ObJEctIVE: the unique pharmacokinetics of bisphosphonates (bPs) in conjunction with their use by an increasing number of women at reproductive age has raised serious concerns about their safety during pregnancy and lactation. bisphosphonates cross the placenta. Animal studies have shown adverse effects on both the fetus and the mother, mostly at doses much higher than those commonly used in humans. Protracted parturition, maternal mortality, embryolethality, severe general underdevelopment and marked skeletal retardation of the fetuses (increased amount of diaphyseal bone trabeculae, decreased diaphyseal length), small fetal weight and abnormal tooth growth have been observed. DEsIGN: We conducted a thorough research of the literature in order to identify human studies concerning this issue. rEsULts: We identified a total of 78 cases involving fetuses whose mothers had been exposed to bPs before conception or during pregnancy, along with 7 cases of bPs exposure prior to or during lactation. the vast majority of mothers and infants did not demonstrate serious adverse effects. However, there were cases of shortened gestational age, low neonatal birth weight and transient hypocalcaemia of the newborns, while the very few reported cases of spontaneous abortions and congenital anomalies probably resulted from maternal underlying diseases and concomitant medication. cONcLUsION: the administration of bisphosphonates in pregnancy should be assessed in view of their potential hazardous effects on both mother and fetus. In cases of absolute or relative indications of bPs prior to pregnancy, close observation of the mother and the infant, especially during the first two weeks of life, is imperative for the successful outcome of pregnancy.

Tumor necrosis factor (TNF) has been implicated in inflammation-associated tumor progression. Although multiple reports identified a role for TNF signaling in established cancers, few studies have assessed the impact of TNF blockade on early tumor formation promotion. We aimed at exploring the effects of TNF neutralization in a preclinical mouse model of lung carcinogenesis. For this, Balb/c mice (n = 42) received four weekly intraperitoneal urethane injections (1 g/kg) and twice-weekly intraperitoneal soluble TNF receptor (etanercept; 10 mg/kg) administered during tumor initiation/promotion, tumor progression, or continuously (months 1, 6, and 1-8 after urethane start, respectively). Lung oncogenesis was assessed after 8 months. In separate short-term studies, Balb/c mice (n = 21) received a single control or urethane injection followed by twice-weekly intraperitoneal control or sTNFR:Fc injections. Lung inflammation was assessed after 1 week. We found that sTNFR:Fc treatment during tumor initiation/promotion resulted in a significant reduction of tumor number but not dimensions. However, sTNFR:Fc administered during tumor progression did not impact tumor multiplicity but significantly decreased tumor diameter. Continued sTNFR:Fc administration was effective in halting both respiratory tumor formation and progression in response to urethane. This favorable impact was associated with impaired cellular proliferation and new vessel formation in lung tumors. In addition, TNF neutralization altered the lung inflammatory response to urethane, evidenced by reductions in TNF and macrophage and increases in interferon γ and interleukin 10 content of the air spaces. sTNFR:Fc treatment of RAW264.7 macrophages downregulated TNF and enhanced interferon γ and interleukin 10 expression. In conclusion, TNF neutralization is effective against urethane-induced lung oncogenesis in mice and could present a lung chemoprevention strategy worth testing clinically.

Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1β and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1β, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.

Background. Periprosthetic joint infection (PJI) is the most severe complication, following joint arthroplasty. Identification of the causal microbial factor is of paramount importance for the successful treatment. Purpose. The aim of this study is to compare the sonication fluid cultures derived from joint prosthetic components with the respective periprosthetic tissue cultures. Methods. Explanted prosthesis components for suspected infection were placed into a tank containing sterile Ringer's solution and sonicated for 1 minute at 40 kHz. Sonication fluid cultures were examined for 10 days, and the number and identity of any colony morphology was recorded. In addition, periprosthetic tissue specimens (>5) were collected and cultured according to standard practice. The duration of antimicrobial interruption interval before culture sampling was recorded. Results. Thirty-four patients composed the study group. Sonication fluid cultures were positive in 24 patients (70.5%). Sixteen of thirty four periprosthetic tissue cultures (47.1%) were considered positive, all revealing the same microbial species with the respective sonication fluid cultures: 3 tissue samples showed polymicrobial infection. All tissue cultures were also found positive by the sonication fluid culture. Conclusions. Sonication fluid cultures represent a cheap, easy, accurate, and sensitive diagnostic modality demonstrating increased sensitivity compared to periprosthetic tissue cultures (70.5 versus 47.1%).

