Management of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP)-A Case Report.

Background and Objectives: This study reports a case of a 62-year-old patient experiencing a significant decline in vision over the past three months. The initial best-corrected visual acuity (BCVA) of 20/20 in both eyes diminished to 20/200 in the right eye (RE) and counting fingers (CF) in the left eye (LE) within this timeframe. The patient was diagnosed with stage 4 ovarian cancer just one month before the significant vision deterioration. Materials and Methods: A thorough ophthalmologic examination revealed a notable progression of cataracts and the presence of subretinal fluid on the posterior pole, accompanied by choroidal thickening. The right eye exhibited multifocal, orange-pigmented, and elevated choroidal lesions, while the left eye's fundus examination was impeded by dense cataracts. Optical coherence tomography (OCT) revealed bilateral choroidal thickening with overlying folds and subretinal fluid, and ultrasound imaging of the choroidal lesions indicated moderate homogenous internal reflectivity. Results: The patient received a diagnosis of BDUMP (bilateral diffuse uveal melanocytic proliferation), a paraneoplastic syndrome marked by simultaneous, bilateral, painless vision loss and the rapid onset of bilateral cataracts with serous retinal detachments. Despite cataract extraction, the expected visual recovery was not achieved (RE: CF; LE: 2/200, respectively). Plasmapheresis showed some success in stabilizing vision loss attributed to serous retinal detachments. Conclusions: BDUMP necessitates addressing the underlying malignancy for effective treatment. Left untreated, it can lead to near blindness within a year. The prognosis remains grim, with an average survival time ranging from 12 to 15.7 months from the time of diagnosis. Considering this case report, it is crucial to establish effective management plans and further investigate potential treatment methods and predictive markers centered around BDUMP. Collaboration between healthcare professionals and researchers is crucial in addressing the complexities of BDUMP, as the timely diagnosis and treatment of the disease remains a top priority.

Enlarged Foveal Avascular Zone after Whiplash Injury-Acquired Berlin's Edema.

We describe a case of optical coherence tomography angiography (OCTA) changes in the foveal avascular zone (FAZ) in a patient that had suffered Berlin's edema after a whiplash neck injury. The patient reported central scotoma throughout the 1-year follow-up, confirmed by visual field examination. OCTA showed FAZ enlargement of the left eye as compared to the healthy right eye in the superficial capillary layer and even more in the deep capillary layer. To the best of our knowledge, FAZ enlargement has not been previously described by OCTA after whiplash-related macular injury.

Autologous Neurosensory Retinal Free Flap Treatment for a Large Macular Hole.

A patient presented with a large chronic macular hole (MH) of 700 µm. Best-corrected visual acuity (BCVA) was 20/200. Since the MHs edges were attached and stiff, an autologous neurosensory retinal flap was harvested and placed into the MH to close it. Perfluoro-n-octane heavy liquid (PFC) was instilled over the flap and exchanged with silicone oil (1,000 cs). Seven days postoperatively, the MH was closed, with a BCVA of 20/80 that improved to 20/60 at months 1 and 3. Optical coherence tomography and angiography showed patch incorporation with fovea formation and normal circulation. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e89-e92.].

Comparison of Verisyse and Veriflex Phakic Intraocular Lenses for Treatment of Moderate to High Myopia 36 Months after Surgery.

PURPOSE: To compare refractive stability, endothelial cell count (ECC), incidence of complications, and patients' satisfaction between a rigid Verisyse (group I, n = 198) and foldable Veriflex (group II, n = 212) phakic intraocular lenses (pIOL) over 36 months postop. MATERIALS AND METHODS: This was a retrospective study. Patients' satisfaction and incidence of photic phenomena were evaluated at one month and one year postop. Data were analyzed to determine difference between groups for astigmatism, mean spherical equivalent (MRSE), uncorrected (UDVA) and corrected (CDVA) monocular distance visual acuity, complication rate (acute and chronic), and ECC. Differences were considered statistically significant when p < 0.05. RESULTS: Group II cases had significantly higher UDVA, CDVA, and lower astigmatism during the entire follow-up. There was no significant difference in mean MRSE or mean ECC postoperatively. In both groups, mean ECC reduced significantly at one month postop, followed by a gradual linear decline between 1 and 36 months of 22.4 cells/mm2/annum (group I) and 13.32 cells/mm2/annum (group II). Overall complication rates were ≤ 10% with no significant inter-group differences. Group I patients reported lower incidence of halos at one month but more problems with night vision at one year compared with group II. Overall satisfaction was high and total incidence of reported photic phenomena was low. CONCLUSION: Both Verisyse and Veriflex pIOLs are effective in correcting myopia. The Veriflex lens demonstrated better refractive outcome; however, subclinical inflammation observed in the Veriflex group and potential influence of inflammation on ECC loss require further investigation.

