Cardiovascular Safety of Antifracture Medications in Patients With Osteoporosis: A Narrative Review of Evidence From Randomized Studies

ABSTRACT Osteoporosis and cardiovascular (CV) disease share common risk factors and pathophysiology. Low bone mineral density (BMD) and fractures appear to increase the risk for multiple CV diseases. Equally, prevalent CV disease appears to predispose to bone loss and increase fracture rates. This relationship has naturally provoked the hypothesis that stopping bone loss may result in some CV benefit. Secondary analyses of safety and adverse event data from many randomized controlled trials (RCTs) have attempted to clarify this putative association. Recently, the discontinuation of odanacatib (anti‐cathepsin K monoclonal antibody) over stroke concerns and the imbalance in ischemic events in romosozumab‐treated (anti‐sclerostin monoclonal antibody) women compared to bisphosphonate‐treated women, has provided further justification to better characterize potential CV benefits and harms of osteoporosis medications. This review delves into the seminal, and other major RCTs of osteoporosis medications and, using both published data and additional information provided on trial registration pages, examines the evidence for CV safety and harms of these medications. Accepted and emerging “off‐target” effects are explored for validity, biological plausibility, and clinical importance. A brief research agenda is provided to stimulate the next wave of clinical development and CV understanding of osteoporosis medications. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


Introduction
O steoporosis is a systemic skeletal disorder characterized by the loss of bone mass and deterioration in bone microarchitecture. These microstructural alterations combine to compromise bone strength leading to skeletal fragility and increased susceptibility of fracture. (1) Fractures are a devastating outcome. Recovery from a fracture is costly, takes many months and indeed some never truly recover and lose independence. Indeed, mortality and the development of comorbid disease, greatly increases after most types of fractures but particularly hip fractures. (2) Recent health economic literature suggests that fractures pose a higher disease and cost burden than most cancers (except lung cancer) but do not attract as much public attention or institutional funding. (3) Osteoporosis does not exist in isolation and indeed may either precede, develop concomitantly, or present secondary to other comorbid diseases, analogous to how cardiovascular (CV) disease may develop subsequently to type 2 diabetes mellitus. The association between CV disease and osteoporosis is of profound importance because CV disease is overrepresented as a cause of death in patients who have fractured; and fractures are common in patients with known CV disease. Atherosclerosis shares many risk factors with osteoporosis and is hypothesized to establish in the decades of life when the net flux of available calcium becomes deranged; "switching" from skeleton deposition to renal filtration and deposition in vessel walls and other soft tissues. (4) Certainly, on a biological level, there appears to be bidirectionality between bone and vascular disease. (5) Mechanisms underlying common aging, such as chronic inflammation as well as the decline in renal function predisposing to chronic kidney disease (itself significantly effecting calcium and mineral balance) are all thought to interact in the eventual comanifestation of osteoporosis and CV disease (Table 1).

Why Is It Important to Understand the CV Benefits and Harms of Osteoporosis Medications?
Given this context, there is a natural case suggesting that perhaps improvements in skeletal health and fracture reduction may lead to nonskeletal benefit, particularly where CV diseases are concerned. Indeed, greater appreciation of the need for CV disease management alongside fracture risk is warranted across clinical specialties in order to do our best to improve the overall outcomes experienced by patients. By understanding these nonskeletal benefits and harms, we are doing our due diligence by the patient because treatment uptake is affected markedly by perceived risks of harmful albeit extremely rare side effects; most recently regarding prescription of bisphosphonates (BPs). (12) Understanding what treatments can accomplish, in the widest possible sense, may impact the overall cost utility landscape of such medications rather than a narrow focus on bone health alone.
