Sabina Herrera

Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies

The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)—either its N-terminal 1–34 fragment or the whole molecule of 1–84 aminoacids—whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies.

Current and future treatments of secondary osteoporosis

Osteoporosis is commonly associated with menopause and ageing. It can, however, also be caused by diseases, lifestyle, genetic diseases, drug therapies and other therapeutic interventions. In cases of secondary osteoporosis, a common rule is the management of the underlying condition. Healthy habits and calcium and vitamin D supplementation are also generally advised. In cases of high risk of fracture, specific antiosteoporosis medications should be prescribed. For most conditions, the available evidence is limited. Special attention should be paid to possible contraindications of drugs used for the treatment of postmenopausal or senile osteoporosis. Bisphosphonates are the most widely used drugs in secondary osteoporosis, and denosumab or teriparatide have been also assessed in some cases. Important research is needed to develop more tailored strategies, specific to the peculiarities of the different types of secondary osteoporosis.

Bone Density, Microarchitecture, and Tissue Quality Long-term After Kidney Transplant.

Background Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is used to assess bone health in kidney transplant recipients (KTR). Trabecular bone score and in vivo microindentation are novel techniques that directly measure trabecular microarchitecture and mechanical properties of bone at a tissue level and independently predict fracture risk. We tested the bone status of long-term KTR using all 3 techniques. Methods Cross-sectional study including 40 KTR with more than 10 years of follow-up and 94 healthy nontransplanted subjects as controls. Bone mineral density was measured at lumbar spine and the hip. Trabecular bone score was measured by specific software on the dual-energy x-ray absorptiometry scans of lumbar spine in 39 KTR and 77 controls. Microindentation was performed at the anterior tibial face with a reference-point indenter device. Bone measurements were standardized as percentage of a reference value, expressed as bone material strength index (BMSi) units. Multivariable (age, sex, and body mass index-adjusted) linear regression models were fitted to study the association between KTR and BMD/BMSi/trabecular bone score. Results Bone mineral density was lower at lumbar spine (0.925 ± 0.15 vs 0.982 ± 0.14; P = 0.025), total hip (0.792 ± 0.14 vs 0.902 ± 0.13; P < 0.001), and femoral neck (0.667 ± 0.13 vs 0.775 ± 0.12; P < 0.001) in KTR than in controls. BMSi was also lower in KTR (79.1 ± 7.7 vs 82.9 ± 7.8; P = 0.012) although this difference disappeared after adjusted model (P = 0.145). Trabecular bone score was borderline lower (1.21 ± 0.14 vs 1.3 ± 0.15; adjusted P = 0.072) in KTR. Conclusions Despite persistent decrease in BMD, trabecular microarchitecture and tissue quality remain normal in long-term KTR, suggesting important recovery of bone health.

Clinical experience with microindentation in vivo in humans

Densitometry and imaging techniques are currently used in clinical settings to measure bone quantity and spatial structure. Recently, Reference Point Indentation has opened the possibility of directly assessing the mechanical characteristics of cortical bone in living individuals, adding a new dimension to the assessment of bone strength. Impact microindentation was specifically developed for clinical studies and has been tested in several populations where there are discrepancies between bone density and fracture propensity, such as type 2 diabetes, atypical femoral fracture, stress fractures, glucocorticoid treatment, patients with osteopenia and fragility fractures, and individuals infected with HIV, among others. Microindentation will complement, not replace, existing bone analysis methods, particularly where bone mineral density does not fully explain fracture propensity. The available evidence provides solid proof of concept; future studies will fully define the role of microindentation for the assessment of bone health both in clinics and in research.

Bone Density, Microarchitecture, and Tissue Quality After Long-Term Treatment With Tenofovir/Emtricitabine or Abacavir/Lamivudine

