Журнал «Боль. Суставы. Позвоночник» 1 (09) 2013

Introduction

The pharmacological armamentarium for the management of osteoporosis has considerably expanded. Indeed, ability to substantially reduce fracture risk with a generally favourable risk-benefit ratio is now documented in well-conducted large clinical trials for a series of different molecules encompassing different pharmacological classes and different modes of action [1]. Osteoporosis is a highly prevalent problem in the ageing population, and the absolute number of affected subjects increases as a consequence of demographic evolutions. Albeit at present only a fraction of these patients at risk are treated, progress is being made and awareness increases of the consequences of osteoporotic fractures in terms of personal suffering and burden for the public health. Therefore, a large and steadily increasing number of patients are likely to be exposed for prolonged periods of treatment to osteoporosis medication. Availability of several treatment alternatives confronts the clinician with the difficulty to make the best choice for the individual patient, whereas the large-scale and prolonged prescription of osteoporosis medication puts much emphasis on safety issues.

To compare treatments, there is little evidence available from direct comparative trials, and no direct comparisons are available with fracture incidence as primary evaluation criterion. To select the ‘best choice treatment’ for their individual patient, clinicians thus depend on indirect comparisons, with little possibility of reliable differentiation in terms of efficacy, taking into account a variety of drug characteristics in relation to the patient’s clinical profile and preferences. In this context, consideration of the nonskeletal actions of the osteoporosis medications will not seldom intervene in the final choice, be it positively in terms of perceived potential ‘added value’ or negatively because of perceived potential risk for the patient. Aside from controversies related to potential long-term osseous adverse effects of osteoporosis treatments, a number of alleged extra-skeletal safety issues have been raised in the recent literature concerning as widely prescribed treatments as calcium and bisphosphonates (BPs). The present document is the result of a national consensus based on a systematic review and a critical appraisal of the literature. It aims at providing the clinicians with an overview of what is the state of our knowledge on potentially deleterious or beneficial non-skeletal actions of the main pharmacological treatments of osteoporosis.

Methods

We included randomised controlled trials (RCTs), metaanalyses as well as epidemiologic retrospective or prospective studies and well documented case reports considering nonskeletal actions of osteoporosis treatments. Relevant articles related to treatment with calcium, vitamin D, bisphosphonates, selective oestrogen receptor modulators (SERMs), strontium ranelate, teriparatide, parathyroid hormone (PTH) and denosumab were identified through a systematic search, from 1966 to 2011, in MEDLINE and databases such as Cochrane Controlled Register. Following this extensive search of the literature, a critical appraisal was obtained through a consensus expert meeting.

Calcium

In the elderly, low calcium intake and vitamin D deficiency result in a negative calcium balance. This stimulates the secretion of PTH and induces age-associated secondary hyperparathyroidism, which enhances bone turnover and accelerates bone loss [2]. Adequate intake of calcium and vitamin D, through diet and/or supplements, reverses this secondary hyperparathyroidism and is recommended in the prevention of osteoporotic fractures [1, 3]. More specifically, the National Institutes of Health (NIH) in the USA proposes a recommended dietary allowance for calcium of 1,000 mg in men aged 50–70 years and 1,200 mg in men older than 70 years and women older than 50 years. In combination with vitamin D substitution, calcium supplements have proven anti-fracture efficacy when targeted to persons at risk of calcium and/or vitamin D insufficiency, including elderly or institutionalized individuals, osteoporosis patients on antiresorptive or anabolic medication and persons receiving glucocorticoids [4–8]. Benefits are most apparent when a daily dose of 1,000–1,200 mg calcium is complemented with 800 IU vitamin D [6, 8]. This section reviews the evidence for the positive and negative non-skeletal effects of calcium [9].

