Drugs (2020) 80:1537–1552 https://doi.org/10.1007/s40265-020-01364-2 REVIEW ARTICLE Assessment of Cardiovascular Safety of Anti‑Osteoporosis Drugs N. R. Fuggle1 · C. Cooper1,2 · N. C. Harvey1 · N. Al‑Daghri3 · M.‑L. Brandi4 · O. Bruyere5 · A. Cano6 · E. M. Dennison1 · A. Diez‑Perez7,8 · J.‑M. Kaufman9 · S. Palacios10 · D. Prieto‑Alhambra11 · S. Rozenberg12 · T. Thomas13 · F. Tremollieres14 · R. Rizzoli15 · J. A. Kanis16,17 · J. Y. Reginster3,5,18 Published online: 28 July 2020 © The Author(s) 2020 Abstract The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanis- tic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associ- ated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphos- phonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital. 1 Introduction Key Points Osteoporosis is characterised by a reduction in bone min- Osteoporosis and cardiovascular disease are the potential eral density and an increased risk of fractures. As with consequences of shared mechanisms. cardiovascular disease, the prevalence increases in older Anti-osteoporosis medications are associated with poten- age so that osteoporosis and cardiovascular disease (and tial increases in cardiac risk (romosozumab, calcium cardiovascular risk factors) often coexist in the same supplementation, menopausal hormonal therapy), no patient. Given the age group of patients with osteoporosis effect on cardiac risk (vitamin D) or reduced cardiac risk [1], the occurrence of cardiovascular morbidity is a sig- (bisphosphonates). nificant consideration. Any interventions associated with an increased cardiovascular risk should be identified and Selective estrogen receptor modulators, such as ralox- clear guidance provided on their prescription to maximise ifene, and menopausal hormonal therapy are associated the benefit–risk of any potential therapy. We are therefore with increased risk of venous thromboembolic disease. left with a central question, namely, “To what extent are Romosozumab therapy is contra-indicated in those with the available drug therapies for osteoporosis associated a history of myocardial infarction or ischaemic stroke. with cardiovascular adverse events?” In order to answer this question, an expert working group was convened by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Dis- * C. Cooper orders (ESCEO) and by the International Osteoporosis cc@mrc.soton.ac.uk Foundation (IOF). The available evidence was reviewed Extended author information available on the last page of the article Vol.:(0123456789) 1538 N. R. Fuggle et al. on calcium supplements, vitamin D replacement, meno- coronary syndromes’. Thirdly, in this study, cardiovascular pausal hormone therapy (MHT), selective estrogen recep- events were self-reported and then adjudicated via health tor modulators (SERMs), bisphosphonates, denosumab, records, which could introduce reporting bias. The adjudica- parathyroid hormone (PTH) analogues and romosozumab. tion reduced the effect size of the risk of MI, with the lower band of the 95% CI dropping to 1.01, bordering significance. These issues, together with the evidence from the Women’s Health Initiative (WHI) trial of calcium and vitamin D, 2 Calcium Supplementation which found no adverse effect signal (MI/coronary death HR 1.04, 95% CI 0.92–1.18; stroke HR 0.95, 95% CI 0.82–1.10) Inadequate calcium consumption is associated with an [5], made it difficult to interpret the cardiovascular effect of increased risk of fragility fracture and deterioration in calcium supplementation, and warranted further examina- bone mineral density [2]. Therefore calcium supplements tion through data assimilation. can be beneficial for bone health. However, high con- Fifteen calcium trials were meta-analysed, and a signifi- sumption of calcium could theoretically lead to arterial cantly increased risk of MI was observed (HR 1.27, 95% and soft tissue calcification, the development of athero- CI 1.01–1.59), although there was no excess risk of stroke, sclerotic plaques and cardiovascular morbidity. Although death or the composite endpoint in the trial-level data [6]. considerable current research has suggested a relation- However, in individual patient-level analyses, there was an ship between pharmacological calcium supplementation interaction between treatment and dietary calcium intake and the risk of heart disease, critical evaluation of this when the outcome of interest was MI. This interaction was literature suggests that the observed associations may not observed in the patients with a spontaneous calcium intake be of clinical relevance. above, but not below, the median. Thus, clarity was sought Safety events can be mislabelled. This was the case in through further interrogation of the WHI calcium trial a 2006 randomised, placebo-controlled trial of calcium dataset in a meta-analysis together with seven other stud- supplementation in osteoporosis, in which the incidence of ies [7] to distil out the effect of personal supplementation ischaemic heart disease (IHD) in the calcium supplemen- alongside calcium supplementation. In those patients who tation group was not significantly different to that in the were not taking over-the-counter calcium or vitamin D sup- placebo group (7.7% vs 7.0%, hazard ratio [HR] 1.12, 95% plements, there was a 13% increase in the risk of cardio- confidence interval [CI] 0.77–1.64). This was despite the vascular events in those in the calcium arm (HRs from 1.13 fact that gastrointestinal adverse events were misclassified to 1.22, p values ranging from 0.04 to 0.05) [7]. However, as IHD, which would potentially lead to exaggeration of those who were taking over-the-counter supplements at the the effect of calcium supplementation on cardiovascular time of the study were at no increased risk of cardiovas- health [3]. However, randomised placebo-controlled trials cular events. Calcium or calcium and vitamin D increased have often been powered to address the primary outcome the risk of MI (HR 1.24, 95% CI 1.07–1.45) and the com- (change in bone density or fracture), rather than cardio- posite of MI or stroke (HR 1.15, 95% CI 1.03–1.27). The vascular safety. This focus serves to limit the assessment authors concluded that there was an increased risk of MI of safety-associated endpoints. and stroke due to calcium supplementation and that this In order to address this issue, Bolland et al. performed had been “obscured” in the previous WHI study by the the Auckland Calcium Trial, which compared calcium (1 g use of personal calcium and vitamin D supplements. There of elemental calcium as citrate salt daily) versus placebo in are a few caveats to this assertion [8]. Firstly, if Bonfer- 730 women over 60 months and focused on cardiovascular roni correction had been performed, the association with health as the primary outcome [4]. The results showed that MI and stroke would be non-significant. Secondly, there there was an increased risk of myocardial infarction (MI) in was no evidence of a dose effect if supplementation was the calcium group (risk ratio [RR] 2.24, 95% CI 1.20–4.17). assessed in fifths of supplement intake. Thirdly, this was This was very much the ‘index finding’ in the investiga- not a true time-to-event analysis, with more than one event tion of calcium supplementation and cardiac risk, but there allowed to count in one patient. Fourthly, the safety data are several important issues to note. Firstly, the baseline were recorded in a heterogeneous fashion depending on cardiovascular status of the calcium and placebo groups the study and, as has been said previously, were not pri- was different, with the calcium group having a greater bur- mary endpoints of the trials. These caveats are significant den of cardiovascular disease than the placebo group. Sec- and numerous enough to call into question the findings of ondly, there was a trend towards a reduced risk of angina the above analysis, and these findings are contradicted by in the calcium group (RR 0.71, 95% CI 0.50–1.01), which re-analyses and further follow-up of the WHI dataset, the is puzzling, considering that both MI and angina can (in results of more recent meta-analyses and by large obser- the case of unstable angina) sit under the bracket of ‘acute vational studies. Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1539 Indeed a study by Prentice et al. re-examined the effect of calcium and vitamin D supplementation in the WHI clinical trial and observational study, with a specific focus on frac- tures, cardiovascular disease, cancer and all-cause mortality [9] and the duration of therapy. They found no associations with risks of cardiovascular disease, including MI, coronary heart disease, total heart disease or stroke. In support of this finding, at 5 years of follow-up, no significant associations were observed with any cardiovascular disease outcomes (Fig. 1) [10]. Due to the emergence of new data since the meta-analy- sis by Bolland et al. [6], an updated meta-analysis was per- formed in 2015 by Lewis et al. [11] particularly examining randomised controlled trial data comparing calcium (and vitamin D) supplements to non-treatment or placebo controls and limiting their analyses to females alone. They included 18 studies, with a total of 63,563 participants with 3390 coronary heart disease events and 4157 deaths, and found no associations between primary outcomes (coronary heart Fig. 1  Results taken from the Women’s Health Initiative (WHI) trial disease and mortality) or secondary outcomes (acute MI, of calcium and vitamin D (CaD) showing the cumulative hazard of angina and chronic coronary heart disease). coronary heart disease (CHD) against time. Intervention (left) and Further observational studies have found no increased post-intervention (right) follow-up are depicted. There was no sig- nificant difference in the rates of CHD between the CaD and placebo cardiovascular risk with calcium supplementation. A study arms [10] using the UK Biobank (a cohort of 500,000 men and women in the UK, aged 40–69 years at baseline) showed incident cardiovascular disease in the 10.6% of women and 2.6% of There appears to be no convincing signal for cardiovascu- men who took calcium supplements [12]. Subsets of patients lar disease due to calcium [9, 10], even when taken without on calcium supplements alone were compared to those on concurrent vitamin D supplementation. Moreover, although calcium and vitamin D, and no effect was observed in the the theory of increased calcium deposition within blood ves- incidence of MI, IHD or any cardiovascular outcomes over sels exists, there are no data available that provide chemi- the 5–10 years of follow-up. Within such observational cal evidence of this effect [8, 15]. Indeed, calcium intake, studies, there are potential epidemiological issues, includ- whether from supplementation or directly from diet, reduces ing confounding by indication, time-varying confounding, blood pressure [16], improves lipid profile [17] and leads to depletion of susceptible subjects and over-the-counter use of transient increases in extracellular and serum calcium and calcium and vitamin D, which is common in the UK. One thence a short-lived decrease in PTH [18], none of which explanation for the apparent confusion in this area may be are overtly deleterious to the