Objectives: HIV infection has been associated with reduced bone mineral density (BMD). Antiretroviral therapy (ART) has a deleterious effect on BMD, but its effect on bone fragility is not clear. The objective of this study is to analyze the BMD, microarchitecture, and tissue quality of bone in patients receiving long-term tenofovir- or abacavir-based ART. Design: We conducted a cross-sectional study in patients with HIV undergoing tenofovir or abacavir ART for more than 5 years. Methods: We measured BMD using dual X-ray absorptiometry ,bone michroarchitecture using trabecular bone score (TBS), and bone tissue quality using microindentation. TBS is a dual X-ray absorptiometry–based software that is more highly correlated with bone fragility than BMD. Microindentation (BMSi) directly assesses bone quality at the tissue level. Results: A total of 63 patients were included in this study, with 36 belonging to the TDF-FTC group and 27 to the ABC-3TC group. Patients receiving TDF-FTC treatment showed lower BMD values than those in the ABC-3TC group. We found no differences in TBS or microindentation between the 2 groups. However, after adjusting for sex, age, body mass index, and 25[OH]vitD we found lower BMSi and thus poorer bone properties in the TDF-FTC group than in the ABC-3TC group [beta coefficient −3.594 (confidence interval: 95% −0.12 to −7.61); P = 0.043]. Conclusions: Long-term treatment with TDF-FTC leads to impaired bone health, not only in terms of BMD but also in terms of bone quality, another determinant of overall bone strength. To complement BMD-based predictions, these other techniques may also be used to identify patients with excess fracture risk.

The Framingham function overestimates the risk of ischemic heart disease in HIV-infected patients from Barcelona.

Background: Cardiovascular risk (CVR) assessment helps to identify patients at high CVR. The Framingham CVR score (FRS) is the most widely used methods but may overestimate risk in regions with low incidence of cardiovascular disease. The objective was to compare the 10-year performance of the original and the adapted REGICOR – Framingham CVR functions in HIV-infected individuals. Methods: We carried out a longitudinal study of HIV-infected patients with CVR evaluation in a hospital in Barcelona between 2003 and 2013. Statistics: Risk probability was calculated using the FRAMINGHAM function and REGICOR adaptation to the Spanish population, and individuals were categorized in three groups (low, 0 < 5%; moderate, 5–10%; and high, >10%). For each risk group, the number of events over 10 years was calculated using the Kaplan–Meier method, and the expected number of events was calculated by multiplying the frequency of participants in the group by the mean of the probabilities from the risk function. We used the X2 goodness-of-fit test to assess agreement between observed and expected. Results: Six hundred and forty-one patients were followed up for a median of 10.2 years, and 20 ischemic heart events (IHE) were observed. The mean (95% CI) number of IHEs per 1000 person-years was 3.7 (2.06–5.27). The estimates from the Framingham and REGICOR functions were 40 and 14 IHEs, respectively. The estimate from the original Framingham function differed significantly from the observed incidence (p < 0.001), whereas that from the REGICOR-adapted function did not (p = 0.15). In terms of the number of cardiovascular events (38 events observed), the REGICOR function significantly underestimated risk (p = 0.01), whereas the estimate from the Framingham function was similar to observed (p:0.93). Conclusions: The FRS significantly overestimates risk of IHE events in our HIV-infected patients, while the REGICOR function is a better predictor of these events. In terms of cardiovascular events, the REGICOR function significantly underestimates risk, whereas the FRS is a better estimator. We recommend using CVR scales and adjusting them to the origin of the population being studied.

Assessment of Bone Health in Patients With Type 1 Gaucher Disease Using Impact Microindentation.

Gaucher disease (GD), one of the most common lysosomal disorders (a global population incidence of 1:50,000), is characterized by beta‐glucocerebrosidase deficiency. Some studies have demonstrated bone infiltration in up to 80% of patients, even if asymptomatic. Bone disorder remains the main cause of morbidity in these patients, along with osteoporosis, avascular necrosis, and bone infarcts. Enzyme replacement therapy (ERT) has been shown to improve these symptoms. This cross‐sectional study included patients with type 1 Gaucher disease (GD1) selected from the Catalan Study Group on GD. Clinical data were collected and a general laboratory workup was performed. Bone mineral density (BMD) was measured at the lumbar spine and hip using dual‐energy X‐ray absorptiometry (DXA). Patients with bone infarcts or any other focal lesion in the area of indentation visible on imaging were excluded. Bone Material Strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. Analysis of covariance (ANCOVA) models were fitted to adjust for age, sex, weight, and height. Sixteen patients with GD1 and 29 age‐ and sex‐matched controls were included. GD1 was associated with significantly lower BMSi (adjusted beta –9.30; 95% CI, –15.18 to –3.42; p = 0.004) and reduced lumbar BMD (adjusted beta –0.14; 95% CI, –0.22 to –0.06; p = 0.002) and total hip BMD (adjusted beta –0.09; 95% CI, –0.15 to –0.03; p = 0.006), compared to GD1‐free controls. Chitotriosidase levels were negatively correlated with BMSi (linear R2 = 51.6%, p = 0.004). Bone tissue mechanical characteristics were deteriorated in patients with GD1. BMSi was correlated with chitotriosidase, the marker of GD activity. Bone disorder requires special consideration in this group of patients, and microindentation could be an appropriate tool for assessing and managing their bone health.

