therapy of osteoporosis (DVO) in trauma patients : a treatment algorithm]. / Identifikation, Diagnostik und leitliniengerechte Osteoporosetherapie (DVO) unfallchirurgischer Patienten : Ein Behandlungsalgorithmus.

Osteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.

[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.

[New strategies for exercise training in osteoporosis]. / Innovatives Bewegungstraining bei Osteoporose.

In the prevention and treatment of osteoporosis, movement with muscle strengthening and proprioceptive training plays a major role. This was taken into consideration in the guidelines by the governing body on osteoporosis (Dachverband Osteoporose, DVO) from 2014 on prophylaxis, diagnosis and treatment of osteoporosis and in the DVO guidelines from 2008 on physiotherapy and exercise therapy for osteoporosis. Increases in lumbar bone density of between 0.5 % and 2.5 % can be achieved in women by strengthening exercises with high resistance. With this combination and strengthening of the quadriceps muscle a reduction of falls and hence the fracture risk could also be achieved. In traumatology, training for muscle strengthening is not always possible, especially for elderly patients. Practically relevant alternatives are regular walking and aquatraining, which may also lead to a significant increase in bone mineral density. Furthermore, large effects can be achieved with alternating side whole-body vibration (WBV) training with whole body vibration plates with only 3 days of training per week and with short training periods (15-20 min). Rates of increase in leg strength between 20 % and almost 40 % and in bone density between 0.5 % and 4 % in 6 months have been described. Whether and with what intensity whole body vibration therapy could be used for e.g. more rapid healing of fractures, is currently unclear. Initial positive results have been described in animal models.

[New DVO guideline for osteoporosis management 2014 and its importance for trauma surgeons]. / Neue Osteoporose-Leitlinie DVO 2014 und ihre Bedeutung für den Unfallchirurgen.

Osteoporosis-associated fractures represent a growing challenge in the treatment of orthopedic patients. In November 2014 a new revision of the guidelines on osteoporosis by the German Osteology Society (Dachverband Osteologie DVO) was adopted, in which additional risk factors for fractures and further treatment options have been included. On the one hand the existing model used to diagnose osteoporosis and estimate a high fracture risk as a guidance for the use of specific anti-osteoporotic therapy in patients without a fragility fracture was maintained and further refined. On the other hand the guideline includes the option to initiate a specific osteoporosis therapy without a prior bone densitometry in patients with typical radiographs of a proximal femur fracture and higher grade vertebral fractures, suspicious for osteoporosis, depending on the overall clinical context. This may reduce the treatment gap of osteoporosis in Germany. In this paper the changes in the DVO guidelines 2014 on osteoporosis are summarized, focusing on the most important changes with practical relevance for orthopedic surgeons.

[Osteological interdisciplinary management : exemplified by a bilateral proximal humeral fracture]. / Osteologisch-interdisziplinäres Management : Am Beispiel einer bilateralen proximalen Humerusfraktur.

Following locking plate osteosynthesis of a proximal humeral fracture, a 62-year-old male patient suffered mild secondary dislocation. Subsequent bone densitometry identified an osteoporosis. Laboratory testing and sonography revealed an underlying primary hyperparathyroidism. In the short term, the patient suffered a similar proximal humeral fracture of the contralateral side. Given the knowledge about the underlying osteoporosis a cement-augmented locking plate osteosynthesis was carried out to treat the fracture. Parathyroidectomy was performed shortly thereafter and laboratory parameters returned to normal. Secondary fractures did not arise. Treatment of this patient in a certified osteoporosis center with a multimodal management led to systematic interdisciplinary diagnostics, a specific surgical therapy and ended in an excellent result.

Urinary bone resorption markers (deoxypyridinoline and C-terminal telopeptide of type I collagen) in healthy persons, postmenopausal osteoporosis and patients with type I diabetes.