cardiovascular system. Indeed in the definition of cardiovascular events. However, even a the blood pressure and lipid effects may well be beneficial. large study including coronary artery computed tomography To conclude, calcium supplements and oral calcium (CT) scans and a mean of 7 years of supplements in ~ 750 intake of 1000 mg daily appear to reduce fracture risk, par- women (aged 50–59 at baseline) demonstrated no associa- ticularly in institutionalised compared to community-dwell- tion [13]. ing individuals, but there is no evidence for cardiovascular The most recent meta-analysis at the time of writing was adverse events [9]. There is uncertainty regarding the cardio- performed in 2019 by Yang et al. Their meta-analysis of 42 vascular risk of a high daily intake of calcium (in excess of studies (26 prospective cohort studies and 16 randomised 1200–1500 mg daily). However, given that higher intakes do controlled trials) of calcium intake, in which cardiovascular not have a proven skeletal benefit, excessive calcium intake disease outcomes were recorded, showed that dietary cal- should be avoided in any case. cium intake of up to 1500 mg/day had no significant effect on the risk of cardiovascular disease as a whole or on stroke in isolation [14]. However, there was an 8% increased risk 3 Vitamin D when MI was examined alone (RR 1.08, 95% CI 1.02–1.15). It should be noted that none of the contributing relative risks Cholecalciferol ­(D3) (referred to here as vitamin D unless on a study level were significant and the majority of studies otherwise stated) has a plethora of functions, with vitamin D were observational, representing a lower quality of evidence. receptors found in nearly all the tissues of the human body. 1540 N. R. Fuggle et al. In the cardiovascular system, vitamin D has effects on the (ViDA) study in New Zealand included about 5000 par- vascular wall, renin-angiotensin system and cardiac muscle. ticipants (aged 65.9 years, 41.9% women) who were ran- In the context of osteoporosis, current guidance recom- domised to vitamin D ­ 3, 100,000 IU per month (including mends vitamin D replacement of 800 international units a 200,000 IU loading dose at baseline) and followed up for (IU) daily in postmenopausal women at an increased risk 3.3 years. Vitamin D did not protect against cardiovascular of fragility fracture, those at an increased risk of vitamin D disease [28], but vitamin D supplementation improved arte- deficiency and those symptomatic of low vitamin D [19]. rial function in those with vitamin D deficiency. There are safety issues associated with both an excess The most recent meta-analysis investigating the effect and a deficiency of vitamin D. Overloading with unusually of vitamin D supplementation on cardiovascular disease high doses of vitamin D can precipitate hypercalcaemia and included 21 randomised controlled trials (including VIDA hypercalciuria. High extracellular calcium concentration in and VITAL), with more than 83,000 individuals, and, once the context of primary hyperparathyroidism or vitamin D again, found that vitamin D supplementation did not confer overdose-dependent prolonged hypercalcaemia, vitamin D cardiovascular protection [29]. It should be noted that many toxicity or any other cause of prolonged hypercalcaemia is of these individuals were healthy and not osteoporotic. associated with arrhythmias (including ventricular prema- In conclusion, at the usual dosages of vitamin D (800 IU ture beats, PR interval prolongation, shortening of the QT daily) used to prevent vitamin D deficiency in patients with and broadening of the QRS complex) and calcification (of osteoporosis [30], there is no evidence for increased cardio- the arterial wall and soft tissues, including the myocardium) vascular events. Findings of a protective effect are largely [20, 21]. There are observational data from Scandinavian from observational datasets, and these have not been borne registries [22], supported by murine studies [23], that sug- out in randomised controlled trials with cardiovascular dis- gest a reverse J-shaped association between cardiovascular ease as the primary or co-primary outcome or in Mendelian risk and serum 25-hydroxy vitamin D levels, with increased randomisation studies. The association between low vitamin cardiovascular risk with lower (12.5 nmol/L) and higher D and cardiovascular disease may therefore be an epiphe- (125 nmol/L) extremes. nomenon or potentially be due to differences in reference However, a 3-year randomised controlled trial of high-dose ranges [31]. vitamin D (up to 10,000 IU per day over 3 years) demonstrated no difference in tibial arterial calcification [24]. On the other hand, a meta-analysis of observational data has shown that 4 Menopausal Hormonal Therapy if a patient is vitamin D deficient, insufficient or inadequate there is an increased risk of cardiovascular adverse events [25]. Current evidence suggests that MHT is an effective therapy Whether this is a causal association remains in question, as for fracture prevention in the early menopause, with reduc- the same finding has not been borne out in Mendelian ran- tions in hip and vertebral fractures [32]. domisation [25]. A participant-level meta-analysis of vitamin The postmenopausal state is inherently associated with D intervention studies for cardio-metabolic outcomes found a greater risk of cardiovascular disease than the pre-meno- no effect of vitamin D on systolic blood pressure or glycated pausal state. This was observed in women aged 40–50 years haemoglobin (HbA1c), although there was a reduction in at the advent of the Framingham cohort with a higher inci- low-density lipoprotein cholesterol of − 0.10 mmol/L (95% dence of coronary heart disease and cardiovascular events CI − 0.20 to − 0.00), − 0.10 mmol/L (95% CI − 0.18 to − 0.02) [33–35]. and − 0.07 mmol/L (95% CI − 0.14 to − 0.00) for subgroups It is important to understand the history and chronology with < 75, < 100 and < 125 mmol serum levels of vitamin D, of the investigation of cardiovascular disease and MHT, respectively [26]. which can be divided into four phases. Data from the UK Biobank suggest that there is no asso- The first phase (pre-2002) was characterised by the sup- ciation between calcium and vitamin D supplementation and position that the benefits of MHT outweighed the risks, and incident ischaemic cardiovascular events or death [12]. it was widely used for prevention and treatment of menopau- The Vitamin D and Omega-3 Trial (VITAL) randomised sal symptoms. It was therefore one of the most prescribed over 25,000 individuals (mean age 67 years, 50.6% women) medications at the time, peaking in 2001, with 40% of post- who received either 2000 IU per day of vitamin D or placebo menopausal women using MHT [36, 37]. Observational (and either omega-3 supplementation or placebo). Partici- studies of the time suggested a potential benefit to cardiac pants were followed up for a median of 5.3 years. Investiga- health (with up to a 50% reduction in coronary heart dis- tors found that there was no association between cardiovas- ease). However, more recently, these studies have been heav- cular disease and vitamin D supplementation [27]. ily criticised due to methodological flaws [38]. However, vitamin D supplementation does not appear to The second phase was marked in 2002 by the publication prevent cardiovascular disease. The Vitamin D Assessment of data from the WHI. This study included postmenopausal Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1541 females aged 50–79 who had taken MHT for a mean of When all women taking MHT were analysed together, 5.2 years. Those women with an intact uterus (n = 16,608) regardless of hormonal constituents of MHT, the absolute were randomised to placebo or combination MHT (conju- risk of all cardiovascular adverse events was low in the gated equine estrogens [CEE] and medroxy-progesterone youngest group (50–59 years) (absolute excess risk − 6 per acetate [MPA]) due to the risks of endometrial cancer asso- 10,000 person-years), but higher in the 70–79 years age ciated with unopposed estrogen use. Those in the combi- subset (absolute excess risk 17 per 10,000 person-years) nation MHT arm had an increased risk of coronary heart [47]. The risk of stroke did not vary significantly with age, disease (HR 1.29, 95% CI 1.02–1.63), stroke (HR 1.41, 95% although it was increased in those patients taking hormone CI 1.07–1.85) and pulmonary embolism (HR 2.13, 95% CI therapy (HR 1.32, 95% CI 1.12–1.56). 1.39–3.25) [39]. Those who had undergone hysterectomy These findings had two main effects. Firstly, it shifted the (n = 10,739) were randomised to placebo or CEE alone. adverse effects of concern away from coronary heart disease In the CEE-only arm, an increased risk of stroke only was and towards thromboembolic disease (comprising VTE and observed (HR 1.39, 95% CI 1.10–1.77) [39]. This signal embolic stroke) [48]. Secondly, it spawned the concept of a of increased cardiovascular and thromboembolic risk with window of opportunity in which to use MHT, which became combination MHT and increased risk of stroke with both a theory named the ‘Timing Hypothesis’. This hypothesis combination and CEE-only MHT prompted a statement was also supported by non-human primate randomised con- that MHT led to an increased risk of cardiovascular disease trolled trials, which found that estrogen replacement reduced “irrespective of age, ethnicity or health” and was followed atherosclerosis if provided soon after ovariectomy (though by a wave of research into the safety of MHT. The usage of not if commenced years later) [49]. MHT was significantly affected, with reduced use of oral The development of atherosclerotic plaques is known formulations [40] and an increase in transdermal MHT [41]. to increase with increasing age, and it may well be that Nevertheless, it should be acknowledged that the previous the delivery of MHT to those with established atheroscle- observational studies were in younger participants, who rotic disease, predominantly after the age of 60 years, may largely had menopausal symptoms, which the majority in not have the same protective effects against the develop- the WHI study did not, and the age of the WHI participants ment of plaques as in younger women under the age of was older than the mean age of menopause in Europe or 60, or within 10 years of the menopause. Indeed, with the North America, 51 years [37]. advance of atherosclerotic plaques, there is a loss of estro- It is therefore appropriate that the third phase of MHT gen receptor expression (ERα and ERβ) in the vasculature, investigation was marked by analysis of the age-stratified which leads to a loss of estrogen-related vasculoprotection data (into age ranges of 50–59, 60–69 and 70–79 years) and an increase in the pro-inflammatory effects of exoge- from the WHI study [41], which led to some interesting and nous estrogens, which could lead to worsening of vasculo- practice-influencing findings. In the original WHI study, pathology [49, 50]. There is therefore a possible biochemi- 16,608 participants received combined MHT. Women in cal and histopathological mechanism behind the ‘Timing their 70s had an increased absolute risk of coronary heart Hypothesis’, and it was further