The scientific associations between the skeleton and heart and vessels are strong but has not been translated into a clinical message that bone protection may offer CV protection. For example, in women who experience bone loss over time, increases in systolic blood pressure were greatest in those who experienced the greater reduction in bone density. (13) This observation is not limited to women; data from the United States show that in men (and women), CV disease is exhibited by those who experience bone loss. (14) We have also begun to appreciate the vascular-bone relationship, of how vascular disease can lead to poorer skeletal outcome. In older women, atherosclerotic vascular disease (ASVD) including vascular calcification is highly prevalent and is associated with a higher risk of fractures. (15) Though there is little awareness of this in daily clinical practice, patients with underlying stroke or ischemic heart disease go on to experience near double the number of fractures compared to those who are disease-free. (9,16) Finally, there is a regulatory rationale to understand the CV effects of osteoporosis medications. The latest drugs off the pipeline have been subjected to intense CV scrutiny, which is of course appropriate given their prospective widespread use in an older population. Indeed, the cathepsin K monoclonal antibody, odanacatib, was discontinued by the sponsor (Merck) owing to concerns over increases rates of stroke compared to placebo ( (17) Furthermore, another monoclonal antibody, against sclerostin, romosozumab, has been approved by the US Food and Drug Administration (FDA) with a black-box warning for potential increases in stroke and myocardial infarction owing to an imbalance in adjudicated CV events in a large active-comparator trial. (18) In other words, both the patients and the prescriber will need to agree that any short-term increase in cardiovascular morbidity is more than offset by long-term prevention of serious fractures. This renewed interest in "off-target" effects, particularly CV effects, of antifracture medications thus warrants further exploration. This concept is already applied in the diabetes setting where new glucose-lowering medications must also have satisfactory results for both safety and efficacy in a CV outcome trial.
What Is the Purpose and Scope of this Review?
The purpose of this review is to provide a comprehensive overview of the antifracture medication prescribing landscape and examine the evidence for CV safety and harms of these medications. This review focuses on recent larger randomized controlled trials (RCTs) with reference to key historical and seminal trials in the development of some medications. Particular attention will be paid to studies conducted in postmenopausal women and older men with osteoporosis/low BMD and to nonhormonal treatments with proven antifracture efficacy. Further, this review will focus on the meaningful collective outcome of the disease processes leading to CV events as properly examining mechanistic pathways such as vascular calcification is challenging in the setting of large RCTs. A previous review on this topic was framed as practical guide for the new clinician. (19) This review is also aimed at the prescribing clinician with the additional intention to provide a foundation from which conversations about medication safety can be had with patients. The CV safety of antifracture medications needs to be explored in the context of patients with osteoporosis/low BMD having a high underlying vascular disease burden and so CV outcomes of osteoporosis RCTs may be confounded by indication. Furthermore, this review is also aimed at the interested scientist, as we explore knowledge gaps in the bone-CV field.
What Is "Accepted" to Be Known?

No apparent mortality benefits
BPs are pyrophosphate analogues that have high affinity for hydroxyapatite crystals in bone with a half-life of several years.  (11) BPs have a long history, with the first clinical use noted in 1969. (20) Their main effects appear to be on inhibiting resorption by being taken up by osteoclasts and promoting their apoptosis, thereby tipping the remodeling balance in favor of greater deposition to resorption. The idea that BPs could have some potential CV effects stemmed from observations that etidronate (a first-generation, non-nitrogen-containing-BP) could delay the calcification process in the vasculature and outside the skeleton. (21,22) Later generation, nitrogen-containing BPs including oral alendronate, risedronate, and intravenous (iv) zoledronic acid have been shown to inhibit the farnesyl pyrophosphate synthase pathway in osteoclasts, which is a downstream step from the actions of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in the production of mevalonate in the cholesterol synthesis pathway. (23) Given the robust literature surrounding the cardioprotective and mortality