PURPOSE: Deoxypyridinoline (DPD) is a derivative of hydroxypyridinium, which is released during bone resorption into the blood stream and is eliminated unmodified with urine. A further collagen-derived marker of bone resorption is the C-terminal telopeptide of type I collagen (beta-CTX-I, here abbreviated as CTX), which is released in bone resorption and almost entirely excreted by the kidneys. The aim of our study was to investigate different well-described patient groups as well as normal probands in view of differences and expected correlations of these two parameters: patients with insulin-dependent diabetes mellitus, postmenopausal women with osteoporosis and healthy control persons. MATERIALS AND METHODS: We used a solid-phase chemiluminescence enzyme immunoassay (Pyrilinks D-IMMULITE) for urinary DPD measurement and for the assessment of urinary CTX we used a quantitative ELISA (Osteometer Biotec A-S, CrossLaps ELISA). RESULTS: We found a highly significant correlation between both parameters in the group of healthy persons (r = 0.75, p < 0.05, n = 28) as well as in the group of patients with diabetes mellitus type I (r = 0.79, p < 0.05, n = 65). Also, a significant correlation was observed between DPD and CTX (r = 0.583, p < 0.05, n = 88) in the group of female osteoporotic patients. CONCLUSIONS: Despite good correlations between DPD and CTX in all of the investigated groups, these urinary markers were of limited diagnostic significance in the group of postmenopausal osteoporosis due to a wide spread (few patients showed concentrations above the range of healthy persons) in this newly diagnosed drug-naïve patient collective.

Evaluation of human fibroblast growth factor 23 (FGF-23) C-terminal and intact enzyme-linked immunosorbent-assays in end-stage renal disease patients.

Hyperphosphataemia, calcitriol deficency and secondary hyperparathyroidism (sHPT) are common complications in end-stage chronic kidney diseases (CKD). Fibroblast Growth Factor 23 (FGF-23) is a phosphaturic peptide, secreted by the osteoblast precursors, that also inhibits renal 1-alpha-hydroxylase activitiy and tubular phosphate reabsorption by the inhibition of sodium-dependant renal phosphate transport (Na-Pi-IIa). Consequences are a decreaese of serum 1,25 dihydroxyvitamin D3 and phosphaturia. Therefore, FGF-23 plays a role in hyperphosphataemia in association with CKD and may be involved in the pathogenesis of sHPT. Increased FGF-23 may contribute to maintaining a normal serum phoshpate level in face of a processing CKD, but if the creatinine clearance is reduced to lower than 30 ml/min the capacity of this regulative mechanism ends and hyperphosphataemia results. In our investigation of end-stage renal diseases markedly increased serum FGF-23, associated with hyperphosphataemia, phosphaturia and decreased serum calcitriol and sHPT, were found. Furthermore preanalytical testing for the stability of FGF-23 was performed by comparing samples which were stored at -20 degrees C with samples that have been stored for 6 days at +4 degrees C. The simultaneous investigation of serum and EDTA plasma FGF-23 certifies the advantage of EDTA plasma in subjects with an intact renal function.

Orthopaedic limb salvage with a mega prosthesis in a patient with haemophilia A and inhibitors - a case report.

Inhibitors against FVIII or FIX in patients with haemophilia are a common and serious complication. Until recently, elective surgery was associated with major bleeding despite the availability of a sufficient substitution therapy. We report about the major orthopaedic reconstruction of the right limb in a patient with severe haemophilia A and inhibitors. This reconstruction was the after effect of a traumatic periprosthetic fracture of the right femur after total knee replacement 6 months ago. This fracture could be stabilized by internal fixation. Two months later, a non-traumatic femur fracture occurred. Therefore, we removed the distal part of the femur and the joint replacement, and implanted a custom made tumour prosthesis (Type MUTARS (c), Münster). These three successive operations, which included emergency and elective surgery, were performed within 8 months. This is, to the best of our knowledge, the first patient with inhibitors undergoing such a complicated reconstruction of a limb. We conclude that successful elective orthopaedic surgery could be accomplished safely in this patient with high responding inhibitors using recombinant FVIIa. After a follow-up of 9 months, no major complications were seen.

Pregnancy-associated osteoporosis: an underestimated and underdiagnosed severe disease. A review of two cases in short- and long-term follow-up.

Pregnancy-associated osteoporosis is an uncommon condition characterized by the occurrence of painful fractures during late pregnancy or lactation. To date the pathophysiology of this entity of bone disorder is still uncertain, and its therapeutical management is poorly defined. We report two clinical cases: a 10-years follow-up with pain medication and intermittent antiresorptive therapy courses, subsequent traumatic vertebral fracture and actually fracture of scaphoid after inadequate trauma. Beside this long-term course a young female patient with pregnancy-associated osteoporosis and painful lumbar and also thoracic vertebral fractures is described. She was treated with an osteoanabolic therapy, at the timepoint of first follow-up at 6 months of treatment a solid increase of bone mineral density and sustained pain reduction was observed.

[DVO guideline 2006. What changes have there been in the diagnosis, prevention and treatment of osteoporosis?]. / DVO-Leitlinie 2006. Was hat sich geändert in der Diagnostik, Präention und Therapie der Osteoporose?

The main changes in the updated DVO guideline 2006 on prevention, diagnosis and treatment of osteoporosis in postmenopausal women and in older men concern the evaluation of individual fracture risks and the selection of medicamentous therapy by means of new thresholds. A 30% risk of osteoporotic vertebral or hip fracture per decade is recommended as the threshold for implementation of pharmacological therapy. Evaluation of the individual absolute fracture risk is based on a combination of the results of densitometry at the lumbar spine and femur, age, gender, and other risk factors that are specifically associated with osteoporosis. Patient's mobility is assessed by carrying out special mobility tests. Further changes seen in the 2006 update of the DVO guideline are therapy proposals taking account of new pharmaceutical developments. New effective medications are rh-PTH (1-34), or teriparatide, strontium ranelate, and ibandronate (bisphosphonate) for monthly oral administration. Minimally invasive operative techniques for use in vertebral fractures in combination with medicamentous antiosteoporosis therapy are also included in the 2006 update of the DVO guideline. Thus, in the 2006 update of the DVO-guideline we have a practice-oriented 53 guideline that is adapted to individual fracture risk and gives recommendations on the prevention, diagnosis and treatment of osteoporosis.

[The laryngeal mask in pediatric adenotonsillectomy. A meta-analysis of medical studies]. / Die Larynxmaske bei Adenotonsillektomie bei Kindern. Gefährliche Spielerei oder medizinischer Fortschritt?

Anaesthesia both for adenotomy (AT) and for tonsillectomy (TE) frequently presents a challenge. On one hand, children scheduled for adenotomy often have upper airway infections and are thus at risk of laryngo- and bronchospasm; on the other hand the ENT surgeon and the anaesthetist have to share the "workspace" in the patient's mouth. Since the succinyl choline debate in the early 1990s, the question of the best muscle relaxant has gone hand in hand with that of the most appropriate means of securing the airway. The concept of the laryngeal mask as airway was initially greeted with scepticism. Following several years' use of the mask for this purpose in AT and TE in young children, we report our experience and summarise the literature on this topic. The laryngeal mask represents a safe alternative to intubation, provided there is close cooperation with the ENT surgeon.

[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradien-9(11),16-oic acid-18]. 3rd communication (author's transl)]. / Biotransformation und Pharmakokinetik von Grandiflorensäure [Kauradien-9(11),16-säure-18] 3. Mitteilung: Untersuchungen zur Pharmakokinetik an Ratten.

Absorption, metabolism and excretion of 14C-GFA following i.v., i.p. and oral application are investigated in rats. After i.p. administration GFA is completely absorbed, after oral dosage about 83% are absorbed. GFA is excreted by 100% via bile and undergoes extensive enterohepatic circulation. After administration of 20 mg/kg 14C-GFA nearly all radioactivity is eliminated after 96 h, more than 80% via the faeces.

[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradiene-9(11),16-oic acid-18] / 1st communication (author's transl)]. / Biotransformation und Pharmakokinetik von Grandiflorensäure [Kauradien-9(11),16-säure-18] 1. Mitt.: Spektroskopische Untersuchungen

Grandiflorenic acid is oxidized by several partial-synthetic ways. The spectroscopic properties of the resulting compounds are compared in mass-, IR- and 1H-NMR-spectrometer.