investigated through two disease, venous thromboembolism (VTE) and stroke com- randomised controlled trials: the Kronos Early Estrogen pared to women in their 50s [42–44]. Women in their 60s Prevention Study (KEEPS) [51] and Early Versus Late had an increased risk of VTE and stroke (though not coro- Intervention Trial With Estradiol (ELITE) [52]. KEEPS nary heart disease) compared to women in the youngest age found a mixed effect on biomarkers of cardiovascular risk, group, and the highest cardiovascular event risk was for but no detectable effect of MHT (oral and transdermal VTE, which increased with increasing age [42]. The results estrogens combined with oral progesterone vs placebo) on for the 50–59 years age group (or for those less than 10 years either the advancement or retardation of atherosclerotic since the menopause) can be seen in Fig. 2, which shows progression (as measured by carotid artery intima-media an increased risk of VTE and stroke, but apparent benefit thickness) in ‘recently menopausal’ women [51]. ELITE regarding coronary artery disease and overall mortality. randomised 643 healthy women to oral 17β-estradiol and In the unopposed estrogen group (n = 10,739), younger progesterone vaginal gel or placebo, stratified according women (aged 50–59 years) were at a low absolute risk of to time since the menopause. Again, using carotid artery all adverse events, although the highest risk was associated intima-media thickness, they found no significant differ- with VTE, which, similar to the findings of the combined ence between MHT and placebo in those > 10 years since MHT group, increased with increasing age [45, 46]. The the menopause, but a significantly lower carotid intima- highest absolute risk of a cardiovascular adverse event was media thickness (CIMT) change in those on MHT com- associated with thrombotic (ischaemic) stroke in the 60–69 pared to placebo in those < 6 years since the menopause and 70–79 years age groups [46]. [52]. This supports the ‘Timing Hypothesis’ and suggests 1542 N. R. Fuggle et al. Fig. 2  The risk–benefit profile for estrogenic and combined menopausal hormone therapy in numbers of women (aged 50–59 years, or less than 10 years since the menopause) per 1000 per 5 years of use. Looking specifically at the cardiovascular risks, risks of venous thromboembolism and stroke are increased through the use of both combined and estro- gen-only formulations, although there appears to be a protective effect on coronary heart disease and overall mortality [48] that a window of opportunity for the use of MHT exists in that interventions should be withheld whilst further informa- those < 10 years since the menopause. tion is gathered. This is relevant when considering the initial findings of The benefit/risk balance for MHT is most favourable in the WHI study, in which the participants were typically over younger, recently postmenopausal women [58, 59] (those the age of 60 years [39]. This would place the participants in who are less than 60 years old or within 10 years of the onset an older age category when, potentially, atherosclerotic dis- of the menopause), in the context of menopausal symptoms ease is already more advanced and the advantages of MHT, and low baseline risk of breast cancer, cardiovascular and in a cardiovascular respect, are lost. cerebrovascular events and venous thromboembolic disease Regarding stroke, the risk of ischaemic stroke with MHT [59, 60]. MHT reduces fracture risk in populations unse- may be solely related to oral route of administration, with lected for low bone mineral density, but the evidence for lower oral doses associated with lower risk and transdermal long-term persisting benefits after cessation of treatment administration associated with low risk or no risk at all [53, is limited [39, 58]. International guidance on MHT varies, 54]. with a global consensus statement in 2016 recommend- Considering VTE, observational studies and possible ing that MHT could be commenced for women aged less biological mechanisms suggest a lower risk of VTE with than 60 years (or within 10 years of the menopause) for low-dose transdermal therapy [55] and some progestogens the reduction of fracture risk, whereas other guidelines have (MPA, norpregnane derivatives and continuous combined suggested that a reduction in fracture should be viewed as an regimens) may be associated with a greater risk of VTE additional benefit in the context of treatment of menopausal in oral MHT users [53]. The risk of VTE may therefore be symptoms [59, 61]. Although transdermal preparations are affected by the estrogenic route of administration, the dosage associated with a lower risk of VTE, any beneficial effects of progestogen and the type of progestogen used [48, 56]. on fracture risk are yet to be proven [59]. Indeed, the effect of progestogens depends on their down- In conclusion, while guidelines differ in the approach stream mineralocorticoid and androgenic effects. to skeletal health as a primary treatment indication, there The fourth phase is characterised by reflections on the is a general consensus that MHT has an important role in story of MHT thus far, which has been aptly expressed in younger, recently postmenopausal women with low base- the following statement by Manson et al: “The reluctance to line risk of breast cancer, cardiovascular and cerebrovascular treat menopausal symptoms has derailed and fragmented the events and venous thromboembolic disease for the treatment clinical care of midlife women, creating a large and unneces- of menopausal symptoms, in which context, its positive sary burden of suffering” [57]. This is a sobering thought, effects on bone health are an additional and welcome benefit. although when safety concerns exist, it is absolutely right Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1543 5 Tibolone coronary events over 4 years (RR 0.60, 95% CI 0.38–0.95) [69]. However, after 8 years of follow-up, there was no pro- Tibolone is a synthetic steroid with estrogenic, progesto- tective or detrimental effect of raloxifene [70]. genic and androgenic properties used primarily for the treat- In the Raloxifene for the Use of the Heart (RUTH) trial, ment of postmenopausal osteoporosis and postmenopausal there was no demonstrable cardiac benefit of raloxifene com- symptoms and was the subject of the Long-Term Interven- pared to placebo; neither was there a significant difference in tion on Fractures with Tibolone (LIFT) study, a randomised, mortality rates, cardiovascular disease or stroke [71]. How- placebo-controlled trial. Over a median 34 months of treat- ever, those in the raloxifene arm were at an increased risk ment, compared to placebo, tibolone was associated with a of fatal stroke (HR 1.49, 95% CI 1.00–2.24; absolute risk reduced risk of vertebral fracture (70 cases vs 126 cases per increase 0.7 per 1000 woman-years). A similar trend was 1000 person-years; relative hazard 0.55, 95% CI 0.41–0.74) observed with lasofoxifene (although the HR did not reach and a reduced risk of nonvertebral fracture (122 cases vs 166 significance: HR 2.39, 95% CI 0.84–6.78), potentially sup- cases per 1000 person-years; relative hazard 0.74, 95% CI porting a class effect [72]. 0.58–0.93), but an increased risk of stroke (relative hazard In conclusion, there appears to be a significant increase in 2.19, 95% CI 1.14–4.23), which led to the discontinuation the risk of VTE with SERMs, and this should guide clinical of the study by the safety board [60]. practice. There is no evidence to support the use of ralox- ifene for cardiac benefit in women at high risk for cardio- vascular disease, and there may be an increased risk of fatal 6 Selective Estrogen Receptor Modulators stroke with SERMs, but not overall strokes, cardiovascular disease or mortality rate. The major SERM used in the treatment of osteoporosis is raloxifene, although bazedoxifene (which may be combined with conjugated estrogens) and lasofoxifene (which has a 7 Bisphosphonates limited distribution in parts of Europe) are included in this drug class. When examining the cardiovascular safety of the bisphos- SERMs have potential effects on lipid profile [61], inflam- phonates, the key issues are the possible association with matory mediators [62], platelet function [63], coagulation atrial fibrillation and the potential atherosclerotic protection [61] and glucose metabolism [64], although none of these afforded by this group of anti-osteoporosis interventions. effects are consistently demonstrated in the basic scientific The cardioprotective effects of bisphosphonates are literature. Although vasodilatory effects have been observed debated [73, 74]. Animal studies in pigeons fed an ath- [65], there is no effect on blood pressure in clinical studies erogenic diet demonstrated a reduction in atherosclerotic [66]. Significant associations with cardiovascular disease plaque size and percentage with a non-nitrogen bispho- have been observed in trials and, latterly, in meta-analysis. sphonate, etidronate [75]. A study in monkeys has also One such meta-analysis demonstrated a significant demonstrated reduction in diet-induced atherosclerosis increase in the risk of venous thromboembolic disease following treatment with anti-calcifying agents, includ- (including deep venous thrombosis [DVT] and pulmonary ing bisphosphonates, independent of changes in circulating emboli [PE]) from the analysis of nine trials (24,523 post- lipid profiles [76]. menopausal women), with an increased odds of any VTE Other mechanisms for the potential cardiovascular benefit (odds ratio [OR] 1.62, 95% CI 1.25–2.09), DVT (OR 1.54, of bisphosphonates include improvement of arterial elas- 95% CI 1.13–2.11) and PE (OR 1.91, 95% CI 1.05–3.47) ticity, decrease in systemic vascular resistance and carotid [67] associated with raloxifene usage. Similar associations artery intima-media thickness [77], inhibition of the meva- are observed with lasofoxifene (with a dose-related increase lonate pathway (preventing ischaemia-induced myocardial in cumulative incidence of VTE) [68], and there was a trend remodelling and cardiac function) [78], inhibition of intra- towards an increased risk of VTE with bazedoxifene (RR vascular calcification [79] and a decrease in circulating γδ 1.56, 95% CI 0.92–2.64). The increased risk of VTE with T cells, which are known to stimulate atherosclerotic pro- SERMs is therefore supported by the current literature. gression [80]. However, with coronary artery disease, there has been more These findings from animal studies are interesting, but conjecture. it must be noted that they could be potentially due to dose The Multiple Outcomes of Raloxifene Evaluation effects, as higher doses were used in animal models than are (MORE) study was a randomised, placebo-controlled trial, utilised in clinical trials and practice. Indeed, the evidence and in a subset of women at high cardiac risk (cardiovascular discussed below pertains to the doses used in the context of risk score ≥ 4), raloxifene appeared to be protective against osteoporosis, which are lower than those employed within the context of oncology. 