benefits of inhibiting this pathway, BPs too have been studied in this respect with mixed effects. First, BPs appear to offer no mortality benefit as a class in women and men. (24) In a meta-analysis of 21 trials of BPs (n = 22,623 treated) versus placebo (n = 20,244), BP treatment was associated with a nonsignificant 5% reduced relative risk (RR) of overall mortality (event rates: 3.78% versus 4.35%; 95% CI for RR, 0.86 to 1.04). (24) This finding was replicated in sensitivity analysis of zoledronic acid although with a larger effect size of 22% (4.17% versus 4.07%; RR = 0.88; 95% CI, 0.68 to 1.13). Analysis of alendronate-only studies (four trials) demonstrated a null effect (1.55% versus 1.61%; RR = 1.00; 95% CI, 0.71 to 1.40). Interestingly, analysis of nitrogen-containing BPs (essentially combining alendronate, risedronate, and zoledronic acid) trended toward significance (2.98% versus 3.62%; RR = 0.90; 95% CI, 0.81 to 1.00). Furthermore, excluding zoledronic acid from analysis of nitrogen-containing BPs marginally altered the effect estimate (2.34% versus 2.90%; RR = 0.92; 95% CI, 0.79 to 1.07) suggestive of an oral BP-specific effect. These rates and effect estimates are mentioned in detail as the moderate to large effect sizes and upper limits of the confidence bounds (1.00, 1.04, and 1.07) suggests that a clinically meaningful reduction in mortality cannot be excluded given the weight of evidence and results from observational cohorts. The metaanalysis did not perform population specific sensitivity analyses (men-only, hip fracture only, etc.) and thus these data indicate there may yet exist a certain population with osteoporosis who may experience a mortality benefit despite not necessarily being prescribed for this effect. Given the high CV burden in patients with osteoporosis, they may be interested in understanding these potential off-target effects despite clinical suspicion that they are "too good to be true". (25) Finally, there appeared to be no mortality benefit for BPs in trials longer than 3 years, which was an interesting concept given the perceived risk reduction seen in the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial occurred in the first 12 months (26) and risk reductions appeared evident at approximately the 16-month mark of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT) trial by Lyles and colleagues. (27) This would point to some transient effect that could potentially be related to medication adherence (observational data support this (28) ) or represent a true, underappreciated clinical effect mediated through the skeleton. There is a complete paucity of head-to-head studies examining this and there is limited data exploring these effects in other agents (29,30) to elucidate if any potential mortality benefit is mediated through skeletal effects.

Zoledronic acid may increase the risk of atrial fibrillation
Despite no apparent effect of BPs as a class on overall mortality, cause-specific effects have been explored in greater detail. One of the most well-described effects has been the apparent increase in atrial fibrillation associated with iv zoledronic acid ( Table 2). This was first described in the HORIZON Pivotal Fracture Trial by Black and colleagues from 2007. (31) This trial followed on from the clinical development of alendronate as an antifracture agent a decade earlier. (37) The aim of the HORIZON study was to investigate if the more potent zoledronic acid had similar effects to oral alendronate. The intravenous nature of zoledronic acid was appealing to patients because it was required only once yearly rather than daily or weekly as per the oral formulation, which caused gastric problems. HORIZON enrolled over 7700 women aged between 65 and 89 years and randomly assigned to either 5 mg iv zoledronic acid or placebo both with additional daily calcium (1000 to 1500 mg) and vitamin D (400 to 1200 IU). There was an imbalance in overall adverse events, mostly attributable to postinfusion symptoms. Importantly, this seminal trial provided the first robust description for effects of BPs on atrial fibrillation. In those receiving iv zoledronic acid, there were more atrial fibrillation events ( (38) The rationale for why BPs may provoke arrhythmia is uncertain. Some preclinical studies point to potential disruption of calcium handling dynamics in cardiomyocytes by BPs. (39) Other important triggers initiating atrial fibrillation may arise from focally discharging cells located most commonly at the pulmonary vein ostia. These foci may lead to frequent atrial ectopy and paroxysms of atrial fibrillation. This effect is particularly relevant to the iv administration, which is clouded by flulike symptoms postinjection. (40) BPs can also stimulate release of inflammatory cytokines, which are implicated in increasing the risk of atrial fibrillation but through mechanisms that have not been fully