Ioannis P. Stathopoulos

The use of bisphosphonates in women prior to or during pregnancy and lactation.

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.

Case report: Teriparatide treatment in a case of severe pregnancy -and lactation- associated osteoporosis.

OBJECTIVEPregnancy- 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 REPORTWe 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.RESULTSThirteen 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.CONCLUSIONTRP 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.

Radiation-free distal locking of intramedullary nails: Evaluation of a new electromagnetic computer-assisted guidance system

Distal locking of intramedullary nails (IMNs) is a difficult part of intramedullary nailing (IMN) that could be time-consuming and expose the surgeon, the surgery personnel and the patient to a considerable amount of radiation as fluoroscopy is usually guiding the procedure. Utilization of electromagnetic fields for that purpose offers an attractive alternative. The SURESHOT™ Distal Targeting System (Smith & Nephew, Inc., Memphis, TN, USA) is a novel commercially available radiation-free aiming system that utilizes computerized electromagnetic field tracking technology for the distal locking of IMNs. In order to evaluate the efficacy of the system we conducted the present study. Nineteen patients (six females-thirteen males, mean age 39.5 years, range 17-85 years) with closed diaphyseal fracture of the femur (eight patients) or the tibia (eleven patients) were treated with IMN using the SURESHOT™ Distal Targeting System for the distal interlocking. All targeting attempts were successful at first try and followed by correct positioning of the screws. Mean time for distal locking of tibial IMNs (two screws) was 219sec (range 200-250sec). Mean time for distal locking of femoral IMNs (two screws) was 249 (range 220-330sec). In the current study the SURESHOT™ Distal Targeting System proved to be accurate, fast and easy to learn.

Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis

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.

Chondroprotective effect of high‐dose zoledronic acid: An experimental study in a rabbit model of osteoarthritis

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 = 10) received 0.6 mg/kg intravenous injection of ZOL on day 1, 15, and 29 and placebo group (n = 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.

Severe osteoporosis and mutation in NOTCH2 gene in a woman with Hajdu-Cheney syndrome

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder characterised by acro-osteolysis, skull deformation and generalised osteoporosis. Recently, truncating mutations in the last exon of NOTCH2, a protein-coding gene, were found to be responsible. We present the case of a young woman with HCS in whom clinical and radiologic diagnosis was confirmed with DNA tests.

Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with atypical femoral fractures after long-term bisphosphonate administration.

OBJECTIVE: Despite the existence of numerous case series, no evidenced-based medical management for atypical fractures associated with bisphosphonate (BP) treatment has been established. DESIGN: We report the outcome of teriparatide (TRP) administration followed by strontium ranelate (SR) in a woman with a complete and an incomplete contralateral atypical fracture of the femoral diaphysis (AFF) associated with BP treatment. The spontaneous complete AFF was managed with intramedullary nailing, discontinuation of BP and initiation TRP. RESULTS: Eleven months later, she suffered a contralateral incomplete AFF. At the completion of the TRP treatment, she had only slight discomfort in the femur with the incomplete AFF. BMD testing revealed increase of 7.61% at the lumbar spine (LS) and 0.8% at the hip. Following TRP, 1-year SR treatment resulted in further BMD increase of 9.2% at the LS and 1.4% in the hip, while she does not report any pain. Bone markers remain within the normal range. CONCLUSION: Our case indicates that sequential therapy with TRP and SR in cases of AFF might be a rational treatment option. However, there is a need for additional information concerning the effect of TRP and SR, given alone or sequentially, in these patients in order to incorporate these drugs into the management of AFF.

Conservative treatment of an anterior-lateral ankle dislocation without an associated fracture in a diabetic patient: a case report

Anterior or anterior-lateral dislocation of the ankle is a rare condition that can be treated conservatively as well as any other similar types of ankle dislocations without associated fractures. We present a case report of an anterior-lateral ankle dislocation with a concomitant avulsion injury of the ankles anterior capsule in a diabetic patient that was treated conservatively. At the patients visit 12 months after the initial injury, he was asymptomatic with full range of motion of the ankle joint. To our knowledge, we could not identify this type of an injury in a diabetic patient that was treated successfully with conservative treatment in the existing literature.

Strategies for Managing Bone Defects of the Lower Extremity

Management of posttraumatic segmental bone loss as a result of severe open injuries of the lower extremity, high-energy closed injuries, and following failed initial treatment of complex fractures that develop pseudarthrosis continues to challenge reconstructive surgeons. There are numerous strategies for dealing with such injuries but the outcome is unpredictable. The procedure is rarely only one stage and complications frequently arise. In most cases the reconstruction process is long and difficult and amputation must be part of the decision-making process. All traditional treatment strategies have advantages and major drawbacks. To overcome some limitations, biologic treatments have been developed based on specific pathways of bone physiology and healing.

Recurrent Dislocation of The Extensor Carpi Ulnaris Tendon in a Water-Polo Athlete.

Introduction: Dislocation/subluxation of the Extensor Carpi Ulnaris (ECU) tendon is a rare condition in the general population, but is a common problem among athletes that subject their wrists to forceful rotational movements. Pain and snapping sensation at the dorsoulnar aspect of the wrist especially during supination are the predominant symptoms that often necessitate surgical intervention. Case Presentation: We present a case of a professional water-polo athlete with recurrent ECU tendon dislocation, in whom a combination of direct repair of the tendon’s subsheath and reinforcement with an extensor retinaculum graft led to definitive resolution of her symptoms and resulted in her uneventful return to high-level sport activities 4 months postoperatively. Conclusions: The treatment of symptomatic ECU instability is still controversial, especially for acute dislocations. Depending on the type of injury many surgical techniques have been proposed. Combination of direct repair of the tendon’s subsheath and reinforcement with an extensor retinaculum graft is a reliable option.