1544 N. R. Fuggle et al. The present analysis concerns doses used in the treat- The connection between bisphosphonates and arrhythmia ment of osteoporosis. Regarding the mortality and morbidity has an equally mixed picture. Early analysis of the safety data from the early phase 3 controlled trials for risedronate, data from the HORIZON trial demonstrated a significantly there is a discernible trend towards reduced cardiovascular higher incidence of arrhythmia in the zoledronate arm (6.9% mortality, though not on overall mortality, in those treated vs 5.3% in the placebo arm, p = 0.003) and that within this with risedronate compared to placebo [81]. However, a group ‘serious atrial fibrillation’ (atrial fibrillation that closer examination reveals a more mixed picture. The rates resulted in a serious adverse event) was significantly more of cardiovascular adverse events (rather than mortality), common (1.3% vs 0.5% in the placebo arm, p < 0.001) [82]. coronary artery disease and stroke were numerically very A similar trend had been previously observed in the Frac- similar for placebo, 2.5 mg risedronate and 5 mg risedronate, ture Intervention Trial (of alendronate) [88], but although with no significant difference seen. When focussing on any the cumulative incidence of serious atrial fibrillation had cardiovascular mortality, the protective effect of risedronate numerically increased with alendronate, the rise had not was only observed in the 2.5-mg group (RR 0.69, 95% CI been statistically significant. 0.49–0.99) and not in those taking 5 mg (RR 0.84, 95% CI Further studies sought to investigate this association, 0.60–1.17). A similar picture was seen with stroke mortality with conflicting findings. A case–controlled study from a for the 2.5-mg (RR 0.36, 95% CI 0.17–0.78) and 5-mg (RR healthcare database in the USA found that a greater num- 0.64, 95% CI 0.34–1.20) groups. There was no protective ber of atrial fibrillation case patients than controls had ever effect observed for mortality from coronary artery disease, used alendronate (6.5% vs 4.1%, p = 0.03) and that when which, given the proposed biological mechanisms for bis- comparing ever-users (of bisphosphonates) to never-users, phosphonate cardiovascular protection, would be suspected the ever-users had a higher risk of incident atrial fibrillation to be the most amenable pathology to treatment. (OR 1.86, 95% CI 1.09–3.15) [89]. However, a European Zoledronic acid was the subject of the Health Outcomes population-based, case–control study (comparing ~ 13,500 and Reduced Incidence with Zoledronic Acid Once Yearly patients with atrial fibrillation or flutter to ~ 68,000 controls) (HORIZON) trial [82], which found similar rates of cardio- found no evidence of increased risk of arrhythmia with bis- vascular events and stroke, although there was a reduction phosphonates [90]. This finding was supported by another of 28% in all-cause mortality in the zoledronic acid group European case–control, register-based cohort study, which (9.8% mortality vs 13.3% mortality, p = 0.01) [83]. In the found that the highest risk of atrial fibrillation was in the Fracture Prevention with Zoledronate in Older Women with subgroup of patients who only received the bisphosphonates Osteopenia trial [84] (in osteopenic rather than osteoporotic once and the longer the patient was adherent to bisphospho- older women with an 18-month interval in zoledronic acid nates, the lower the risk of atrial fibrillation [91]. administration), the HR for MI in the zoledronic acid group An interesting hypothesis from the latter study was that was 0.60 (95% CI 0.36–1.00) and the rate ratio was 0.58 fracture patients were inherently more likely to experience (95% CI 0.35–0.94). For a pre-specified composite cardio- atrial fibrillation (compared to non-fracture controls) and vascular endpoint (sudden death, MI, coronary artery revas- more likely to receive bisphosphonates, thus confounding cularisation or stroke), the HR was 0.76 (95% CI 0.53–1.08) the association [91]. This theory was supported in the afore- and the rate ratio was 0.72 (95% CI 0.53–0.98) [85]. mentioned study of two large prospective databases, which The absence of a true cardiovascular benefit of bisphos- found that patients on bisphosphonates were inherently older phonate therapy is supported by findings from an analysis with a greater cardiovascular disease burden, thus increasing of two large (> 47,000 participants), long-term, prospective their risk of atrial fibrillation. databases in the USA, which demonstrated no statistical dif- Considering that the majority of the signal is for an ference in the long-term rates of MI or death [86]. Interest- increased risk of atrial fibrillation with bisphosphonate ingly, in this study, the patients who underwent coronary therapy came from the HORIZON trial and zoledronic acid, angiography were investigated as a high-risk subgroup and, it should be acknowledged that in the Recurrent HORIZON again, no benefit of bisphosphonate therapy was observed trial (consisting of a more elderly, infirm, post-hip frac- [86]. ture population), there was no significant increase in seri- The possible cardioprotective effects of bisphosphonates ous atrial fibrillation [83]. Neither was atrial fibrillation remain under scrutiny, and there is certainly not sufficiently increased in those on zoledronate in the PREVENTION robust, cohesive data to support a recommendation for this study (a 6-year randomised, placebo-controlled trial of 2000 class of medications to be used to treat cardiovascular dis- women) [84]. ease, or even to recommend using them to treat osteoporosis Therefore, in conclusion, there is no substantial signal for in those at high risk of MI or stroke. A recent meta-analysis the development of atrial fibrillation with bisphosphonates reported that mortality was not altered by bisphosphonate at present, though further studies examining and powered to treatment [87]. answer this exact question are warranted. Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1545 8 Denosumab 9 Parathyroid Hormone Analogues Denosumab (60 mg, every 6 months) is a fully human mono- It has long been known, initially from animal studies, that clonal antibody and inhibitor of receptor activator of nuclear PTH has chronotropic effects via receptors in cardiac myo- factor-κB (RANK) ligand, which prevents the maturation cytes and transient dilatory effects on the peripheral vascu- and activity of osteoclasts and therefore acts to reduce bone lature, leading to an increase in heart rate and reduction in resorption. There is a potential, though tenuous, link with blood pressure, respectively [94]. These effects may have cardiovascular health via RANK-ligand, RANK and oste- manifested as adverse events in the trials for the two PTH oprotegerin (OPG). OPG is found in calcifications in the analogues that are currently used in osteoporosis clinical aorta and renal arteries, and transgenic overexpression of practice: teriparatide and abaloparatide. OPG leads to inhibition of these calcified vascular lesions. The Summary of Product Characteristics for teriparatide Indeed, when an atherogenic mouse model was treated with lists nausea, headache and dizziness as potential adverse OPG, there was a significant reduction in calcified lesions. effects, which could potentially be related to the cardio- RANK-ligand itself is known to induce calcification of vas- vascular mechanisms described above from animal studies. cular smooth muscle, and the development of vascular cal- Indeed in the VERtebral Fracture Treatment Comparisons cifications depends on RANK-ligand–mediated expression in Osteoporotic Women (VERO) trial comparing teripara- of bone morphogenetic protein-2 (BMP-2) and matrix Gla tide to risedronate, there was a significantly higher inci- protein. Thus OPG could potentially inhibit the formation of dence of dizziness (teriparatide 30 [4.4%], risedronate 12 vascular calcifications by blocking RANK-ligand and there [1.8%], p = 0.007) in those taking teriparatide, but there was is thus a plausible biological mechanism for some prevention no excess incidence of cardiovascular adverse events [95]. of cardiovascular pathology when treated with denosumab. Even in post-marketing surveillance, there was no percepti- This is, however, not borne out by the evidence from ran- ble signal of increased risk of cardiovascular adverse events, domised controlled trials. as demonstrated by a Japanese, prospective, observational The Fracture Reduction Evaluation of Denosumab in study [96]. Osteoporosis Every 6 Months (FREEDOM) study was a A similar story was observed in the Abaloparatide Com- phase 3, multicentre, double-blind, placebo-controlled trial parator Trial in Vertebral Endpoints (ACTIVE) [97], which of denosumab over 3 years [92]. It included a total of 7868 included teriparatide and placebo arms. In the abaloparatide women (with 31.7% of these ≥ 75 years), and throughout this arm, discontinuation of the study drug was most commonly initial trial period, there was no significant difference in car- due to nausea (1.6%), dizziness (1.2%), headache (1.0%) and diovascular events, stroke, coronary heart disease, peripheral palpitations (0.9%). Dizziness had a higher incidence in the vascular disease or atrial fibrillation [92]. Despite the fact abaloparatide group (10.0%) than in the teriparatide group that FREEDOM was not powered to investigate mortality, (7.3%) or placebo group (6.1%). However, ‘dizziness’ is a there was a non-significant trend towards reduced mortality symptom with both potential cardiovascular and neurologi- in the denosumab group (1.8% participants in denosumab cal aetiology, and it is therefore interesting that the more car- group vs 2.3% participants in the control group, p = 0.08) diovascular endpoint of orthostatic hypotension was defined [92]. as an adverse event of special interest and was very similar In 2014, there was a further analysis of a subset of 2363 across all three arms (17.1% in the teriparatide arm, 16.4% women (1142 placebo, 1221 denosumab) from the FREE- in the placebo arm and 15.5% in the teriparatide arm) sug- DOM trial who were at high risk of cardiovascular disease gesting a lack of association. Palpitations were most com- (as defined by the RUTH criteria) [93]. In this study, aortic mon with abaloparatide (5.1%), with a lower incidence with calcification and progression was assessed using a semi- teriparatide (1.6%), and placebo being the lowest (0.4%). quantitative method from lateral spine radiographs. There There was no excess risk of MI, falls or syncope. was no significant difference in aortic calcification progres- In conclusion, animal models have demonstrated poten- sion over the 3 years of the trial between the placebo (22%) tial effects of PTH on the cardiovascular system [94], and and denosumab (22%) groups and no difference in cardio- these may lead to increased rates of dizziness [95] with PTH vascular risk across the two groups (in the high cardiovas- analogues. However, whether this increased risk is mani- cular risk population) [93]. fested via the cardiovascular system is not clear, and there In conclusion, although a plausible biological connec- is certainly no current evidence to suggest an increased risk tion exists between denosumab and cardiovascular disease, of atherosclerotic or thromboembolic cardiac disease with there is no evidence from human trials to support a positive this group of interventions. or negative effect on cardiovascular risk, at least at the dose used in osteoporosis therapy. 