Category Archives: Drugs

Aspirin Prevents Bone Loss in Ovariectomized Rats

Abstract

[Effect of cyclooxygenase-2 on bone loss in ovariectomized rats].

To investigate mechanism of cyclooxygenase-2 (COX-2) in bone loss in a postmenopausal osteoporosis (PMOP) rat mode with ovarietomy (OVX).
Forty female Sprague Dawley adult rats at age of 3 months were randomly divided into 4 groups, 10 in each group, including sham-operated (sham) group, OVX group, OVX treated with nilesteriol (OVX + E) group and OVX treated with aspirin (OVX + P) group. All rats in OVX, OVX + E and OVX + P groups underwent ovarietomy under abdominal anesthesia with 10% chloral hydrate. Rats in sham group were only taken with fat tissue with same weight under bilateral ovary. After surgery, penicillin was administered to prevent infection. At day 7 after surgery, agents were given by intragastric administration for 12 weeks. Nilestriol at 1.0 mg/kg was used in OVX + E group once a week, aspirin at 45 mg×kg⁻¹(×d⁻¹ was used in OVX + P group once a day. Saline with same volume was used in rats in sham and OVX groups. All agents were administered one time per day. Dose of agents were adjusted by weight per week. At end of study, bone mineral density (BMD) of right femurs and lumbar vertebrae 3-5 (L(3-5)) were measured. Morphology of bone was detected by hematoxylineosin, and expression of COX-2 was determined by immunohistochemistry staining.
(1) BMD:BMD of right femur and L(3-5) was (0.209 ± 0.010) g/cm² and (0.230 ± 0.012) g/cm² in sham group and (0.181 ± 0.008) g/cm² and (0.201 ± 0.016) g/cm² in OVX group, which reached statistical difference (P < 0.01). BMD of right femur and L(3-5) was (0.203 ± 0.009) g/cm² and (0.224 ± 0.028) g/cm² in OVX + E group and (0.200 ± 0.011) g/cm² and (0.204 ± 0.003) g/cm² in OVX + P group, which were all higher than those in OVX group (P < 0.01, P < 0.05). However, there was no statistical difference in BMD between OVX + E and OVX + P group (P > 0.05). (2) Morphology of bone:bone trabeculae became fewer and degenerated in OVX group. However, bone trabeculae were regular and dense in OVX + P group and OVX + E group, which were similar to those in sham group. (3) Expression of COX-2:cells with COX-2 positive and expression of COX-2 around bone trabeculae in OVX group were more than those in sham, OVX + E and OVX + P group.
COX-2 plays an important role in PMOP. Aspirin could prevent bone loss by decreasing COX-2 expression in OVX rats.

Guo Y, Zhang CY, Tian Y, DI JM…
Zhonghua Fu Chan Ke Za Zhi Jun 2012
PMID: 22932114

Review: NSAIDs Controversy

Abstract

Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence-based review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review.

Konstantinidis I, Papageorgiou SN, Kyrgidis A, Tzellos TG…
Rev Recent Clin Trials Mar 2013
PMID: 23016823

Review: NSAIDs May Impair Bone Healing

Abstract

[No evidence of malicious effect of NSAID treatment on bone healing].

The use of NSAIDs for postoperative pain management following orthopaedic surgery or during conservative treatment of fractures is controversial. Experimental animal models suggest NSAIDs inhibit bone healing. In a review of the literature, there was no clinical evidence to support categorical discard of NSAID for postoperative pain relief in uncomplicated cases. However, NSAID should be considered a potentiel risk factor of impaired bone healing and avoided in patients with a high risk of pseudoarthrosis. Recommended daily doses should be respected and duration of treatment should be limited.

Janum S, Kristensen BB
Ugeskr. Laeg. Nov 2012
PMID: 23195353

Aspirin Delays Bone Healing in Rabbits

Abstract

Effect of aspirin on bone healing in a rabbit ulnar osteotomy model.

Aspirin is frequently prescribed following orthopaedic surgery. Although there is substantial evidence that some nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with delayed bone healing, there have been few studies of the effects of aspirin on bone healing and, to our knowledge, none on the effects of physiologic dosages.
Following ulnar osteotomy, fifty-six rabbits were administered a placebo (nine rabbits), indomethacin (nine rabbits given 12.5 mg/kg daily), or aspirin at various doses and schedules (2.7 mg/kg daily for ten rabbits, 10 mg/kg daily for nine rabbits, 50 mg/kg twice daily for ten rabbits, and 100 mg/kg three times daily for nine rabbits). The aspirin doses were chosen to span the clinical dosing range. The indomethacin group served as a positive control and as a relative comparison with the effect of aspirin. Radiographs were obtained every two weeks and the animals were killed at eight weeks. Mechanical testing was performed on all rabbits except for six selected for histological evaluation.
Aspirin delayed bone healing, as demonstrated radiographically and with mechanical testing, in a dose-dependent fashion at salicylate levels equivalent to those resulting from typical human dosing (low-dose aspirin). Receiver operating characteristic analysis demonstrated a plasma salicylate threshold above 20.7 μg/mL predicting delayed bone healing. This approximates a single human dose of 325 mg. Salicylate levels above this threshold were associated with delayed bone healing similar to that caused by indomethacin. Aspirin dosing frequency did not affect bone healing. Mechanical testing was highly predictive of radiographic healing. The interobserver reliability of radiographic assessment of healing at six and eight weeks (kappa = 0.83 and 0.79, respectively) compared favorably with interobserver reliability in previous studies assessing cortical bridging.
In a rabbit ulnar osteotomy model, aspirin delayed bone healing with a threshold equivalent to a human dose of 325 mg.