Calcium as potentially protective against cardiovascular events

Observational research has suggested an inverse relationship between calcium intake and vascular diseases. In the Iowa Women’s Health Study in 34,486 postmenopausal women aged 55 to 69 years, Bostick and colleagues found that the highest quartile of total calcium intake (> 1,425 mg/day), when compared to the lowest quartile (< 696 calcium/day), was associated with a 33 % reduction in ischaemic heart disease mortality (risk ratio (RR) 0.67, 95% confidence interval (CI) 0.47 to 0.94). According to the analysis, this risk reduction was dependent of the high total intake of calcium and could be attained by diet, supplements or both [10]. Similarly, Knox found a strong negative correlation between dietary calcium intake and mortality ratios for ischemic heart disease [11]. In the Nurses’ Health Study cohort of 85,764 women aged 39 to 59 years followed for 14 years, women in the highest quintile of total calcium intake (median calcium 1,145 mg/day) had a lower risk of stroke (RR 0.69, 95% CI 0.50–0.95) than those in the lowest quintile (median calcium 395 mg/day) [12].

To explain this observed protection against vascular diseases, potential beneficial effects of calcium on a number of vascular risk factors have been postulated. In particular, reductions in blood pressure, serum lipid concentration and body weight might be involved, although the data, to some extent, remain inconsistent [9]. An inverse relationship between calcium and blood pressure has been observed in several studies. In a meta-analysis of randomised controlled trials, both dietary calcium intake and calcium supplements were associated with reduced blood pressure, with a trend towards larger effects with dietary intake. However, the effect size was relatively small, with a mean reduction in systolic and diastolic blood pressure of -1.44 mmHg (95% CI -2.20 to -0.68) and -0.84 mmHg (95% CI -1.44 to −0.24), respectively [13]. In line with these findings, a recent trial showed significantly lower rates of hypertension amongst women aged over 45 years with a dietary calcium intake of at least 679 mg/day. In women in the highest quintile of dietary calcium intake (1,000 to 2,560 mg calcium/day), the relative risk reduction was 13% (RR 0.87, 95% CI 0.81 to 0.93). However, in women taking calcium supplements, even in the highest dosed quintile (1,000–2,100 mg), the risk of hypertension was unchanged (RR 1.07, 95% CI 0.97 to 1.18) [14]. A recent Cochrane review concluded that any association between calcium supplements and reduction in blood pressure is uncertain and that poor quality of individual trials and heterogeneity between trials do not allow any firm conclusions [15]. Any antihypertensive effect, if real, is at best small and transient [16].

Another potential cardioprotective mechanism might be a reduction in serum lipid concentration, due to the binding of calcium to fatty acids and bile acids in the gut, resulting in malabsorption of fat, and a direct effect on adipocytes with increased lipolysis [17–19]. In a randomised controlled trial in men, a diet fortified with calcium significantly reduced total cholesterol, LDL cholesterol and apolipoprotein B [18]. Similarly, in a randomised placebo-controlled trial in postmenopausal women, a supplement of 1,000 mg calcium during 12 months increased high-density lipoprotein (HDL) cholesterol levels and HDL to low-density lipoprotein (LDL) cholesterol ratio [20]. In another randomised study in men and women, however, no significant effect of calcium supplements (1,000–2,000 mg) was seen on total cholesterol or HDL cholesterol [21]. It is unclear, therefore, if and to what extent calcium determines lipid profile.

Reduced body weight has been implicated as well. Several large epidemiological studies have suggested that dietary calcium intake and calcium supplements may be associated with weight loss [22, 23], an effect that might be mediated by the same mechanisms affecting lipid profile [23]. However, several systematic reviews of randomised controlled trials argued against an inverse relationship between calcium (both dietary intake and supplements) and body weight [24–26], suggesting that any conclusions are preliminary and that the implications of calcium intake for body weight remain to be clarified.

Calcium supplements potentially associated with an increase in cardiovascular risk