1546 N. R. Fuggle et al. 10 Romosozumab ovariectomised cynomolgus monkeys in response to romo- sozumab [114]. Romosozumab is a humanised monoclonal antibody, In human conditions associated with reduced activity of approved by the Food and Drug Administration (FDA) [98] sclerostin, neither van Buchem’s disease nor sclerosteosis and European Medicines Agency (EMA) [99], which inhib- demonstrate cardiovascular disease manifestations [115, its sclerostin. Sclerostin is an effective antagonist of Wnt 116], although it should be noted that a substantial propor- signalling, and thus romosozumab acts as an anabolic agent tion of homozygous individuals die in early adulthood (mean for bone formation and as an inhibitor of bone resorption. age of death 33 years) due to complications of increased Controversy exists regarding the cardiovascular safety of intracranial pressure [117], and the effect of sclerostin inhi- this drug from the point of biological plausibility, the out- bition in an older age-group may be different. comes of randomised controlled trials [100–102] and the As described above, although there are potential hypoth- output of meta-analyses [103]. Current guidance (in some eses, there is not a robust demonstration of a biological basis regions) advocates against use in those with a history of MI for cardiovascular disease related to romosozumab. and ischaemic stroke and recommends a judicious approach The FRActure study in postmenopausal woMEn with in those with a high baseline risk of cardiovascular disease osteoporosis (FRAME) was a randomised controlled trial [99, 104]. comparing romosozumab to placebo, before transitioning The arguments for the biological plausibility of adverse onto denosumab [100, 101]. In this trial, there were no cardiovascular effects of romosozumab centre on a potential observed associations between romosozumab and cardio- role in arterial calcification. Sclerostin is the product of the vascular adverse events, including major adverse cardiac SOST gene and is primarily secreted by osteocytes. It plays events (MACE) (a composite of non-fatal MI, non-fatal an important role in bone turnover by upregulating bone stroke and cardiovascular death), with an HR of 1.1 (95% CI formation and downregulating bone resorption [101, 105]. 0.7–1.7). In the FRAME extension study, the percentage of Beyond the skeleton, increased sclerostin expression has positively adjudicated adverse cardiac events did not differ been observed in smooth muscle tissue in areas of vascular significantly, with 3.6% for romosozumab and 3.5% for pla- calcification [106]. At these sites, sclerostin may act to limit cebo [118]. However, it should be noted that the participant the formation of calcified plaques [107] and confer a degree population included women with a broad range of osteopo- of cardiovascular benefit. rosis severity, rather than being focused only on those with In a murine model of increased cardiovascular risk, apoli- severe disease. poprotein E (apoE)-null mice (prone to aortic aneurysm and The Active-Controlled Fracture Study in Postmenopau- atherosclerosis) were provided with an infusion of angio- sal Women with Osteoporosis at High Risk (ARCH) [102] tensin II [108]. They were then subjected to sclerostin from compared romosozumab to alendronate, before transitioning either transgenic overexpression or exogenous recombinant onto long-term alendronate therapy. Unlike FRAME, ARCH murine sclerostin. Increased sclerostin, from either source, did focus on individuals with severe osteoporosis, and there- was found to be protective against aortic aneurysm forma- fore the participant group was older and had a higher base- tion and atherosclerosis. This was further supported by data line prevalence of cardiovascular disease and risk. from experiments in which a murine model of glucocorti- Although ARCH was designed and powered to assess effi- coid-induced osteopenia was crossed with a Sost-deficient cacy in the treatment of osteoporosis, the primary cardiac (and therefore sclerostin-deficient) mouse [109], with result- safety endpoint was serious cardiovascular adverse events ant sudden death in ~ 10% of mice. On post-mortem, histo- (composed of MACE outcomes [non-fatal MI, non-fatal pathological evidence of peracute haemopericardium and stroke and cardiovascular death] plus heart failure and non- cardiac tamponade was observed. These murine data support coronary heart disease), and this did not differ significantly the theory of a cardiovascular protective effect of sclerostin. between treatment groups (2.5% romosozumab and 1.9% This has resulted in the hypothesis that romosozumab- alendronate; HR 1.32, 95% CI 0.87–2.01, p = 0.2) [102]. induced sclerostin inhibition could modulate Wnt-β-catenin In post hoc analyses of MACE, the incidence was 2.0% in signalling [110] via a compensatory increase in expression the romosozumab group and 1.1% in the alendronate group, of Dickkopf Wnt signalling pathway inhibitor 1 (DKK1) indicating a significant preponderance for cardiovascular [111] to result in vascular calcification and destabilisation disease with romosozumab (HR 1.7, 95% CI 1.1–2.6) [99]. of atherosclerotic plaques [112]. Examining the constituent parts of MACE separately, an However, this effect of romosozumab has not been clearly increased risk of cardiovascular ischaemia was observed in demonstrated in animal models. Indeed, the administration the romosozumab group (n = 2040) compared to the alen- of romosozumab did not significantly alter DKK1 levels in dronate group (n = 2014) (OR 2.65, 95% CI 1.03–6.77) a rat model of progressive renal osteodystrophy [113] or [102]. However, there was no increased risk of cerebrovas- cular disease (OR 2.27, 95% CI 0.93–5.22) or cardiovascular Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1547 mortality (OR 1.42, 95% CI 0.68–2.97) when analysed in (1.14, 95% CI 0.85–1.53). In support, a recent meta-analysis isolation, rather than being included with cardiovascular of six trials found a 39% increased risk of 4-point MACE ischaemia in the MACE composite endpoint [102]. It is (including death, MI, stroke and cardiac failure) with romo- important to note that, in ARCH, any undisclosed cause of sozumab, which was statistically significant [103]. When death was recorded as a cardiovascular death, which may examining the cardiovascular adverse event profile of each have led to overestimation [99]. Interestingly, the incidence arm in these trials, it is important to remember that the pri- of heart failure, non-coronary revascularisation and periph- mary outcomes were efficacy rather than safety related. It is eral vascular ischaemic events not requiring revascularisa- also important to note that the results of this meta-analysis tion was lower in the romosozumab arm [102]. are driven by the results of ARCH and that the marked dif- A numerical preponderance towards cardiac adverse ferences in study populations and design make meta-analysis events was observed (as a non-primary outcome) in pla- an ineffective approach for ARCH and FRAME [99]. ceBo-contRolled study evaluatIng the efficacy anD safety of The delay in the decision regarding the benefit–risk bal- romosozumab in treatinG mEn with osteoporosis (BRIDGE) ance of romosozumab when considering cardiovascular (which examined the bone health of 170 males) [119]. Only safety is understandable. The studies undertaken in patients ten participants experienced positively adjudicated serious with a relatively mild deficit in bone mineral density (the cardiovascular adverse events, 4.9% with romosozumab and best example of which is FRAME) suggest no increase in 2.5% in the placebo group. the risk of a major cardiovascular events, but appear to have Therefore, the bulk of evidence against the cardiac safety equivocal benefits on non-spine fractures [100, 101]. How- of romosozumab comes from the ARCH trial [102]. This ever, those studies focussing on older, frail patients with has been the subject of commentaries defining the possible more severe osteoporosis and previous fracture demon- explanations for the increased risk of MACE with romo- strate marked effectiveness against recurrent fracture but an sozumab shown in this study as being due to increased car- increased risk of MACE and cardiovascular ischaemia with diac risk of romosozumab, or the decreased cardiac risk with romosozumab [102]. alendronate or the result of a chance finding [120]. Debate may continue as to the extent to which the imbal- Previously in this paper, we examined the potential car- ance in cardiovascular events and mortality represents a diovascular protective effect of bisphosphonates and con- protective effect of bisphosphonates on IHD compared to cluded that there was no robust evidence to support this sup- an adverse increase in risk attributable to romosozumab or position (particularly over the short, 12-month study period whether it is a simply a chance effect [120]. of ARCH). Indeed, there is evidence against either drug For this reason, the EMA have reasonably concluded that effect, as once participants were switched to alendronate, romosozumab can be used for postmenopausal women with there was no change in cardiovascular disease risk [99]. severe osteoporosis who are at a high risk of fracture, but Additionally, there was no apparent inflection of the slope not in those with a history of MI or stroke [121]. In those of the cumulative incidence plot of time to first occurrence individuals with a high baseline cardiovascular risk, a robust of MACE as participants switched from romosozumab to risk–benefit assessment should be performed [99]. We now alendronate [99], suggesting that there was either no change have to wait for data from pharmacovigilance studies that in the risk of MACE or that the risk of MACE accrued by have been instigated worldwide to assess this benefit–risk romosozumab was constant after the 12 months of treatment. balance in larger populations when drug use can be evalu- The ARCH population had significantly greater car- ated on a more routine clinical basis. diovascular risk factors and a greater history of previous cardiovascular events than the FRAME population, which may have implications for the safety of the drug in an older 11 Conclusions population. In addition, when all the data were considered together, there were more deaths in patients aged over In conclusion, despite past studies demonstrating an asso- 75 years given the medicine [121]. However, subgroup ciation with coronary heart disease, there are no consistent analyses from ARCH demonstrated no difference in the data to suggest an association between calcium and coro- cardiovascular risk between high- and low-risk subgroups nary artery disease, and vitamin D supplementation does not (including those aged < 75 or ≥ 75, ever or never smokers appear to be associated with increased cardiac risk. There is and use of cardiovascular disease medications at baseline) a window of opportunity until 10 years after the menopause [99]. in which to use MHT without apparent detriment regard- When all these results were meta-analysed for the asso- ing cardiovascular disease. SERMs are associated