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Abstract

There is mounting evidence of an association between osteoporosis and cardiovascular disease that extends beyond shared risk factors for these conditions. In turn, the medications used to treat each of these conditions can have effects that impact the other organ system: medications used in heart disease have the potential to affect bone health, while osteoporosis medications may modify cardiovascular health. While data in this subject area are limited by the paucity of large randomized controlled trials with bone mineral density or fracture risk as primary outcomes, this review explores the data available that can provide some insight into these reciprocal effects of medications on bone and heart health. Data on bone health effects of the loop and thiazide diuretics, beta blockers, calcium channel blockers, statins, warfarin, sodium-glucose cotransporter 2 inhibitors, metformin, and medications impacting the renin–angiotensin–aldosterone system are examined; the cardiovascular effects of osteoporosis therapies and vitamin D are also discussed. Importantly, while most data in this realm are inconclusive, recognizing the parallels between cardiovascular and bone disorders and how this is reflected in medication effects might prompt the clinician to consider the indirect impact of drug regimens when making therapeutic choices for patients with osteoporosis and heart disease.

Keywords

anti-osteoporotic medications bone density cardiovascular disease fracture osteoporosis

Introduction

Cardiovascular disease (CVD) and osteoporosis are major public health concerns in the United States and worldwide.^1–3 According to data from the National Health and Nutrition Examination Survey (NHANES) 2015–2018, the overall CVD prevalence (coronary heart disease, heart failure, and stroke only) was 9.3% (26.1 million) in 2018.¹ Similar NHANES data in 2017–2018 revealed that approximately 12.6% of adults aged 50 years or older have osteoporosis and 43.1% are at risk of developing osteoporosis, with the trend of osteoporosis among women increasing from 14.0% in 2007–2008% to 19.6% in 2017–2018.² While both diseases have traditionally been thought to have little in common, there is growing evidence that CVD and osteoporosis may not only share clinical risk factors but also share common pathophysiologic pathways.^4–6 Advancing age, menopause, decreased physical activity, diabetes mellitus, rheumatologic conditions, tobacco, and alcohol use all diminish bone health and are linked to the development of atherosclerosis.^4,5,7

Several observational studies have found a link between osteoporosis and CVD. In 25,000 women above 50 years of age, Park et al. discovered that the diagnosis of osteoporosis and lower bone mineral density (BMD) was independently associated with an increased risk of atherosclerotic CVD-related death, non-fatal myocardial infarction, and non-fatal ischemic stroke. Furthermore, even after controlling for age, BMI, hypertension, type 2 diabetes, hyperlipidemia, tobacco use, and prior fracture, osteoporosis was associated with a doubling of the risk of cardiovascular death.⁸ Tankó et al.⁹ also found that women with osteoporosis had a 3.9-fold higher risk of cardiovascular events than women with low bone mass, and that this increased risk could not be explained by common risk factors alone. In a population-based study in Olmsted County, Minnesota, patients with a new diagnosis of heart failure had increased risk of prior fractures (OR 1.39, 95% CI 1.07–1.81), particularly hip fractures.¹⁰ Others supported these data, as evidenced by a meta-analysis published in 2019 which found that heart failure was associated with increased risk of all fractures (RR 1.66, 95% CI 1.14–2.43), particularly hip fractures (RR 3.45, 95% CI 1.86–6.40).¹¹ Furthermore, previous meta-analyses have indicated an association between low bone density and surrogate markers of CVD as signified by carotid artery calcification, carotid intima-media thickness, and pulse wave velocity.¹²