Whereas spontaneous calcium intake, up to 800 mg/day, was not related to any cardiovascular deleterious effects, the cardiovascular safety of calcium supplements has been questioned. Rather than having a neutral or even beneficial effect, increased exposure to calcium might actually increase cardiovascular risk. In a meta-analysis published in 2010 by Bolland and colleagues in the British Medical Journal, more than 12,000 individuals from 15 double-blind placebocontrolled randomised trials were enrolled, and an increase in the incidence of myocardial infarction of about 30 % was seen in individuals on calcium supplements (≥ 500 mg daily) compared to those on placebo [27]. More specifically, the analysis of patient level data showed that the relative risk of incident myocardial infarction in individuals allocated to calcium increased by 31 % (HR 1.31, 95% CI 1.02 to 1.67) and trial level analysis showed a similar increase in risk by 27 % (HR 1.27, 95% CI 1.01 to 1.59). However, no significant increase was observed in the incidence of a number of related vascular endpoints, including the incidence of stroke (HR 1.20, 95% CI 0.96 to 1.50), death (HR 1.09, 95% CI 0.96 to 1.23) and the composite end point of myocardial infarction, stroke and sudden death (HR 1.18, 95% CI 1.00 to 1.39).

The findings of this meta-analysis were partly driven by a previous randomised placebo-controlled trial from the same group that contributed 17 % to the overall weight [28]. In this trial, calcium supplements were associated with a significant increase in HDL cholesterol levels but, nevertheless, also an increase in the risk of myocardial infarction [20, 28]. The authors postulated that calcium supplements may acutely elevate serum calcium levels [29] and, as a result, may enhance vascular calcification [28]. In fact, in a number of observational studies, high serum calcium levels have been associated with vascular calcification and an increased risk of vascular events, including myocardial infarction, stroke and death [30, 31]. Further support for a potentially deleterious effect of an acute increase in serum calcium comes from the observation that, in the meta-analysis, dietary intake was not associated with myocardial infarction, in line with observations that calcium from dairy products hardly affects serum calcium levels [27].

Whilst the meta-analysis of Bolland and colleagues should be interpreted as a strong signal that calcium supplements (without vitamin D) may potentially increase the risk of myocardial infarction, several limitations and even inconsistencies should be taken into account as well. First, the statistical outcome was only borderline significant (HR 1.31, 95% CI 1.02 to 1.67; p00.035), with a broad 95% confidence interval that approached 1 in the lower limit, suggesting that the findings have to be interpreted with caution. Also, the studies included in the analysis had been designed to assess the effects of calcium on bone density and fracture risk. None of the included trials had cardiovascular outcomes as primary or even secondary endpoint. As a result, cardiovascular events had not been adjudicated in a standardized manner, which may have resulted in over- or underreporting. Third, whilst the meta-analysis provided evidence for an increased risk of myocardial infarction, no increase was observed in the incidence of stroke, death or the composite end point of myocardial infarction, stroke and sudden death. In addition, trials that combined calcium and vitamin D supplements, the recommend strategy to prevent fractures in most elderly individuals, were excluded. In this context, it should be noted that a number of large-scale studies of calcium combined with vitamin D did not document an increase in cardiovascular risk [32, 33]. It is possible but not known if correction of vitamin D deficiency might counteract any potential detrimental vascular effect of calcium supplements [34, 35]. Finally, with the exception of the relatively small-sized trial from the same group [28], individual trials with calcium supplements did not show a significant increase in cardiovascular risk. In fact, a recent randomised placebo-controlled trial by Lewis et al., not included in the meta-analysis, did not find a higher risk of death or first-time hospitalization from atherosclerotic vascular disease in patients on calcium supplements [36]. A subset analysis even suggested a cardioprotective effect of calcium supplements in patients with pre-existing cardiovascular diseases. Nevertheless, the meta-analysis by Bolland et al. should be taken seriously, not as conclusive evidence but as a significant safety signal. Future studies with calcium should be designed to include careful assessment of cardiovascular endpoints, preferably by independent and blinded adjudication.

Calcium and cancer risk

There is also much controversy about the effect of calcium on the risk of cancer, with observational studies showing no effect, a protective effect or even an increased cancer risk [37]. Because the topic is diverse and the findings inconsistent, this section will only briefly discuss the association between calcium exposure and colorectal cancer, breast cancer and prostate cancer, since these have received most attention in recent years [9].

Whilst several observational studies concluded that calcium intake does not affect the risk of colorectal cancer [38], a number of cohort studies did find evidence for a protective effect of high total calcium intake (dietary intake plus supplements) [37, 39, 40]. In one of the main studies, a NIH-funded 7-year prospective trial in 293,907 men and 198,903 women aged 50 to 71 years, the risk reduction for colorectal cancer in the highest compared to the lowest quintile of total calcium intake was 0.79 (95% CI 0.70 to 0.89) in men and 0.72 (95% CI 0.61 to 0.86) in women [37]. Moreover, in a meta-analysis of randomised controlled trials in patients with previously removed colorectal adenomas and randomly assigned to calcium (1,200, 1,600 or 2,000 mg) or placebo, calcium supplements were significantly associated with a reduction in the risk of recurrent adenomas, considered as the precursors of colorectal cancer [41]. In line with these findings, the American College of Gastroenterology recommends daily dietary supplementation with 3 g calcium carbonate (1,200 mg calcium) in the prevention of recurrent colorectal adenomas [42].

Despite these data from observational studies and adenoma prevention trials, it is still uncertain if calcium supplements prevent colorectal cancer because large-scale long-term randomised controlled trials are not available. The only major randomised placebo-controlled study, the Women’s Health Initiative (WHI) trial in 36,282 postmenopausal women, found no effect of daily supplementation with 1,000 mg calcium and 400 IU of vitamin D for 7 years on colorectal cancer risk [43]. A Cochrane review concluded that there is not sufficient evidence to currently recommend the general use of calcium supplements in the prevention of colorectal cancer and that more research is needed [44].

The relationship between calcium exposure and breast cancer is not clear either. Some observational studies in premenopausal women found an inverse relationship between calcium intake and breast cancer [45–47], but some did not [37, 48]. Similarly, in trials in postmenopausal women, a protective effect has been reported [47], but most studies were negative [37, 45, 46, 48]. If and to what extent the source of calcium intake (dietary intake versus supplements) plays any role is not known [48]. Overall, an independent effect of calcium on the incidence of breast cancer remains uncertain.

In men, epidemiological studies have suggested that a higher total intake of calcium might be associated with an increased risk of developing prostate cancer. In these studies, total intake of calcium varied from more than 1,500 mg to more than 2,000 mg/day [49–51]. Calcium could potentially suppress the active form of vitamin D (1,25-OH2-D3), known to have an antiproliferative effect on prostate cancer cells [50, 52]. However, other studies could not confirm this association and found no or only a weak relationship between calcium intake and prostate risk [37, 53–55], even at very high intakes of calcium [37, 54]. As with colon cancer and breast cancer, conclusive evidence is lacking and more studies are required.

Calcium and the risk of kidney stones

Since most kidney stones are composed of calcium oxalate, an association with calcium intake is a theoretical concern. In the prospective Nurses’ Health Study, women who took supplemental calcium (1 to ≥ 500 mg/day) had a small but significant increase in the risk of incident symptomatic kidney stones (RR 1.20, 95% CI 1.02–1.41) compared to those who did not take supplements [56]. Women in the highest quintile of dietary calcium intake (median calcium 1,303 mg/day had, however, a lower risk (RR 0.65, 95% CI 0.50–0.83) compared to those in the lowest quintile (median calcium 391 mg/day). Other trials also showed a slightly increased risk of kidney stones in individuals on supplemental calcium (1,000 mg/day) [32] and a lower risk in individuals on a diet rich in calcium [57, 58].

The lower incidence of kidney stones in individuals on high dietary calcium intake is likely due to binding of dietary calcium with dietary oxalate in the gut, with reduced intestinal absorption and urinary excretion of oxalate. Calcium supplements, on the other hand, do not bind dietary oxalate when taken without meals. A combination of maintained oxalate excretion and increased calcium absorption and excretion from supplements increases the risk of stone formation [59].

In addition to beneficial musculoskeletal effects, especially when combined with vitamin D, calcium supplements have been suggested to protect against colorectal and breast cancer and to reduce some vascular risk factors. At the same time, safety questions have been raised about the role of calcium supplements in potentially increasing cardiovascular events, prostate cancer and kidney stones. Whilst these safety concerns have to be taken seriously, currently available evidence is not conclusive. In future research, priority should be given to well-designed long-term studies to assess cardiovascular and other safety endpoints.

To be continued