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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0573
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5212-5216
Copyright © 2005 by The Endocrine Society

Effects of a ß-Blocker on Bone Turnover in Normal Postmenopausal Women: A Randomized Controlled Trial

Ian R. Reid, Jenny Lucas, Diana Wattie, Anne Horne, Mark Bolland, Gregory D. Gamble, James S. Davidson and Andrew B. Grey

Department of Medicine (I.R.R., J.L., D.W., A.H., M.B., G.D.G., A.B.G.), University of Auckland, New Zealand; and LabPlus (J.S.D.), Auckland Hospital, New Zealand

Address all correspondence and requests for reprints to: Dr. I. R. Reid, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: i.reid{at}auckland.ac.nz.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Introduction: The central nervous system has been demonstrated to regulate bone mass in mice, possibly via the ß2-adrenoreceptors on osteoblasts. ß-blockers increase bone mass in mice, and some observational studies have suggested a beneficial effect of these drugs on bone in humans

Experimental Subjects: We studied 41 normal postmenopausal women.

Materials and Methods: We conducted a randomized, placebo- controlled trial, comparing the effects on bone markers of propranolol 160 mg/d and placebo over 3 months.

Results: Serum osteocalcin declined by almost 20% in the first 2 wk of propranolol treatment, and this effect increased over time (P < 0.0001). Other osteoblast markers, procollagen type-I N-terminal propeptide and total alkaline phosphatase activity, were not significantly changed by propranolol. Urine free deoxypyridinoline declined by approximately 10% between 0 and 6 wk (P = 0.019) in the ß-blocker group and was stable thereafter. Serum C-terminal telopeptide of type I collagen also showed a small decrease, but this was not significantly different between groups. Serum albumin concentrations decreased by more than 2 g/liter in the first 2 wk of propranolol treatment, remaining stable subsequently (P = 0.007). Serum creatinine tended to increase in the propranolol group (P = 0.06), as did weight. Bone densities in the lumbar spine and total proximal femur did not change significantly in either group.

Conclusions: The present study provides no evidence that ß-blocker drugs stimulate bone formation; if anything, propranolol reduces osteoblast activity. It also influences renal function and fluid balance, effects that might indirectly affect bone metabolism. Current evidence does not justify the use of ß-blockers for treatment of osteoporosis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ONE OF THE most important conceptual advances in our understanding of bone metabolism in recent years has been the demonstration that the central nervous system can play an important regulatory role. Thus, Ducy et al. (1) have shown that bone formation and bone mass in mice are responsive to intracerebroventricular administration of the hormone leptin, and Baldock et al. (2) have complemented this with the demonstration that neuropeptide Y signaling in the hypothalamus also has profound effects on these endpoints. These observations were extended by Takeda et al. (3), who concluded that the central effects of leptin were mediated by the sympathetic nervous system, ultimately acting through ß2-adrenergic receptors on osteoblasts, which negatively regulate the proliferation of these cells. These studies further demonstrated that the systemic administration of ß-agonists resulted in decreased bone formation and bone loss in mice, whereas the administration of propranolol, a nonselective ß-blocker, had the opposite effects. This has led to the suggestion that ß-blockers may be a potential therapy for osteoporosis.

This work provided a stimulus to examine the effect of ß-blocker use on clinical indices of bone health in humans. Pasco et al. (4) have done this using data from the Geelong Osteoporosis Study. Their cohort of 569 fracture cases and 775 controls suggested that the odds ratio for any fracture in ß-blocker users was 0.68 (95% confidence interval, 0.49–0.96), a finding that was little affected by adjustment for age, weight, other medications, and lifestyle factors. In addition, bone densities at the total hip and ultradistal forearm were approximately 0.2 SD higher in ß-blocker users. Schlienger et al. (5) have recently analyzed 30,000 cases and 120,000 controls from the United Kingdom General Practice Research Database and reported an odds ratio for fracture of 0.77 in ß-blocker users. However, prospective data from the Danish Osteoporosis Prevention Study suggest that ß-blocker use is associated with an increased risk of fracture (6) and no change in bone density. Additional information is available from the Study of Osteoporotic Fractures, which provides both cross-sectional and prospective data and shows an inconsistent association between ß1-selective blocker use and lower fracture risk, none between fracture risk and nonselective ß-blocker use, and no associations with bone density (7). A recent analysis of the EPIDOS database also failed to find a relationship between ß-blocker use and fracture risk (8). Thus, epidemiological data are inconsistent regarding the clinical effects of these drugs on bone.