Maintenance low dose systemic glucocorticoids have limited impact on bone strength and mineral density among incident renal allograft recipients: A pilot prospective cohort study

Soon after kidney transplant (KT), a decrease in parathormone and bone mineral density (BMD) occur, but little is known on the impact of KT on novel bone quality parameters including trabecular bone score (TBS) and bone material strength index (BMSi). We aimed to study BMD, TBS and BMSi in the first year after KT, in patients not treated with any bone therapy. A cohort including 36 patients underwent KT on a low-glucocorticoid-dose protocol (5 mg daily-prednisone from post-operative-day 42 onwards) and was observed for 12 months prospectively. At 3 months, phosphorus and parathormone decreased, while calcium increased. We also observed at 3 months a transient mild 2.9% bone loss at femoral neck (BMD change 0.752 ± 0.15 vs 0.730 ± 0.15; p = 0.004), but no change at either spine or total hip. Both TBS and BMSi remained stable. At 12 months, lumbar (but not total hip or femoral neck) BMD slightly decreased by 2.1% vs baseline (0.950 ± 0.15 vs 0.930 ± 0.5; p = 0.046), while TBS and BMSi remained unmodified. In KT patients on low-dose glucocorticoids and no bone therapy, there were small BMD decreases at femoral neck (at 3 months) and lumbar spine (at 12 months), but no change in either TBS or BMSi. Low-dose post-KT glucocorticoid treatment shows limited impact on bone, supporting steroid-restrictive protocols.

Original articleCharacterization and rapid control of a vancomycin-resistant Enterococcus faecium (VREF) outbreak in a renal transplant unit in Spain: The environment mattersCaracterización y control rápido de un brote de Enterococcus faecium resistente a vancomicina en una unidad de trasplantados renales en España: el ambiente importa

Objective To describe a clonal outbreak due to vancomycin-resistant Enterococcus faecium (VREF) in the nephrology and renal transplant unit of a tertiary teaching hospital in Barcelona, Spain, and to highlight how active patient and environment surveillance cultures, as well as prompt and directed intervention strategies, mainly environmental, helped to successfully bring it under control.

52-year-old man with recurrent urinary tract infection, Munchausen's syndrome

Munchausen’s syndrome is considered to be a factitious disorder ith predominantly physical symptoms. It was first described by sher in 19511 and, despite having passed 60 years, making an ccurate diagnosis of factitious disorder is still as challenging for linicians. Individuals with chronic and severe forms change names and ometimes modify their stories to avoid tracking and long-term ollow-up is rarely reported.2 A retrospective study in a psyhiatric centre found a 6% of prevalence.3 The Diagnostic and tatistical Manual of Mental Disorders (DSM-5)4 defines that the haracteristics of all forms of factitious disorder are intentional roduction of feigned physical or psychological signs or symptoms, resence of illness behaviour reflecting a wish to assume the sick ole, confronting physicians with self-induced symptoms or isease and absence of external incentives (e.g., economic gain, voiding legal responsibility, etc.) These criteria define an extremely heterogeneous population ith coexisting medical and psychiatric disorders and usually seen y non-psychiatrics. Therefore it is under-recognized and underppreciated, leading to unnecessary morbidity and mortality, and remendous cost to healthcare systems.5–7 To illustrate the difficulties at arrive to a proper diagnosis we eport a rare case of a man who visited repeatedly different hospials with recurrent abdominal pain. A 52-year-old man presented to the emergency department ith dysuria, urgency, dark urine, right low-back and flank pain nd an isolated temperature determination of 38.2 ◦C, with no other ymptoms. When asked, the patient denied previous visits to other ospitals, despite we being able to see his past medical history. owever, electronic records showed a previous admission at our entre in 2003 due to renal colic, without any evidence of urolithisis that derived by the placement of a pigtail catheter due to ersistence of pain. He was again admitted in 2012 due to chronic rostatitis by extended-spectrum beta-lactamases producing Klebiella pneumoniae and pyelonephritis by Streptococcus viridians, eceiving broad-spectrum antibiotics. When going through his electronic medical records (due to hosital sharing of medical records), it was found that in the last years, he had visited several emergency departments 103 times