with a ciation between romosozumab and cardiovascular disease, significantly increased risk of VTE and may be associated the associations were non-significant for MACE (1.39, 95% with fatal stroke. Bisphosphonates cannot be recommended CI 0.97–2.00) and serious adverse cardiovascular events 1548 N. R. Fuggle et al. for cardiac benefit, and associations with atrial fibrillation regulation or exceeds the permitted use, you will need to obtain permis- are inconsistent. There is no evidence of adverse cardiac sion directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by-nc/4.0/. effects with denosumab or PTH analogues. The signal on cardiovascular disease adverse events with romosozumab needs post-marketing surveillance, which will be crucial in confirming cardiovascular safety. References 1. Xia W, Cooper C, Li M, et al. East meets West: current practices Compliance with Ethical Standards and policies in the management of musculoskeletal aging. Aging Clin Exp Res. 2019;31(10):1351–73. https​://doi.org/10.1007/ Funding The ESCEO Working Group was funded by the ESCEO. The s4052​0-019-01282​-8. ESCEO receives unrestricted educational grants to support its educa- 2. Chandran M, Tay D, Mithal A. Supplemental calcium intake in tional and scientific activities from non-governmental organisations, the aging individual: implications on skeletal and cardiovascu- not-for-profit organisations, non-commercial or corporate partners. lar health. Aging Clin Exp Res. 2019;31(6):765–81. https​://doi. The choice of topics, participants, content and agenda of the Working org/10.1007/s4052​0-019-01150​-5. Groups as well as the writing, editing, submission and reviewing of 3. Prince RL, Devine A, Dhaliwal SS, et al. Effects of calcium sup- the manuscript are the sole responsibility of the ESCEO, without any plementation on clinical fracture and bone structure: results of a influence from third parties. 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med. 2006;166(8):869–75. https​://doi.org/10.1001/ archi​nte.166.8.869. Conflicts of interest NRF, AC, JMK, NA, CC have nothing to disclose. 4. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in FT reports personal fees for lectures and expertise from Amgen, Ar- healthy older women receiving calcium supplementation: ran- row, Lilly France, TEVA and Theramex and non-financial support domised controlled trial. BMJ. 2008;336(7638):262–6. https​:// from Besins Healthcare France. MLB reports honoraria from Amgen, doi.org/10.1136/bmj.39440​.52575​2.BE. Bruno Farmaceutici, Calcilytix and Kyowa Kirin, academic grants 5. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementa- and/or speaker fees from Abiogen, Alexion, Amgen, Bruno Farma- tion and cardiovascular events. Circulation. 2007;115(7):846–54. ceutici, Eli Lilly, Kyowa Kirin, MSD, NPS Pharma, Servier, Shire and https​://doi.org/10.1161/circu​latio​naha.106.67349​1. Spa and consultancy work for Alexion, Bruno Farmaceutici, Kyowa 6. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supple- Kirin, Servier and Shire. SR reports advisory board participation, con- ments on risk of myocardial infarction and cardiovascular events: sultancy work, speakers’ fees and research grants from Mylan, Abbot, meta-analysis. BMJ. 2010;341:c3691. https​://doi.org/10.1136/ Amgen, Ceres and Gilead. NCH reports consultancy work and lec- bmj.c3691​. ture fees and honoraria from Alliance for Better Bone Health, Amgen, 7. Bolland MJ, Grey A, Avenell A, et al. Calcium supplements with MSD, Eli Lilly, Servier, Shire, UCB, Kyowa Kirin, Consilient Health- or without vitamin D and risk of cardiovascular events: reanaly- care, Radius Health and Internis Pharma. DPA’s research group has sis of the Women’s Health Initiative limited access dataset and received research grants from Amgen, Servier and UCB and speaker meta-analysis. BMJ. 2011;342:d2040. https​://doi.org/10.1136/ tuition fees and advisory or consultancy fees (all paid to his depart- bmj.d2040​. ment) from Amgen and UCB. TT reports personal fees for lectures and 8. Harvey NC, Biver E, Kaufman JM et al. (2017) The role of cal- expertise from Amgen, Arrow, Biogen, BMS, Chugai, Expanscience, cium supplementation in healthy musculoskeletal ageing: an Gilead, Grunenthal, LCA, Lilly, Medac, MSD, Nordic, Novartis, expert consensus meeting of the European Society for Clinical Pfizer, Sandoz, Sanofi, Theramex, Thuasne, TEVA and UCB and and Economic Aspects of Osteoporosis, Osteoarthritis and Mus- reports financial support or fees for research activities from Amgen, culoskeletal Diseases (ESCEO) and the International Foundation Bone Therapeutics, Chugai, MSD, Novartis, Pfizer and UCB. EMD for Osteoporosis (IOF). 28 (2):447-462. https​://doi.org/10.1007/ reports consultancy fees for UCB and Pfizer. JAK reports institutional s0019​8-016-3773-6. grant support from Radius Health and Amgen. JYR reports consult- 9. Prentice RL, Pettinger MB, Jackson RD, et al. Health risks and ing fees or advisory board participation for IBSA-Genevrier, Mylan, benefits from calcium and vitamin D supplementation: Women’s Radius Health and Pierre Fabre, lecturing fees for IBSA-Genevrier, Health Initiative clinical trial and cohort study. Osteoporos Int. Mylan, Cniel and Dairy Research Council (DRC) and grant support 2013;24(2):567–80. https:​ //doi.org/10.1007/s00198​ -012-2224-2. from IBSA-Genevrier, Mylan, Cniel and Radius Health. RR reports 10. Cauley JA, Chlebowski RT, Wactawski-Wende J, et al. Calcium speaker fees from Abiogen, Amgen, EMF and Sandoz and advisory plus vitamin D supplementation and health outcomes five years board fees from Echolight, Mylan, ObsEva, Rejuvenate and Theramex. after active intervention ended: the Women’s Health Initiative. OB reports grants from Biophytis, IBSA, MEDA, Servier and SMB J Women’s Health (2002). 2013;22(11):915–29. https​://doi. and personal fees from Amgen, Aptissen, Biophytis, IBSA, MEDA, org/10.1089/jwh.2013.4270. Sanofi, Servier, SMB and UCB. ADP reports speaker and advisory 11. Lewis JR, Radavelli-Bagatini S, Rejnmark L, et al. The effects fees from Amgen, Lilly, Theramex, UCB and Sandoz. of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collabora- Open Access This article is licensed under a Creative Commons Attri- tive meta-analysis of randomized controlled trials. J Bone Miner bution-NonCommercial 4.0 International License, which permits any Res. 2015;30(1):165–75. https​://doi.org/10.1002/jbmr.2311. non-commercial use, sharing, adaptation, distribution and reproduc- 12. Harvey NC, D’Angelo S, Paccou J, et al. Calcium and vitamin D tion in any medium or format, as long as you give appropriate credit supplementation are not associated with risk of incident ischemic to the original author(s) and the source, provide a link to the Creative cardiac events or death: findings from the UK Biobank Cohort. Commons licence, and indicate if changes were made. The images or J Bone Miner Res. 2018;33(5):803–11. https​://doi.org/10.1002/ other third party material in this article are included in the article’s jbmr.3375. Creative Commons licence, unless indicated otherwise in a credit line 13. Manson JE, Allison MA, Carr JJ, et al. Calcium/vitamin D sup- to the material. If material is not included in the article’s Creative plementation and coronary artery calcification in the Women’s Commons licence and your intended use is not permitted by statutory Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1549 Health Initiative. Menopause. 2010;17(4):683–91. https​://doi. Cardiol. 2019;4(8):765–75. https:​ //doi.org/10.1001/jamac​ardio​ org/10.1097/gme.0b013​e3181​d683b​5. .2019.1870. 14. Yang C, Shi X, Xia H, et al. The evidence and controversy 30. Kanis JA, Cooper C, Rizzoli R, et al. Executive summary of between dietary calcium intake and calcium supplementation and European guidance for the diagnosis and management of the risk of cardiovascular disease: a systematic review and meta- osteoporosis in postmenopausal women. Aging Clin Exp Res. analysis of cohort studies and randomized controlled trials. J Am 2019;31(1):15–7. https​://doi.org/10.1007/s4052​0-018-1109-4. Coll Nutr. 2019. https​://doi.org/10.1080/07315​724.2019.16492​ 31. Grübler MR, März W, Pilz S, et al. Vitamin-D concentrations, 19. cardiovascular risk and events—a review of epidemiological evi- 15. Heaney RP, Kopecky S, Maki KC, et al. A review of cal- dence. Rev Endocr Metab Disord. 2017;18(2):259–72. https​:// cium supplements and cardiovascular disease risk. Adv Nutr. doi.org/10.1007/s1115​4-017-9417-0. 2012;3(6):763–71. https​://doi.org/10.3945/an.112.00289​9. 32. Zhu L, Jiang X, Sun Y, et al. Effect of hormone therapy on the 16. Cormick G, Ciapponi A, Cafferata ML, et al. Calcium supple- risk of bone fractures: a systematic review and meta-analysis of mentation for prevention of primary hypertension. Cochrane randomized controlled trials. Menopause. 2016;23(4):461–70. Database Syst Rev. 2015. https​://doi.org/10.1002/14651​858. https​://doi.org/10.1097/gme.00000​00000​00051​9. cd010​037.pub2. 33. Kannel WB, Hjortland MC, McNamara PM, et al. Meno- 17. Reid IR. Effects of calcium supplementation on circulating pause and risk of cardiovascular disease: the Framingham lipids: potential pharmacoeconomic implications. Drugs Aging. study. Ann Intern Med. 1976;85(4):447–52. https ​ : //doi. 2004;21(1):7–17. https:​ //doi.org/10.2165/000025​ 12-200421​ 010- org/10.7326/0003-4819-85-4-447. 00002​. 34. Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardio- 18. Goltzman D, Mannstadt M, Marcocci C. Physiology of the vascular mortality after early bilateral oophorectomy. Menopause calcium-parathyroid hormone-vitamin D axis. Front Horm Res. (New York, NY). 2009;16(1):15–23. https​://doi.org/10.1097/ 2018;50:1–13. https​://doi.org/10.1159/00048​6060. gme.0b013​e3181​8888f​7. 19. Kanis JA, Cooper C, Rizzoli R, et al. European guidance for 35. Lisabeth LD, Beiser AS, Brown DL, et al. Age at natural meno- the diagnosis and management of osteoporosis in postmeno- pause and risk of ischemic stroke: the Framingham Heart Study. pausal women. Osteoporos Int. 2019;30(1):3–44. https​://doi. Stroke. 2009;40(4):1044–9. https​://doi.org/10.1161/STROK​ org/10.1007/s0019​8-018-4704-5. EAHA.108.54299​3. 20. Pepe J, Cipriani C, Sonato C, et al. Cardiovascular manifesta- 36. Bassuk SS, Manson JE. The Timing Hypothesis: do coronary tions of primary hyperparathyroidism: a narrative review. Eur risks of menopausal hormone therapy vary by age or time since J Endocrinol. 2017;177(6):R297–308. https​://doi.org/10.1530/ menopause onset? Metab Clin Exp. 2016;65(5):794–803. https​ EJE-17-0485. ://doi.org/10.1016/j.metab​ol.2016.01.004. 21. Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in 37. Chester RC, Kling JM, Manson JE. What the Women’s Health clinical practice. J Electrocardiol. 2010;43(5):390–5. https​://doi. Initiative has taught us about menopausal hormone therapy. Clin org/10.1016/j.jelec​troca​rd.2010.06.004. Cardiol. 2018;41(2):247–52. https​://doi.org/10.1002/clc.22891​. 22. Durup D, Jørgensen HL, Christensen J, et al. A reverse J-shaped 38. Hernán MA, Alonso A, Logan R, et al. Observational studies association between serum 25-hydroxyvitamin D and car- analyzed like randomized experiments: an application to post- diovascular disease mortality: the CopD study. J Clin Endo- menopausal hormone therapy and coronary heart disease. Epi- crinol Metab. 