Do Selective Serotonin Reuptake Inhibitors (SSRIs) Cause Fractures?

Recent meta-analyses report a 70 % increase in fracture risk in selective serotonin reuptake inhibitor (SSRI) users compared to non-users; however, included studies were observational and limited in their ability to establish causality. Here, we use the Bradford Hill criteria to explore causality between SSRIs and fractures. We found a strong, consistent, and temporal relationship between SSRIs and fractures, which appears to follow a biological gradient. However, specificity and biological plausibility remain concerns. In terms of specificity, the majority of available data have limitations due to either confounding by indication or channeling bias. Self-controlled case series address some of these limitations and provide relatively strong observational evidence for a causal relationship between SSRIs and fracture. In doing so, they suggest that falls contribute to fractures in SSRI users. Whether there are also underlying changes in skeletal properties remains unresolved. Initial studies provide some evidence for skeletal effects of SSRIs; however, the pathways involved need to be established before biological plausibility can be accepted. As the link between SSRIs and fractures is based on observational data and not evidence from prospective trials, there is insufficient evidence to definitively determine a causal relationship and it appears premature to label SSRIs as a secondary cause of osteoporosis. SSRIs appear to contribute to fracture-inducing falls, and addressing any fall risk associated with SSRIs may be an efficient approach to reducing SSRI-related fractures. As fractures stemming from SSRI-induced falls are more likely in individuals with compromised bone health, it is worth considering bone density testing and intervention for those presenting with risk factors for osteoporosis.     

Hypercalcemia in Breast Cancer: An Echo of Bone Mobilization During Lactation?

Hypercalcemia is a frequent complication of breast cancer which causes significant morbidity and mortality. Most commonly, it occurs in patients with multiple skeletal metastases. However, in a significant minority of patients, calcium levels become elevated in the absence of skeletal disease. In both instances, hypercalcemia is the result of pathological bone resorption caused by the secretion of cytokines that stimulate osteoclast differentiation and activity. One of these cytokines is parathyroid hormone-related protein (PTHrP). PTHrP is also secreted by normal breast cells during lactation to increase bone resorption and liberate skeletal calcium stores for the purposes of milk production. Therefore, the pathophysiology of hypercalcemia in breast cancer patients mimics the physiological processes that normally regulate calcium metabolism during lactation. Current therapy for hypercalcemia in breast cancer patients relies on the inhibition of bone resorption by a class of drugs known as bisphophonates. Newer therapies in development target cytokines involved in the recruitment and activation of osteoclasts by tumor cells.     

Are Bone Turnover Markers Capable of Predicting Callus Consolidation During Bone Healing?

The aim of this study was to determine the ability of the following bone turnover markers to monitor the course of callus consolidation during bone healing: Carboxy-terminal propeptide of procollagen type I (PICP), skeletal alkaline phosphatase (sALP), and amino-terminal propeptide of type III procollagen (PIlINP). Since interfragmentary movements have been proven to possess the ability to document the progression of bone healing in experimental studies, correlations between bone turnover markers and interfragmentary movements in vivo were investigated. Therefore, two different types of osteosyntheses representing different mechanical situations at the fracture site were compared in an ovine osteotomy model. Blood samples were taken preoperatively and postoperatively in weekly intervals over a nine-week healing period. At the same intervals, interfragmentary movements were measured in all sheep. After nine weeks, animals were sacrificed and the tibiae were evaluated both mechanically and histologically. Wide interindividual ranges were observed for all bone turnover markers. The systemic PICP level did not increase with callus consolidation. The bone-healing model seemed to influence the systemic level of PIIINP and sALP but no general correlation between bone turnover markers and interfragmentary movements could be detected. No differences between the different types of osteosyntheses and thus the different mechanical situations were observed. All analyzed markers failed as general predictors for the course of callus consolidation during bone healing.     

