Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma

Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs. The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates. We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ. The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid. All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy)

Temporal patterns of wild boar associations.

<p>Stability of associations were estimated using lagged association rates (LARs). The LARs were compared to null association rates (LAR if individuals associated randomly) and the best fitting model is shown for each LAR (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone-0099875-t004" target="_blank">Table 4</a> for description). Standard error bars were obtained by jackknifing.</p

The social network of wild boar from Białowieża National Park, Poland.

<p>The network was constructed based on associations data in 2008 (A) and 2009 (C). Nodes and numbers symbolise individual animals, lines represent social ties. The thickness of the line corresponds to the strength of social bond. Colours represent social units determined by partitioning of the social network. Spatial distribution of the individuals within the study area in 2008 (B) and 2009 (D). Location of the individual’s symbol corresponds to its home range centre and colours indicate social units. Rhomb indicates individual with unidentified sex.</p

Proportions and temporal characteristics of the social components in the wild boar population.

<p>The models fitted to the lagged association rates (LARs; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone-0099875-g002" target="_blank">Figure 2</a>) consist of a proportion of constant companions, rapid disassociations, and casual acquaintances of two types: permanent acquaintances lasting for particular period of time and casual acquaintances that last for shorter periods. This values correspond to percentage of each social component in the population. The standard error (SE range around the mean) of each parameter was estimated by jackknifing procedure. For a more detailed description and formulation of the models see Whitehead 1999 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone.0099875-Whitehead3" target="_blank">[31]</a> and 2008 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone.0099875-Whitehead5" target="_blank">[57]</a>.</p

Correlation coefficients between association strength and genetic relatedness in the wild boar population.

<p>Correlation coefficients (<i>r</i>) and statistical significance (<i>p</i>) were obtained using Mantel and partial Mantel (controlling for spatial overlap of utilised area) tests based on 10.000 permutations. Correlations for adult males in 2009 were not calculated due to low sample size. <i>n</i> – number of pairwise comparisons. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone.0099875.s001" target="_blank">Table S1</a> for the relatedness and association matrix among all analysed individuals.</p

Mean (± SE) pairwise relatedness and spatial overlap between individuals in the wild boar social network.

<p>Average relatedness and spatial overlap are given for individuals sharing membership of the social unit (within) and those associated with different units (between). Social units result from network partitioning based solely on associations frequency (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone-0099875-g001" target="_blank">Figure 1</a>). Statistical significance of the differences was obtained with randomisation tests based on 10.000 permutations. <i>n</i> – number of dyads. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone.0099875.s001" target="_blank">Table S1</a> for the relatedness and spatial overlap matrix among all analysed individuals.</p

Temporal patterns of wild boar associations.

<p>Stability of associations were estimated using lagged association rates (LARs). The LARs were compared to null association rates (LAR if individuals associated randomly) and the best fitting model is shown for each LAR (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099875#pone-0099875-t004" target="_blank">Table 4</a> for description). Standard error bars were obtained by jackknifing.</p

The median-joining network of the haplotypes obtained with 598 wild boar and domestic pig mtDNA sequences from GenBank and 254 wild boar sequences from this study.

<p>The size of each circle is proportional to the haplotype frequency. Colours represent regions of sequence origin. European samples are grouped into Eastern Europe (European part of Russia, Belarus, Ukraine, Moldova, Romania, Serbia), Central Europe (Germany, Austria, Switzerland, Slovenia, Hungary, Poland, Czech Republic, Slovakia, Denmark), and Western Europe (Belgium, France, Netherlands, United Kingdom). For more details on countries included in the regions see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091401#pone.0091401.s001" target="_blank">Table S1</a>. Thick-line circles show presence of domestic pig sequences. Numbers on the lines indicates the number of mutations (no number indicates single mutation).</p

Observed (bars) and simulated (line) mismatch distributions of the mtDNA haplotypes found in this study, in the whole sample (total) and in three subpopulations determined by SAMOVA.

<p>Observed (bars) and simulated (line) mismatch distributions of the mtDNA haplotypes found in this study, in the whole sample (total) and in three subpopulations determined by SAMOVA.</p

Bayesian skyline plots showing effective population size of wild boar over time in Central and Eastern Europe.

<p>Median estimates are shown as solid thick line, 95% highest posterior density (HPD) intervals are represented by dotted lines.</p