OBJEcTIVE: Pregnancy-and lactation-associated osteoporosis (PLO) is an uncommon disease. The majority of cases are seen in the third trimester or early post-partum in primagravid women and the prominent clinical feature of PLO is severe and prolonged back pain and height loss. The prevalence and aetiology of this disorder are as yet unclear and there are no guidelines for its treatment. cAsE rEPOrT: We report the outcomes of teriparatide (TrP) treatment in a woman suffering from severe PLO with 6 vertebral fragility fractures, severe back pain and very low BMD. rEsULTs: Thirteen months after the initiation of therapy, the patient was almost free of back pain. There was no new clinical vertebral fracture. Her laboratory tests were all normal. BMD increased by 24.4% at the lumbar spine, 9.9% and 4.6% at the left and the right total hip and 12.6% and 7.8% at the left and right femur neck, respectively. cONcLUsION: TrP treatment simultaneously with weaning and calcium and vitamin D supplementation seems to considerably increase BMD, improve severe back pain and quality of life and prevent further occurrence of vertebral fractures, making TrP a helpful tool in restoring bone strength in PLO patients. Key words: Lactation, Osteoporosis, Pregnancy, Premenopausal osteoporosis, TeriparatideCase report HORMONES 2012, 11(4):495-500 Address for correspondence: Kalliopi Lampropoulou-Adamidou, MD, MSc, Laboratory for the Research of the Musculoskeletal System "Th. Garofalidis", KAT General Hospital of Athens, 10 Athinas Str., 14561, Kifissia, Athens, Greece, Tel.: +306984229202, +302108018123, Fax: +302108018122, E-mail: kilampropoulou@gmail.com of PLO was made by Nordin et al in 1955. 1 It is characterised by the occurrence of fragility fracture(s), most commonly involving the lower thoracic and/ or lumbar vertebral bodies. The majority of cases are seen in the third trimester or early post-partum in primagravid women and the prominent clinical feature of PLO is severe and prolonged back pain and height loss. The prevalence and the ae tiology of this disorder are unclear. To date, more than 120 cases have been reported, mostly as individual case reports.2 Due to the lack of controlled trials and the rarity of the disease there are no formal guidelines.

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To address the need to impact the subchondral bone-articular cartilage interaction for the treatment of degenerative osteoarthritis (OA), bisphosphonates may be used as a means to inhibit the subchondral bone resorption. The purpose of the present study is to evaluate the chondroprotective effect of zoledronic acid (ZOL) in a model of OA. Eighteen adult male rabbits underwent an anterior cruciate ligament transection and were separated into two groups: ZOL group (n ¼ 10) received 0.6 mg/kg intravenous injection of ZOL on day 1, 15, and 29 and placebo group (n ¼ 8) received saline. The animals were euthanized at 8 weeks. Macroscopically, the ZOL group had significantly milder ulcerations, cartilage softening and fibrillation compared to the placebo group. Microscopically, morphology of the articular cartilage was better in the ZOL treated group compared with the placebo group, without complete disorganization in any section of the ZOL group. Furthermore, the chondrocytes in the ZOL treated group were mainly cloning, indicating cartilage repairing and regeneration process, while in the placebo group hypocellularity predominated. Additionally, subchondral necrosis was evident in some specimens of the placebo group. Zoledronic acid, in a high-dose regimen, proved to be chondroprotective in a well-established animal model of OA. ß