Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ).

BACKGROUND: Bisphosphonate drugs can be used to prevent and treat osteoporosis and to reduce symptoms and complications of metastatic bone disease; however, they are associated with a rare but serious adverse event: osteonecrosis of the maxillary and mandibular bones. This condition is called bisphosphonate-related osteonecrosis of the jaw or BRONJ. BRONJ is diagnosed when people who are taking, or have previously taken, bisphosphonates have exposed bone in the jaw area for more than eight weeks in the absence of radiation treatment. There is currently no "gold standard" of treatment for BRONJ. The three broad categories of intervention are conservative approaches (e.g. mouth rinse, antibiotics), surgical interventions and adjuvant non-surgical strategies (e.g. hyperbaric oxygen therapy, platelet-rich plasma), which can be used in combination. OBJECTIVES: To determine the efficacy and safety of any intervention aimed at treating BRONJ. SEARCH METHODS: We searched the following databases to 15 December 2015: the Cochrane Oral Health Group Trials Register, the Cochrane Breast Cancer Group Trials Register (20 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, EMBASE via Ovid, CancerLit via PubMed, CINAHL via EBSCO and AMED via Ovid. We scanned the references cited in retrieved articles and contacted experts in the field, the first authors of included papers, study sponsors, other bisphosphonates investigators and pharmaceutical companies. We searched for ongoing trials through contact with trialists and by searching the US National Institutes of Health Trials Register (clinicaltrials.gov) and the World Health Organization Clinical Trials Registry Platform. We also conducted a grey literature search to September 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of any treatment for BRONJ with another treatment or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed the risk of bias in the included trials and extracted data. When in dispute, we consulted a third review author. MAIN RESULTS: One small trial at high risk of bias met the inclusion criteria. The trial randomised 49 participants, most of whom had cancer. It compared standard care (defined as surgery, antibiotics and oral rinses at the discretion of the oral-maxillofacial surgeon) to standard care plus hyperbaric oxygen therapy (2 atmospheres twice a day for 40 treatments). The trial measured the percentage of participants who improved or healed at three, six, 12 and 18 months and last contact. It also measured mean weekly pain scores.At three months, the study found that the participants in intervention group were more likely to have an improvement in their osteonecrosis than the standard care group participants (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.01 to 3.74). There was no clear difference between the groups for the outcome 'healed' at three months (RR 3.60, 95% CI 0.87 to 14.82). There was no clear difference between the groups for improvement or healing when they were evaluated at six, 12 and 18 months and last contact.The study did not give any information on adverse events.Although the findings suggest adjunctive hyperbaric oxygen improved BRONJ, the quality of the evidence is very low since the only study was underpowered and was at high risk of bias due to lack of blinding, cross-over of participants between groups and very high attrition (50% at 12 months and 80% at 18 months in this study, which was designed for an intended follow-up of 24 months). AUTHORS' CONCLUSIONS: There is a lack of evidence from randomised controlled trials to guide treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). One small trial at high risk of bias evaluated hyperbaric oxygen therapy (HBO) as an adjunct to "standard" care and could not confirm or refute the effectiveness of HBO. There are two ongoing trials of teriparatide treatment for BRONJ. We found no randomised controlled trials of any other BRONJ treatments. High quality randomised controlled trials are needed. We provide recommendations for their focus and design.

Alteration of circulating Placental Leucine Aminopeptidase (P-LAP) activity in preeclampsia.

OBJECTIVE: Placental Leucine Aminopeptiadse (P-LAP) also known as oxytocinase, is secreted by syncytiotrophoblast and increases gradually during pregnancy until delivery. It is a regulator of uterine contractions, of vascular resistance and of volume of the retroplacental blood pool. Recently, it was shown that it could also regulate metalloproteinase 9 activity and thus, invasiveness of trophoblastic cells. Since development of preeclampsia could be initiated by decreased cytotrophoblastic invasion of spiral arterioles and a reduced uteroplacental perfusion, we speculate that circulating P-LAP activity could be decreased during preeclampsia. MATERIALS AND METHODS: Case-control study was evaluated in 84 women. P-LAP activity was measured in n=51 healthy pregnant women at term, and compared with n=16 normotensive women delivering preterm and n=17 women diagnosed with pre-eclampsia. P-LAP activity was determined by colorimetry in plasma samples using L-Leucine-p-nitroanilide as substrate. RESULTS: P-LAP activity was significantly lower in sera of preeclamptic women (0.91+/-0.122 mDO/min) as compared to normotensive controls (1.41+/-0.103 mDO/min; p=0.003) irrespective of time of delivery. CONCLUSIONS: These findings confirm the probable involvement of P-LAP in trophoblast invasion and development of preeclampsia.

Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy.

Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.