Lack WD, Fredericks D, Petersen E, Donovan M…
J Bone Joint Surg Am Mar 2013
PMID: 23407637

Tylenol is a Risk Factor for Fracture in Women

Abstract

Paracetamol (acetaminophen) use, fracture and bone mineral density.

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.

Williams LJ, Pasco JA, Henry MJ, Sanders KM…
Bone Jun 2011
PMID: 21396491

Vitamin D3 + K2 + Sr + Mg + DHA as Effective as Bisphosphonates in Women

Abstract

Combination of Micronutrients for Bone (COMB) Study: bone density after micronutrient intervention.

Along with other investigations, patients presenting to an environmental health clinic with various chronic conditions were assessed for bone health status. Individuals with compromised bone strength were educated about skeletal health issues and provided with therapeutic options for potential amelioration of their bone health. Patients who declined pharmacotherapy or who previously experienced failure of drug treatment were offered other options including supplemental micronutrients identified in the medical literature as sometimes having a positive impact on bone mineral density (BMD). After 12 months of consecutive supplemental micronutrient therapy with a combination that included vitamin D(3), vitamin K(2), strontium, magnesium and docosahexaenoic acid (DHA), repeat bone densitometry was performed. The results were analyzed in a group of compliant patients and demonstrate improved BMD in patients classified with normal, osteopenic and osteoporotic bone density. According to the results, this combined micronutrient supplementation regimen appears to be at least as effective as bisphosphonates or strontium ranelate in raising BMD levels in hip, spine, and femoral neck sites. No fractures occurred in the group taking the micronutrient protocol. This micronutrient regimen also appears to show efficacy in individuals where bisphosphonate therapy was previously unsuccessful in maintaining or raising BMD. Prospective clinical trials are required to confirm efficacy.

Genuis SJ, Bouchard TP
J Environ Public Health 2012
PMID: 22291722 | Free Full Text

Beta Blocker Prevents Bone Loss in Pediatric Burn Patients

Abstract

Long-term propranolol use in severely burned pediatric patients: a randomized controlled study.

To determine the safety and efficacy of propranolol given for 1 year on cardiac function, resting energy expenditure, and body composition in a prospective, randomized, single-center, controlled study in pediatric patients with large burns.
Severe burns trigger a hypermetabolic response that persists for up to 2 years postburn. Propranolol given for 1 month postburn blunts this response. Whether propranolol administration for 1 year after injury provides a continued benefit is currently unclear.
One-hundred seventy-nine pediatric patients with more than 30% total body surface area burns were randomized to control (n = 89) or 4 mg/kg/d propranolol (n = 90) for 12 months postburn. Changes in resting energy expenditure, cardiac function, and body composition were measured acutely at 3, 6, 9, and 12 months postburn. Statistical analyses included techniques that adjusted for non-normality, repeated-measures, and regression analyses. P < 0.05 was considered significant.
Long-term propranolol treatment significantly reduced the percentage of the predicted heart rate and percentage of the predicted resting energy expenditure, decreased accumulation of central mass and central fat, prevented bone loss, and improved lean body mass accretion. There were very few adverse effects from the dose of propranolol used.
Propranolol treatment for 12 months after thermal injury, ameliorates the hyperdynamic, hypermetabolic, hypercatabolic, and osteopenic responses in pediatric patients. This study is registered at clinicaltrials.gov: NCT00675714.

Herndon DN, Rodriguez NA, Diaz EC, Hegde S…
Ann. Surg. Sep 2012
PMID: 22895351

Beta Blockers Reversed Bone Loss in Calorie Restricted Rats

Abstract

Blocking β-adrenergic signaling attenuates reductions in circulating leptin, cancellous bone mass, and marrow adiposity seen with dietary energy restriction.