2015;100(6):2339–46. https​://doi.org/10.1210/ demiology (Cambridge, Mass). 2008;19(6):766–79. https​://doi. jc.2014-4551. org/10.1097/EDE.0b013​e3181​875e6​1. 23. Ellam T, Hameed A, ul Haque R, et al. Vitamin D deficiency and 39. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits exogenous vitamin D excess similarly increase diffuse atheroscle- of estrogen plus progestin in healthy postmenopausal women: rotic calcification in apolipoprotein E knockout mice. PLoS One. principal results from the Women’s Health Initiative rand- 2014;9(2):e88767. https​://doi.org/10.1371/journ​al.pone.00887​ omized controlled trial. JAMA. 2002;288(3):321–33. https​:// 67. doi.org/10.1093/ajcn/nqy07​8. 24. Billington EO, Burt LA, Rose MS, et al. Safety of high-dose 40. Hersh AL, Stefanick ML, Stafford RS. National use of postmeno- vitamin D supplementation: secondary analysis of a randomized pausal hormone therapy: annual trends and response to recent controlled trial. J Clin Endocrinol Metab. 2019. https​://doi. evidence. JAMA. 2004;291(1):47–53. https​://doi.org/10.1001/ org/10.1210/cline​m/dgz21​2. jama.291.1.47. 25. Bouillon R. Vitamin D and cardiovascular disorders. Osteoporos 41. Simon JA. What’s new in hormone replacement therapy: focus Int. 2019;30(11):2167–81. https​://doi.org/10.1007/s0019​8-019- on transdermal estradiol and micronized progesterone. Clim 05098​-0. J Int Menopause Soc. 2012;15(Suppl 1):3–10. https​: //doi. 26. Swart KM, Lips P, Brouwer IA, et al. Effects of vitamin D sup- org/10.3109/13697​137.2012.66933​2. plementation on markers for cardiovascular disease and type 2 42. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin diabetes: an individual participant data meta-analysis of rand- and risk of venous thrombosis. JAMA. 2004;292(13):1573–80. omized controlled trials. AM J Clin Nutr. 2018;107(6):1043–53. https​://doi.org/10.1001/jama.292.13.1573. https​://doi.org/10.1093/ajcn/nqy07​8. 43. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. 27. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and Effect of estrogen plus progestin on stroke in postmenopau- prevention of cancer and cardiovascular disease. N Engl J Med. sal women: the Women’s Health Initiative: a randomized 2019;380(1):33–44. https​://doi.org/10.1056/NEJMo​a1809​944. trial. JAMA. 2003;289(20):2673–84. https​://doi.org/10.1001/ 28. Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high- jama.289.20.2673. dose vitamin D supplementation on cardiovascular disease in the 44. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus pro- Vitamin D Assessment Study: a randomized clinical trial. JAMA gestin and the risk of coronary heart disease. N Engl J Med. Cardiol. 2017;2(6):608–16. https:​ //doi.org/10.1001/jamac​ardio​ 2003;349(6):523–34. https​://doi.org/10.1056/NEJMo​a0308​08. .2017.0175. 45. Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and 29. Barbarawi M, Kheiri B, Zayed Y, et al. Vitamin D supplementa- conjugated equine estrogen in women without a uterus. Arch tion and cardiovascular disease risks in more than 83 000 indi- Intern Med. 2006;166(7):772–80. https​://doi.org/10.1001/archi​ viduals in 21 randomized clinical trials: a meta-analysis. JAMA nte.166.7.772. 1550 N. R. Fuggle et al. 46. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects and homocysteine levels. Maturitas. 2006;53(3):252–9. https​:// of conjugated equine estrogen on stroke in the Women’s Health doi.org/10.1016/j.matur​itas.2005.05.006. Initiative. Circulation. 2006;113(20):2425–34. https​: //doi. 63. Nanetti L, Camilletti A, Francucci CM, et al. Role of ralox- org/10.1161/CIRCU​LATIO​NAHA.105.59407​7. ifene on platelet metabolism and plasma lipids. Eur J 47. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal Clin Invest. 2008;38(2):117–25. https ​ : //doi.org/10.111 hormone therapy and risk of cardiovascular disease by age and 1/j.1365-2362.2007.01905​.x. years since menopause. JAMA. 2007;297(13):1465–77. https​:// 64. Grover-Páez F, Zavalza-Gómez AB, Anaya-Prado R. Ralox- doi.org/10.1001/jama.297.13.1465. ifene modifies the insulin sensitivity and lipid profile of 48. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone postmenopausal insulin resistant women. Gynecol Endo- therapy: an Endocrine Society scientific statement. J Clin Endo- crinol. 2013;29(7):674–7. https ​ : //doi.org/10.3109/09513​ crinol Metab. 2010;95(7 Suppl 1):s1–66. https:​ //doi.org/10.1210/ 590.2013.78862​8. jc.2009-2509. 65. Colacurci N, Manzella D, Fornaro F, et al. Endothelial func- 49. Mikkola TS, Clarkson TB. Estrogen replacement ther- tion and menopause: effects of raloxifene administration. J Clin apy, atherosclerosis, and vascular function. Cardiovasc Endocrinol Metab. 2003;88(5):2135–40. https:​ //doi.org/10.1210/ Res. 2002;53(3):605–19. https ​ : //doi.org/10.1016/s0008​ jc.2002-02155​7. -6363(01)00466​-7. 66. Cagnacci A, Zanni AL, Volpe A. Administration of raloxifene 50. Hodis HN, Collins P, Mack WJ, et al. The timing hypothesis does not influence 24-hour ambulatory blood pressure of post- for coronary heart disease prevention with hormone therapy: menopausal women with osteopenia: a double-blind placebo- past, present and future in perspective. Clim J Int Meno- controlled study. Am J Obstet Gynecol. 2003;188(5):1278–82. pause Soc. 2012;15(3):217–28. https​://doi.org/10.3109/13697​ https​://doi.org/10.1067/mob.2003.299. 137.2012.65640​1. 67. Adomaityte J, Farooq M, Qayyum R. Effect of raloxifene ther- 51. Harman SM, Black DM, Naftolin F, et al. Arterial imaging out- apy on venous thromboembolism in postmenopausal women. A comes and cardiovascular risk factors in recently menopausal meta-analysis. Thromb Haemost. 2008;99(2):338–42. women: a randomized trial. Ann Intern Med. 2014;161(4):249– 68. Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in 60. https​://doi.org/10.7326/M14-0353. postmenopausal women with osteoporosis. N Engl J Med. 52. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of 2010;362(8):686–96. https​://doi.org/10.1056/NEJMo​a0808​692. early versus late postmenopausal treatment with estradiol. N Engl 69. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and J Med. 2016;374(13):1221–31. https​://doi.org/10.1056/NEJMo​ cardiovascular events in osteoporotic postmenopausal women: a1505​241. four-year results from the MORE (Multiple Outcomes of Ralox- 53. Baber RJ, Panay N, Fenton A, et al. 2016 IMS recommenda- ifene Evaluation) randomized trial. JAMA. 2002;287(7):847–57. tions on women’s midlife health and menopause hormone ther- https​://doi.org/10.1001/jama.287.7.847. apy. Clim J Int Menopause Soc. 2016;19(2):109–50. https​://doi. 70. Ensrud K, Genazzani AR, Geiger MJ, et al. Effect of raloxifene org/10.3109/13697​137.2015.11291​66. on cardiovascular adverse events in postmenopausal women 54. Canonico M, Scarabin PY. Oral versus transdermal estrogens with osteoporosis. Am J Cardiol. 2006;97(4):520–7. https​://doi. and venous thromboembolism in postmenopausal women: what org/10.1016/j.amjca​rd.2005.09.083. is new since 2003? Menopause. 2016;23(6):587–8. https​://doi. 71. Barrett-Connor E, Mosca L, Collins P, et al. Effects of ralox- org/10.1097/gme.00000​00000​00066​5. ifene on cardiovascular events and breast cancer in postmeno- 55. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone pausal women. N Engl J Med. 2006;355(2):125–37. https​://doi. replacement therapy and risk of venous thromboembolism: org/10.1056/NEJMo​a0624​62. nested case-control studies using the QResearch and CPRD 72. Ensrud K, LaCroix A, Thompson JR, et al. Lasofoxifene and databases. BMJ. 2019;364:k4810. https​://doi.org/10.1136/bmj. cardiovascular events in postmenopausal women with osteopo- k4810​. rosis: five-year results from the Postmenopausal Evaluation and 56. Sturdee DW, Pines A, International Menopause Society Writ- Risk Reduction with Lasofoxifene (PEARL) trial. Circulation. ing G, et al. Updated IMS recommendations on postmenopausal 2010;122(17):1716–24. https​://doi.org/10.1161/CIRCU​LATIO​ hormone therapy and preventive strategies for midlife health. NAHA.109.92457​1. Clim J Int Menopause Soc. 2011;14(3):302–20. https​://doi. 73. McFarlane SI, Muniyappa R, Shin JJ, et al. Osteoporosis and org/10.3109/13697​137.2011.57059​0. cardiovascular disease: brittle bones and boned arteries, is there 57. Manson JE, Kaunitz AM. Menopause management–getting clini- a link? Endocrine. 2004;23(1):1–10. https​://doi.org/10.1385/ cal care back on track. N Engl J Med. 2016;374(9):803–6. https​ ENDO:23:1:01. ://doi.org/10.1056/NEJMp​15142​42. 74. Bevilacqua M, Dominguez LJ, Rosini S, et al. Bisphosphonates 58. Yates J, Barrett-Connor E, Barlas S, et al. Rapid loss of hip and atherosclerosis: why? Lupus. 2005;14(9):773–9. https​://doi. fracture protection after estrogen cessation: evidence from org/10.1191/09612​03305​lu221​9oa. the National Osteoporosis Risk Assessment. Obstet Gynecol. 75. Wagner WD, Clarkson TB, Foster J. Contrasting effects of 2004;103(3):440–6. https​://doi.org/10.1097/01.aog.00001​14986​ ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the regres- .14806​.37. sion of two types of dietary-induced atherosclerosis. Athero- 59. Menopause: diagnosis and management; NG23. National Insti- sclerosis. 1977;27(4):419–35. https​://doi.org/10.1016/0021- tute for Health and Care Excellence, London. 2015. 9150(77)90161​-7. 60. Cummings SR, Ettinger B, Delmas PD, et al. The effects of 76. Kramsch DM, Aspen AJ, Rozler LJ. Atherosclerosis: preven- tibolone in older postmenopausal women. N Engl J Med. tion by agents not affecting abnormal levels of blood lipids. 2008;359(7):697–708. https:​ //doi.org/10.1056/NEJMoa​ 08007​ 43. Science (New York, NY). 1981;213(4515):1511–2. https​://doi. 61. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on org/10.1126/scien​ce.67927​06. serum lipids and coagulation factors in healthy postmenopausal 77. Gonnelli S, Caffarelli C, Tanzilli L, et al. Effects of intravenous women. JAMA. 1998;279(18):1445–51. https:​ //doi.org/10.1001/ zoledronate and ibandronate on carotid intima-media thickness, jama.279.18.1445. lipids and FGF-23 in postmenopausal osteoporotic women. Bone. 62. Gol M, Akan P, Dogan E, et al. Effects of estrogen, raloxifene, 2014;61:27–32. https​://doi.org/10.1016/j.bone.2013.12.017. and hormone replacement therapy on serum C-reactive protein Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs 1551 78. Yang Y, Rong X, Lv X, et al. Inhibition of mevalonate pathway in postmenopausal women with osteoporosis and high cardio- prevents ischemia-induced cardiac dysfunction in rats via RhoA- vascular risk. J Bone Miner Res. 2014;29(2):450–7. https​://doi. independent signaling pathway. Cardiovasc Ther. 2017. https​:// org/10.1002/jbmr.2043. doi.org/10.1111/1755-5922.12285​. 94. Jordan LR, Dallemagne CR, Cross RB. Cardiovascular effects 79. Zhou S, Fang X, Xin H, et al. Effects of alendronate on the of parathyroid hormone in conscious sheep. Exp Physiol. Notch1-RBP-Jκ signaling pathway in the osteogenic differ- 1991;76(2):251–7. https​://doi.org/10.1113/expph​ysiol​.1991. entiation and mineralization of vascular smooth muscle cells. sp003​491. Mol Med Rep. 2013;8(1):89–94. https ​ : //doi.org/10.3892/ 95. Kendler DL, Marin F, Zerbini CAF, et al. Effects of teripara- mmr.2013.1489. tide and risedronate on new fractures in post-menopausal 80. Giollo A, Rossini M, Gatti D, et al. Amino-bisphosphonates and women with severe osteoporosis (VERO): a multicentre, dou- cardiovascular risk: a new hypothesis involving the effects on ble-blind, double-dummy, randomised controlled trial. Lan- gamma-delta T cells. J Bone Miner Res. 2019;34(3):570–1. https​ cet. 2018;391(10117):230–40. https​://doi.org/10.1016/s0140​ ://doi.org/10.1002/jbmr.3660. -6736(17)32137​-2. 