Three-year corneal graft survival rate in high-risk cases treated with subconjunctival and topical bevacizumab.

PURPOSE: To evaluate the effect of combined subconjunctival and topical bevacizumab treatment on corneal graft survival rate in high-risk eyes. METHODS: Prospective, consecutive, interventional case series. Fifty eyes of 50 high-risk patients scheduled for penetrating keratoplasty (PK) were included in the study; two Stevens-Johnson syndromes (SJS), five corneal combustions due to chemical burn, seven post-traumatic vascularised leucomas, 11 post-infectious vascularised leucomas, 19 rejected grafts and six corneal ulcers. Additional surgeries such as autologous limbal stem cell and/or amniotic membrane transplantation were performed together with PK in ten cases. All eyes received subconjunctival injection of 0.5 ml bevacizumab (25 mg/ml) after PK. Eyes with more than two quadrants of neovascularisation (NV) received bevacizumab drops (25 mg/ml) postoperatively for up to 12 weeks. Donor grafts were followed up for best-corrected visual acuity, graft clarity, change in NV, endothelial cell density loss (ECD), and adverse events. Mean follow-up was 36.5 months (range 32-61). RESULTS: Best-corrected visual acuity increase was statistically significant in 82 % (41/50) of eyes 3 years after PK (paired t-test, p = 0.02). Thirty-five (70 %) high-risk grafts remained clear throughout the 3-year follow-up period. Decrease of corneal NV was observed in 84 % (42/50) of eyes treated with bevacizumab. ECD changed from preoperative 2,864 ± 301 down to 1,905 ± 187 cells/mm(2) at 3 postoperative years. A non-healing epithelial defect was recorded in one patient with SJS after 12 weeks of topical bevacizumab. CONCLUSION: Combined subconjunctival and topical bevacizumab treatment may improve corneal graft survival rate in the majority of high-risk cases.

Systemically available bone morphogenetic protein two and seven affect bone metabolism.

PURPOSE: Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long-bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones. METHODS: Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro-CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies. RESULTS: TPTx resulted in bone loss, which was restored by systemic administration of 10-70 µg/kg of BMP-2 and 10-250 µg/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts. CONCLUSIONS: Surprisingly, both BMP-2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss.

Positive pressure during penetrating keratoplasty can be solved with a modified graft-over-host technique.

PURPOSE: To describe a modified graft-over-host (MGOH) surgical technique which was used to prevent serious complications in cases of positive vitreal pressure during penetrating keratoplasty (PKP) and to compare the endothelial cell density (ECD) loss and clinical outcome between eyes undergoing MGOH or standard PKP. METHODS: In the proposed MGOH technique, the donor graft is sutured over the recipient cornea as soon as signs of positive pressure are noticed, even before cutting the recipient cornea, and the surgery is continued by consecutive cutting of the recipient and continuous suturing of the donor cornea, quadrant by quadrant. Donor grafts were prospectively followed up for the graft clarity, ECD loss and the amount of astigmatism. RESULTS: Of 220 cases scheduled for standard PKP in years 2009-2011, eight were operated by MGOH technique. Despite the fact that the donor cornea is situated over the recipient almost throughout the whole MGOH procedure, the ECD loss is equal between eyes operated on by MGOH technique and standard PKP, and none of the grafts had primary graft failure. The only disadvantage was an increased amount of astigmatism that was not as significant once the sutures were taken out. CONCLUSION: Modified graft-over-host technique seems to be a safe and effective method to prevent complications during PKP complicated by positive vitreal pressure.

Treatment of anti-vascular endothelial growth factor-resistant diabetic macular edema with dexamethasone intravitreal implant.

