Monthly Archives: August 2013

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

Beta Blocker Lowers Fracture Risk in Men and Women

Abstract

Association between beta-blocker use and fracture risk: the Dubbo Osteoporosis Epidemiology Study.

In animal model, mice treated with beta-blockers (BB) had increased bone mass. In humans, high bone mass is associated with reduce fracture risk. The present study sought to test the hypothesis that BB use is associated with reduced fracture risk.
Data from 3488 participants (1285 men) aged 50 years and above in the Dubbo Osteoporosis Epidemiology Study (DOES) were analyzed. Baseline characteristics of participants were obtained at the initial visit which had taken place between 1989 and 1993. Bone mineral density (BMD) at the lumbar spine and femoral neck was measured by dual energy X-ray absorptiometry (GE-LUNAR Corp, Madison, WI). Two hundred and sixty two (20%) men and 411 (19%) women had been on BB, as ascertained by direct interview and verification with medication history. The incidence of fragility fractures was ascertained during the follow-up period (1989-2008).
In men, BB use was associated with higher BMD at the femoral neck (0.96 versus 0.92 g/cm², P < 0.01), higher lumbar spine (1.32 versus 1.25 g/cm², P < 0.01), and lower fracture risk than those not on BB (odds ratio [OR]: 0.49; 95% CI: 0.32-0.75). In women, BB users also had higher femoral neck BMD (0.83 versus 0.81 g/cm², P < 0.01), higher lumbar spine BMD (1.11 versus 1.06 g/cm², P < 0.01), and lower risk of fracture than non-users (OR 0.68, 95% CI: 0.53-0.87). The associations between BB use and fracture risk were independent of age, BMD, and clinical risk factors. Subgroup analysis suggested that the association was mainly found in selective BB, not in non-selective BB.
Beta-blockers use, particularly selective BB, was associated with reduced fracture risk in both men and women, and the association was independent of BMD.

Yang S, Nguyen ND, Center JR, Eisman JA…
Bone Mar 2011
PMID: 21047567

Review: Beta Blockers in Space

Abstract

Sympathetic neural influence on bone metabolism in microgravity (Review).

Bone loss is one of the most important complications for astronauts who are exposed to long-term microgravity in space and also for bedridden elderly people. Recent studies have indicated that the sympathetic nervous system plays a role in bone metabolism. This paper reviews findings concerning with sympathetic influences on bone metabolism to hypothesize the mechanism how sympathetic neural functions are related to bone loss in microgravity. Animal studies have suggested that leptin stimulates hypothalamus increasing sympathetic outflow to bone and enhances bone resorption through noradrenaline and β-adrenoreceptors in bone. In humans, even though there have been some controversial findings, use of β-adrenoblockers has been reported to be beneficial for prevention of osteoporosis and bone fracture. On the other hand, microneurographically-recorded sympathetic nerve activity was enhanced by exposure to microgravity in space as well as dry immersion or long-term bed rest to simulate microgravity. The same sympathetic activity became higher in elderly people whose bone mass becomes generally reduced. Our recent findings indicated a significant correlation between muscle sympathetic nerve activity and urinary deoxypyridinoline as a specific marker measuring bone resorption. Based on these findings we would like to propose a following hypothesis concerning the sympathetic involvement in the mechanism of bone loss in microgravity: An exposure to prolonged microgravity may enhance sympathetic neural traffic not only to muscle but also to bone. This sympathetic enhancement increases plasma noradrenaline level and inhibits osteogenesis and facilitates bone resorption through β-adrenoreceptors in bone to facilitate bone resorption to reduce bone mass. The use of β-adrenoblockers to prevent bone loss in microgravity may be reasonable.

Mano T, Nishimura N, Iwase S
Acta Physiol Hung Dec 2010
PMID: 21138811

Beta Blocker Suppresses Resorption in Rats

Abstract

Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation.

Bones are widely innervated, suggesting an important role for the sympathetic regulation of bone metabolism, although there are controversial studies. We investigated the effects of propranolol in a model of experimental periodontal disease.
Rats were assigned as follows: animals without ligature; ligated animals receiving vehicle and ligated animals receiving 0.1, 5 or 20 mg·kg(-1) propranolol. After 30 days, haemodynamic parameters were measured by cardiac catheterization. Gingival tissues were removed and assessed for IL-1β, TNF-α and cross-linked carboxyterminal telopeptides of type I collagen (CTX) by elisa, or intercellular adhesion molecule 1 (ICAM-1), receptor activator of NF-κ B ligand (RANKL) and osteoprotegerin (OPG) by Western blot analysis. Sections from the mandibles were evaluated for bone resorption. Also, we analysed the ability of propranolol to inhibit osteoclastogenesis in vitro.
Propranolol at 0.1 and 5 mg·kg(-1) reduced the bone resorption as well as ICAM-1 and RANKL expression. However, only 0.1 mg·kg(-1) reduced IL-1β, TNF-α and CTX levels as well as increased the expression of OPG, but did not alter any of the haemodynamic parameters. Propranolol also suppressed in vitro osteoclast differentiation and resorptive activity by inhibiting the nuclear factor of activated T cells (NFATc)1 pathway and the expression of tartrate-resistant acid phosphatase (TRAP), cathepsin K and MMP-9.
Low doses of propranolol suppress bone resorption by inhibiting RANKL-mediated osteoclastogenesis as well as inflammatory markers without affecting haemodynamic parameters.