To further explore this important question, we conducted a randomized controlled trial assessing the effects of the nonselective ß-blocker propranolol on bone metabolism in normal postmenopausal women. Propranolol was chosen because this is the agent shown to rapidly change bone formation rates in mice and because the available selective ß-blockers would not be expected to block the ß2-adrenergic receptors on osteoblasts.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Subjects were normal postmenopausal women who were more than 5 yr postmenopausal and aged more than 55 yr. Women with illnesses or receiving therapies likely to affect bone were ineligible, as were those with any other major systemic disease or with contraindications to the use of ß-blockers. Lumbar spine bone density was not below the age-appropriate normal range (i.e. Z-score > –2).

Subjects were recruited by newspaper advertisement. One hundred thirty-four women responded to the advertisements, 63 of whom did not meet the inclusion/exclusion criteria. An additional 30 decided not to proceed further with the study. Forty-one subjects were randomized. Two women, both randomized to propranolol, did not complete the study, one because of a rash and the other because of insomnia.

Protocol

A randomized trial, comparing propranolol 160 mg daily (as a single slow-release tablet; Pacific Pharmaceuticals, Auckland, New Zealand) with placebo over a period of 3 months has been carried out. Blood and urine samples were collected fasting between 0800 and 1000 at baseline, 2 wk, 6 wk, and 3 months. Bone mineral density of the lumbar spine and proximal femur was measured by dual-energy x-ray absorptiometry using a Lunar Expert instrument (GE-Lunar, Madison WI; software version 1.7) at baseline and 3 months.

Subjects were randomized to one of two treatment groups using a predetermined schedule, based on computer-generated random numbers. All subjects and study personnel were blinded to treatment allocation throughout. The study was approved by the Auckland Ethics Committee, and written informed consent was provided by each participant.

Measurements

Serum calcium, albumin, creatinine, and total alkaline phosphatase activity and urine creatinine were measured on a Roche Modular autoanalyzer. The Roche Elecsys 2010 platform was used for serum osteocalcin, serum ß-C-terminal telopeptide of type I collagen (ßCTX, ß-CrossLaps), and serum procollagen type-I N-terminal propeptide (PINP). Urine free deoxypyridinoline (fDPD, Pyrilinks-D) was assayed using a DPC Immulite 2000 analyzer. Coefficients of variation of these markers are as follows: osteocalcin, 5.5%; ßCTX, 5.1%; PINP, 1.9%; fDPD, 13%. Each turnover marker was assayed at the end of the study period in a single batch. Samples were stored at –70 C.

Statistics

The primary endpoints of the study were the two specific markers of bone formation, osteocalcin and PINP. The study was, therefore, designed to detect a 1 SD difference between the treatment groups in the change in either of these markers. Because recruitment made allowance for dropouts, the number of completing subjects provides 80% power at the 5% significance level to detect differences of at least 90% of 1 SD between the placebo and propranolol arms.