There are several common pathways that have been proposed to lead to osteoporosis and CVD. Changes in the expression of factors and proteins that can impact tissue mineralization,^13–16 proliferation of inflammatory mediators^17–19 changes in lipid metabolism,^20,21 hormonal fluxes, such as rise in parathyroid hormone (PTH),^22–24 electrolyte disturbances, such as hyponatremia, and changes in the sympathetic nervous system^25–27 are all examples of factors that can not only influence vascular health but may also impact bone metabolism. Given the presence of common pathways that can lead to osteoporosis and CVD, the aim of this review is to explore the question of whether medications prescribed to treat a cardiac condition may have bone effects—or if medications intended to treat osteoporosis may have cardiovascular effects. This narrative review focuses on the most commonly used cardiovascular and osteoporosis medications, and their effects on bone and cardiovascular health. The PubMed Library was searched for English language articles from relevant peer-reviewed publications using search terms including “fracture,” “osteoporosis,” “low bone density,” “cardiovascular disease,” “heart failure,” and the names of the various medications discussed in this review. The studies reviewed were diverse. Cell culture and animal studies were included to elucidate the mechanisms by which medications affected bone or cardiovascular health. Otherwise, the review focused on the discussion of findings from clinical studies, including placebo-controlled trials, secondary analyses, cross-sectional studies, and meta-analyses. The findings were critiqued and incorporated in a narrative review.

Cardiovascular medications and their effects on bone health

Of the commonly prescribed medications for cardiovascular conditions, some have been shown to be beneficial, while others have a more detrimental effect to bone health.^28,29 Highlighted in the medications section below are some of the studies that have examined the bone effects of cardiovascular medications.

Loop diuretics

Loop diuretics have been linked with an increase in urinary calcium elimination which results in a decrease in serum calcium and increase in PTH levels. A group of otherwise healthy postmenopausal women with osteopenia confirmed by a dual-energy X-ray absorptiometry (DXA) scan was randomly assigned to receive bumetanide or a placebo. After 12 months, in women on bumetanide treatment, PTH increased by 5.6% (p = 0.001) compared to placebo. Bumetanide treatment increased the bone resorption marker C-telopeptide while decreasing the bone formation marker osteocalcin. When compared to the placebo group, BMD in the bumetanide group decreased at the spine, femur, and ultradistal forearm.³⁰ In a case series of elderly patients admitted for heart failure evaluation and treatment, loop diuretics were associated with an increase in the risk of osteoporosis (OR 2.52, 95% CI 1.20–5.27) after adjusting for other risk factors, such as age, weight, gender, and other medication use.³¹

In a group of 55,780 women aged 55–82 years participating in the Nurses’ Health Study, use of loop diuretics was associated with an increase in risk for radiologically confirmed vertebral fractures after multiple variable adjustments (RR 1.59, 95% CI 1.12–2.25).³² The use of loop diuretics was found to increase the risk of hip fractures in a large cohort study from the Norwegian database that included 28,883 postmenopausal women aged 70 years and older (standardized ratio 1.6, 95% CI 1.3–1.9).²⁸ In a retrospective case series of patients above the age of 50 years admitted to the emergency department for osteoporotic fractures, patients admitted for osteoporotic fractures used more diuretic agents (p < 0.0001), including loop diuretics, spironolactone, and amiloride (p = 0.02, 0.02, and 0.01, respectively).³³ A meta-analysis of 13 studies examining the relationship between loop diuretic use and fracture risk included 842,644 participants and 108,247 fractures. This study found that participants who used loop diuretics had a 15% higher risk of all fractures (95% CI 1.04–1.26, p < 0.01) and a higher risk of hip fractures (RR 1.14, 95% CI 1.08–1.19, p < 0.01) than those who did not use loop diuretics.³³ Although not confirmed in randomized controlled trials (RCTs), the data presented here suggest that using loop diuretics increases the risk of osteoporosis and osteoporotic fractures, including hip and spine fractures, by increasing urinary calcium excretion and bone degradation.

Thiazide diuretics

Thiazide diuretics are thought to benefit bone health, most likely due to a decrease in renal calcium excretion. In a randomized short-term study of otherwise healthy postmenopausal women with low BMD, bendroflumethiazide treatment was associated with a dose-dependent decrease in urinary calcium excretion, and a moderate dose-dependent increase in bone formation marker, osteocalcin.³⁰ A recent meta-analysis examined the use of thiazides and fracture risk in 19 case-control studies with 496,568 participants (79% were female and average age was 72 years) and 21 cohort studies with 4,418,602 participants (63% were female and average age was 73 years). The findings from the case-control studies showed a 13% reduction in fractures (RR 0.87, 95% CI 0.7–0.99); the findings from the cohort studies showed a trend toward fracture reduction but did not reach statistical significance (RR 0.93, 95% CI 0.83–1.05).³⁴ A cohort in the Rotterdam study, a prospective, population-based study of elderly people, showed a reduction in hip fractures after prolonged (> 365 days) thiazide treatment (HR 0.99, 95% CI 0.97–0.99).³⁵ A Cochrane meta-analysis of 21 studies with 399,362 participants found a reduction in hip fractures in adults above 40 years of age with current thiazide use compared to non-users (RR 0.76, 95% CI 0.64–0.89), but the quality of evidence was rated low.³⁶