PURPOSE: To investigate the efficiency of intravitreal dexamethasone implant in patients with chronic diabetic macular edema nonresponsive to three consecutive monthly intravitreal injections of anti-vascular endothelial growth factor administered previously. METHODS: Fifteen patients (16 eyes) were included in this 4-month prospective clinical trial. Main observed outcomes were the changes between initial and monthly visits in best-corrected visual acuity, central foveal thickness, and intraocular pressure (IOP). Patients included had central foveal thickness of >225 µm (measured by optical coherence tomography) and were nonresponsive to previously administered 3 consecutive monthly intravitreal injections of 1.25-mg bevacizumab. Administration of intravitreal dexamethasone implant was performed at baseline, and patients were followed-up monthly. RESULTS: Statistically significant changes from baseline were observed in best-corrected visual acuity (at 2 months), central foveal thickness (at 1, 2, and 3 months), and IOP (at Months 1, 2, and 3) as follows: mean best-corrected visual acuity significantly increased from 0.29 Snellen lines at baseline to 0.39 lines after 2 months (P = 0.0381). At Months 1, 2, and 3, the mean central foveal thickness significantly decreased, from 462 µm at baseline, to 366 µm (P = 0.0343), 346 µm (P = 0.0288), and 355 µm (P = 0.0370), respectively. When compared with baseline IOP of 15.38 mmHg (12-19 mmHg), IOP increased significantly at Months 1, 2, and 3: 18.93 mmHg (range, 16-24 mmHg; P = 0.0003), 19.5 mmHg (range, 16-27 mmHg; P = 0.0003), and 17.5 mmHg (range, 15-21 mmHg; P = 0.0048), respectively. CONCLUSION: Dexamethasone intravitreal implant may present an alternative option in the treatment of chronic diabetic macular edema nonresponsive to three consecutive monthly bevacizumab injections administered previously. However, IOP measures were only slightly increased. It seems that the effect of dexamethasone may last till 4 months after initial injection.

Potential beneficial role of sevelamer hydrochloride in diabetic retinopathy.

Patients with chronic kidney disease (CKD) experience co-morbid illnesses, including cardiovascular disease and retinopathy. Sevelamer hydrochloride (Renagel®); a non-calcium phosphate binder reduces coronary artery and aortic calcification as compared to calcium containing phosphate binders and additionally effects inflammatory biomarkers such as C-reactive protein (CRP), and lowers LDL cholesterol in patients with CKD. Since retinopathy is proven to be associated with increased coronary calcification, shared pathophysiological processes may contribute to both microvascular and macrovascular disease. We here suggest three different mechanisms of possible sevelamer's influence on the retinopathy: (1) by direct effect on the microvasculature through lowering CRP and LDL, involved in endothelial dysfunction and atherogenesis, (2) indirectly by attenuation of vascular calcification of aorta and carotid internal artery, it reduces ischaemia and improves circulation in the opthalmic artery and hence postponing retinopathy, (3) through hypertension by reducing atherosclerosis and calcification of carotid arteries, sevelamer decreases stiffness and intima-media wall thickness, therefore lowering blood pressure, which is well known to increase progression of diabetic retinopathy. So far no studies have yet been published on the direct influence of sevelamer on the retinopathy which we believe has good theoretical background. With its combined macrovascular and microvascular effect, sevelamer could potentially postpone and/or decrease retinopathy in diabetic patients with hypertension, and that are on hemodialysis or even predialysis patients.

Biomechanical properties of bones from rats treated with sevelamer.

Sevelamer hydrochloride is used for ten years in patients on dialysis as a phosphate binder. We have previously shown that oral application of sevelamer prevents the bone loss and increases the bone volume in ovariectomized rats. In this study we further analysed the biomechanical properties of bones from rats treated with sevelamer utilizing a threepoint bending test to determine the mechanical properties of the cortical bone of the mid-shaft femur, while the indentation test was used to determine the mechanical properties of cancellous bone in the marrow cavity of the distal femoral metaphysis. Parameters analyzed included: maximum load (F(u)), stiffness (S), energy absorbed (W), toughness (T) and ultimate strength (sigma). The intrinsic properties, stress, elastic modulus and toughness were determined from measured maximum load, strains, stiffness, energy absorbed, outer and inner diameters, and calculated bone cross-sectional moment of inertia. Sevelamer was given to rats for 25 weeks with a content of 3% of sevelamer in a standard diet, starting immediately following ovariectomy (OVX). Animals were divided to the following groups: (1) Sham; (2) Sham + sevelamer 3%; (3) OVX; (4) OVX + sevelamer 3%. Our results showed that sevelamer particularly influenced the rat trabecular bone by increasing the maximum load for 26.2%, energy absorbed for 24.2% and the ultimate strength for 26.2% in sham animals treated with sevelamer 3%, as compared to sham rats. Sevelamer 3% in OVX rats also increased the maximum load for 71.4%, stiffness for 70.7%, energy absorbed for 55.9% and the ultimate strength for 71.3% as compared to OVX controls. In the three bending test sevelamer had a very little effect on preventing loss of bone strenght in the cortical bone. These results collectively suggest that sevelamer improves bone biomechanical properties, mainly affecting trabecular bone quality in both normal and ovariectomized rats.