Procedures of the statistical analysis system SAS (version 9.2; SAS Institute, Inc., Cary, NC) were used for all analyses. All statistical tests were two-tailed, and a 5% significance level was maintained throughout. All treatment evaluations were performed on the principle of intention to treat. A mixed-models approach to repeated measures was used to examine the time course of response in treatment and control arms at baseline and at 2, 6, and 12 wk. The correct covariance structure was determined by likelihood ratio test [i.e. the first order auto regression matrix was compared against an unstructured covariance matrix]. Maximum likelihood imputation was used to ensure all the randomized patients could be included in the model. P values and SE for significant main and interaction effects were constructed using the method of Tukey.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The baseline characteristics of the study subjects are shown in Table 1Go. None were smokers. Compliance with trial medication, as assessed by tablet counts, was 93% and was not different between treatments (P = 0.29).


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  		TABLE 1. Characteristics of study subjects at baseline

 
The effects of propranolol on markers of bone turnover are shown in Figs. 1–5GoGoGoGoGo. Serum osteocalcin declined by almost 20% in the first 2 wk of propranolol treatment, and this effect tended to become more marked subsequently (Fig. 1Go). A second osteoblast marker, PINP, was not decreased by propranolol treatment (Fig. 2Go). There was also no significant effect of treatment on serum total alkaline phosphatase activity (Fig. 3Go), although a trend toward a decrease was apparent in the propranolol group.



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  		FIG. 1. The effects of propranolol or placebo on serum osteocalcin concentrations in normal postmenopausal women. P(tx*time) is the P value for the time-treatment interaction. Data are mean ± SEM percent change from baseline.

 


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  		FIG. 2. The effects of propranolol or placebo on serum concentrations of PINP in normal postmenopausal women. P(tx*time) is the P value for the time-treatment interaction. Data are mean ± SEM percent change from baseline.

 


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  		FIG. 3. The effects of propranolol or placebo on serum total alkaline phosphatase activity (ALP) in normal postmenopausal women. P(tx*time) is the P value for the time-treatment interaction. Data are mean ± SEM percent change from baseline.

 


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  		FIG. 4. The effects of propranolol or placebo on fasting urine excretion of fDPD, expressed as a ratio to creatinine (Cr), in normal postmenopausal women. P(tx*time) is the P value for the time-treatment interaction. Data are mean ± SEM percent change from baseline.

 


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  		FIG. 5. The effects of propranolol or placebo on serum concentration of ßCTX in normal postmenopausal women. P(tx*time) is the P value for the time-treatment interaction. Data are mean ± SEM percent change from baseline.

 
Two biochemical markers of bone resorption were assessed. Urine fDPD declined by approximately 10% between 0 and 6 wk and was stable thereafter. The difference between groups was significant. Serum CTX also showed a small decrease in response to propranolol, but this was not significantly different between groups.

Serum albumin concentrations were comparable between groups at baseline (propranolol, 42.8 g/liter; placebo, 43.1 g/liter) but decreased by more than 2 g/liter in the first 2 wk of propranolol treatment, remaining stable subsequently. There was no change in the placebo group. At 12 wk, the respective levels were 41.2 and 42.6 g/liter (P for time x treatment interaction, 0.007). Serum total calcium concentrations paralleled those of albumin, but there were no between-group differences in albumin-adjusted calcium concentrations (P = 0.88). Serum creatinine concentrations also tended to diverge between groups; baseline values were 0.84 mg/dl (0.074 mmol/liter) in both groups, but at 12 wk, concentrations were 0.90 mg/dl (0.080 mmol/liter) in the propranolol group and 0.81 mg/dl (0.072 mmol/liter) in those on placebo (P = 0.06, by t test).