A positive effect of thiazide use on BMD was shown in a population-based prospective cohort of elderly men and women. The study found that taking thiazides reduced the risk of osteoporosis (RR 0.08, 95% CI 0.02–0.14).³⁷ A 3-year RCT of long-term thiazide treatment on bone density was conducted in a group of healthy elderly adults who were randomly assigned to receive hydrochlorothiazide (HCTZ) 12.5 and 25 mg daily or placebo. At 3 years, women who received HCTZ 25 mg had a modest dose-dependent increase in BMD compared to placebo of 1.43 (95% CI 0.25–2.60)% at the hip and 1.30 (95% CI −0.22 to 2.8)% at the spine. This was less significant in men, possibly because there were fewer participants enrolled.³⁸

Although thiazide diuretics have been shown to be beneficial on BMD and fracture risk, there are some concerns, including the risk of hyponatremia, associated with thiazide treatment. Chronic hyponatremia is considered a fracture predictor to the extent that it has been proposed to the fracture risk assessment tool (FRAX).³⁹ Long-term mild hyponatremia (130–135 mmol/L) in a prospective study of community-dwelling participants above 55 years of age was associated with increased non-vertebral (HR 1.39, 95% CI 1.11–1.73, p < 0.04) and vertebral fractures (OR 1.61, 95% CI 1.00–2.59, p = 0.049) after adjusting for risk factors.⁴⁰ A case-control study of patients admitted to the emergency department with moderate hyponatremia revealed a ninefold increase in fall risk. Patients with hyponatremia had a decrease in steady gait and attention.⁴¹ In a population-based study in the Netherlands and the NHANES III database, participants above the age of 50 years had a higher risk for osteoporosis when their lower sodium levels were low.^42,43 A meta-analysis of 15 studies found hyponatremia to be associated with an increased risk for falls (OR 2.14, 95% CI 1.71–2.67, p = 0.00), and fracture data from eight of these studies found hyponatremia to be associated with an increased risk of fractures (OR 1.61, 95% CI 1.35–1.93, p = 0.00).⁴⁴

The effect of thiazide-associated hyponatremia was evaluated in patients from Taiwan’s national insurance database. Thiazide-associated hyponatremia was associated with an increase in total fracture (Incidence RR 1.44, 1.15–1.80, p = 0.001) when compared to a matched control group in this group of patients, of whom 86% were above 60 years of age.⁴⁵ In the Nurses’ Health Study, women above the age of 55 years treated with thiazides had a higher risk of vertebral fractures (HR 1.47, 95% CI 1.18–1.85).³² A link to treatment duration could not be evaluated, and sodium levels were not included in the analysis. The duration of thiazide treatment was discovered to be important in a cohort of Medicare beneficiaries above the age of 65 years. Within 2 weeks of starting treatment, the risk of fracture increased (standard mortality ratio, HR 1.40, 95% CI 0.78–2.52).²⁹ Similar data were found in a population-based cohort study of thiazide initiation within 2 years after stroke. Short-term use of thiazides for less than 90 days increased the risk of vertebral fracture compared to non-use (aHR = 1.38, 95% CI 1.02–1.88, p = 0.039). There was no difference in vertebral fracture risk with longer term thiazide use.⁴⁶ The observed increase in fracture risk with thiazide-induced hyponatremia was only found in univariate analysis, but was no longer evident after controlling for age and BMI in two retrospective studies in the elderly.^47,48

In summary, thiazide diuretics have been shown to reduce the risk of fractures while slightly increasing bone density. Thiazide-associated hyponatremia, however, was found to attenuate this benefit, which is concerning for the risk of falls and fractures.

