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Paracetamol (acetaminophen) use, fracture and bone mineral density
Abstract
Paracetamol is the most widely prescribed simple analgesic and antipyretic. It exerts its effects via cyclooxygenase and endocannabinoid pathways, which may affect signalling in bone cells and hence influence bone metabolism. Given the high rates of paracetamol use in the community and the evidence linking its mechanism of action to bone metabolism, we aimed to investigate the association between paracetamol use, fracture, and bone mineral density (BMD) in women participating in the Geelong Osteoporosis Study (GOS). Cases (n = 569) were women aged ≥ 50 years identified from radiological reports as having sustained a fracture between 1994 and 1996. Controls (n = 775) were women without fracture recruited from the same region during this period. BMD was measured at the spine, hip, total body and forearm using dual energy absorptiometry. Medication use, medical history and lifestyle factors were self-reported. There were 69 (12.1%) paracetamol users among the cases and 63 (8.1%) among the controls. Paracetamol use increased the odds for fracture (OR = 1.56, 95%CI 1.09-2.24, p = 0.02). Adjustment for BMD at the spine, total hip and forearm did not confound the association. However, incorporating total body BMD into the model attenuated the association (adjusted OR = 1.46, 95%CI 1.00-2.14, p = 0.051). Further adjustment for age, weight, physical activity, smoking, alcohol, calcium intake, medication use, medical conditions, falls and previous fracture did not explain the association. These data suggest that paracetamol use is a risk factor for fracture, although the mechanism of action remains unclear.
... Paracetamol (acetaminophen) is a drug with analgesic, antipyretic and mild antiinflammatory properties, and is one of the most used medications worldwide [147]. Its mechanism of action involves the cyclooxygenase (COX) and cannabinoids pathways, decreasing prostaglandins production and in turn affecting bone turnover [140]. ...
... Changes in BMD and bone fragility with an increased risk of fractures have been the most studied [143]. Several authors have reported no difference in BMD between paracetamol users and non-users [147,149]. No significant differences were found according to dose and pattern of users (intermittent vs. continuous) [143]. ...
Simple Summary
Forensic anthropologists analyze human remains to assist in the identification of the deceased, predominantly by assessing age-at-death, sex, stature, ancestry and any unique identifying features. Whilst methods have been established to create this biological profile of the skeleton, these may be influenced by a number of factors. This paper, for the first time, provides an overview from a reading of the clinical and pharmacological literature to explore whether the intake of drugs can affect the skeleton and whether these may have implications for forensic anthropology casework. In effect, drugs such as tobacco, heroin, and prescription medications can alter bone mineral density, can increase the risk of fractures, destroy bone and changes to the dentition. By considering how drugs can affect the skeleton, forensic anthropologists can be aware of this when attempting to identify the deceased.
Abstract
Forensic anthropologists rely on a number of parameters when analyzing human skeletal remains to assist in the identification of the deceased, predominantly age-at-death, sex, stature, ancestry or population affinity, and any unique identifying features. During the examination of human remains, it is important to be aware that the skeletal features considered when applying anthropological methods may be influenced and modified by a number of factors, and particular to this article, prescription drugs (including medical and non-medical use) and other commonly used drugs. In view of this, this paper aims to review the medical, clinical and pharmacological literature to enable an assessment of those drug groups that as side effects have the potential to have an adverse effect on the skeleton, and explore whether or not they can influence the estimation of age-at-death, sex and other indicators of the biological profile. Moreover, it may be that the observation of certain alterations or inconsistencies in the skeleton may relate to the use of drugs or medication, and this in turn may help narrow down the list of missing persons to which a set of human remains could belong. The information gathered from the clinical and medical literature has been extracted with a forensic anthropological perspective and provides an awareness on how several drugs, such as opioids, cocaine, corticosteroids, non-steroidal anti-inflammatory drugs, alcohol, tobacco and others have notable effects on bone. Through different mechanisms, drugs can alter bone mineral density, causing osteopenia, osteoporosis, increase the risk of fractures, osteonecrosis, and oral changes. Not much has been written on the influence of drugs on the skeleton from the forensic anthropological practitioner perspective; and this review, in spite of its limitations and the requirement of further research, aims to investigate the current knowledge of the possible effects of both prescription and recreational drugs on bones, contributing to providing a better awareness in forensic anthropological practice and assisting in the identification process of the deceased.
... Briefly, the cells cultured in α-minimum essential medium (α-MEM) containing 10% fetal bovine serum (FBS) at 37°C under humidified conditions of 5% CO 2 /95% air were seeded into 35-mm diameter dishes (5 × 10 5 cells/dish) for an osteoprotegerin assay and reverse and the indirect action to modulate the endogenous cannabionoid system are recently proposed as candidates of signaling mechanism (Ghanem et al. 2016). As for undesired effects of acetaminophen, it has been reported that acetaminophen use could be a high risk factor for bone fracture as well as the decline of bone mineral density (Williams et al. 2011). However, it remains to be investigated how acetaminophen affects bone tissue. ...
... Based on our present findings in osteoblast-like MC3T3-E1 cells that acetaminophen inhibited the osteoprotegerin synthesis stimulated by PGE 2 and PGF 2α , it seems likely that acetaminophen, an analgesic agent, might accelerate bone resorption and impaired bone remodeling. Therefore, it is possible that the novel mechanism of acetaminophen shown here is implicated in the high risk of the development of bone fracture and fragile bone observed in the population prescribed with the widely used analgesics (Warner et al. 1999;Williams et al. 2011;Wheatley et al. 2019). The clinically critical acetaminophen concentration of serum was considered to be ranged between 50 to 250 μg/mL (approximately 0.3 to 1.6 μM (Abuknesha et al. 2011). ...
Acetaminophen is one of the most widely used analgesic and antipyretic medicines, whose long-period use has reportedly been associated with an increased risk of bone fracture. However, the mechanism underlying this undesired effect remains to be investigated. The homeostatic control of bone tissue depends on the interaction between osteoblasts and osteoclasts. Osteoprotegerin produced by osteoblasts is known to play an essential role in suppressing osteoclast induction. We have previously reported that prostaglandin (PG) E2 and PGF2α induce osteoprotegerin synthesis through p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effects of acetaminophen on the osteoprotegerin synthesis induced by PGE2 and PGF2α in MC3T3-E1 cells. Acetaminophen significantly suppressed the osteoprotegerin release stimulated by PGE2 and PGF2α. The PGE2-induced expression of osteoprotegerin mRNA was also reduced by acetaminophen. Acetaminophen markedly downregulated the phosphorylation of SAPK/JNK stimulated by PGE2 and PGF2α, but not those of p38 MAPK or p44/p42 MAPK. SP600125, an inhibitor of SAPK/JNK, suppressed the levels of PGE2- and PGF2α-upregulated osteoprotegerin mRNA expression. Taken together, these results strongly suggest that acetaminophen reduces the PGE2- and PGF2α-stimulated synthesis of osteoprotegerin in osteoblasts, and that the suppressive effect is exerted via attenuation of SAPK/JNK. These findings provide a molecular basis for the possible effect of acetaminophen on bone tissue metabolism.
... In contrast, reasons for loss of follow-up were not well documented, with only one 18 describing strategies to address incomplete follow-up. For the case-control studies, the risk of bias was low for most studies 19 21 25 26 except for one 20 which did not provide sufficient information regarding the cases and controls, as well as how exposure to aspirin was measured. The risk of bias for identifying confounders, measuring outcomes and using appropriate statistical analysis was low for all cross-sectional studies. ...
... 14 16 23 39 Meta-analysis Effect estimates (ie, ORs) for the association between aspirin use and fracture risk were manually calculated for two studies. 20 25 The MD in BMD outcomes were reported by three studies, 22 24 39 with the remaining studies reporting percentage difference in BMD. 14-17 23 Using equations (1) and (2), the SMD and SE for the SMD was calculated for each study and used in the meta-analysis. ...
Objectives
This review provides insights into the potential for aspirin to preserve bone mineral density (BMD) and reduce fracture risk, building knowledge of the risk-benefit profile of aspirin.