Prognostic importance of PAI-1 in node negative breast cancer patients--results after 10 years of follow up.

The serine protease urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play key roles in the proteolytic cascade involved in physiological and pathological degradation of the extracellular matrix. The aim of this study was to determine the prognostic importance of PAI-1 expression in tumor cells in node-negative breast cancer patients that did not receive adjuvant chemotherapy. We used immunohistochemistry (IHC) as a detection method. The study retrospectively included 133 ductal invasive breast cancer patients from the Clinical Hospital Center Zagreb, Croatia, surgically treated in a two-year interval (1998-1999) with 10 years of follow up. The Cox proportional hazard regression test with stepwise variable selection was used to calculate the relative effect of investigated data on patients' prognosis. Univariate analysis showed that all investigated factors, such as lymph node involvement (p=0.025), tumor grade (p<0.001), estrogen receptor status (p=0.011), vascular invasion (p=0.001), HER2 overexpression (p<0.001), and proliferative index (p<0.001), had a statistically significant influence on patients' OS. Multivariate statistical analysis showed that only HER-2 (p<0.001) can be considered an independent, statistically significant poor prognostic factor. In patients with negative lymph nodes that did not receive adjuvant chemotherapy, we found a significant correlation in overall survival (p=0.009), which is favorable for PAI-1 negative tumors. In conclusion, it seems that PAI-1 in primary breast cancer tissue correlates with disease aggressiveness and has a strong prognostic impact on primary breast cancer, and is a strong prognostic factor for node-negative patients that did not receive chemotherapy.

1-year follow-up study of endothelial cell density loss after penetrating keratoplasty.

High endothelial cell density (ECD) is essential for the corneal graft clarity. We evaluated ECD loss in 120 eyes that underwent penetrating keratoplasty (PK) in Eye Clinic Svjetlost in a one year follow up period. Patients were divided into 3 groups of high (N = 35), intermediate (N = 31) and low risk (N = 54) for graft failure. Postoperative central endothelial density, coefficient of variation in cell area (polymegathism), percentage of hexagonal cells (pleomorphism) in comparison to preoperative donor cell measurements were determined in the following postoperative time-points of 1, 2, 3, 6, 9 and 12 months. There were no significant differences in the preoperative ECD values, storage time, donor age or surgical procedures between groups. Throughout all time points intermediate group had the greatest statistically significant ECD loss as compared to high and low risk groups. There were no significant differences between high and low risk group. After 12 month post PK, intermediate risk group had 28.38% ECD loss as compared to 24.07% in high and 23.03% ECD loss in low risk group. Coefficient of variation in cell area (CV) was for high risk group 0.34, intermediate 0.40 and low risk 0.31 which was not significantly different between groups. Percentage of plemorphism in high risk was 54%, intermediate 58% and in low risk 48% which was significantly different as compared to other two groups. Our study showed that corneal pathology is among others, very important prognostic factor for ECD after PK. However, longer follow up period is needed.

First results of Intracor procedure in Croatia.

This study reports early outcomes of a cohort of presbyopic patients treated with Intracor. The study took place from December 2010 to May 2011 and was conducted in University Eye Hospital "Svjetlost", Zagreb, Croatia. 95 eyes were enrolled in this prospective clinical trial (49 patients with non dominant eye and 23 with bilateral treatment). All patients gave informed consent prior to enrollment. Follow up consisted of uncorrected and corrected distant and near visual acuity, record of topographic changes, visual disturbances and patient satisfaction at 1 week, 1 and 3 months after the surgery. In this study Intracor procedure presented as both safe and effective with all eyes gaining several lines of uncorrected near visual acuity (UNVA), and achieving good uncorrected distant visual acuity(UDVA) as well. UDVA was affected by a mild myopic shift, which was effective in reducing mild preexisting hyperopia in some patients but led to a mild myopic outcome in previously emmetropic patients. Statistically significant improvement in UDVA and UNVA was observed in all time points. At 3 months of postoperative follow up all patients gained several lines of UNVA with monocular UNVA Jaeger system 1.67 +/- 0.28. UDVA showed slight improvement over time and initial myopic shift showed tendency of slight decrease with all patients achieving 1.0. Overall patients satisfaction was very high (98%) with only a few (3 patients, 5 eyes) reporting mild halo and glare at 3 months postop.Intracor procedure has proven its short-term safety and efficacy in treating presbyopia. However, longer follow up period is needed.