We tested whether β-adrenergic blockade attenuates bone loss and increased marrow adiposity during energy restriction (ER) and whether such an effect is associated with changes in serum leptin and leptin expression in bone and marrow tissues. Female 4-mo-old Sprague-Dawley rats were assigned into four groups (n = 10 each): two groups of 40% ER treated with vehicle (ERVEH; saline) or β-blocker (ERBB; DL-propranolol; 250 μg · kg(-1) · h(-1)) during 12 wk, and two groups of ad libitum-fed controls treated with the same two agents (CONVEH, CONBB, respectively). Over 84 days, CONVEH and CONBB rats gained but ERVEH and ERBB rats lost body fat mass; lean mass did not change in any group. Reduction in serum leptin in ERVEH rats was mitigated in ERBB rats (-5.32 vs. -1.15 ng/ml, respectively). The decline in proximal tibia cancellous vBMD observed in ERVEH rats was attenuated in ERBB rats (-85.24 vs. -53.94 mg/cm(3), respectively). Adipocyte number in ERVEH rats was dramatically higher vs. CON rats at week 12, but this increment was abolished by β-blockade in ERBB animals. The number of osteoblastic cells and marrow adipocytes staining positively for leptin in ERVEH rats tended to be lower vs. that of both CON groups, but β-blockade appears to reverse this effect in ERBB rats. In summary, β-adrenergic blockade mitigated metaphyseal bone loss and bone marrow adiposity during energy restriction and attenuated reductions in serum leptin. These data suggest an important role for β-adrenoreceptor signaling pathway in the cancellous bone and marrow fat response to energy restriction.

Baek K, Bloomfield SA
J. Appl. Physiol. Dec 2012
PMID: 22995391

Beta Blockers Prevent Bone Loss from Inner Ear Lesions in Rats

Abstract

Bone remodeling is regulated by inner ear vestibular signals.

Bone remodeling allows the conservation of normal bone mass despite constant changes in internal and external environments. The adaptation of the skeleton to these various stimuli led credence to the notion that bone remodeling is a true homeostatic function, and as such is under the control of specific centers in the central nervous system (CNS). Hypothalamic and brainstem centers, as well as the sympathetic nervous system (SNS), have been identified as regulators of bone remodeling. However, the nature of the afferent CNS stimuli that may modulate CNS centers involved in the control of bone remodeling, with the exception of leptin, remains unclear. Based on the partial efficacy of exercise and mechanical stimulation regimens to prevent microgravity-induced bone loss and the known alterations in vestibular functions associated with space flights, we hypothesized that inner ear vestibular signals may contribute to the regulation of bone remodeling. Using an established model of bilateral vestibular lesions and microtomographic and histomorphometric bone analyses, we show here that induction of bilateral vestibular lesion in rats generates significant bone loss, which is restricted to weight-bearing bones and associated with a significant reduction in bone formation, as observed in rats under microgravity conditions. Importantly, this bone loss was not associated with reduced locomotor activity or metabolic abnormalities, was accompanied with molecular signs of increased sympathetic outflow, and could be prevented by the β-blocker propranolol. Collectively, these data suggest that the homeostatic process of bone remodeling has a vestibulo-sympathetic regulatory component and that vestibular system pathologies might be accompanied by bone fragility.

Vignaux G, Besnard S, Ndong J, Philoxène B…
J. Bone Miner. Res. Apr 2013
PMID: 23553797

Beta Blockers May be Anticatabolic in Rats

Abstract

[Operational mechanism modification of bone mechanostat in an animal model of nutritional stress: effect of propranolol].

Propranolol (P) treatment exerts a preventive effect against the detrimental consequences to bone status in mildly chronically food-restricted growing rats (NGR) by an increment in cortical bone and by improving its spatial distribution.
To study the effect of beta-blocker on operational mechanism of bone mechanostat in an animal model of nutritional stress,

weanling male Wistar rats were randomly assigned to four groups: control (C), C + P (CP), NGR and NGR + P (NGRP). C and CP rats were fed freely with the standard diet. NGR and NGRP rats received, for 4 weeks, 80% of the amount of food consumed by C and CP respectively, the previous day, corrected by body weight. Propranolol (7 mg/kg/day) was injected ip 5 days per week, for four weeks in CP and NGRP rats. C and NGR received saline injections at an identical dosage regimen. Body weight and length were determined during the experimental period. Dietary intake was registered daily. Animals were sacrificed after 4 weeks of food restriction. Immediately, cuadriceps, femur and tibiae from each animal were dissected and weighed, and histomorphometric and mechanical studies were performed. Serum a-CTX, osteocalcin, intact PTH, calcium and phosphorous were determined. Body protein (% prot) was measured in all groups.
Food restriction induced detrimental effects on body and femoral growth, load-bearing capacity (Wf), % prot and cuadriceps weight in NGR us. C (p < 0.01). beta-blocker did not modify anthropometric and bone morphometric parameters in NGRP and CP vs. NGR and C, respectively (p > 0.05). However, Wf NGRP vs. NGR was significantly higher (p < 0.01). alpha-CTX was significantly higher in NGR vs. C (p < 0.01). No significant differences were observed in alpha-CTX levels between CP, NGRP and C (p > 0.05). Serum osteocalcin, intact PTH, calcium and phospho- rous showed no significant difference between groups (p > 0.05).
These results suggest that modeling increase in bone mass and strength in NGRP rats could be due to an anticatabolic interaction of the beta-blocker propranolol on operational mechanism of bone mechanostat in an animal model of nutritional stress.

Pintos PM, Lezón CE, Bozzini C, Friedman SM…
Rev. Invest. Clin.
PMID: 23745443