Methods
We conducted a systematic review and exploratory meta-analysis of observational studies. Electronic searches of MEDLINE and Embase, and a manual search of bibliographies was undertaken for studies published to 28 March 2018. Studies were included if: participants were men or women aged ≥18 years; the exposure of interest was aspirin; and relative risks, ORs and 95% CIs for the risk of fracture or difference (percentage or absolute) in BMD (measured by dual energy X-ray absorptiometry) between aspirin users and non-users were presented. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for observational studies. Pooled ORs for any fracture and standardised mean differences (SMDs) for BMD outcomes were calculated using random-effects models.
Results
Twelve studies met the inclusion criteria and were included in the meta-analysis. Aspirin use was associated with a 17% lower odds for any fracture (OR 0.83, 95% CI 0.70 to 0.99; I ² =71%; six studies; n=511 390). Aspirin was associated with a higher total hip BMD for women (SMD 0.03, 95% CI −0.02 to 0.07; I ² =0%; three studies; n=9686) and men (SMD 0.06, 95% CI −0.02 to 0.13, I ² =0%; two studies; n=4137) although these associations were not significant. Similar results were observed for lumbar spine BMD in women (SMD 0.03, 95% CI −0.03 to 0.09; I ² =34%; four studies; n=11 330) and men (SMD 0.08; 95% CI −0.01 to 0.18; one study; n=432).
Conclusions
While the benefits of reduced fracture risk and higher BMD from aspirin use may be modest for individuals, if confirmed in prospective controlled trials, they may confer a large population benefit given the common use of aspirin in older people.
... There are also conflicting reports about the effect of paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) on bone mineral density (BMD) and fracture risk [5][6][7][8]. Eating patterns and dietary habits have been found to affect the bone mass also [9][10][11]. ...
... On the basis of this, higher BMD was found in NSAIDs users than the non-users [42,43] but this was not associated with fracture risk reduction [42]. Paracetamol was shown to inhibit osteoblast activity in vitro [44] and paracetamol use was found as a risk factor for fracture [8]. Similar to our study Danish Osteoporosis Prevention Study (DOPS) reported no association between paracetamol, NSAID consumption and BMD [6], but NSAID was associated with an increased fracture risk in DOPS. ...
... 32,33 Other studies indicate that ACE may increase the risk of stress fracture, raising concerns about chronic effects on bone health. 34,35 Taken together, These observations suggest that ACE may have adverse effects on various aspects of bone physiology and bone health. 36 A limitation to studying drugs in animals and humans is dosage. ...
Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6‐week, low‐dose ACE regimen on muscle and bone adaptations in exercising and non‐exercising rats. Nine‐week‐old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross‐sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three‐point bending and microcomputer tomography were measured in the femur. Follow‐up experiments in human primary muscle cells were used to explore supra‐physiological effects of ACE. Data were analyzed using a two‐way ANOVA for treatment (ACE or placebo) and condition (exercise or non‐exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment‐by‐condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated‐AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho‐4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post‐exercise.
... Several studies investigated the effect of aspirin on bone resorption and remodeling. Some studies found aspirin to preserve bone mineral density (BMD) [14][15][16][17][18][19] , whereas others didn't find such an association [20][21][22] . Considering the conflicting nature of the available results and the gravity of the topic, we sought to investigate this relationship further by analyzing data from thousands of patients through the National Health and Nutrition Examination Survey (NHANES) database. ...
Bone fractures are a global public health concern, yet no thorough investigation of low-dose aspirin usage to prevent fractures in the elderly has been conducted. Many interventional human and animal studies have tried to detect the correct role of low-dose aspirin on fractures in elderly persons. The literature doesn't consist of a retrospective observational study that includes a large number of older individuals and evaluates the accurate effect of aspirin on the fractures post falling from low heights. This cross-sectional includes 7132 elderly persons and aimed to detect if there was a link between taking low-dose aspirin to prevent fractures in the elderly. Data was extracted from the National Health and Nutrition Examination Survey (NHANES) database for 2017-2020 and 2013-2014. Demographic and examination data were collected during in-home interviews and study visits to a mobile examination center. Standardized questionnaires were used to collect information such as age, gender, race, educational level, and family income-to-poverty ratio. Body mass index (BMI), weight, standing height, upper leg length, upper arm length, arm circumference, and wrist circumference were all measured during the examination. The study examined 8127 patients, with 7132 elderly patients suitable for data analysis. The odds ratio of fractures due to a fall from standing height or less was 0.963 (95 percent confidence interval 0.08-1.149) in low-dose aspirin users, while having parents with osteoporosis had a related risk of 1.23. (95 percent confidence interval 0.81-1.8). The total number of fractures was 1295; with hip fractures constituting up to 13.82%, wrist fractures of 66.56%, and spine fractures of 19.61%. There was no significant difference in femur and spine bone mineral density (BMD) in the two groups (use low dose aspirin and don't use). Females had a 5.6 times greater fracture risk related to a fall from standing height or less (1 time or more) than males (P-value < 0.001). Furthermore, taking aspirin had no effect on the occurrence of fractures from standing height or less in older people (P-value = 0.468). In addition, the logistic regression after performing the propensity matching score confirmed that there was no impact of taking aspirin on the occurrence of fractures (P-value > 0.05). This cross-sectional study reveals that taking low-dose aspirin to prevent fractures in the elderly is statistically insignificant. However, fractures are more common in older persons, especially in older women; thus, more widespread injury prevention initiatives and access to osteoporosis prevention and diagnosis for older people should improve to minimize the overall burden. Fractures are a significant public health problem, and their incidence is steadily increasing worldwide. In 2019, it was estimated that there were more than 178 million fractures worldwide, with the incidence remarkably increasing in older age groups, mainly due to osteoporosis 1,2. By 2025, it is estimated that the incidence of fractures OPEN
... The effect on the osteoblastic differentiation varies depending on the drug, dose and duration of treatment. 10- 12 Williams et al., 16 indicated that paracetamol is a risk factor in fractures when administered chronically since it inhibits cyclooxygenase and endocannabinoids, which may negatively affect bone cells signals. Zhang et al.,17 reported that, at high doses, indomethacin inhibited collagen formation in primary tenocytes, delaying healing and bone formation. ...
Objective: To evaluate the effects of administering diclofenac and ketoprofen, as well as the effects of environmental oxygen pressure variation on mandibular bone regeneration. Methods: Thirty-six guinea pigs were distributed into two equal groups. Mandibular bone defects were performed on both groups. Group A was monitored under oxygen pressure at altitude (3320msl, 107mm Hg). Group B was monitored at sea level oxygen pressure (150msl, 157mm Hg). Each group was subdivided into 3 equal groups (A1, A2, A3 and B1, B2, B3). Subgroups A1 and B1 were given diclofenac; subgroups A2 and B2 ketoprofen; subgroups A3 and B3 NaCl. Bone regeneration was evaluated histologically on days 15 and 30. Results: After 15 days in the group controlled at sea level, the level of osteoblasts presented by the control subgroup was significantly higher (28.00±2.65) compared to the diclofenac subgroup (16.00±6.25) and to the ketoprofen subgroup (18.00±4.36); (p=0.041). After 15 days in the group controlled at altitude, the level of osteoblasts was significantly higher in the control subgroup (38.00±5.29) compared to the diclofenac subgroup (21.67±6.35) and to the ketoprofen subgroup (19.33±2.52); p=0.007. After 30 days in the group at sea level there was no difference found in the cell counting; p>0.05. After 30 days in the group controlled at altitude, the level of osteoblast was significantly higher in the control subgroup (58.00±4.58) compared to the diclofenac subgroup (34.33±4.73) and the ketoprofen subgroup (34.00±11.14); (p=0.003). Conclusion: The administration of diclofenac and ketoprofen produced lower mandibular bone regeneration, the effect being significantly more negative at sea level.