Radioprotectant and Radiosensitizer Effects on Sterility of γ-irradiated Bone

Gamma radiation is widely used to sterilize bone allografts but may impair their strength. While radioprotectant use may reduce radiation damage they may compromise sterility by protecting pathogens. We assessed the radioprotective potential of various agents (L-cysteine, N-acetyl-L-cysteine, L-cysteine-ethyl-ester and L-cysteine-methyl-ester) to identify those which do not protect spores of Bacillus subtilis. We hypothesized charge of these agents will affect their ability to radioprotect spores. We also determined ability of these radioprotectants and a radiosensitizer (nitroimidazole-linked phenanthridinium) to selectively sensitize spores to radiation damage by intercalating into the nucleic acid of spores. Spores were treated either directly in solutions of these agents or treated after being embedded and sealed in bone to assess the ability of these agents to diffuse into bone. L-cysteine and L-cysteine-ethyl-ester did not provide radioprotection. Positively charged L-cysteine-methyl-ester protected the spores, whereas positively charged L-cysteine-ethyl-ester did not, indicating charge does not determine the extent of radioprotection. The spores were sensitized to radiation damage when irradiated in nitroimidazole-linked phenanthridinium solution and sensitization disappeared after rinsing, suggesting nitroimidazole-linked phenanthridinium was unable to intercalate into the nucleic acid of the spores. Some cysteine-derived radioprotectants do not shield bacterial spores against gamma radiation and may be suitable for curbing the radiation damage to bone grafts while achieving sterility. One or more of the authors (OA, JS, SAK) has received funding from a research grant from the Musculoskeletal Transplant Foundation.     

Is Nitric Oxide a Mediator of the Effects of Low-Intensity Electrical Stimulation on Bone in Ovariectomized Rats?

Low-intensity electrical stimulation (LIES) may counteract the effects of ovariectomy (OVX) on nitric oxide synthase (NOS) expression, osteocyte viability, bone structure, and microarchitecture in rats (Lirani-Galvão et al., Calcif Tissue Int 84:502–509, 2009). The aim of the present study was to investigate if these effects of LIES could be mediated by NO. We analyzed the effects of NO blockage (by l-NAME) in the response to LIES on osteocyte viability, bone structure, and microarchitecture in OVX rats. Sixty rats (200–220 g) were divided into six groups: sham, sham-l-NAME (6 mg/kg/day), OVX, OVX-l-NAME, OVX-LIES, and OVX-LIES-l-NAME. After 12 weeks, rats were killed and tibiae collected for histomorphometric analysis and immunohistochemical detection of endothelial NOS (eNOS), inducible NOS (iNOS), and osteocyte apoptosis (caspase-3 and TUNEL). In the presence of l-NAME, LIES did not counteract the OVX-induced effects on bone volume and trabecular number (as on OVX-LIES). l-NAME blocked the stimulatory effects of LIES on iNOS and eNOS expression of OVX rats. Both l-NAME and LIES decreased osteocyte apoptosis. Our results showed that in OVX rats l-NAME partially blocks the effects of LIES on bone structure, turnover, and expression of iNOS and eNOS, suggesting that NO may be a mediator of some positive effects of LIES on bone.     

How Much Sterile Saline Should be Used for Efficient Lavage During Total Knee Arthroplasty? Effects of Pulse Lavage Irrigation on Removal of Bone and Cement Debris

Bone and polymethyl methacrylate (PMMA) debris particles generated during total knee arthroplasty (TKA) reportedly cause third-body wear. The present study investigated the volume of pulse lavage sufficient for removal of intraoperative PMMA and bone particles. Subjects comprised 8 patients who underwent cemented TKA. Pulse lavage with 8 L of sterile saline was performed using a pulsatile irrigator. During pulse lavage, aspirated fluid was collected in a 1-L aliquot, and the number and size of bone and PMMA particles in each fluid were measured. Image analysis revealed that the number of particles peaked at first lavage and gradually decreased until eighth lavage. Significant differences were found between the first vs second, second vs third, and third vs fourth lavage. However, no significant differences were found beyond the fourth lavage. This study indicated that 4 L of pulse lavage is effective for removing the particles during cemented TKA.     

Is Decreased Ultraviolet Exposure During Childhood the Cause of the Increased Prevalence of Atopic Dermatitis?

There is a recent accumulation of data suggesting that decreased exposure to ultraviolet light in childhood could be a major factor contributing to the increasing rates of atopic dermatitis in children and adolescents. It would be worthwhile to study the relationship between vigilant sun protective behaviors in children and the incidence of atopic dermatitis.It is a well-established fact that sun exposure and ultraviolet A/ultraviolet B phototherapy are beneficial for patients with a diagnosis of atopic dermatitis,1 so it is no surprise that there is a growing body of evidence that ultraviolet-induced immunomodulation or a lack thereof is playing a roll in the increasing prevalence of atopic disease both in the United States and other countries.2,3 In addition, a recent study found an association between increased sun exposure and a reduced risk of atopic dermatitis in children and adolescents.4The data in the United States and worldwide show a steady increase in the rates of atopic dermatitis in children, and one must wonder if the vigilant use of sunscreen and sun avoidance in children as recommended by the American Academy of Pediatrics5 is one of the underlying reasons behind this trend. An article in Pediatrics looking at office visits for atopic dermatitis as a surrogate for the prevalence of atopic dermatitis in a patient population from newborns to age 18 throughout the United States from 1997 to 2004 showed a statistically significant increase in the number of visits over time even though the number of office visits for all diagnoses remained stable.6 It appears that as sunscreen use for children has become more widespread in the United States, the number of children diagnosed with atopic dermatitis has increased as well.Multiple studies have found that atopic eczema is more prevalent in affluent children.7-12 The literature shows that this same population of individuals with higher socioeconomic status in the United States and other countries is also more stringent about sun protective behaviors.13-14 As one might expect given the findings from studies on socioeconomic status, people with lower socioeconomic status living in rural areas are both less likely to engage in sun-protective behaviors and less likely to develop atopic dermatitis.15 A multitude of studies show that growing up on a farm protects against the development of allergic disease,16-23 which taken together with the other literature on socioeconomic status supports our hypothesis that increased time outdoors, decreased sun-protective behavior, and thus increased exposure to ultraviolet light decreases the incidence of atopic disease. One might infer that the trend toward children spending less time outdoors and more time inside watching television and playing video games is also directly affecting the increase in atopic disease.Given the recent accumulation of data regarding the relationship between atopic disease and ultraviolet-induced immunomodulation, the authors believe the question of if ultraviolet avoidance in childhood increases the risk of atopic dermatitis deserves additional study. If there does appear to be a correlation, we should consider whether we need to create less stringent guidelines for ultraviolet avoidance.     

Is There a Role for NFAT Inhibitors in the Prevention of Bone Destruction?

Pathologic conditions resulting from excessive bone destruction include osteoporosis, rheumatoid arthritis, metastases, periprosthetic osteolysis, cherubism, and others. A scarcity of molecular targets in bone has thwarted the development of drugs to combat these conditions. Nuclear factor of activated T-cells (NFAT) is a master regulator of osteoclastogenesis and is induced by RANKL. The immunosuppressive drugs, Cyclosporin A and Tacrolimus, inhibit osteoclast formation by targeting the NFAT/calcineurin pathway. These NFAT inhibitors should be considered in the treatment of osteoclastic hyper-resorptive syndromes.     

Effects of Nicotine Administration and Nicotine Cessation on Bone Histomorphometry and Bone Biomarkers in Sprague–Dawley Male Rats

Nicotine is a major alkaloid of tobacco, which can increase free radical formation, leading to osteoporosis. The effects of nicotine administration and cessation on bone histomorphometry and biomarkers were studied in 28 Sprague–Dawley male rats. Rats aged 3 months and weighing 250–300 g were divided into four groups: control (C, normal saline for 4 months), nicotine for 2 months (N2), nicotine for 4 months (N4), and nicotine cessation (NC). The NC group was given nicotine for the first 2 months and then allowed to recover for the following 2 months without nicotine. Histomorphometric analysis was done using an image analyzer. ELISA kits were used to measure serum osteocalcin (bone formation marker) and pyridinoline (PYD, bone resorption marker) levels at month 0, month 2, and month 4. All test groups showed a significant decrease in BV/TV, Ob.S/BS, dLS/BS, MAR, BFR/BS, and osteocalcin levels and an increase in sLS/BS and PYD levels compared to group C. No significant differences were observed in all parameters measured among the test groups, except for MAR and BFR/BS. In conclusion, nicotine administration at a dose of 7 mg/kg for 2 and 4 months has detrimental effects on bone metabolism. Nicotine administration at 7 mg/kg for 2 months is sufficient to produce significant effects on bone histomorphometric parameters and biomarkers. In addition, prolonging the treatment for another 2 months did not show any significant differences. Cessation of nicotine for 2 months did not reverse the effects.     

Effects of Octenidine HCl on Liver Tissue: Could It Be an Alternative Scolicidal for Hidatid Disease?

Octenidine HCl is new topical antiseptic solution for wounds and abdominal washing that has been found to be highly effective for inactivating scolices in an in vitro study. However, the effects of octenidine HCl on the liver are not yet known. The aim of this study was to determine if there are any histopathologic changes after injecting octenidine HCl into the liver. A group of 50 male Sprague-Dawley rats were included in the study and randomly divided into five groups of 10 rats each, as follows: sham group; 0.09% NaCl group; 20% NaCl group; undiluted octenidine HCl group; 1% octenidine HCl group. The scolicidal agents (0.3 ml) were directly injected into the left lobe of the liver (except in the sham group). At 3 and 7 days after the injection, the rats were sacrificed, and the left lobe of the liver was harvested. Liver tissue was scored for degree of necrosis and the diameter of the necrosis examined under light microscopy. The highest scores were found in the undiluted octenidine HCl group, although a similar effect was observed in the 20% NaCl group. There was no necrosis in the sham group, the 0.09% NaCl group, or the 1% octenidine HCl group. All of the injury was coagulation-type necrosis. No mortality was observed throughout the study. The 1% octenidine HCl solution could thus be used as a scolicidal agent in liver tissue, whereas the undiluted form of octenidine and 20% NaCl solutions were shown to cause necrosis when directly injected into liver tissue in our animal model. This study was presented at the 25th International Surgical Research Congress, Konya, Turkey, May 2004     

Telomere Shortening Occurs Early During Breast Tumorigenesis: A Cause of Chromosome Destabilization Underlying Malignant Transformation?

Chromosomal instability appears early during breast carcinogenesis and is considered a major driving force in malignant transformation. While current evidence suggests that centrosomal and mitotic checkpoint defects may, in large part, account for numerical chromosomal abnormalities, the mechanisms underlying structural chromosomal abnormalities remain largely unknown. Telomeres stabilize and protect chromosomal termini, but shorten due to cell division and oxidative damage. Moderate telomere shortening signals a tumor suppressive growth arrest in normal cells. Critically short telomeres, in the setting of abrogated DNA damage checkpoints, cause chromosomal instability due to end-to-end chromosomal fusions, subsequent breakage, and rearrangement, resulting in an increased cancer incidence in animal models. Recent results from high resolution in situ telomere length assessment in human breast tissues indicate that significant telomere shortening is prevalent in preinvasive breast lesions (DCIS), as well as focal areas of histologically normal epithelium from which breast carcinoma is thought to arise. Telomere shortening is therefore a strong candidate for the cause of structural chromosome defects that contribute to breast cancer development.     

The Effects of Kinesio? Taping on Proprioception at the Ankle

An experiment was designed to determine if Kinesio™ taping the anterior and lateral portion of the ankle would enhance ankle proprioception compared to the untaped ankle. 30 subjects, 15 men, 15 women, ages 18-30 participated in this study. Exclusion criteria: Ankle injury < 6 months prior to testing, significant ligament laxity as determined through clinical evaluation by an ATC, or any severe foot abnormality. Experiment utilized a single group, pretest and posttest. Plantar flexion and inversion with 20° of plantar flexion reproduction of joint position sense (RJPS) was determined using an ankle RJPS apparatus. Subjects were barefooted, blindfolded, and equipped with headphones playing white noise to eliminate auditory cues. Subjects had five trials in both plantar flexion and inversion with 20° plantar flexion before and after application of the Kinesio™ tape to the anterior/lateral portion of the ankle. Constant error and absolute error were determined from the difference between the target angle and the trial angle produced by the subject. The treatment group (Kinesio™ taped subjects) showed no change in constant and absolute error for ankle RJPS in plantar flexion and 20° of plantar flexion with inversion when compared to the untaped results using the same motions. The application of Kinesio™ tape does not appear to enhance proprioception (in terms of RJPS) in healthy individuals as determined by our measures of RJPS at the ankle in the motions of plantar flexion and 20° of plantar flexion with inversion.

Key Points

• Proprioception research
• Evaluation of a new taping method
• Augmentation of sensory feedback
• Rehabilitation technique

Key words: Reproduction of joint position sense, Kinesio™ Tape, target angle     

Effects of Different Dosages of Parathyroid Hormone-Related Protein 1–34 on the Bone Metabolism of the Ovariectomized Rat Model of Osteoporosis

Intermittent and low-dose parathyroid hormone (PTH) injection to stimulate bone formation has been used in the treatment of osteoporosis. The N-terminal fragment 1–34 of PTH is quite similar in structure and function to N-terminal PTH-related protein (PTHrP). PTH(1–34) and PTHrP also share a coreceptor, the PTH/PTHrP receptor. Therefore, some studies have suggested that PTHrP could effectively stimulate bone formation, similar to PTH. We used an ovariectomized (OVX) rat model of osteoporosis to study the effects of PTHrP(1–34) on bone metabolism by measuring bone mineral density (BMD), bone histomorphometrics, and biomechanical parameters. We found that subcutaneous injection of PTHrP(1–34) (40 or 80 μg/kg body weight every day) in OVX rats increased lumbar and femoral BMD, improved bone biomechanical properties, enhanced bone strength, and promoted bone formation. We selected 40 μg/kg as the preferred therapeutic dose of PTHrP(1–34) and investigated the effects of frequency of treatment (per 1, 2, 3, or 7 days) on bone metabolism in OVX rats. We found that injection of PTHrP(1–34) once per day or every other day significantly improved the BMD and strength of OVX rats. Serum calcium and phosphate levels in all treated rats did not vary significantly from control rats. Based on our results, intermittent low-dose PTHrP(1–34) injection promoted bone formation in OVX rats, suggesting a high potential for therapeutic use in osteoporosis patients.     

Does Exercise Modify the Effects of Zoledronic Acid on Bone Mass,Microarchitecture, Biomechanics,and Turnover in Ovariectomized Rats?

Regular activity has effects on bone size, shape, and density, resulting in an increase in mechanical strength. The mechanism of action that underlies this improvement in bone strength is mainly linked to an increase in bone formation. Zoledronic acid (Z), in contrast, may prevent bone strength changes in ovariectomized (OVX) rodents by its potent antiresorptive effects. Based on these assumptions we hypothesized that combined effects of exercise (E) and Z may produce higher benefits on bone changes resulting from estrogen deficiency than either intervention alone. At 6 months of age, 60 female Wistar rats were OVX or sham operated (SH) and divided into five groups: SH, OVX, OVX-E, OVX-Z, and OVX-ZE. OVX rats were treated with a single IV injection of Z (20 μg/kg) or vehicle and submitted or not to treadmill exercise (15 m/min, 60 min/day, 5 days/week) for 12 weeks. Whole-body BMD and bone turnover markers were analyzed longitudinally. At sacrifice, femurs were removed. BMD by DXA, three-point bending test, and μCT were performed to study biomechanical and trabecular structure parameters, respectively. After 12 weeks, bone volume fraction decreased in OVX rats, whereas bone turnover rate, trabecular spacing, and structure model index increased compared with those in the SH group (P < 0.05). Zoledronic acid prevented the ovariectomy-induced trabecular bone loss and its subsequent trabecular microarchitectural deterioration. Treadmill exercise running was shown to preserve the bone strength and to induce bone turnover changes in favor of bone formation. However, the combined effects of zoledronic acid and running exercise applied simultaneously did not produce any synergetic or additive effects.     

Specific Effects of γ-Linolenic,Eicosapentaenoic, and Docosahexaenoic Ethyl Esters on Bone Post-ovariectomy in Rats

Long chain polyunsaturated fatty acids (LCPUFAs) are involved in the regulation of bone metabolism. Increased dietary consumption of n-3, and possibly some n-6, LCPUFAs may limit postmenopausal bone loss. The aim of this study was to determine the effects on bone of specific fatty acids within the n-3 and n-6 LCPUFA families in ovariectomized (OVX) rats. Rats were OVX or sham-operated and fed either a control diet (OVX and sham) or a diet supplemented with 0.5 g/kg body weight/day of γ-linolenic (GLA), eicosapentaenoic (EPA), docosahexaenoic (DHA) ethyl esters or a mixture of all three (MIX) for 16 weeks. Bone mineral content (BMC), area, and density and plasma concentrations of insulin-like growth factor-I, vitamin D, selected biochemical markers of bone metabolism, and parathyroid hormone (PTH) were determined. The OVX-induced decrease in lumbar spine BMC was significantly attenuated by DHA but not by EPA or GLA supplementation or supplementation with a mixture of all three LCPUFAs. Endosteal circumferences of tibiae were significantly greater in DHA and EPA compared to OVX. Plasma C-terminal telopeptide of type I collagen and osteocalcin concentrations were not significantly different in the DHA group compared to OVX. Femur BMC decreased by a significantly greater amount in GLA than OVX, and final plasma PTH concentrations were significantly higher in GLA compared to all other groups. In conclusion, DHA ameliorated OVX-induced bone mineral loss. GLA exacerbated post-OVX bone mineral loss, possibly as a result of PTH-induced bone catabolism.     

Effects of circumcision on male sexual function: debunking a myth?

PURPOSE: Claims of superior sexual sensitivity and satisfaction for uncircumcised males have never been substantiated in a prospective fashion in the medical literature. We performed such a study to investigate these assertions. MATERIALS AND METHODS: The Brief Male Sexual Function Inventory (BMSFI) was administered to sexually active males older than 18 years before undergoing circumcision. After a minimum interval of 12 weeks after the operation, the survey was again administered. The 5 domains of the BMSFI (sexual drive, erections, ejaculation, problem assessment overall satisfaction) were each given a summed composite score. These scores before and after circumcision were then analyzed by Wilcoxon signed-rank testing. RESULTS: All 15 men who participated in the study between September 1999 and October 2000 were available for followup. Mean patient age plus or minus standard deviation was 36.9 +/- 12.0 years. There was no statistically significant difference in the BMFSI composite scores of reported sexual drive (p >0.68), erection (p >0.96), ejaculation (p >0.48), problem assessment (p >0.53) or overall satisfaction (p >0.72). CONCLUSIONS: Circumcision does not appear to have adverse, clinically important effects on male sexual function in sexually active adults who undergo the procedure.