Surgical treatment of residual esotropia.

Residual esotropia is a common problem following bilateral medial rectus (MR) recessions for esotropia. The patient was 30 years old men who underwent bilateral MR recession of both eyes in the childhood. Recession was repeated on the right eye few years after the first surgery, but residual esotropia progressed. Prior to our surgery residual angle of esotropia was 50PD degrees with restriction of abduction and elevation of the left eye. Sinechiolysis et myectomia of right MR and sinechiolysis and recession of left MR were performed using operating microskop. One week after surgery residual angle was 4 PD. Motility of both eyes was free except slight residual reduction of left eye elevation. During postoperative period of 2 years residual angle was not greater than 8 PD, with good motility of both eyes. We suggest that sinechiolysis and myectomia of MR together with recession of the prior operated muscle, when possible, can be a reasonable surgical option in the treatment of large-angle residual esotropia.

Selective laser trabeculoplasty in the treatment of pseudoexfoliation glaucoma in patients allergic to all anti-glaucoma drops.

Secondary chronic open-angle glaucoma associated with pseudoexfoliation (PEX) syndrome accounts for approximately 25% of all glaucomas and represents the most common identifiable cause of glaucoma overall. Selective laser trabeculoplasty (SLT) is effective in reducing intraocular pressure (IOP) in glaucomatous patients and has the advantage of preserving surrounding structures. We report here SLT treatment of a 82 year old female with a secondary developed open-angle pseudoexfoliation glaucoma allergic to all anti glaucoma eye drops especially those which contain bensalconium chloridum as preservative. Since patient was allergic also to methyl-cellulose, we performed SLT with water as a mediator. Patient had PEX syndrome for 10 years, immature cataracts on both eyes, and best corrected visual acuity (BCVA) 0.7 on the right and 0.2 on the left eye. We have monitored intraocular pressure (IOP), the changes in the visual field and optic nerve. Preoperative IOP was 28 mmHg on the right and 30 mmHg on the left eye. The follow up period was 24 months with time points for measured parameters every 3 months. After 18 months IOP remained in the normal values (average 17 mmHg) on the right eye, but on the left eye it increased up to 28 mmHg. SLT re-treatment was carried out on the left eye and the IOP stabilized again on the values between 16-18mmHg. There were no significant change in the visual field and optic nerve configuration before and after SLT (C/D value for right eye: 0.3-0.4; C/D left eye: 0.5). Based on this case report, SLT seems to be very effective treatment for maintaining regular IOP in patient with PEX who is allergic to all types of medications.

Amniotic membrane transplantation in the treatment of persistent epithelial defect on the corneal graft.

It has been shown that amniotic membrane transplantation (AMT) improves healing of the epithelium defects as it serves as a basement membrane for endothelial cells growth, prevents inflammatory cell infiltration and reduces apoptosis in keratocytes. Having in mind the healing properties of AM we investigated the efficacy of AMT in persistent epithelial defect (PED) on the corneal graft. 80 corneal grafts were prospectively followed up for presence of PED 10 months after surgery. PED was detected in 12 cases (15%) having surgery for: rejected graft (n = 4), keratoconus (n = 3), keratoconus following PK on a second eye (n = 3), corneal perforation (n = 1) and Stevens-Johnson keratopathy (n = 1). Epithelial defect (ED) developed 14 +/- 7 days after surgery in 10 cases and 1.5 month in other two. All patients were primarily conservatively treated with subconjuctival steroids and artificial tears for 10 days and systemic steroid therapy if needed after, until the period of 2 weeks. 4 patients were healed. Since ED was unresponsive to all previous treatments for more than 2 weeks, one layer of AM was placed on the corneal lesion in 5 patients, and in 3 cases of deep PED several layers of AM were placed. Healing of the defect was obtained in 7/8 (87.5%) eyes. In 1 patient second AM transplantation was necessary. Mean epithelization time was 2 weeks (range 1-3 weeks) in monolayer and 3 weeks (range 2-4 weeks) for multilayer cases. 5 out of 8 patients retained the same best corrected visual acuity (BCVA) while 3/8 patients improved their vision more than 2 lines. Preoperative corneal thickness of 255 +/- 40 mm increased to 455 +/- 90 mm. AM transplantation facilitates healing of corneal epithelium. PED on the corneal graft unresponsive to conventional treatment can be effectively cured when covered with one or more amniotic membrane layers.