elucidated. (41,42) These data were enough to include in atrial fibrillation as a rare but of uncertain causal origin side effect that clinicians should be aware of in current regulatory agency recommendations. (43) More recent data cast doubt on this understanding. A recent trial of similar design to the HORI-ZON trial specifically enrolled 2000 women in the osteopenic range (that is, having a BMD T-score between À2.5 and À1.0). In a secondary publication of prespecified safety data, Reid and colleagues (32,33) demonstrated similar event rates for any atrial fibrillation 14.8 (95% CI, 11.9 to 18.3) events per 1000 zoledronic acid treated and 15.6 (95% CI, 12.6 to 19.1) events per 1000 placebo-treated women. The crude event rates were much larger than HORIZON for both all atrial fibrillation events (8.8% versus 9.5%; RR = 0.95; 95% CI, 0.72 to 1.26) and for number of women with at least one episode of atrial fibrillation (5.4% versus 5.5%; RR = 0.98; 95% CI, 0.68 to 1.41). In comparing HORIZON with the more recent trial in patients with osteopenia, it may be argued that the women with osteopenia have a lesser underlying CV disease burden (given the shared underlying risk factors for both CV disease and osteoporosis), and thus the administration of zoledronic acid was not sufficient to provoke paroxysms. Cohort studies have demonstrated inconsistent findings regarding this pre-presumptive association and thus continual investigation and post-market monitoring is prudent. (44) Zoledronic acid may reduce the risk of myocardial infarction Contrary to the history of zoledronic acid and atrial fibrillation, rates of myocardial infarction have not been shown to be increased with zoledronic acid treatment. In the abovementioned trial by Reid and colleagues, (32,33) (32,33) These data, although prespecified, were secondary endpoints and thus warrant interpretation with caution. This effect is another point of difference between the trial by Black and colleagues (31) in women with osteoporosis. There were fewer myocardial infarction events in zoledronic acid-treated women (38 [1.0%] versus 45 [1.2%]), but this did not reach statistical significance (RR = 0.84; 95% CI, 0.54 to 1.29). Similar to effects on overall mortality, these data may indicate that BP may exhibit some transient effect which is support by cohort data on medication adherence. Furthermore, given the potential action of BP on the cholesterol synthesis pathway, there is biological rationale to support an effect on ASVD. Further data are needed to understand if the background ASVD is important in determining CV effects on BPs or if indeed BPs have clinically significant effects in reversing ASVD as per statins. Abdominal aortic calcification (AAC) is recognized to be a surrogate indicator of ASVD and indeed predicts CV and non-CV outcomes. (15,(45)(46)(47) In an exploratory substudy of the HORIZON-PFT, progression of AAC was examined following 3 years of treatment. AAC progression (defined as a change in semiquantitative AAC score) was similar between treatment groups ( (48) This did not differ by baseline AAC score, nor did change in total hip (r = À0.02, p = 0.66) or femoral neck BMD (r = 0.03, p = 0.54) correlate with AAC change. This overall suggests against a link between the skeleton and calcification in the vasculature as a potential mechanism explaining CV benefits or harms of BPs. However, it should be noted that the semiquantitative AAC scale (0 to 8) may not be sensitive enough to detect changes over the follow-up period and the intraobserver fidelity was moderate (0.62). Studies using more sensitive techniques and scoring systems may yet observe differences. Understanding subtle changes in AAC is important as it remains to be seen if an AAC score of 0 has similar prognostic power as a coronary artery calcium score of 0. (49,50) Oral bisphosphonates have a good safety profile regarding CV events Similar to the seminal trials by Black and colleagues (37) and Liberman and colleagues (51)

Denosumab has null effects on CV events
Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), which exerts potent antiresorptive effects. The largest trial conducted in the clinical development of denosumab was the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study. (30) This double-blind, placebocontrolled trial enrolled 7808 postmenopausal women aged 60 to 90 years. Prespecified safety data included serious CV events, strokes, and coronary heart disease. Analysis of these secondary endpoints demonstrated no statistical difference in event rates between the treatment groups ( . This finding was consistent across baseline AAC status (score ≤6 versus score >6) and, importantly, renal function (estimated glomerular filtration rate ≤45 versus >45). (58) Again, this supports a view that a mechanism independent of calcium handling may explain the benefits or harms of antiresorptive therapies.

Parathyroid hormone analogues have null effects on CV events
Parathyroid hormone (PTH) stimulates bone resorption physiologically in order to maintain appropriate circulating calcium levels. However, the osteoclasts responsible for bone resorption release chemokines and other hormones that eventually promote the maturation of osteoblasts resulting in increases in bone formation. This apparent paradoxical effect is utilized clinically, where synthetic analogues of PTH such teriparatide (PTH 1-34, the first 34 amino acids of the hormone) and abaloparatide (PTH-related protein analogue) are the chief anabolic agents in the physician's armamentarium. In terms of CV safety, the key trial in the clinical development of teriparatide by Neer and colleagues in 2001, (59)  , which was similar to the experience with teriparatide two decades earlier. (60) Interestingly, in the majority of trials, the direction of effect supports a notion of CV risk reduction, which indirectly supports the underlying theory of skeletal health being linked to CV health (Table 4).

Romosozumab may increase the risk of ischemic events
Romosozumab is a monoclonal antibody that binds and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption. In a trial of romosozumab against placebo, the Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) trial ($3600 postmenopausal women each arm), there was no imbalance in the number of adjudicated serious CV events ( (18) Of note, participants in the ARCH trial included the highest proportion of patients with a previous history of CV disease 73%, compared to 66% and 65%, in Placebo-Controlled Study Evaluating the Efficacy and Safety of Romosozumab in Treating Men With Osteoporosis (BRIDGE) and FRAME, respectively. Thus, it has been suggested that perhaps the drug treatment has exacerbated (or provoked) already underlying CV disease and thus a black box warning for romosozumab is in place for any patient who has experienced a major CV event. (64)(65)(66) This position is not supported by recent a meta-analysis, where romosozumab was not shown to increase the risk of a composite cardiovascular outcome of stroke, coronary artery disease, heart failure, and atrial fibrillation (RR = 1.26; 95% CI, 0.95 to 1.68) or a three-point major adverse cardiovascular event (MACE) outcome (RR = 1.41; 95% CI, 0.99 to 2.02). However, the lower bounds of the CIs in these estimates cannot exclude a statistically or clinically important effect, that is to say the lower bounds of the CIs only just cross unity; therefore, the majority of the effect lies in the positive direct (namely more events meaning romosozumab is associated with relative harm). Interestingly, there was an increase in a four-point MACE outcome (RR = 1.39; 95% CI, 1.01 to 1.90). This suggests that assessing CV risks of romosozumab is limited by power (given that a four-point outcome includes more events than a threepoint outcome). Therefore an event-driven analysis and ongoing postmarketing analysis should be considered. (56) Emerging topics in the cardiovascular effects of antifracture medications Differential arrhythmic and atherogenic effects of oral and intravenous bisphosphonates?
Meta-analyses have proven largely unhelpful in clarifying the potential harmful and/or beneficial effects of bisphosphonates on cardiovascular outcomes. (35,36,(67)(68)(69) There exists much variation in analysis approach (any versus specific BP), included literature (RCTs, industry sponsored only studies, cohort studies, and case-control studies) and outcomes. Collectively, the message is unclear. In the case of drugs with extensive experience, such as BPs with over 50 years of clinical use, real-world evidence can complement RCT evidence. (70) There could be several reasons why many RCTs of BPs on CV outcomes have not provided firm conclusions. For example, the trials may be underpowered to detect an adequate number of events, the trial being too short (again a question of being event-driven) and population characteristics (did the patients have too severe CV disease to benefit from mild risk reduction or too mild a disease so not enough events occur over follow-up). Recent real-world evidence for CV effects of BPs appear to indicate cardioprotection and possibly a signal toward differential atherogenic and arrhythmic effects. In a cohort of individuals undergoing bone density testing (clinically matched on indication), oral BP (96% alendronate) use was associated with a reduction in atrial fibrillation, heart failure, and stroke but not myocardial infarction. (71) Small experimental studies in humans have emerged attempting to define the mechanism for this demonstrating acute QT effects on electrocardiography (ECG) following zoledronic acid infusion. (72) However, this may just be a feature of the autonomic response to an infusion. Further to differential atherogenic and arrhythmic effects, other cohort studies indicate there may be differential oral and iv effects of BPs, with the iv zoledronic acid associated with greater harms than oral BPs. (44) This is supported by a meta-analysis of the pivotal RCTs for ibandronate, which showed that although ibandronate was deemed to be safe overall, there was a greater crude rate of atrial fibrillation events in patients receiving intravenous ibandronate (0.5%) compared to the oral formulation (0.3%). (73) Denosumab safety may support the cardioprotective hypothesis of BPs The context of intense CV scrutiny of romosozumab and BPs was the scientific motivation to reanalyze the specific CV safety data of denosumab. Two previous meta-analyses have reported on the CV safety of denosumab, but findings were limited, including omission of the pivotal trial in the clinical development of denosumab that reported CV safety. (56) (55) These findings mirror what was evidenced by the romosozumab trials-namely treatment arms experiencing elevated CV events in a BP-controlled trial but not in a placebo-controlled trial. This provides indirect evidence for cardioprotection by BPs. Furthermore, recent studies in postmenopausal women suggest that RANKL inhibition does not alter markers of ASVD, further supportive of the imbalance of events seen in the meta-analysis being attributable to suppression of events in BP arms. (74) Of note, the meta-analysis did not perform sensitivity analyses for BP type to elucidate if effects were specific to oral or iv formulations, so direct comparisons to the zoledronic acid trials are limited. This is particularly relevant given that the MACE outcome only reached significance upon inclusion of atrial fibrillation an outcome for which zoledronic acid has perceived effects.
PTH-analogues may have autonomic heart rate effects of clinical importance At the request of the FDA, investigators of the "Abaloparatide Comparator Trial in Vertebral Endpoints" (ACTIVE) study performed a comprehensive post hoc cardiovascular safety study of trial participants. (75) Heart rates, blood pressure, and adverse events presumed related to increased heart rates were recorded. Overall rates of treatment-emergent adverse events were higher in participants receiving study medications as expected. However, treatment-emergent adverse events related to elevated heart rates that lead to trial discontinuation were substantially more frequent in abaloparatide-treated ( Ongoing uncertainty of the cardiovascular significance of romosozumab There has been substantial interest in understanding if sclerostin inhibition imposes CV risk since the publication of the ARCH trial (Table 5). This was recently reviewed briefly by Langdahl and colleagues (76) and Fixen and Tunoa. (77) Both reviews concluded romosozumab to be safe in this respect and warned against overinterpreting low event rates. There is biological rationale for why this may be the case. In a murine model of atherosclerosis, the SOST gene (which encodes sclerostin) was expressed in the aorta and upregulation of SOST conferred vasculoprotection. (78) This finding supports the clinical experience of patients with sclerosteosis, a genetic mutation leading to the overexpression of the SOST gene and thus exhibit naturally high levels of sclerostin. These people exhibit marked bone deposition, but importantly, appear to be at no increased risk of CV disease. (79) This would seem at odds with a uniquely designed genetic analysis of single nucleotide polymorphisms (SNPs) of the SOST gene associated with increased BMD from several large population databases. This analysis revealed at least one SNP that imposed an elevated CV risk, particularly for myocardial infarction and coronary revascularization. (80) This finding would support the black- box warning by the FDA. However, when considered in the context of myocardial infarction risk reduction in the zoledronate trial of osteopenic women, suggestive of cardioprotection by BPs, these data provide a compelling research justification an RCT with a vascular primary outcome. Presently, it is still uncomfortably uncertain if the romosozumab increases CV events or BPs suppress CV events.

The Future
In the big data age, it is becoming easier to investigate in a rapid and high throughout manner, "off-target" effects of common medications, albeit not without the risk of confounding. There is a business case for this; most drugs have a finite lifespan under patent so the window for pharmaceutical companies to financially exploit their invention is limited. Repurposing of existing medications known to be safe by expanding the indication thus has enormous attraction. A recent success story of this has been the CV efficacy of sodium-glucose co-transporter 2 inhibitors in patients without diabetes. (81) Equally, from a public health standpoint there is merit in looking for and confirming putative "offtarget" effects. Many osteoporosis medications, particularly alendronate, are currently available as a generic. Thus, if a genuine "off-target" effect is established (that is to say, demonstrated in an adequately powered RCT) and regulatory authorities grant an expanded indication, this could potentially save healthcare systems a significant amount of money. This is already happening, one example being ticagrelor. Originally marketed as an anti-platelet agent for the treatment and prevention of stroke and coronary outcomes, the pivotal efficacy trial demonstrated reduced pulmonary events, and this has been followed up with studies demonstrating antimicrobial properties. (82)(83)(84) The natural endpoint of repurposing is eventual incorporation into the approval process. There is precedent for this, as new agents for diabetes must now demonstrate safety as well as CV efficacy. One may argue that the links between bone disease and CV disease is just as strong as that between diabetes and CV disease. Thus, given the risk of CV outcomes imposed by osteoporosis and the high ASVD burden in this population, there can be an argument for this to also occur for new skeletal agents. The experience of romosozumab shows that the field seeks this evidence; and it would be wiser to have this data produced in the setting of a large, well-designed RCT rather than relying on the eventual churn of reviews and subpar meta-analyses. Such large, welldesigned RCTs are near prohibitively expensive and pharmaceutical companies are likely to resist subjecting their novel agents to this scrutiny. Thus, there is a role for well-designed cohort studies to provide real-world evidence and work in tandem with RCTs. (85,86)

Conclusion and Research Agenda
The literature examining the potential CV harms or benefits of antifracture medications is now quite substantial. This is helped by more rigorous reporting, where registered trials are required to report adverse drug reactions (ADRs). The systematic collection of ADRs both in trials and population-wide health systems through electronic medical records and claims databases means that the body of real-world evidence is substantial. Generally, these findings have been complimentary to findings in RCTs. However, this has not led to firm conclusions. First, adverse event reporting from RCTs means that the majority of evidence on this topic is secondary and subject to bias and being underpowered. Meta-analyses, in an attempt to overcome the issue of power, have largely proved unhelpful and are often poorly conducted. By way of example, a meta-analysis of PTH-analogues included the pivotal trial by Neer and colleagues. (59) This trial was included in summary estimates despite not reporting specific CV events in the primary publication nor are data available on the trial's registration page. Not reporting events does not necessarily mean zero events. The overarching question of the CV safety for antifracture medications can only definitively be answered in an RCT. There is particular need for an RCT of BPs with a primary vascular endpoint in order to allay criticism that interpretation of safety data needs to be cautious. Further, such an RCT needs to be eventdriven to avoid overinterpretation of low event rates. There may be an ethical concern for conducting such a trial of "repurposing" a medication. Is it justified to apply a medication to examine an "off-target" effect if proven treatments for those "off-target" effects already exist? However, patients with osteoporosis have a high ASVD burden and likely other adverse risk markers so the balance of benefit and harm may fall marginally in favor of the trial. Overall, there is need to optimize CV management for improved skeletal outcomes. Furthermore, there is need to better understand the clinical and biological links between skeletal and CV disease because antifracture medications appear to have no effect on aortic calcification (a robust marker of both skeletal and CV risks). (48,58) Therefore, exploring other mechanisms such as potential electrophysical effects, antithrombotic effects, effects on autonomic function after iv infusion, or plaque stabilization effects may offer a window into the bone-vascular axis. In conclusion, the clinical message should be that osteoporosis medications have a very good safety record and that there is a clear research need to study the potential CV benefits that may, perhaps surprisingly, accompany restoration of bone health. (71,87,88)