Bone densities in the lumbar spine and total proximal femur did not change significantly in either group (spine: placebo, 0.5 ± 0.8%; propranolol, 1.4 ± 1.0%; P value for between-groups comparison in change from baseline, 0.93; total hip: placebo, 0.5 ± 0.6%, propranolol, 0.26 ± 0.4%; P = 0.67). Body weight did not change in the placebo group during the study (0.0 kg), but in the propranolol group it increased 0.6 kg (95% confidence interval, 0.06–1.08), although there was not a significant between-groups difference (P = 0.20). Blood pressures were comparable at baseline (133 ± 3/78 ± 2 and 138 ± 5/76 ± 2 in the placebo and propranolol groups, respectively) and at 12 wk (125 ± 4/75 ± 1 and 127 ± 8/71 ± 2, respectively), but pulse rates showed the expected change (77 ± 2 and 83 ± 3 at baseline and 78 ± 2 and 62 ± 3 at 12 wk; P < 0.0001).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study does not support the hypothesis that ß-blockade results in increased bone formation; if anything, the opposite is true. Thus, osteocalcin showed a substantial and significant decrease, and there was no suggestion of any increase in the other two formation markers assessed. The reason for these differences in the response of the formation markers is not apparent but could imply a direct effect of the ß-adrenergic system on the regulation of the osteocalcin gene, as is the case for glucocorticoids (9). It might also be explained by the recent demonstration that another nonselective ß-blocker, carvedilol, is cytotoxic to a human osteoblastic cell line in culture (10). The suppression of osteocalcin seen in the present study precisely parallels the finding of an epidemiological study in Danish women, which reported that serum osteocalcin levels were 20% lower in ß-blocker users compared with controls (6). These findings raise the worrying possibility that these widely used drugs in conventional doses might actually inhibit bone formation in humans.

The bone resorption measurements in the present study show a decrease in fDPD without any change in CTX. Because CTX is released directly from bone as a result of osteoclastic resorption, whereas fDPD is generated in the kidneys as a result of the catabolism of the cross-linking telopeptides (11), it is possible that the effect of propranolol on renal function causes the fall in fDPD. Others have reported that propranolol reduces glomerular filtration rate (12, 13), which is reflected in the present study in an increase in serum creatinine very similar to that previously reported (12). Wilkinson et al. (12) reported that, despite equal mean reductions in blood pressure with propranolol and atenolol, creatinine clearance fell significantly only during treatment with propranolol, suggesting that intrarenal ß2-adrenoceptors may be of importance in the regulation of renal function. Possibly they also directly influence renal generation of fDPD. Renal function also impacts on CTX, in that levels are increased in subjects with renal failure (14). This is probably attributable to secondary hyperparathyroidism, and there is no evidence of increased CTX levels with the minor perturbations of renal function seen in the present study. Certainly, the pattern of responses observed here is not that of established antiresorptive agents, such as bisphosphonates, which have their greatest effects on the levels of C- or N-telopeptides, lesser effects on the pyridinolines, and only a very delayed effect on formation markers (15).

The changes in serum albumin observed in the present study do not appear to have been described previously. However, Sederberg-Olsen and Ibsen (16) found that propranolol increased extracellular fluid volume by 575 ml at 2 months and 758 ml at 4 months, which is consistent with the weight change we found in the propranolol group and would be expected to affect the level of serum albumin in the direction we observed. Hvarfner et al. (17) assessed the effects of propranolol on calcium metabolism in subjects with essential hypertension. They found increases in ionized calcium and decreases in PTH at 6 months, although total serum calcium was stable. Serum albumin was not reported but can be interpolated from the total and adjusted calcium data provided. This calculation suggests that propranolol use was associated with a reduction in serum albumin of about 1.2 g/liter at 3 months, very similar to the changes found in the present study. Others have studied the effects of ß-blockade on PTH secretion. Although there may be acute changes after iv infusions of ß-blockers (18), most long-term studies of nonselective agents do not show any effect (19, 20), so PTH is not likely to be a major contributor to the effects seen in the present study. These observations, together with the data on renal function described above, attest to the widespread distribution of adrenoreceptors, emphasizing that any effects of propranolol on bone or calcium metabolism might be mediated by a variety of indirect mechanisms.

Although the immediate stimulus to study the effects of ß-blockers on bone came from the recent work of Karsenty and colleagues (1, 3) on central nervous system regulation of bone formation, there is a significant body of earlier work that supports a role for the sympathetic nervous system in skeletal metabolism. Thus, others have demonstrated the presence of ß-adrenoreceptors on osteoblasts (21, 22), and Moore et al. (23) showed these to be of the ß2 subtype, although Kellenberger et al. (24) also found ß1 and ß3 in some cell preparations. ß-Agonists have been shown to stimulate production of bone-active cytokines (e.g. IL-6, IL-11, and prostaglandin E2) (25, 26, 27), PTH (28) and receptor activator of nuclear factor {kappa}B ligand (26) and to increase osteoclastogenesis (26). Norepinephrine has been shown to increase bone resorption in bone organ culture, and propranolol to have the opposite effect (23, 29). These findings suggest that the sympathetic nervous system mainly impacts on bone resorption rather than on formation as suggested by Takeda et al. (3), and this is supported by the recent demonstration that propranolol reduces osteoclast markers but does not affect serum osteocalcin in ovariectomized mice (30). In contrast, Minkowitz et al. (31) have demonstrated increased mineral apposition rates in the femurs of propranolol-treated rats. Levasseur et al. (32) have shown positive effects of propranolol on bone density in tail-suspended rats, but their data do not allow a distinction to be made between effects on formation and resorption. In contrast, others have shown positive effects of ß-agonists on osteoblasts (33) or bone mass (34, 35). Consistent with these variable findings, sympathectomy produces variable effects on bone turnover in vivo (36, 37, 38).

An additional way to gain insights into the effects of the sympathetic nervous system on bone metabolism is to study animals in which the various ß-adrenoreceptor subtypes have been knocked out. Preliminary data have been presented indicating that the ß-agonist isoproterenol causes bone loss in wild-type mice by stimulating both formation and resorption and that these effects are absent in the ß2-receptor knockout mice (39). Pierroz et al. (40) have also shown that isoproterenol reduces bone mass as well as fat mass and androgen levels in wild-type mice. In addition, they found that deletion of both the ß1- and ß2-receptors reduced bone size, cortical thickness, and total body bone mineral content but did not change trabecular bone density (40). When all three adrenergic receptors are knocked out (41), fat mass is increased, but total body bone mineral content, cortical thickness, and trabecular bone volume are also higher than in wild-type animals. These findings indicate that each of the adrenergic receptors has a different impact on bone and that some of these effects might be indirect (e.g. by way of effects on soft tissue composition). Therefore, some of the differences between the results of the present study and those found in animal studies may arise from differences in interactions between the ß-receptors or differences in the balance of direct and indirect effects in the various models. Therefore, the use of more selective ß-blockers in the present study might have produced different outcomes.

In conclusion, the present study is the first direct assessment in humans of the effects of ß-blockade on bone turnover and provides no support for the suggestion that such therapy increases bone formation. If anything, propranolol reduces indices of osteoblast activity and might therefore have a deleterious effect on bone. This possibility is supported by one of the observational studies of fractures (6) and also by the upward trend in fracture numbers in the only analysis of fractures in randomized controlled trials of ß-blockers (7). An overview of cell and animal studies suggests that the sympathetic nervous system is an important regulator of skeletal homeostasis, but considerably more work is required before it will be clear how the actions of the three ß-adrenoreceptors across a variety of tissues integrate to influence bone strength. The available epidemiological data are potentially confounded by many factors and do not provide consistent evidence that currently available ß-blockers confer significant protection against fractures. Therefore, these drugs should not be used in the treatment of osteoporosis at present.


   Footnotes
 
This work was supported by the Health Research Council of New Zealand. M.B. is the recipient of a Fellowship from the Australian and New Zealand Bone and Mineral Society.

First Published Online July 5, 2005

Abbreviations: ßCTX, ß-C-terminal telopeptide of type I collagen; fDPD, free deoxypyridinoline; PINP, procollagen type-I N-terminal propeptide.

Received March 16, 2005.

Accepted June 28, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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A. Grey, M. Bolland, G. Gamble, D. Wattie, A. Horne, J. Davidson, and I. R. Reid
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