Rodrigues WF, Madeira MF, da Silva TA, Clemente-Napimoga JT…
Br. J. Pharmacol. Apr 2012
PMID: 21950592 | Free Full Text

Beta Blockers Associated with Fractures in Postmenopausal Women with Heart Disease

Abstract

Beta-blocker use is associated with fragility fractures in postmenopausal women with coronary heart disease.

An association between cardiovascular disease and osteoporosis is described. A number of drugs often used by patients with coronary heart disease, such as thiazides, statins and beta-blockers, have shown controversial effects on bone. 1) To study the possible association between coronary heart disease (CHD) and bone mass density (BMD), quantitative ultrasound measurements (QUS) and the prevalence of fragility and vertebral fractures. 2) To study the possible influence of a number of drugs, statins, thiazides and beta-blockers, on BMD and fractures.
Case-control study performed on 74 postmenopausal women who had recently suffered from CHD, and 111 age-matched controls. BMD was measured by Dual X-Ray Absorptiometry (DXA) at the lumbar spine and proximal femur. Quantitative Ultrasound (QUS) was also measured at the heel. Vertebral fractures were diagnosed by lateral, thoracic and lumbar X-rays. The occurrence of non-vertebral fractures was determined by examination of medical records.
Patients with CHD had higher values of BMI. They had a higher prevalence of arterial hypertension and hyperlipidemia, and consequently higher consumption of beta-blockers and statins, but not of thiazides, and had lower alcohol consumption. Patients with CHD had higher BMD values, measured by DXA at the proximal femur, than controls, but there were no differences in DXA values at the lumbar spine or QUS at the heel between the two groups. The prevalence of all fragility factures was slightly higher in patients with CHD, but not to a significant extent. The prevalence of vertebral fractures was similar in the two groups. In a logistic analysis to identify factors associated with all fractures, beta-blockers were positively associated with fragility fractures, and DXA at the femoral neck was inversely associated with fragility fractures.
Postmenopausal women with CHD have higher values of BMD at the proximal femur but, despite this, show a slight but non-significant increase in the prevalence of fragility fractures. Beta-blockers are independently associated with fragility fractures, but thiazides and statins are not.

Sosa M, Saavedra P, Gómez de Tejada MJ, Mosquera J…
Aging Clin Exp Res Apr 2011
PMID: 20463439

Beta Blockers Improved Bone in Hypertensive Rats from Beta2 Blockade

Abstract

Effects of propranolol on bone metabolism in spontaneously hypertensive rats.

The effects of propranolol (PRO), a nonselective beta-adrenergic receptor (beta-AR) antagonist with membrane-stabilizing action on bone metabolism, were examined in spontaneously hypertensive rats (SHR) showing osteoporosis with hyperactivity of the sympathetic nervous system. Treatment of SHR with PRO at 1 and 5 mg/kg p.o. for 12 weeks increased bone mass of the lumbar vertebra and proximal tibia without affecting blood pressure, but PRO at 50 and 100 mg/kg with hypotensive action did not increase bone mass. Next, the effects of PRO at 0.1, 1, and 10 mg/kg on bone status were examined in more detail. Compared with the SHR control, not only bone mass but also biomechanical parameters of strength and toughness of the lumbar vertebrae were increased in SHR treated with PRO at 0.1 and 1 mg/kg, suggesting antiosteoporotic action. PRO at 1 mg/kg statistically increased histomorphometry indices of bone formation, whereas PRO at doses of 0.1, 1, and 10 mg/kg decreased those of bone resorption. Antiosteoporotic effect of PRO is attenuated at 10 mg/kg compared with 0.1 and 1 mg/kg. In addition, treatment with timolol, a nonselective beta-AR antagonist without membrane-stabilizing action, or butoxamine, a selective beta2-AR antagonist, at 1 mg/kg increased bone mass in SHR. These results suggested that treatment of SHR with beta-blockers at low dose improved bone loss and bone fragility. This antiosteoporotic effect of beta-blockers seems to be caused by the blocking action of beta2-AR, regardless of the membrane-stabilizing action.

Sato T, Arai M, Goto S, Togari A
J. Pharmacol. Exp. Ther. Jul 2010
PMID: 20404011 | Free Full Text

It is possible that a beta1 blocker, like Metoprolol, would not be effective.