81. Steinbuch M, D’Agostino RB, Mandel JS, et al. Assessment of 96. Nishikawa A, Ishida T, Taketsuna M, et al. Safety and effective- mortality in patients enrolled in a risedronate clinical trial pro- ness of daily teriparatide in a prospective observational study gram: a retrospective cohort study. Regulatory toxicology and in patients with osteoporosis at high risk of fracture in Japan: pharmacology: RTP. 2002;35(3):320–6. https​://doi.org/10.1006/ final report. Clin Interv Aging. 2016;11:913–25. https​://doi. rtph.2002.1550. org/10.2147/CIA.S1072​85. 82. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic 97. Miller PD, Hattersley G, Riis BJ, et al. Effect of abalopara- acid for treatment of postmenopausal osteoporosis. N Engl J tide vs placebo on new vertebral fractures in postmenopausal Med. 2007;356(18):1809–22. https​://doi.org/10.1056/NEJMo​ women with osteoporosis: a randomized clinical trial. JAMA. a0673​12. 2016;316(7):722–33. https​://doi.org/10.1001/jama.2016.11136​. 83. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic 98. Final summary minutes of the Bone, Reproductive and Urologic acid and clinical fractures and mortality after hip fracture. N Engl Drugs Advisory Committee Meeting (January 16). Food and J Med. 2007;357(18):1799–809. https​://doi.org/10.1056/NEJMo​ Drug Administration, Center for Drug Evaluation and Research. a0749​41. 2019. 84. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with 99. Evenity: EPAR public assessment report. European Medicines zoledronate in older women with osteopenia. N Engl J Med. Agency. 2019. 2018;379(25):2407–16. https​://doi.org/10.1056/NEJMo​a1808​ 100. Cosman F, Crittenden DB, Ferrari S, et al. FRAME Study: the 082. foundation effect of building bone with 1 year of romosozumab 85. Reid IR, Horne AM, Mihov B, et al. Effects of zoledronate on leads to continued lower fracture risk after transition to deno- cancer, cardiac events, and mortality in osteopenic older women. sumab. J Bone Miner Res. 2018;33(7):1219–26. https​://doi. J Bone Miner Res. 2020;35(1):20–7. https​://doi.org/10.1002/ org/10.1002/jbmr.3427. jbmr.3860. 101. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab 86. Bunch TJ, Anderson JL, May HT, et al. Relation of bisphos- treatment in postmenopausal women with osteoporosis. N Engl phonate therapies and risk of developing atrial fibrillation. The J Med. 2016;375(16):1532–43. https​://doi.org/10.1056/NEJMo​ American journal of cardiology. 2009;103(6):824–8. https​://doi. a1607​948. org/10.1016/j.amjca​rd.2008.11.037. 102. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alen- 87. Cummings SR, Lui L-Y, Eastell R, et al. Association between dronate for fracture prevention in women with osteoporosis. N drug treatments for patients with osteoporosis and overall mortal- Engl J Med. 2017;377(15):1417–27. https​://doi.org/10.1056/ ity rates: a meta-analysis. JAMA Intern Med. 2019. https​://doi. NEJMo​a1708​322. org/10.1001/jamai​ntern​med.2019.2779. 103. Lv F, Cai X, Yang W, et al. Denosumab or romosozumab 88. Black DM, Thompson DE, Bauer DC, et al. Fracture risk therapy and risk of cardiovascular events in patients with pri- reduction with alendronate in women with osteoporosis: the mary osteoporosis: systematic review and meta- analysis. Bone. Fracture Intervention Trial. FIT Research Group. J Clin Endo- 2020;130:115121. https​://doi.org/10.1016/j.bone.2019.11512​1. crinol Metab. 2000;85(11):4118–24. https​://doi.org/10.1210/ 104. Shoback D, Rosen CJ, Black DM, et al. Pharmacological man- jcem.85.11.6953. agement of osteoporosis in postmenopausal women: an Endo- 89. Heckbert SR, Li G, Cummings SR, et al. Use of alendronate and crine Society Guideline update. J Clin Endocrinol Metab. 2020. risk of incident atrial fibrillation in women. Arch Intern Med. https​://doi.org/10.1210/cline​m/dgaa0​48. 2008;168(8):826–31. https:​ //doi.org/10.1001/archin​ te.168.8.826. 105. Appelman-Dijkstra NM, Papapoulos SE. Clinical advantages 90. Sørensen HT, Christensen S, Mehnert F, et al. Use of bisphos- and disadvantages of anabolic bone therapies targeting the WNT phonates among women and risk of atrial fibrillation and flut- pathway. Nat Rev Endocrinol. 2018;14(10):605–23. https​://doi. ter: population based case-control study. BMJ (Clin Res ed). org/10.1038/s4157​4-018-0087-0. 2008;336(7648):813–6. https ​ : //doi.org/10.1136/bmj.39507​ 106. Zhu D, Mackenzie NC, Millan JL, et al. The appearance and .55164​4.BE. modulation of osteocyte marker expression during calcification 91. Abrahamsen B, Eiken P, Brixen K. Atrial fibrillation of vascular smooth muscle cells. PLoS ONE. 2011;6(5):e19595. in fracture patients treated with oral bisphosphonates. J https​://doi.org/10.1371/journ​al.pone.00195​95. Intern Med. 2009;265(5):581–92. https ​ : //doi.org/10.111 107. Evenepoel P, Goffin E, Meijers B, et al. Sclerostin serum levels 1/j.1365-2796.2008.02065​.x. and vascular calcification progression in prevalent renal trans- 92. Cummings SR, San Martin J, McClung MR, et al. Denosumab plant recipients. J Clin Endocrinol Metab. 2015;100(12):4669– for prevention of fractures in postmenopausal women with 76. https​://doi.org/10.1210/jc.2015-3056. osteoporosis. N Engl J Med. 2009;361(8):756–65. https​://doi. 108. Krishna SM, Seto SW, Jose RJ, et al. Wnt signaling pathway org/10.1056/NEJMo​a0809​493. inhibitor sclerostin inhibits angiotensin II-induced aortic aneu- 93. Samelson EJ, Miller PD, Christiansen C, et al. RANKL inhibi- rysm and atherosclerosis. Arterioscler Thromb Vasc Biol. tion with denosumab does not influence 3-year progression of 2017;37(3):553–66. https:​ //doi.org/10.1161/atvbah​ a.116.308723​ . aortic calcification or incidence of adverse cardiovascular events 1552 N. R. Fuggle et al. 109. Javaheri B, Herbert E, Hopkinson M, et al. Sost haploinsuffi- 115. Balemans W, Van Hul W. Identification of the disease-causing ciency provokes peracute lethal cardiac tamponade without res- gene in sclerosteosis–discovery of a novel bone anabolic target? cuing the osteopenia in a mouse model of excess glucocorticoids. J Musculoskelet Neuronal Interact. 2004;4(2):139–42. Am J Pathol. 2019;189(4):753–61. https:​ //doi.org/10.1016/j.ajpat​ 116. van Lierop AH, Appelman-Dijkstra NM, Papapoulos SE. Scle- h.2018.12.007. rostin deficiency in humans. Bone. 2017;96:51–62. https​://doi. 110. Kuipers AL, Miljkovic I, Barinas-Mitchell E, et al. Wnt path- org/10.1016/j.bone.2016.10.010. way gene expression is associated with arterial stiffness. J 117. Hamersma H, Gardner J, Beighton P. The natural history of scle- Am Heart Assoc. 2020;9(3):e014170. https​://doi.org/10.1161/ rosteosis. Clin Genet. 2003;63(3):192–7. https​://doi.org/10.103 jaha.119.01417​0. 4/j.1399-0004.2003.00036​.x. 111. Florio M, Gunasekaran K, Stolina M, et al. A bispecific antibody 118. Lewiecki EM, Dinavahi RV, Lazaretti-Castro M, et al. One year targeting sclerostin and DKK-1 promotes bone mass accrual of romosozumab followed by two years of denosumab maintains and fracture repair. Nat Commun. 2016;7:11505. https​://doi. fracture risk reductions: results of the FRAME Extension study. org/10.1038/ncomm​s1150​5. J Bone Miner Res. 2019;34(3):419–28. https​://doi.org/10.1002/ 112. Di M, Wang L, Li M, et al. Dickkopf1 destabilizes atherosclerotic jbmr.3622. plaques and promotes plaque formation by inducing apoptosis of 119. Lewiecki EM, Blicharski T, Goemaere S, et al. A phase III ran- endothelial cells through activation of ER stress. Cell Death Dis. domized placebo-controlled trial to evaluate efficacy and safety 2017;8(7):e2917. https​://doi.org/10.1038/cddis​.2017.277. of romosozumab in men with osteoporosis. J Clin Endocrinol 113. Moe SM, Chen NX, Newman CL, et al. Anti-sclerostin antibody Metab. 2018;103(9):3183–93. https​://doi.org/10.1210/jc.2017- treatment in a rat model of progressive renal osteodystrophy. J 02163​. Bone Miner Res. 2015;30(3):499–509. https​://doi.org/10.1002/ 120. Cummings SR, McCulloch C. Explanations for the difference in jbmr.2372. rates of cardiovascular events in a trial of alendronate and romo- 114. Ominsky MS, Boyd SK, Varela A, et al. Romosozumab sozumab. Osteoporos Int. 2020. https​://doi.org/10.1007/s0019​ improves bone mass and strength while maintaining bone qual- 8-020-05379​-z. ity in ovariectomized cynomolgus monkeys. J Bone Miner Res. 121. Approval of the marketing authorisation for Evenity (romo- 2017;32(4):788–801. https​://doi.org/10.1002/jbmr.3036. sozumab): re-examination leads to recommendation to approve. 2019. Affiliations N. R. Fuggle1 · C. Cooper1,2 · N. C. Harvey1 · N. Al‑Daghri3 · M.‑L. Brandi4 · O. Bruyere5 · A. Cano6 · E. M. Dennison1 · A. Diez‑Perez7,8 · J.‑M. Kaufman9 · S. Palacios10 · D. Prieto‑Alhambra11 · S. Rozenberg12 · T. Thomas13 · F. Tremollieres14 · R. Rizzoli15 · J. A. Kanis16,17 · J. Y. Reginster3,5,18 1 11 MRC Lifecourse Epidemiology Unit, University Nuffield Department of Orthopaedics, Rheumatology of Southampton, Tremona Road, Southampton SO16 6YD, and Musculoskeletal Sciences (NDORMS), University UK of Oxford, Oxford, UK 2 12 NIHR Musculoskeletal Biomedical Research Unit, University Department of Obstetrics and Gynecology, CHU St Pierre, of Oxford, Oxford, UK Laboratoire de Santé Génésique Université Libre de 3 Bruxelles, Brussels, Belgium Chair for Biomarkers of Chronic Diseases, Biochemistry 13 Department, College of Science, King Saud University, Department of Rheumatology, Hôpital Nord, CHU de Riyadh, Kingdom of Saudi Arabia Saint-Etienne, and INSERM U1059, Université de Lyon, 4 Saint‑Etienne, France Unit of Bone and Mineral Diseases, Department of Surgery 14 and Translational Medicine, University Hospital of Florence, Menopause Centre, Hôpital Paule de Viguier, University University of Florence, 50139 Florence, Italy Hospital of Toulouse and INSERM U1048-I2MC, Equipe 9, 5 Toulouse, France WHO Collaborating Centre for Public Health Aspects 15 of Musculoskeletal Health and Aging, Liège, Belgium Service of Bone Diseases, Geneva University Hospitals 6 and Faculty of Medicine, 1211 Geneva 14, Switzerland Department of Obstetrics and Gynecology, University 16 of Valencia and INCLIVA Health Research Institute, Mary McKillop Institute for Health Research, Australian Valencia, Spain Catholic University, Melbourne, Australia 7 17 Hospital del Mar Research Institute (IMIM), Centro Centre for Metabolic Bone Diseases, University of Sheffield de Investigación Biomédica en Red de Fragilidad y Medical School, Sheffield, UK Envejecimiento Saludable (CIBERFES), Barcelona, Spain 18 Division of Public Health, Epidemiology and Health 8 Internal Medicine Department, Hospital del Mar, Universitat Economics, University of Liège, CHU Sart Tilman B23, Autònoma de Barcelona, Barcelona, Spain 4000 Liège, Belgium 9 Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium 10 The Palacios Institute of Women’s Health, Madrid, Spain