... In a study that was conducted on women aged ≥ 50 year, paracetamol use has been associated with a 56% increase in fracture risk due to its mechanism of action to bone metabolism. 27 Paracetamol has been known to act via COX-2, just like other NSAIDs. In some circumstances, such as in studies on NSAID-induced gastric damage, the inhibition of COX-1 and COX-2 was needed in rats because COX-2 might substitute COX-1 in producing cytoprotective prostaglandins. ...
Introduction: Some analgesic drugs may have adverse effects on bone remodelling and, thus, on orthodontic tooth movement rate (OTM). GV-0 is synthesized by reacting vanillin and cyclopentanone catalyzed in acidic condition, and it has been revealed as a selective COX-2 inhibitor. This study was aimed to investigate the effect of pentagamavunon-0 (PGV-0), one of the curcumin analogues, on OTM. Methods: This study was conducted on 50 male Wistar rats (350-450 g) which were randomly divided into five groups (n = 10 each): 1) no treatment group (NT), 2) orthodontic treatment only (ORT), 3) ORT plus 0.4% sodium carboxymethyl cellulose (Na-CMC) analgesic carrier, 4) ORT plus 200 mg/kg BW Paracetamol (PCT) as the positive control, and 5) ORT plus PGV-0 (50 mg/kg BW (PGV-0). Results: Drug and day interaction was statistically significant on two-way ANOVA. Post-hoc analyses showed that OTM increased from day 3 to 7 in all orthodontic groups over the same distance (p>0.05). Maximum OTM was found on day 6, which was significantly farther than the distance on day 4. On day 7, OTM was less than on day 6. OTM in all orthodontic groups, including in the PGV-0 group, was higher than in the NT group (p0.05). Post-hoc analysis (intra days) revealed that OTM in PGV-0 and other orthodontic treatment groups increased. Conclusion: After a single orthodontic force, PGV-0 does not inhibit tooth movement in rats from day 1 to day 7. Therefore, it is possible to develop PGV-0 as an alternative analgesics during orthodontic therapy.
Keywords: Analgesic drug, orthodontics, tooth movement, curcumin.
... 6 Risk factors for low BMD and possible bone fractures include low body mass index, history of fractures, sex and menopause, low intake of calcium and vitamin D, smoking, high alcohol consumption, physical inactivity, and history of use of certain drugs including glucocorticoids and some psychotropic drugs. [7][8][9] A series of diseases are also associated with low bone density along with factors concerning lifestyle and nutrition. As an example, such diseases as type 1 diabetes, inflammatory bowel disease, and schizophrenia have been associated with reduced bone mineral density. ...
Aim
The present study aims to employ dental volumetric tomography to examine bone mineral density among men that used antidepressants in the SSRI group for a long time.
Method
The present study was conducted through the utilisation of data related to patients that presented to the Faculty of Dentistry of Dicle University and had a dental volumetric tomography (DVT) scan for any reason. The patients were divided into 2 groups based on the use of antidepressants: Group 1 included 68 patients as the control group, and Group 2 consisted of 68 patients that used antidepressants. Radiomorphometric measurements were performed on DVT data: DVT-Mandibular Index (DVT-MI), DVT-Cortical Index (DVT-CI), Hounsfıeld Unit (HU) CORTICAL, and HU SPONGIOSIS values were calculated.
Results
The group of patients that used antidepressants exhibited a significant increase in DVT CI and a significant decrease in HU CORTICAL, HU SPONGIOSIS and DVT MI values. These findings were suggestive of osteoporosis.
Conclusion
Long-term use of antidepressants should be taken into consideration as a risk factor for osteoporosis in men.
... The effect on the osteoblastic differentiation varies depending on the drug, dose and duration of treatment. 10- 12 Williams et al., 16 indicated that paracetamol is a risk factor in fractures when administered chronically since it inhibits cyclooxygenase and endocannabinoids, which may negatively affect bone cells signals. Zhang et al.,17 reported that, at high doses, indomethacin inhibited collagen formation in primary tenocytes, delaying healing and bone formation. ...
... 4 Studies have suggested its harmlessness may have been overestimated. 5 Reports showing the associations of acetaminophen consumption with increased asthma, 6 renal toxicity, 7 increased attention-deficit/hyperactivity disorder in children, 8 increased risk of bone fracture, 9 increased hematologic malignancy, 10 and interactions with other drugs, such as warfarin, 11 have highlighted the need for caution in its use. Plainly, even a rare or small adverse effect may become clinically significant in such a widely used drug. ...
BACKGROUND
Acetaminophen is the most widely used analgesic today. A recent systematic review found increased adverse events and mortality at therapeutic dosage. Our aim was to challenge these results in a large sample of older adults living in nursing homes (NHs).
DESIGN
Prospective study using data from the Impact of Educational and Professional Supportive Interventions on Nursing Home Quality Indicators project (IQUARE), a multicenter, individually tailored, nonrandomized controlled trial in NHs across southwestern France.
SETTING/PARTICIPANTS
We studied data from 5429 participants living in 175 NHs (average age, 86.1 ± 8.1 years; 73.9% women).
MEASUREMENTS
All prescriptions obtained at baseline were analyzed by a pharmacist for acetaminophen use as stand‐alone or associated. Myocardial infarction (MI) and strokes were reported from participants' medical records at 18‐month follow‐up. Dates of death were obtained. Data collection was done through an online questionnaire at baseline and at 18 months by NH staff. Analyses were realized in our total population and a population matched on propensity score of acetaminophen intake. Six models were run for each outcome.
RESULTS
A total of 2239 participants were taking, on average, 2352 ± 993 mg of acetaminophen daily. Results for mortality were: hazard ratio (HR) = 0.97 (95% confidence interval [CI] = 0.86‐1.10). No associations between acetaminophen intake and the risk of mortality or MI were found. In one of our models, acetaminophen intake was associated with a significant increased risk of stroke in diabetic subjects (HR = 3.19; 95% CI = 1.25‐8.18; P = .0157).
CONCLUSION
Despite old age, polypharmacy, and polymorbidity, acetaminophen was found safe for most, but not all, of our NH study population. Pain management in NHs is a health priority, and acetaminophen remains a good therapeutic choice as a first‐line analgesic. More studies are needed on older diabetic patients.
... Their data suggested that paracetamol use is a risk factor for fracture, despite an mechanism of action remains unclear. Incorporating total body BMD into the model attenuated the association [38] . ...
ABSTRACT Objective: The aim of this study was to investigate the effect of ketoprofen and paracetamol on bone mineral density (BMD) in rabbits at healing site postoperatively, when given the drug in therapeutic doses for three different follow-up periods (15,30,45) days after operation in mandibular bone.
Materials and Methods: Twenty seven male rabbits with almost same age, weight and circumstance were chosen for this study. All animals were submitted to operation in mandibular bone region. Groove of 2mm diameter and 6mm length was drilled by heavy duty dental engine. After operation rabbits were randomly divided into three groups (Control, Ketoprofen, Paracetamol), each group contain 9 rabbits. Group1(control): received no treatment. Group2: Ketoprofen group received IV(4mg/kg ). Group3: Paracetamol group received IV (35 mg/kg) Paracetamol for 15,30, 45 days respectively. BMD were measured after 15,30,45 days respectively for all rabbits at healing site by using densitometric software analysis. Results: Statistical analysis showed significant differences between all three groups. The estimated BMD showed significant decrease in Ketoprofen group (42.00±1.00) compare to control and paracetamol groups after 15 days of treatment (118.0±01.15)( 80.33±0.57) respectively. Also in the present study we found that significant decrease in BMD after 30 days of operation in Ketoprofen group(70.33±0.58) compare to control and paracetamol groups(119.33±0.58) (84.66±0.57) respectively. After 45 day of daily administrated paracetamol no significant difference in BMD between paracetamol and control(144.33±0.52)(131.00±1.00) groups respectively but significant differently with Ketoprofen group (96.66±0.57). Conclusions: We concluded that Ketoprofen and paracetamol administration for long period after fracture bone decrease BMD in rabbits compared to control groups and Ketoprofen groups showed more decline over time in BMD than paracetamol groups. Key words: BMD (Bone Mineral Density) bone healing. densitometry analysis, Ketoprofen, paracetamol
... Also, acetaminophen, the most widely prescribed analgesic and antipyretic, is associated with an increased risk of fractures, the mechanisms of which are unknown. 59 Treatment of pain with a peripherally acting drug, such as ibuprofen, can reduce the chronic pain that is associated with OP more effectively than a centrally acting medication, such as tramadol. Thus, it is advisable to prescribe ibuprofen rather than tramadol to treat OP-associated chronic pain in postmenopausal women, taking into account the risk of gastrointestinal side effects. ...