Sevelamer restores bone volume and improves bone microarchitecture and strength in aged ovariectomized rats.

Sevelamer hydrochloride, a noncalcium phosphate binder, has been shown to reduce coronary artery and aortic calcification, and to improve trabecular bone mineral density in hemodialysis patients with chronic kidney disease. Here, we examined whether sevelamer given orally for 12 wk with normal food could restore bone volume (BV) and strength in aged ovariectomized (OVX) rats starting at 4 wk after OVX. Dual-energy x-ray absorptiometry, microcomputerized tomography, and bone histomorphometry analyses showed that OVX animals receiving sevelamer had increased trabecular BV (51%), trabecular number (43%), trabecular thickness (9%), cortical thickness (16%), mineral apposition rate (103%), bone formation rate (25%), and enhanced cortical and trabecular bone mechanical strength as compared with OVX rats. Sevelamer decreased collagen C telopeptide, increased osteocalcin levels, and decreased phosphate and magnesium levels without affecting calcium levels in the blood. Although sevelamer was not absorbed systemically, it stimulated osteoblast differentiation in BM-derived mesenchymal stem cell cultures, as evaluated by alkaline phosphatase positive colony-forming units, and inhibited recombinant human soluble receptor activator of nuclear factor-kappaB ligand-induced osteoclast differentiation, as evaluated by tartrate-resistant acid phosphatase positive cells in bone mineral-hematopoietic stem cell cultures. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis revealed that 69 proteins were differently expressed after OVX, of which 30% (20 of 69) were reversed to sham activity after sevelamer intake. PTH, fibroblast growth factor-23, and cytokine profile in serum were not significantly changed. Together, these results suggest that sevelamer in food increases the BV and improves biomechanical properties of bone in OVX rats.

Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats.

UNLABELLED: We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSH's actions are mediated by its inhibitory effects on RANKL-induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo. INTRODUCTION: Thyroid-stimulating hormone (TSH) receptor haploinsufficient mice with normal circulating thyroid hormone levels have reduced bone mass, suggesting that TSH directly affects bone remodeling. We examined whether systemic TSH administration restored bone volume in aged ovariectomized (OVX) rats and influenced osteoclast formation and osteoblast differentiation in vitro. MATERIALS AND METHODS: Sprague-Dawley rats were OVX at 6 months, and TSH therapy was started immediately after surgery (prevention mode; n = 80) or 7 mo later (restoration mode; n = 152). Hind limbs and lumbar spine BMD was measured at 2- or 4-wk intervals in vivo and ex vivo on termination at 8-16 wk. Long bones were subjected to microCT, histomorphometric, and biomechanical analyses. The direct effect of TSH was examined in osteoclast and osteoblast progenitor cultures and established rat osteosarcoma-derived osteoblastic cells. Data were analyzed by ANOVA Dunnett test. RESULTS: In the prevention mode, low doses (0.1 and 0.3 microg) of native rat TSH prevented the progressive bone loss, and importantly, did not increase serum triiodothyroxine (T3) and thyroxine (T4) levels in aged OVX rats. In restoration mode, animals receiving 0.1 and 0.3 microg TSH had increased BMD (10-11%), trabecular bone volume (100-130%), trabecular number (25-40%), trabecular thickness (45-60%), cortical thickness (5-16%), mineral apposition and bone formation rate (200-300%), and enhanced mechanical strength of the femur (51-60%) compared with control OVX rats. In vitro studies suggest that TSH's action is mediated by its inhibitory effects on RANKL-induced osteoclast formation, as shown in hematopoietic stem cells cultivated from TSH-treated OVX rats. TSH also stimulates osteoblast differentiation, as shown by effects on alkaline phosphatase activity, osteocalcin expression, and mineralization rate. CONCLUSIONS: These results show for the first time that systemically administered TSH prevents bone loss and restores bone mass in aged OVX rats through both antiresorptive and anabolic effects on bone remodeling.

Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption.

Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17beta-estradiol (E2) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats.