Osteoporos Int (2001) 12:380–384 ß 2001 International Osteoporosis Foundation and National Osteoporosis Foundation
Osteoporosis International
Original Article The Effect of Fluvastatin on Parameters of Bone Remodeling N. H. Bjarnason, B. J. Riis and C. Christiansen Center for Clinical & Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark
Abstract. Statins decrease the hepatic biosynthesis of cholesterol, and reduce the incidence of myocardial infarction in women who have already experienced a myocardial infarction. Statins also reduce the risk of atherosclerosis in diabetic patients, but it is unknown whether they influence the glucose tolerance. It has further been suggested that they may influence bone metabolism. Vitamin C is an antioxidant and it decreases serum cholesterol moderately. Antioxidants may also have other metabolic effects, but these are insufficiently studied. The aim of the present study was to investigate the metabolic effects of the cholesterol-lowering agent fluvastatin and the antioxidant vitamin C. Sixty-eight elderly, postmenopausal women with osteoporosis and mild hypercholesterolemia were randomly assigned to 12 weeks open treatment with either fluvastatin (40 mg daily) + 500 mg vitamin C (n = 45) or vitamin C only (n = 23). We measured biochemical markers of bone formation (serum osteocalcin and total alkaline phosphatase) and bone resorption (serum and urinary CTX), parameters related to diabetes and serum lipids and lipoproteins. Fluvastatin in combination with vitamin C had no effect on bone formation markers. We found a weak decrease in parameters of bone resorption, which was significant from baseline, but not different between the two groups. There were no significant effects on any of the other markers of either fluvastatin or vitamin C. The lipid-lowering effect of fluvastatin was confirmed with a decrease of 20% and 30% in serum total cholesterol and LDL-cholesterol, respectively. We conclude that fluvastatin given in clinically relevant doses has no influence on parameters of bone remodeling. Other statins remain to be investigated. Correspondence and offprint requests to: Dr Nina Hannover Bjarnason, Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark. Tel: + 45 44 68 46 00. Fax: + 45 44 68 42 20. e-mail:
[email protected]
Keywords: Bone formation; Bone resorption; Fluvastatin; Lipids; Postmenopausal osteoporosis; Vitamin C
Introduction Statins are commonly prescribed drugs that inhibit 3hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase and decrease hepatic cholesterol biosynthesis, thereby reducing serum cholesterol concentrations and lowering the risk of heart attack [1,2]. Statins may, however, have other metabolic effects. They decrease the risk of atherosclerosis in diabetic patients [3], but it is unknown whether they influence any diabetic metabolic parameter. They may also influence the bone turnover. Recent studies have even suggested that they may stimulate bone formation, but the data are still preliminary. In a recent paper Mundy et al. [4] reported that in cultured mouse bone cells, lovastatin, simvastatin, mevastatin and fluvastatin all increased the production of bone morphogenetic protein-2 (BMP-2), which stimulates bone growth. Furthermore, the statins increased new bone formation by approximately 2-to 3-fold in a biological model using neonatal calvarial bones from mice. Two of the statins (lovastatin and simvastatin) were furthermore injected in mice and given orally to rats. Subsequently histomorphometry analysis revealed a 50% increase in new bone formation in the mice and significantly increased cancellous bone volume in rats. Vitamin C is an anti-oxidant, and it has been shown to decrease total serum cholesterol moderately [5]. Treatment with a combination of statin and vitamin C may thus have additional positive effects on the cardiovascular system. It has, however, not been studied how such a combination or vitamin C alone influences other metabolic parameters.
Fluvastatin and Bone Turnover
We performed a study in which 68 postmenopausal women aged 65 years or older were treated with either fluvastatin plus vitamin C or vitamin C alone. The objectives of the study were: . to study the effects of statins on bone metabolism . to study the effects of statins on diabetic related parameters . to study the effects of vitamin C on metabolic parameters related to atherosclerotic diseases.
Participants and Methods Participants The participants were women aged 65 years or above with a hip and/or spine bone mineral density (BMD) below –2.0 SD of normal premenopausal women and a serum cholesterol concentration above 5.2 mmol/l. Exclusion criteria were a body mass index above 40 kg/m2, severe or chronic diseases, or medication known to interfere with the results of the study. Of the 89 women who were screened, 3 were excluded because their serum cholesterol was below the range defined by the inclusion criteria, 3 because of conditions expected to interfere with the disease or the trial, 9 because of treatment within the previous 3 months with compounds which may interfere with bone metabolism, 3 because they had participated in another study within the previous 3 months, 1 because of prior allergy to a compound related to fluvastatin and 2 because they did not want to participate. Sixty-eight women were randomized to receive either 500 mg vitamin C (Nycomed Amersham) alone (group A; n = 23) or 40 mg fluvastatin (Lescol, Novartis) + 500 mg vitamin C (group B; n = 45). The medication was administered as oral tablets once daily at bed time. Forty milligrams of fluvastatin is the dose recommended for adults with hypercholesterolemia. Five hundred milligrams of vitamin C is about 10 times the recommended daily dose. Randomization was 2:1 in favor of fluvastatin using a computer-generated random list. Of the 68 women who entered the trial, 6 did not complete it: 1 woman left group A (protocol violation) and 5 women left group B (3 due to gastrointestinal adverse events, 1 for personal reasons and 1 for personal reasons with protocol violation). Another 2 women completed the study but had protocol violations. The safety analysis included all 68 randomized women. The efficacy analysis included all randomized women except 4 (2 in group A and 2 in group B) who were excluded due to protocol violations. This left 21 and 43 women in the efficacy analysis in the vitamin C and the fluvastatin + vitamin C groups, respectively.
Study Design The trial was a single-center, randomized open trial. The study lasted 14 weeks, with examinations 2 weeks before
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the start of medication (visit –2), at the start of medication (visit 0), and after 4, 8 and 12 weeks (visits 4, 8, 12).
Methods The metabolic effects were evaluated by measurements of glucosylated hemoglobin (HbA1c) at weeks 0, 4 and 12 [6], and by an oral glucose tolerance test (OGTT) at visits 0 and 12 weeks [7]. The effect on bone metabolism was determined by biochemical bone marker measurements at visits –2, 0, 4 and 12 weeks. The markers of bone formation were serum total alkaline phosphatase (AP) and serum osteocalcin (OC) [8]. Urinary and serum CrossLaps (U-CTX and S-CTX) were measured as markers of bone resorption [9,10]. All values of U-CTX given in this paper are creatinine-corrected. Serum cholesterol was measured by routine procedures (Cobas Mira Plus). All laboratory analyses were performed in masked fashion. Safety surveillance consisted of recording of adverse events, laboratory analysis, physical examination, and vital signs.
Statistical Analysis No statistical power calculation was performed, since the study was planned to be exploratory and the analysis of the results to be descriptive. All data available from all patients included in the analysis were used in the statistical analysis. These data were normally distributed and were thus not transformed. No ‘last observation carried forward’ was performed. Baseline values and relative changes in biochemical markers over time in the two groups were compared by Student’s t-test for unpaired data. Relative changes over time within groups were analyzed by Student’s t-test for paired data.
Results Tables 1 and 2 give the baseline age, height, weight, body mass index (BMI), serum lipoprotein concentrations (total cholesterol, HDL, LDL) the metabolic parameters (HbA1c, OGTT), and the biochemical markers of bone metabolism (serum AP, serum OC, SCTX and U-CTX). Apart from a difference in S-CTX, which just reched statistical significance, the two groups were comparable. The lipids (serum total cholesterol, HDL-cholesterol and LDL-cholesterol) were measured at baseline and after 4 and 12 weeks and the measurement results are presented in Table 3. The results confirm the previously documented lipid lowering effect of fluvastatin, with highly significant decreases in total and LDL-cholesterol
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Discussion
Table 1. Baseline demographics Vitamin C (n = 23)
Age (years) Body mass index (kg/m2) Height (cm) Weight (kg)
71.1 25.0 160.8 64.5
Fluvastatin +Vitamin C (n = 45)
3.8 71.2 2.9 25.7 3.9 159.7 7.7 65.4
Significance of difference
3.5 4.2 6.3 10.7
NS NS NS NS
Values are mean SD.
(p50.001). There were no effects of vitamin C alone on any of the lipid parameters. The biochemical markers of bone metabolism were likewise measured at baseline and after 4 and 12 weeks (Table 3). There was no effect of the treatments on the markers of bone formation, i.e., serum AP and OC. Concerning U-CTX there was, at 12 weeks, a marginal but statistically significant (p = 0.0457) decrease in the group treated with fluvastatin + vitamin C. Neither fluvastatin in combination with vitamin C nor vitamin C alone had any significant effect on the glucose metabolic parameters. For S-CTX a slight, but significant difference from baseline was found in both groups (p = 0.021 for the fluvastatin group and p = 0.034 for the control group), but also for this parameter, there were no differences between the two groups.