Osteoporosis (OP) is a pathological condition that manifests clinically as pain, fractures, and physical disability, resulting in the loss of independence and the need for long-term care. Chronic pain is a multidimensional experience with sensory, affective, and cognitive aspects. Age can affect each of these dimensions and the pain that is experienced. In OP, chronic pain appears to have sensory characteristics and properties of nociceptive and neuropathic pain. Its evaluation and treatment thus require a holistic approach that focuses on the specific characteristics of this population. Pain management must therefore include pharmacological approaches, physiotherapy interventions, educational measures, and, in rare cases, surgical treatment. Most rehabilitative treatments in the management of patients with OP do not evaluate pain or physical function, and there is no consensus on the effects of rehabilitation therapy on back pain or quality of life in women with OP. Pharmacological treatment of pain in patients with OP is usually insufficient. The management of chronic pain in patients with OP is complicated with regard to its diagnosis, the search for reversible secondary causes, the efficacy and duration of oral bisphosphonates, and the function of calcium and vitamin D. The aim of this review is to discuss the most appropriate solutions in the management of chronic pain in OP.
... Risk factors for low BMD and subsequent fracture include low body mass, previous fracture, female sex and menopause, low calcium and vitamin D intake, smoking, high alcohol consumption, physical inactivity and use of certain medicines such as glucocorticoids, some psychotropics (e.g. antipsychotics) and paracetamol [7][8][9] . In addition to lifestyle and nutrition, a number of diseases can promote low BMD. ...
Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men.
Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression.
Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site).
Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.
Background
Researchers have long been interested in the potential relationship between osteoarthritis (OA), falls, and fractures; however, the evidence supporting this relationship has been conflicting. This study aimed to investigate the association between osteoarthritis and future fracture events.
Materials and Methods
This study was designed as a prospective cohort study. We recruited a total of 440,476 individuals from the UK Biobank to investigate the impact of OA on the incidence of fracture. Among the total population, there were 54,581 participants diagnosed with OA. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).
Results
A total of 26,083 fracture events were documented over a median follow-up period of 13.5 years. After multivariable adjustment, participants with osteoarthritis had an HR (95% CI) of 1.11 (1.08, 1.15) for future fracture events compared to participants without osteoarthritis ( P < 0.0001). Falls explained 16.34% of the association between osteoarthritis and fracture events and 14.15% of the association between knee osteoarthritis and fracture events. The association was not substantially altered across the series of sensitivity analyses.
Conclusion
Osteoarthritis was associated with a greater risk of future fracture events. This finding highlights the importance of preventing future fracture events in people with osteoarthritis.
Trauma patients present a unique challenge to anesthesiologists, since they require resource-intensive care, often complicated by pre-existing medical conditions. This fully revised new edition focuses on a broad spectrum of traumatic injuries and the procedures anesthesiologists perform to care for trauma patients perioperatively, surgically, and post-operatively. Special emphasis is given to assessment and treatment of co-existing disease, including surgical management of trauma patients with head, spine, orthopedic, cardiac, and burn injuries. Topics such as training for trauma (including use of simulation) and hypothermia in trauma are also covered. Six brand new chapters address pre-hospital and ED trauma management, imaging in trauma, surgical issues in head trauma and in abdominal trauma, anesthesia for oral and maxillofacial trauma, and prevention of injuries. The text is enhanced with numerous tables and 300 illustrations showcasing techniques of airway management, shock resuscitation, echocardiography and use of ultrasound for the performance of regional anesthesia in trauma.
Drugs may cause bone loss by lowering sex steroid levels (e.g., aromatase inhibitors in breast cancer, GnRH agonists in prostate cancer, or depot medroxyprogestone acetate – DMPA), interfere with vitamin D levels (liver inducing anti-epileptic drugs), or directly by toxic effects on bone cells (chemotherapy, phenytoin, or thiazolidinedions, which diverts mesenchymal stem cells from forming osteoblasts to forming adipocytes). However, besides effects on the mineralized matrix, interactions with collagen and other parts of the unmineralized matrix may decrease bone biomechanical competence in a manner that may not correlate with bone mineral density (BMD) measured by dual energy absorptiometry (DXA).
This letter comments on the letter by Lai and Lin
Background
N-acetyl-p-aminophenol (APAP, acetaminophen, paracetamol) is a widely used analgesic/antipyretic with weak inhibitory effects on cyclooxygenase (COX) compared to non-steroidal anti-inflammatory drugs (NSAIDs). The mechanism of action of APAP is mediated by its metabolite that activates transient receptor potential channels, including transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or the cannabinoid receptor type 1 (CB1). However, the exact molecular mechanism and target underlying the cellular actions of APAP remain unclear. Therefore, we investigated the effect of APAP on osteoblastic differentiation and cell migration, with a particular focus on TRP channels and CB1.
Methods
Effects of APAP on osteoblastic differentiation and cell migration of MC3T3-E1, a mouse pre-osteoblast cell line, were assessed by the increase in alkaline phosphatase (ALP) activity, and both wound-healing and transwell-migration assays, respectively.
Results
APAP dose-dependently inhibited osteoblastic differentiation, which was well correlated with the effects on COX activity compared with other NSAIDs. In contrast, cell migration was promoted by APAP, and this effect was not correlated with COX inhibition. None of the agonists or antagonists of TRP channels and the CB receptor affected the APAP-induced cell migration, while the effect of APAP on cell migration was abolished by down-regulating TRPV4 gene expression.
Conclusion
APAP inhibited osteoblastic differentiation via COX inactivation while it promoted cell migration independently of previously known targets such as COX, TRPV1, TRPA1 channels, and CB receptors, but through the mechanism involving TRPV4. APAP may have still unidentified molecular targets that modify cellular functions.
Objectives: Patients with osteoarthritis have increased bone mass but no decrease in fractures. The association between self-reported osteoarthritis and incident falls and fractures was studied in postmenopausal women. Methods: The Global Longitudinal Study of Osteoporosis in Women is a prospective multinational cohort of 60?393 non-institutionalised women aged ?55?years who had visited primary care practices within the previous 2?years. Questionnaires were mailed at yearly intervals. Patients were classified as having osteoarthritis if they answered yes to the question, ‘Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?’, and this was validated against primary care records in a subsample. Information on incident falls, fractures and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status. Results: Of 51?386 women followed for a median of 2.9?years (interquartile range 2.1–3.0), 20?409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p<0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p<0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls (HR 1.06 (95% CI 0.98 to 1.15; p=0.13)). Conclusions: Postmenopausal women with self-reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than those without osteoarthritis. These data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures.
The aim of this study was to investigate the possible risk factors related with osteoporosis in women with spontaneous menopause.
Five hundred and one postmenopausal women were divided into three groups as normal, osteopenic and osteoporotic according to their bone mineral density (BMD). By face-to-face interview, parity, age at menarche, age at menopause, duration of fertility, duration of menopause, first pregnancy age, total lactation period, exercise, smoking were assessed. Women with menopause age before 40 years, surgical menopause, who had any anti-osteoporosis treatment, hormone replacement therapy at the time of BMD measurement and corticosteroid use longer than 6 months were excluded from the study.
Among 501 postmenopausal women, 107 women were classified as normal, 170 as osteopenic and 224 as osteoporotic. Among demographic features of patients, there was statistically significant difference between the groups in age, BMI and parity (p < 0.001, p < 0.0001 and p = 0.002, respectively). There were statistically significant differences between the groups in case of age at menopause, duration of fertility and duration of menopause (p = 0.013, p = 0.013 and p < 0.0001, respectively). In the multivariate logistic regression analysis, BMI over 32 and fertility duration over 33 years had a statistically significant protective effect against osteoporosis (OR 0.42, CI 95 % 0.27-0.66; OR 0.36, CI 95 % 0.24-0.56, respectively), but age was positively correlated with osteoporosis (OR 1.13, CI 95 % 1.01-1.17) CONCLUSIONS: Duration of fertility (years of menstruation) longer than 33 years and body mass index higher than 32 seem to protect against postmenopausal osteoporosis. Age is also an independent risk factor for postmenopausal osteoporosis.
Background:
Osteoporosis, together with age, is the main risk factor for hip fracture, the incidence of which has also been associated with an increased risk of falling or co-morbidities and related pharmacological treatments.
Objectives:
The aim of this study was to investigate changes in concomitant pharmacological treatments prescribed before and after hip fracture in elderly patients compared with treatments prescribed to a matched cohort of subjects without hospitalisation for fractures.
Methods:
Data relating to the study population were extracted from a large population-based administrative database of the Italian National Health Authorities. A retrospective analysis was conducted involving female patients (6,431) aged ≥65 years and hospitalised for a hip fracture. The control group comprised age-matched subjects (38,586) not hospitalised for fracture. Changes in drug prescriptions 1 year before and 1 year after hip fracture and differences versus controls were compared.
Results:
Prior to the fracture, patients were taking more anti-Parkinson medications, antidepressants, medications for chronic obstructive pulmonary disease (COPD), bisphosphonates and calcium-vitamin D supplements, although the intake of the routinely monitored drug classes was significantly infrequent. Polypharmacy was less frequent in fractured women before fracture than in controls (22 vs. 25 %, respectively; P < 0.001), but it was more frequent (30 %, P < 0.001) post-fracture. The incidence of fracture was associated with a significant increase in the use of a number of drug classes: insulin, NSAIDs or analgesics, gastroprotectants, loop diuretics, β-blockers, antidepressants, antiparkinson drugs, antiepileptics and drugs for COPD.
Conclusion:
Our study confirms a strong association between the use of some drugs (antidepressants, antiparkinson drugs, drugs for COPD) and the risk of hip fracture, but drug use is globally less common than in controls. Hip fracture is associated with a significant increase in drug use, suggesting a global deterioration of health conditions.
Plants have historically been used in treating many diseases. Eucalyptus globules, a rich source of bioactive compounds, and have been shown to possess antioxidative properties. The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of Eucalyptus globulus extract upon acetaminophen-induced damages in kidney. Our study is realized in the Department of Biology, Faculty of Sciences of Sfax (Tunisia). 32 Wistar male rats; were divided into 4 batches: a control group (n=8), a group of rats treated with acetaminophen (900mg/kg) by intraperitoneal injection during 4 days (n=8), a group receiving Eucalyptus globulus extract (130 mg of dry leaves /kg/day) in drinking water during 42 days after 2 hours of acetaminophen administration (during 4 days) (n=8) and group received only Eucalyptus (n=8) during 42 days. After 6 weeks, animals from each group were rapidly sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, acetaminophen poisoning resulted in an oxidative stress evidenced by statistically significant losses in the activities of catalase (CAT), superoxide-dismutase (SOD), glutathione-peroxidase (GPX) activities and an increase in lipids peroxidation level in renal tissue of acetaminophen-treated group compared with the control group. Acetaminophen also caused kidney damage as evident by statistically significant (p<0.05) increase in levels of creatinine and urea and decreased levels of uric acid and proteins in blood. Histological analysis demonstrated alteration of proximal tubules, atrophy of the glomerule and dilatation of urinary space. Previous administration of plant extract is found to alleviate this acetaminophen-induced damage.
A novel, simple and selective electrochemical method was investigated for the single or simultaneous determination of tyrosine (Tyr) and paracetamol (PC) in aqueous media (phosphate buffer solution, pH 7.5) on MWCNTs-graphene nanosheet nanocomposite modified glassy carbon electrode (MWCNTs-GNS/GCE) using differential pulse voltammetry (DPV). The MWCNTs-GNS/GCE displayed high effective surface area, high porosity, more reactive sites and excellent electrochemical catalytic activity toward the oxidation of Tyr and PC. The peak current of differential pulse voltammograms of Tyr and PC increased linearly with their concentration in the ranges of 0.90-95.4μM Tyr and 0.80-110.0μM PC. The detection limits for Tyr and PC were 0.19μM and 0.10μM, respectively. The proposed sensor was successfully applied for the determination of Tyr and PC in human blood serum and pharmaceutical samples.
Objectives:
Patients with osteoarthritis have increased bone mass but no decrease in fractures. The association between self-reported osteoarthritis and incident falls and fractures was studied in postmenopausal women.
Methods:
The Global Longitudinal Study of Osteoporosis in Women is a prospective multinational cohort of 60,393 non-institutionalised women aged ≥55 years who had visited primary care practices within the previous 2 years. Questionnaires were mailed at yearly intervals. Patients were classified as having osteoarthritis if they answered yes to the question, 'Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?', and this was validated against primary care records in a subsample. Information on incident falls, fractures and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status.
Results:
Of 51 386 women followed for a median of 2.9 years (interquartile range 2.1-3.0), 20 409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p<0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p<0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls (HR 1.06 (95% CI 0.98 to 1.15; p=0.13)).
Conclusions:
Postmenopausal women with self-reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than those without osteoarthritis. These data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures.
The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Here we investigated the role that CB2 plays in regulating bone mass and osteoclast function using a combination of pharmacological and genetic approaches. The CB2-selective antagonist/inverse agonist AM630 inhibited osteoclast formation and activity in vitro, whereas the CB2-selective agonists JWH133 and HU308 stimulated osteoclast formation. Osteoclasts generated from CB2 knockout mice (CB2-/-) were resistant to the inhibitory effects of AM630 in vitro, consistent with a CB2-mediated effect. There was no significant difference in peak bone mass between CB2-/- mice and wild-type littermates, but after ovariectomy, bone was lost to a greater extent in wild-type compared with CB2-/- mice. Furthermore, AM630 protected against bone loss in wild-type mice, but the effect was blunted in CB2-/- mice. We conclude that CB2 regulates osteoclast formation and bone resorption in vitro and that under conditions of increased bone turnover, such as after ovariectomy, CB2 regulates bone loss. These observations indicate that CB2 regulates osteoclast formation and contributes to ovariectomy-induced bone loss and demonstrate that cannabinoid receptor antagonists/inverse agonists may be of value in the treatment of bone diseases characterized by increased osteoclast activity.
Medications to treat pain are in widespread use and any change in the risk of fracture may consequently have a significant impact at a population level. Strong analgesics of the opiate and opiate-like group are associated with an increased risk of fractures probably from an increased risk of falls resulting from the dizziness induced by these drugs. However, not all strong analgesics are associated with an increased risk of fractures. The differences are not readily explained from variations in pharmacokinetic properties. Weak analgesics mainly interact with the prostaglandin system; these drugs include non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid and acetaminophen. Acetaminophen is associated with an increased risk of fractures while acetylsalicylic acid is not. Some but not all NSAIDs are associated with an increased fracture risk, and the differences are not explained by variations in pharmacokinetic properties. More research is needed to determine if some analgesics are safer than others with respect to fracture risk.
Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.
Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.
The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2–/– phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-κB ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries.
• bone remodeling
• HU-308
• osteoblast
• osteoclast
The CB1 cannabinoid receptor has been implicated in the regulation of bone remodeling and bone mass. A high bone mass (HBM) phenotype was reported in CB1-null mice generated on a CD1 background (CD1(CB1-/-) mice). By contrast, our preliminary studies in cb1-/- mice, backcrossed to C57BL/6J mice (C57(CB1-/-) mice), revealed low bone mass (LBM). We therefore analyzed CB1 expression in bone and compared the skeletons of sexually mature C57(CB1-/-) and CD1(CB1-/-) mice in the same experimental setting. CB1 mRNA is weakly expressed in osteoclasts and immunoreactive CB1 is present in sympathetic neurons, close to osteoblasts. In addition to their LBM, male and female C57(CB1-/-) mice exhibit decreased bone formation rate and increased osteoclast number. The skeletal phenotype of the CD1(CB1-/-) mice shows a gender disparity. Female mice have normal trabecular bone with a slight cortical expansion, whereas male CD1(CB1-/-) animals display an HBM phenotype. We were surprised to find that bone formation and resorption are within normal limits. These findings, at least the consistent set of data obtained in the C57(CB1-/-) line, suggest an important role for CB1 signaling in the regulation of bone remodeling and bone mass. Because sympathetic CB1 signaling inhibits norepinephrine (NE) release in peripheral tissues, part of the endocannabinoid activity in bone may be attributed to the regulation of NE release from sympathetic nerve fibers. Several phenotypic discrepancies have been reported between C57(CB1-/-) and CD1(CB1-/-) mice that could result from genetic differences between the background strains. Unraveling these differences can provide useful information on the physiologic functional milieu of CB1 in bone.
The use of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated to not only impair load-induced bone formation but also prevent menopause-associated bone loss. We hypothesized that COX-2 inhibitor use would be associated with increased bone mineral density (BMD) in postmenopausal women not using estrogen therapy and, conversely, with decreased BMD in men.
The Canadian Multicentre Osteoporosis Study is a longitudinal, randomly selected, population-based community cohort. We present data from men (n=2,004) and postmenopausal women age 65 and older (n=2,776) who underwent a BMD measurement and structured interview in the 5th year of the study. The outcome measure was percent difference in BMD (g/cm(2)).
Daily COX-2 inhibitor use was reported by 394 subjects. In men, daily use of COX-2 inhibitors was associated with a lower BMD at all hip sites, with a percent difference of -3.1% [95% confidence interval (CI), -6.0, -0.3] between users and nonusers at total hip. In postmenopausal women not using estrogen replacement therapy, daily COX-2 inhibitor use was associated with higher BMD at most sites [percent difference at total hip: +3.0% (95% CI, 0.3, 5.8)]. These effects appeared to be dose-dependent.
COX-2 inhibitor use was associated with a lower BMD in men and, on the other hand, with a higher BMD in postmenopausal women not using estrogen replacement therapy. Men who have used COX-2 inhibitors may wish to seek BMD measurement to assess their fracture risk. However, COX-2 inhibitors may have utility in postmenopausal women if bone-selective analogs can be developed.
We studied the effects of various nonmorphine pain medications as well as rheumatoid arthritis and osteoarthritis on fracture risk in a nationwide case-control study. Cases were all subjects with any fracture sustained during the year 2000 (n = 124,655) in Denmark. For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetylsalicylic acid (ASA). Adjustments were made for several confounders. The effect of dose was examined by stratifying for cumulated dose (defined daily dose, DDD). For acetaminophen, a small increase in overall fracture risk was observed with use within the last year (odds ratio [OR] = 1.45, 95% confidence interval [CI] 1.41-1.49). For ASA, no increase in overall fracture risk was present with recent use. Significant heterogeneity was present for the NSAIDs; e.g., ibuprofen was associated with an increased overall fracture risk (OR = 2.09, 95% CI 2.00-2.18 for <20 DDD), while celecoxib was not (OR = 0.76, 95% CI 0.51-1.13 for <20 DDD, 2P < 0.01 for comparison). Osteoarthritis was associated with a decreased risk of any fracture if the diagnosis had been made more than 1 year ago (OR = 0.70, 95% CI 0.67-0.72). Rheumatoid arthritis was associated with an increase in overall fracture risk if the diagnosis had been made within the last year (OR = 1.86, 95% CI 1.68-2.07). Weak analgesics may be associated with fracture risk in a varying way. The effects in most cases were small. Falls may be one reason for the increase in fracture risk with some NSAIDs.
Suppression of increased bone resorption is an important issue in treatment of post-menopausal osteoporosis. Celecoxib is a highly selective inhibitor of cyclooxygenase-2 (COX-2), and inhibits osteoclastogenesis in vitro. In the present study, to test whether celecoxib can suppress elevated bone resorption caused by estrogen deficiency in vivo, celecoxib (4 mg/kg) or its vehicle was administered to sham-operated or ovariectomized (OVX) mice (model of post-menopausal osteoporosis). The treatment with celecoxib or vehicle was started immediately after the sham operation or ovariectomy, and lasted for 4 weeks. At 2 and 4 weeks after surgery, OVX mice administered vehicle had significantly higher levels of C-telopeptide, a marker of bone resorption in serum, than sham-operated mice administered vehicle (37% and 60% higher, respectively; p<0.01). At 2 and 4 weeks after surgery, celecoxib treatment significantly decreased serum C-telopeptide levels in OVX mice, but not in sham-operated mice (45% and 41%, respectively; p<0.001). In contrast, in both sham-operated and OVX mice, celecoxib did not significantly affect serum osteocalcin levels (a marker of bone formation) or bone mineral density (BMD) of the femur, which was evaluated by peripheral quantitative computed tomography (pQCT). In conclusion, treating OVX mice with celecoxib significantly suppressed the increase in serum levels of the bone resorption marker, but did not affect levels of the bone formation marker. Also, celecoxib did not prevent the decrease of femoral BMD in OVX mice. The present study suggests the possibility that celecoxib may be used to prevent bone loss caused by estrogen deficiency.
We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the beta-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic beta2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.
Background:
Data have pointed at an impaired fracture healing with fluoroquinolones and thus potentially a decreased bone biomechanical competence.
Objectives:
To study fracture risk associated with antibiotics.
Methods:
Case control study. There were 124,655 fracture cases and 373,962 age and gender matched controls. The main exposure was use of various groups of antibiotics. Confounder control was performed for social variables, contacts to hospitals and general practitioners, alcoholism and a number of other variables.
Results:
An increased risk of any fracture (OR =1. 45, 95% CI: 1. 42 -1. 49), hip (1. 46, 95% CI: 1. 35- 1. 58), forearm (1.67, 95% CI: 1. 55 -1. 80), and spine fractures (1. 38, 95% CI: 1. 18 -1.60) was seen with the use of dicloxacillin and flucloxacillin. There was a dose response relationship for overall risk of fractures, hip, and forearm fractures but not for spine fractures with dicloxacillin and flucloxacillin. None of the other groups of antibiotics against bacteria, tuberculosis, virus, and fungi were systematically associated with any major change in the risk of fractures.
Conclusion:
Dicloxacillin and flucloxacillin seem associated with an increased risk of fractures. The cause for this increase has to be determined but may be related to their use against infections of the bone, the increase thus rather being due to the underlying disease than the drug. Other types of antibiotics especially the fluoroquinolones were not systematically associated with an increased risk of fractures.
BMD was examined in users of NSAIDs (by COX selectivity) and aspirin in the Health ABC cohort (n = 2853). Significantly higher BMD was found in users of relative COX-2 selective NSAIDs with aspirin (COX-2/ASA) compared with nonusers. This suggests a role for COX-2/ASA in osteoporosis.
The purpose of this study was to determine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use, by cyclo-oxygenase selectivity (COX), and aspirin use on bone mineral density (BMD) in participants from the Health, Aging, and Body Composition (Health ABC) population-based cohort. It is known that NSAIDs inhibit the COX enzyme and decrease production of prostaglandins, which are involved in regulation of bone turnover. COX has two isoforms, COX-1 and COX-2. Production of prostaglandins associated with bone loss is primarily mediated through the COX-2 pathway. In addition, aspirin may have effects on bone independent of the prostaglandin pathway.
NSAID (by COX selectivity) and aspirin use and BMD were assessed in 2853 adults (49.5% women, 50.5% men: 43.1% black, 56.9% white; mean age: 73.6 years) from the Health ABC cohort. For the purposes of this analysis, relative COX-1 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of > 1 in whole blood, and relative COX-2 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of < 1 in whole blood. Analysis of covariance was used to compare BMD across each NSAID use and aspirin use category adjusting for age, race, gender, weight, height, study site, calcium and vitamin D supplementation, Womac score, history of rheumatoid arthritis, history of arthritis other than rheumatoid, and smoking status.
After adjustment for possible confounders, current use of relative COX-2 selective NSAIDs with aspirin was associated with higher BMD at the whole body (4.2%, 1.2-7.3 CI) and total hip (4.6%, 0.5-8.8 CI) by DXA and at both trabecular (34.1%, 15.4-52.7 CI) and cortical spine (12.8%, 2.3-23.3 CI) by quantitative computed tomography.
Our data suggest that the combination of relative COX-2 selective NSAIDs and aspirin is associated with higher BMD at multiple skeletal sites in men and women.
INHIBITION of prostaglandin biosynthesis by aspirin-like
drugs1-3 has now been confirmed in several
systems4-7. The theory1 that this anti-enzyme
action is the basis of the clinical effects of aspirin-like drugs has
recently been reviewed8-11 in detail. One of the few
anomalies was that paracetamol (4-acetamidophenol) which has no
anti-inflammatory activity, but is analgesic and
anti-pyretic12, was inactive against dog spleen synthetase
(ED50 = 100 µg ml.-1). A possible
explanation for this discrepancy is that synthetase systems from
different regions of the body show different sensitivities to drugs.
When the steady-state concentrations of peroxide in prostaglandin H synthase assay systems was lowered by added glutathione peroxidase, several agents (meclofenamic acid, mefenamic acid, acetamidophenol and phenylbutazone) became more potent inhibitors of the prostaglandin-forming cyclooxygenase reaction. Paradoxically, these agents stimulated oxygen incorporation in the absence of added peroxidase. On the other hand, dithiothreitol, ibuprofen, flurbiprofen and indomethacin all inhibited the reaction in a dose-dependent manner, and their inhibitory potencies were unaffected by the action of glutathione peroxidase. Aspirin, dl-gamma-tocopherol and salicylic acid were not inhibitory (without preincubation) under the assay conditions employed in this study. The findings demonstrate that the potencies of some anti-inflammatory agents may be diminished by high local peroxide concentrations.
Prostaglandin inhibition by aspirin or nonsteroidal anti-inflammatory drug (NSAIDs) may inhibit bone loss and preserve bone mineral density (BMD) in vitro and in animal models. The effect of these agents on BMD and fracture risk in postmenopausal women in unknown. We assessed the risk factors for osteoporosis and the use of aspirin and NSAIDs in 7786 white women over age 65. Axial BMD was measured at the same time, and fractures were prospectively documented over the subsequent 4 years of follow-up. In age-adjusted analyses, daily use of aspirin or NSAIDs was associated with a 2.3-5.8% increase in BMD of the hip and spine. The relationship persisted even after adjustment for weight, a variety of medications, self-reported arthritis, and for radiographic findings of osteoarthritis, but the multiply adjusted increase in BMD was only 1.0-3.1%. Fracture risk was similar among daily users of aspirin and NSAIDs and nonusers. After adjustment for potential confounders, among daily aspirin users the relative risk of hip fracture was 1.1 (95% confidence interval [CI]: 0.7, 1.6), and among daily NSAID users the risk was 0.9 (CI: 0.6, 1.4). Considering all nonspine fractures together, the risk among aspirin users was 1.0 (CI: 0.8. 1.2), and among NSAID users the risk was also 1.0 (CI; 0.8, 1.2). Regular use of aspirin or NSAIDs may have a modest beneficial effect on BMD in postmenopausal women. This effect persists after adjustment for obesity and the presence of osteoarthritis. However, among women who take aspirin or NSAIDs regularly, there is no clinically significant protective effect on the subsequent risk of fractures.
In vivo, indomethacin blockade of bone formation has been used to illustrate the role of prostaglandins. Indomethacin blocks the constitutive (COX-1) and inducible (COX-2) forms of cyclo-oxygenase, and is therefore nonspecific in its action. To test the hypothesis that COX-2 mediates the bone formation response to loading, rats were treated with vehicle, NS-398 (a specific COX-2 inhibitor) or indomethacin at 0.02, 0.2, or 2.0 mg/kg p.o. 3 h before loading the right tibia in four-point bending. Bending or sham loads of 65 N were applied for one bout of 300 cycles and bone formation assessed 5-8 days after loading. Mechanically induced bone formation at the endocortical surface was calculated by subtracting formation indices of the left leg (control) from those of the right (loaded), and woven bone surface and area were measured at the periosteal surface. Endocortical bone formation was significantly increased by bending but not sham loading (p < 0.05). The increase in the endocortical bone formation rate and mineralizing surface caused by bending was only partially inhibited by indomethacin, even at the highest dose, whereas NS-398 completely blocked bone formation at all doses (p < 0.05). The mineral apposition rate was depressed in a dose-response fashion by NS-398 (p < 0.05), but not by indomethacin. Woven bone formation at the periosteal surface was not prevented by treatment with indomethacin nor NS-398, suggesting that its formation is not dependent on prostaglandin production. These data suggest that induction of COX-2 is important for lamellar bone formation elicited by mechanical strain.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit synthesis of prostaglandins and may help prevent bone loss, but no study has shown the differential association of type or dose of NSAID compound with bone mineral density (BMD). The purpose of this study was to determine the relation of NSAIDs by type and dose to BMD. Participants were 932 Caucasian, community-dwelling women aged 44-98 years from southern California. Data were collected from 1988 to 1991 through the use of standardized medical questionnaires. Medication use was validated by a nurse. BMD at the ultradistal and midshaft radii were measured using single-photon absorptiometry, and at the hip and lumbar spine using dual-energy X-ray absorptiometry. Women (mean age, 72 years) were classified into 818 nonusers and 114 regular daily users of NSAIDs, of which 84 used propionic acid NSAIDs and the remainder used acetic acid NSAIDs. Occasional NSAID users were excluded. Women who used propionic acid NSAIDs, but not acetic acid NSAIDs, had higher BMD at all five sites and significantly higher BMD at the midshaft radius and lumbar spine. These differences remained after controlling for known covariates of osteoporosis. When women with self-reported osteoarthritis were excluded from the model, significantly higher BMD in propionic acid NSAID users was also observed at the femoral neck and total hip. Those who concurrently used estrogen and propionic acid NSAIDs had the highest BMD at all sites, suggesting an additive effect. We conclude that regular daily use of propionic acid NSAIDs, with or without simultaneous use of estrogen, may be helpful in preventing bone loss in older women. However, further research is needed to confirm these results before any clinical practice guidelines can be recommended due to the increased risk of serious complications associated with NSAID use.
Complete fracture ascertainment is critical for fracture cost estimates and planning for future health care facilities. Virtually complete ascertainment is possible for hip fractures because they nearly always require hospitalisation.
To validate the use of radiological reports as a resource for ascertaining fracture cases, using hip fracture as a model.
Hip fracture rates obtained from radiological reports were compared with rates obtained from hospital discharge summaries of medical records using International Classification of Diseases-9 (ICD-9) codes 820.0-820.9 and 733.1 over a three-year period.
Hip fracture cases numbered 589 using radiological reports and 585 using medical records. Discharge summaries failed to identify 15 cases ascertained through radiology reports whereas 11 cases ascertained through medical records were not identified from X-ray reports. The age-specific incidence rates for radiological ascertainment were within the 95% confidence limits of the rates derived from medical records.
Among a population of patients generally admitted to hospital for treatment of their fracture, we were able to identify more cases from radiological reports than from medical records. Incidence rates for hip fracture were comparable using the two methods. Radiological reports provide a valuable resource for identifying incident fractures. This method of case ascertainment would be suitable for identifying both major and minor fractures in regions with self-contained health services where access to all radiological reports is possible.
We measured bone mineral density (BMD in g/cm(2)) of the spine (L2-L4) and femur (four regions) in 1472 and 1487 cases, respectively, of ambulatory white women ages 20-79 years in the USA. A DPX densitometer was used in a mobile setting. The BMD values for women up to 69 years corresponded closely with published values for the USA, the UK, and northern Europe; our values were somewhat lower than those from other studies only in women over 70 years. The USA data were combined with data from Europe to give reference curves on about 12,000 subjects. Decreases of BMD with age in women below 50 years were much smaller than in older women (0.2% versus 0.6-1.0% per year). Femoral bone decreased from the neck region, but not the trochanter with age; the decrease of total femur BMD with age was due to loss from the former region. Loss of bone mineral content (BMC in g) from the femur neck and total femur region did not accelerate until after age 50 years, much like the spine. The apparent decrease of BMD in these regions that begins about age 40 actually is due to an increase of bone area. About 20% of USA women aged 50-79 years had BMD levels for the lumbar spine, or for the femur neck, more than -2.5 SD below the average values in young adult women 20-39 years old. Body weight had several times more impact on BMD than height, and in fact, a change of 1 kg in postmenopausal women was commensurate with the effect of a 1-year change in age. Subjects in the lowest quartile of body weight had T-scores that were 1 SD below those in the highest quartile.
Dietary calcium deficiency may be a risk factor for osteoporosis.
To estimate habitual calcium intakes and prevalence of calcium supplementation among free-living Australian women and validate a calcium-specific food-frequency questionnaire.
Calcium intakes for 1045 randomly selected women (20-92 years) were estimated by questionnaire which was tested against estimates from four day weighed records kept by 32 randomly selected women.
The mean difference between calcium estimates was not statistically significantly different from zero (mean difference=121 mg; standard deviation of differences=357 mg; p>0.05). There was moderate agreement (weighted kappa=0.4) between methods in ranking subjects into tertiles of calcium intake. Mean dietary calcium intakes were 615 mg/day for 20-54 years, 646 mg/day for 55-92 years and 782 mg/day for lactating women. Seventy-six per cent of women aged 20-54 years, 87% of older and 82% of lactating women had intakes below the recommended dietary intake (RDI). There was no association detected between calcium intake and age. Dairy foods provided 79.0% of dietary calcium intake. Calcium supplements were used by 6.6% and multivitamins by a further 4.3% of women. Supplementation was independent of dietary calcium intake and more likely used by postmenopausal women.
Our results suggest that 76% of women consume less than the RDI even when supplemental calcium is included. Furthermore, 14% have less than the minimal requirement of 300 mg/day and would, therefore, be in negative calcium balance and at risk of bone loss. Despite advertising campaigns promoting better nutrition and increased awareness of osteoporosis, many women are failing to achieve an adequate calcium intake.
Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.
Cyclooxygenase (COX)-3, a novel COX splice variant, was suggested as the key to unlocking the mystery of the mechanism of action of acetaminophen. Although COX-3 might have COX activity in canines, and this activity might be inhibited by acetaminophen, its low expression level and the kinetics indicate unlikely clinical relevance. In rodents and humans, COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity; therefore, it is improbable that COX-3 in these species plays a role in prostaglandin-mediated fever and pain. The aim of this review is to evaluate the literature that seeks to point out critical theoretical and methodological limitations of the COX-3 studies that led several investigators to scientifically questionable conclusions.
The mechanism of the analgesic activity of paracetamol (acetaminophen), one of the most widely used drugs for the treatment of pain, is still not clear. Here we show that in rats, using the hot plate test, the analgesic effect of paracetamol is prevented by two antagonists at cannabinoid CB1 receptors (AM281 and SR141716A) at doses that prevent the analgesic activity of the cannabinoid CB1 agonist HU210. Our present results suggest that paracetamol-induced antinociception involves the cannabinoid system.
A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2-/- mice using micro-computed tomography. Our results demonstrated that while COX-2-/- female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2-/- mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2-/- mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2-/- mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice.
To study the effect of morphine and opiates on fracture risk.
Case-control study.
Nationwide register-based study.
Cases were all subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of morphine and opiates. Morphine and other opiates had been used by 10 015 (8.0%) of the case subjects and 12 108 (3.2%) of the controls. Adjustments were made for several confounders including prior fracture, and use of weak analgesics [nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (ASA) and acetaminophene]. The effect of dose was examined by stratifying for cumulated dose (defined daily dose).
Fracture.
Morphine (1.47, 95% CI 1.37-1.58), fentanyl (2.23, 95% CI 1.89-2.64), methadone (1.39, 95% CI 1.05-1.83), oxycodone (1.36, 95% CI 1.08-1.69), nicomorphine (1.57, 95% CI 1.38-1.78), ketobemidone (1.07, 95% CI 1.02-1.13), tramadol (1.54, 95% CI 1.49-1.58) and codeine (1.16, 95% CI 1.12-1.20) were all associated with an increase in overall fracture risk. No increase was present for buprenorphine (0.86, 95% CI 0.79-0.95), pethidine (0.98, 95% CI 0.89-1.08), dextropropoxiphene (1.02, 95% CI 0.90-1.16), and combinations of ASA and codeine (0.94, 95% CI 0.88-1.01).
An increased fracture risk is seen in users of morphine and opiates. The reason for this may be related to the risk of falls due to central nervous system effects such as dizziness.
Cyclooxygenase-2 (COX-2) is highly expressed in osteoblasts, and COX-2 produced prostaglandins (PGs) can increase osteoblastic differentiation in vitro. The goal of this study was to examine effects of COX-2 expression on calvarial osteoblastic proliferation and apoptosis. Primary osteoblasts (POBs) were cultured from calvariae of COX-2 wild-type (WT) and knockout (KO) mice. POB proliferation was evaluated by (3)H-thymidine incorporation and analysis of cell replication and cell cycle distribution by flow cytometry. POB apoptosis was evaluated by annexin and PI staining on flow cytometry. As expected, PGE(2) production and alkaline phosphatase (ALP) activity were increased in WT cultures compared to KO cultures. In contrast, cell numbers were decreased in WT compared to KO cells by day 4 of culture. Proliferation, measured on days 3-7 of culture, was 2-fold greater in KO than in WT POBs and associated with decreased Go/G1 and increased S cell cycle distribution. There was no significant effect of COX-2 genotype on apoptosis under basal culture conditions on day 5 of culture. Cell growth was decreased in KO POBs by the addition of PGE(2) or a protein kinase A agonist and increased in WT POBs by the addition of NS398, a selective COX-2 inhibitor. In contrast, differentiation and cell growth in marrow stromal cell (MSC) cultures, evaluated by ALP and crystal violet staining respectively, were increased in MSCs from WT mice compared to MSCs from KO mice, and exogenous PGE(2) increased cell growth in KO MSC cultures. We conclude that PGs secondary to COX-2 expression decrease osteoblastic proliferation in cultured calvarial cells but increase growth of osteoblastic precursors in MSC cultures.
Paracetamol analgesic mechanism of action is still poorly defined but mainly involves central inhibition of cyclooxygenases. Here we tested the peripheral antinociceptive effects of paracetamol (intraplantar injections) in a rat model of neuropathic pain. Paracetamol dose-dependently decreased mechanical allodynia and lowered nociceptive scores associated with hyperalgesia testing. These effects were inhibited by the administration of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. The participation of the peripheral cannabinoid system in paracetamol analgesia is suggested.
Mechanism of action of paracetamol
- Graham Gg Scott
- Kf
Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther 2005;12: 46–55.
The local antinociceptive effects of 325
- M Dani
- J Guindon
- C Lambert
- P Beaulieu
Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of
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Acetaminophen and the cyclooxygenase
- B Kis
- J A Snipes
- D W Busija
Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle:
and the effects of rheumatoid arthritis and osteoarthritis
and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 2006;79:
338
Canadian Multicentre Osteoporosis Study
Canadian Multicentre Osteoporosis Study. Osteoporos Int 2006;17:1410-9.
342
NSAID use in older women: effect on bone mineral density and fracture risk
NSAID use in older women: effect on bone mineral density and fracture risk. Study
346
of Osteoporotic Fractures Research Group. J Bone Miner Res 1996;11:29-35.
347
ovariectomized mice in vivo
formation, in ovariectomized mice in vivo. Tohoku J Exp Med 2007;211:275-83.
femoral bone morphology and density in COX-2−/− mice
femoral bone morphology and density in COX-2−/− mice. Bone 2006;39:767-72.
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