Beta Blocker Prevents Bone Loss in Rats Receiving Labyrinthectomy

Abstract

Sympathetic B antagonist prevents bone mineral density decrease induced by labyrinthectomy.

We previously showed that bilateral vestibular lesion in rats induces a bone loss in weight bearing bones. To determine whether this effect is mediated by the sympathetic nervous system (SNS), bone mineral density (BMD) was measured in 4 groups of 10 female Wistar rats: bilateral labyrinthectomy (Bilab), Bilab with propranolol treatment, sham operated with or without propranolol. In untreated rats, 30 days after lesion Bilab animals showed a reduced BMD in distal femoral metaphysis comparatively to intact rats (p < 0.001). In treated rats, there was no difference in BMD 30 days after lesion. This protective effect of propranolol against bone loss suggests that the vestibular system influence on bone remodeling is mediated by SNS. If this hypothesis is correct, this could have important consequences in devising countermeasures to spaceflight induced bone loss.

Denise P, Besnard S, Vignaux G, Sabatier JP…
Aviakosm Ekolog Med
PMID: 20169738

Beta Blockers May Blunt Exercise Benefits

Abstract

β-Adrenergic receptor blockade blunts postexercise skeletal muscle mitochondrial protein synthesis rates in humans.

β-Adrenergic receptor (AR) signaling is a regulator of skeletal muscle protein synthesis and mitochondrial biogenesis in mice. We hypothesized that β-AR blockade blunts postexercise skeletal muscle mitochondrial protein synthesis rates in adult humans. Six healthy men (mean ± SD: 26 ± 6 yr old, 39.9 ± 4.9 ml·kg(-1)·min(-1) peak O(2) uptake, 26.7 ± 2.0 kg/m(2) body mass index) performed 1 h of stationary cycle ergometer exercise (60% peak O(2) uptake) during 1) β-AR blockade (intravenous propranolol) and 2) administration of saline (control). Skeletal muscle mitochondrial, myofibrillar, and sarcoplasmic protein synthesis rates were assessed using [(2)H(5)]phenylalanine incorporation into skeletal muscle proteins after exercise. The mRNA content of signals for mitochondrial biogenesis was determined using real-time PCR. β-AR blockade decreased mitochondrial (from 0.217 ± 0.076 to 0.135 ± 0.031%/h, P < 0.05), but not myofibrillar or sarcoplasmic, protein synthesis rates. Peroxisome proliferator-activated receptor-γ coactivator-1α mRNA was increased ∼2.5-fold (P < 0.05) at 5 h compared with 1 h postexercise but was not influenced by β-AR blockade. We conclude that decreased β-AR signaling during cycling can blunt the postexercise increase in mitochondrial protein synthesis rates without affecting mRNA content.

Robinson MM, Bell C, Peelor FF, Miller BF
Am. J. Physiol. Regul. Integr. Comp. Physiol. Aug 2011
PMID: 21613574 | Free Full Text

Given that increased muscle tends to increase bone, this is somewhat negative, even though there is some evidence that beta blockers plus exercise is additive for bone.

Beta Blockers Increase Bone Loss from Steroids in Rats

Abstract

Effects of propranolol on the development of glucocorticoid-induced osteoporosis in male rats.

Glucocorticoid-induced osteoporosis is the most frequently occurring type of secondary osteoporosis. Antagonists of β-adrenergic receptors are now considered to be potential drugs under investigation for osteoporosis. The aim of the present study was to investigate the effects of propranolol, a nonselective β-receptor antagonist, on the skeletal system of mature male rats and on the development of bone changes induced by glucocorticoid (prednisolone) administration. The experiments were performed on 24-week-old male Wistar rats. The effects of prednisolone 21-hemisuccinate sodium salt (7 mg/kg, sc daily) or/and propranolol hydrochloride (10 mg/kg, ip daily) administered for 4 weeks on the skeletal system were studied. Bone and bone mineral mass in the tibia, femur and L-4 vertebra, length and diameter of the long bones, mechanical properties of tibial metaphysis, femoral diaphysis and femoral neck, bone histomorphometric parameters and turnover markers in serum were determined. Prednisolone-induced unfavorable skeletal changes led to disorders in bone mechanical properties. Propranolol not only did not improve bone parameters, but even caused deleterious effects on the skeletal system. Concurrent administration of propranolol with prednisolone did not counteract the changes induced by prednisolone. The results of this study may help to understand the equivocal results of human studies on the effects of β-blockers on the skeletal system. It is possible that the drugs exert biphasic effects on the skeletal system, both favorable and deleterious, depending on the dose or individual susceptibility.

Folwarczna J, Pytlik M, Sliwiński L, Cegieła U…
Pharmacol Rep 2011
PMID: 22001992 | Free Full Text