Polyzois Makras

Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net

Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.

Endocrine manifestations in Langerhans cell histiocytosis

Langerhans cell histiocytosis is a rare, multisystem disease that shows a particular predilection for hypothalamo-pituitary axis involvement. Diabetes insipidus is the most frequent permanent consequence of Langerhans cell histiocytosis, developing in around a quarter of patients. Although the exact prevalence of anterior pituitary hormone deficiencies is not known, it is probably high and is almost always associated with diabetes insipidus. Established pituitary hormone deficiencies are mostly permanent and require prompt diagnosis and treatment, whereas continuous follow-up is needed to detect deficiencies that might evolve later during the course of the disease. Involvement of endocrine tissues other than the pituitary has also been described but is relatively rare. Further studies are needed to evaluate the effect that endocrine deficiencies exert on the overall prognosis of patients with Langerhans cell histiocytosis.

High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas

Objectives  Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA.

Clinical Features of 24 Patients With Rebound‐Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty‐four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty‐three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut‐off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients.

Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab.

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.

Novel therapies for osteoporosis

Since the identification of osteoporosis as a major health issue in aging populations and the subsequent development of the first treatment modalities for its management, considerable progress has been made in our understanding of the mechanisms controlling bone turnover and disease pathophysiology, thus enabling the pinpointing of new targets for intervention. This progress, along with advances in biotechnology, has rendered possible the development of ever more sophisticated treatments employing novel mechanisms of action. Denosumab, a monoclonal antibody against RANKL, approved for the treatment of postmenopausal and male osteoporosis, significantly and continuously increases bone mineral density (BMD) and maintains a low risk of vertebral, non-vertebral, and hip fractures for up to 8 years. Currently available combinations of estrogens with selective estrogen receptor modulators moderately increase BMD without causing the extra-skeletal adverse effects of each compound alone. The cathepsin K inhibitor odanacatib has recently been shown to decrease vertebral, non-vertebral, and hip fracture rates and is nearing approval. Romosozumab, an anti-sclerosin antibody, and abaloparatide, a PTH-related peptide analog, are at present in advanced stages of clinical evaluation, so far demonstrating efficaciousness together with a favorable safety profile. Several other agents are currently in earlier clinical and preclinical phases of development, including dickkopf-1 antagonists, activin A antagonists, β-arrestin analogs, calcilytics, and Src tyrosine kinase inhibitors.

Comparative Effect of Zoledronic Acid Versus Denosumab on Serum Sclerostin and Dickkopf-1 Levels of Naive Postmenopausal Women With Low Bone Mass: A Randomized, Head-to-Head Clinical Trial

CONTEXT Decreased bone formation due to a coupling effect limits bone mass increases after antiresorptive treatment. OBJECTIVE The purpose of this study was to compare the effects of 2 potent antiresorptive agents with different mechanism of action on serum levels of Wnt antagonists, sclerostin and dickkopf-1 (Dkk-1). DESIGN This was an interventional, parallel assignment, open-label, randomized clinical trial. SETTING The study was conducted at the outpatient clinics for metabolic bone diseases of 424 General Military Hospital, Thessaloniki, Greece. PATIENTS AND INTERVENTIONS Naive postmenopausal women with low bone mass were assigned to zoledronic acid infusion (n = 46) or denosumab injection (n = 46). One woman in the zoledronic acid group was lost to follow-up. MAIN OUTCOME MEASURES Serum sclerostin and Dkk-1 levels were the main outcomes. Secondary measurements were serum osteoprotegerin, receptor activator of nuclear factor κB ligand, procollagen type 1 N-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen. RESULTS Serum sclerostin levels significantly decreased in the zoledronic acid (P < .001) but increased in the denosumab group (P = .003). Dkk-1 levels significantly decreased in the zoledronic acid group (P = .006) but did not change in the denosumab group (P = .402). Serum osteoprotegerin remained essentially unchanged in either group, whereas receptor activator of nuclear factor κB ligand decreased in the zoledronic acid group (P = .004) but increased in the denosumab group (P = .037). Bone markers (procollagen type 1 N-terminal propeptide, C-terminal cross-linking telopeptide of type 1 collagen, and total serum alkaline phosphatase) decreased in both groups (all P < .001). CONCLUSIONS Although they both decrease bone resorption, zoledronic acid and denosumab exert opposite effects on Wnt signaling: the former decreases serum levels of both sclerostin and Dkk-1, whereas the latter increases sclerostin and does not affect Dkk-1.

Multiple clinical vertebral fractures following denosumab discontinuation

We read with great interest the cases reports of spontaneous vertebral fractures after denosumab discontinuation byAubryRozier et al. [1]. The authors hypothesized that the cause might be the severe rebound effect on bone turnover observed after denosumab discontinuation. We would like to add in these cases a similar anecdotal case we have recently witnessed. Our patient is a lady who was 51 years old at baseline and already 5 years postmenopausal, marginally osteoporotic [BMD T-score at the lumbar spine (LS) −2.5], but otherwise apparently healthy, with no clinical symptoms or evidence of a prevalent vertebral fracture in conventional X-rays. She was treatment naïve, her body mass index was 24.7 kg/m, and she was not taking any concurrent medication. The patient received denosumab injections every 6 months for 3 years starting from February 2012 (last injection on August 2014). On February 2015, she had become osteopenic (BMD T-score at the LS −1.8); therefore, she was instructed to discontinue treatment. At April 2015, 8 months after the last denosumab injection, she was admitted at the emergency clinics of our hospital with severe back pain. She reported that she had experienced a sharp, breathtaking pain in her mid-lower back a few hours earlier, as she was attempting to pull a drawer of the refrigerator. Magnetic resonance imaging of the spine revealed three incident vertebral fractures at T12, L1, and L3 (Fig. 1). Secondary causes of fracture, such as multiple myeloma, bone metastases, celiac disease, and mastocytosis, were ruled out and the patient was set on a brace and was initiated teriparatide. We retrospectively measured bone turnover markers [BTMs—procollagen type 1 N-terminal propeptide (P1NP— ECLIA, Elecsys total P1NP, Roche Diagnostics GmbH, Mannheim, Germany; intra-assay CV 1.3–3.0 %, inter-assay CV 2.2–4.1 %, normal values 21–78 ng/mL) and C-terminal telopeptide of type 1 collagen (CTx—ECLIA, Elecsys Crosslaps, Roche Diagnostics GmbH, Mannheim, Germany; intra-assay CV 2.0–3.5 %, inter-assay CV 2.8–8.4 %, normal values <1000 pg/mL)] in serum samples obtained from our patient before denosumab initiation, at the end of treatment (at 36 months from baseline and 6 months following the last injection) as well as when she was admitted to the hospital with fractures 2 months later. Both BTMs decreased with treatment and increased significantly when denosumab was discontinued (Fig. 1). The increase was well above baseline for CTx while it remained below baseline levels for P1NP. However, these results should be interpreted with caution, given that fractures themselves raise bone turnover and this probably affected BTMs levels at the time of hospital admission. Putting together ours and Aubry-Rozier et al. cases, all the patients were females and it is interesting that three out of the four were relatively young (54–59 years old); thus, their bone turnover would be expected to be more active and the rebound in BTMs faster and of greater magnitude, as suggested by BTMs fluctuation in our patient. All fractures occurred relat ively soon after denosumab discontinuation (8– 16 months after the last injection). In all cases, the fractures were vertebral, supporting the Bsevere rebound effect^ hypothesis which would be expected to affect cancellous bone first. Furthermore, it is of note, that three out of the four suffered multiple fractures. In addition, our patient, and probably * A. D. Anastasilakis anastath@endo.gr

Outbreak of meningococcal disease after an influenza B epidemic at a Hellenic Air Force recruit training center.

In January 1996, during an outbreak of meningococcal disease at a Hellenic Air Force recruit center in southern Greece, we collected paired serum specimens from 55 randomly selected recruits and tested for antibodies against influenza virus types A and B. Of 55 specimens, 15 (27%) were found to be positive for recent influenza B infection, confirming previous reports that respiratory tract infection due to influenza is probably a predisposing factor for meningococcal disease.

Spontaneous Gonadotrophin Deficiency Recovery in an Adult Patient with Langerhans Cell Histiocytosis (LCH)

Langerhans cell histocytosis (LCH) is a rare disease which exhibits a particular predilection for pituitary involvement leading to diabetes insipidus (DI) and other anterior pituitary hormonal deficiencies that are usually permanent and unresponsive to treatment. We report a 35 year old woman with a 10 year history of multisystemic LCH who developed DI, mild hyperprolactinemia, gonadotrophin and partial growth hormone deficiency following a normal delivery that was accompanied with infundibular thickening on pituitary magnetic resonance imaging (MRI). Following several courses of glucocorticoid administration, that were not associated with any substantial improvement, the patient was started on estrogen replacement therapy and cabergoline. After a three year period free of further relapses she developed irregular uterine bleeding. Following estrogen and cabergoline discontinuation she resumed normal menstruation while a repeated MRI of the pituitary showed an almost normal infundibulum. Endocrine investigation revealed normal gonadotrophin axis and prolactin levels, while the patient continues to menstruate, every 30–40 days, ten months after the resumption of her menstrual cycle. This case demonstrates for the first time that LCH induced pituitary deficiencies can run a variable clinical course and even spontaneously recover.