Six women (5 from group B and 1 from group A) reported abdominal pain. Four of these cases were evaluated as possibly related to drug. Three women had increased serum-gammaglutamyl transferase (GGT) possibly related to drug (all resolved at follow-up visits). Overall, mild gastrointestinal symptoms and increased liver parameters are side effects previously published for fluvastatin. Therefore, the adverse event profile in this study was not considered different from the generally accepted profile for this class of compounds. Research in the mechanism of action of statins has been focused on the lipid-lowering effect, the antiatherosclerotic effect, and the preventive effect in cardiovascular diseases. However, statins may influence other parameters. In 1995 Wang et al. [11] reported that rabbits treated with a combination of steroid and lovastatin showed significantly less bone loss than rabbits treated with steroid alone. Recently, a group of researchers [4] screened more than 30 000 compounds looking for any that could increase the production of BMP-2, which stimulates bone growth. They found that lovastatin (Mevacor, Merck) had this effect. They then designed a study that included several statins which all, when given in relative high doses, had stimulatory effects on bone growth. In the light of these results the researchers did a retrospective analysis of 598 women taking statins to lower their cholesterol. The preliminary
Table 2. Baseline serum lipoproteins, metabolic parameters and biochemical markers of bone turnover by treatment groups Total
Vitamin C (n = 21)
Fluvastatin +Vitamin C (n = 43)
Significance of difference
Cholesterol (mmol/l) HDL-cholesterol (mmol/l) LDL-cholesterol (mmol/l) HbA1C (mmol/l) OGTTa (mmol/l)
7.31 1.84 4.87 5.29 5.19 6.79 159 28.0 4718 308
7.34 1.89 4.86 5.46 5.15 6.35 176 23.2 3736 263
NS NS NS NS NS NS NS NS p50.05 NS
Alkaline phosphatase (U/l) Osteocalcin (nmol/l) S-CTX (pmol/l) U-CTX (mg/mmol)
1.36 0.44 1.44 0.55 0.85 (t0) 1.74 (t120) 48 12.7 1832 155
1.17 0.54 1.18 0.49 0.97 (t0) 1.31 (t120) 63 9.4 1352 94
Values are mean SD. a Serum glucose at baseline and after 120 min.
Table 3. Absolute (mean 1 SD) and relative change (% of baseline) in serum lipoproteins and biochemical markers of bone turnover at 12 weeks Group A: Vitamin C (n = 21)
Group B: Fluvastatin + Vitamin C (n = 43)
Significance of difference
Total
Absolute change
% change
Absolute change
% change
Within group A/B
Groups A vs B
Cholesterol (mmol/l) LDL-cholesterol (mmol/l) HDL-cholesterol (mmol/l) S-CTX (pmol/l) U-CTX (mg/mmol) Osteocalcin (nmol/l)
–0.18 (0.60) –0.08 (0.60) –0.09 (0.21) –354 (712) –35 (75) –0.4 (7.0)
–2.4% –1.6% –5.1% –7.2% –11% –1.3%
–1.4 (1.02) –1.4 (0.93) 0.07 (0.29) –333 (863) –38 (78) –0.8 (5.7)
–20.0% –30.0% 4.0% –6.7% –14% –3.3%
NS/p50.001 NS/p50.001 NS/NS p50.05/p50.05 NS/p50.05 NS/NS
p50.001 p50.001 NS NS NS NS
Fluvastatin and Bone Turnover
results suggest that statin use results in higher hip bone density and decreased hip fracture incidence, but further data are needed. One of the aims of the present trial was to study the effect of statins on bone metabolism in humans. As markers of bone turnover we used parameters that are known to respond to bone-active compounds at least within a 3-month period [12–15]. As markers of bone formation we used serum total alkaline phosphatase and osteocalcin, where at least osteocalcin is considered a sensitive and specific marker [16]. Total alkaline phosphatase may reflect hepatic and biliary disease because the measurement includes both bone and liver isoenzymes [17]. However, such diseases in the medical history were covered by the exclusion criteria, and the slight influence on serum GGT in the 3 women treated with fluvastatin did not lead to changes in total alkaline phosphatase. We did not measure bone specific alkaline phosphatase although this may theoretically have added to the data. None of the formation markers measured showed any sign of increased bone formation. As markers of bone resorption we used U-CTX and SCTX, which are both specific and sensitive [18,19]. The slight and temporary decrease in these markers may indicate decreased bone resorption, but the decreases were only significant from baseline, not from the control group. A mechanism of action cannot be proposed, but is more likely to be associated with vitamin C or chance than with fluvastatin. Mundy et al. [4] used statin doses in their rodent trials that were about 10-fold higher than the doses currently recommended for cholesterol lowering. We, however, used a dose normally recommended for cholesterol lowering in humans. The lack of effects on bone remodeling in this study may be caused by a dose that is too low. Furthermore, our results may not be representative of all other statins. However, it is likely that any statin developed for osteoporosis would have to be manipulated in some way to target the bones instead of, as currently, the liver. The present study was designed to have further aims than to look at the effect of statins on bone remodeling. Since ischemic heart disease is the primary cause of death of patients with non-insulin-dependent diabetes mellitus and increased peripheral insulin resistance is a known risk factor for ischemic heart disease [20], we looked at the effect of statins on parameters related to diabetes. There were, however, with the given dose of fluvastatin, no effects either on the concentration of glucosylated hemoglobin or on insulin resistance. Also, vitamin C had no effects on any of the parameters analyzed. In conclusion, fluvastatin given in doses that result in the normally expected lipid-lowering effect had no effect on bone formation markers. A slight decrease was seen in bone resorption markers, but these changes were only significantly different from baseline and not from the control group, and are therefore highly unlikely to be associated with fluvastatin therapy. Other statins remain to be investigated.
383 Acknowledgement. This study was supported by Novo Nordisk A/S.
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Received for publication 6 June 2000 Accepted in revised form 4 December 2000