Beta-blockers

Beta-blockers have long been used to treat certain types of heart failure by reducing the sympathetic nervous system stimulation (SNS). Data supporting the role of SNS in bone metabolism are less well known. In animal studies, central SNS system activation has been linked to increased osteoblast expression of receptor activator of nuclear factor-B ligand (RANKL) and thus increased osteoclast activity.^25,26 Presence of beta-1 and beta-2 receptors was found on human osteoblasts.²⁷ As a result, it was postulated that adrenergic blockade might have a beneficial effect on bone in humans, especially in the setting of heart failure with increased SNS activity.

A meta-analysis⁴⁹ of 13 studies involving more than 907,000 women and men found that beta-blocker use reduced hip fracture by about 17%. A retrospective analysis of the Korean health insurance database evaluated 501,924 elderly patients who were treated with a single antihypertensive agent and had subsequent fractures measured over 1.5-year period. After controlling for confounding variables, patients treated with antihypertensive agents other than beta-blockers had an increased risk of all fractures in men (aHR 1.56, 95% CI 1.42–1.72) and in women (aHR 1.44, 95% CI 1.36–1.51) and increased risk of hip fractures in men (aHR 2.17, 95% CI 1.45–3.24) and women (aHR 1.61, 95% CI 1.31–1.98) compared to beta-blocker treatment. The protective effect became increasingly significant with treatment for more than 180 days.⁵⁰ In a Framingham study, beta-blockers increased bone density at the femur and spine in a dose-dependent manner. Beta-blocker therapy improved bone microarchitecture and decreased bone resorption marker (C-telopeptide) in postmenopausal women.²⁷ These findings suggested that treatment with beta-blocker was associated with a lower risk of fracture and higher bone density, which was likely related to the decrease in adrenergic signaling in osteoblasts and associated RANKL production.

Statins

Statins lower cholesterol by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is involved in cholesterol synthesis. Since disturbances in lipid metabolism can attenuate bone formation and increase bone turnover while promoting bone marrow adipogenesis, it has been posited that statins may have a benefit to bone health. This class of drugs has been shown to confer bone-protective effects not only in animal studies^51,52 but also in human studies. Edwards et al. compared BMD at the spine and hip in postmenopausal women in the United Kingdom, taking statins for hypercholesterolemia (simvastatin, pravastatin, atorvastatin, and fluvastatin) to that of matched controls. After a median of 48 months, statin users had higher BMD at the spine and hip even when adjusted for age, height, and weight. This difference between statin-treated and control groups persisted even after participants on hormone replacement therapy were excluded from the analysis.⁵³ Other studies—mostly population-based cross-sectional, longitudinal or case-control studies, with none being randomized controlled studies—in various populations have indicated an improvement in BMD measured by DXA,^53–56 bone geometry, and microarchitecture as assessed by high-resolution peripheral quantitative computed tomography⁵⁴ and a reduction in fracture risk^57–61 in patients treated with statins. However, not all studies have found a correlation between statin therapy and significant improvement in bone turnover marker,^62,63 or in BMD.^63–65 Several meta-analyses have examined the relationship between bone health and statin therapy and discovered that statin therapy correlates with lower rates of fractures^66–68 and increased BMD, although improvement in BMD was observed at variable sites.^66,68–70

A prospective RCT of 212 patients with hyperlipidemia treated with simvastatin (40 or 80 mg per day adjusted to meet lipid targets), fenofibrate, or gemfibrozil showed that individuals treated with simvastatin had increased marker of bone formation (N-terminal propeptide of procollagen type 1), reduced marker of bone resorption (C-telopeptide), and increased BMD at the distal radius after 18 months of treatment when compared to the non-statin group.⁷¹ In a population-based nested case-control study in the United Kingdom, patients receiving statin therapy had a nearly halved fracture risk (OR 0.55, 95% CI 0.44–0.69) when compared to those who were not treated with lipid-lowering medications. Furthermore, those treated with other lipid-lowering agents did not appear to have a significant reduction in fracture risk.⁷² However, Ray et al. discovered no significant difference in hip fracture rates between statin users and those treated with other lipid-lowering agents. Ray et al.⁷³ suggested that the bone-protective effect of statins may result from confounding factors: statin-treated populations may include younger statin-treated patients with long-standing statin use, whereas older and more frail patients may not be candidates for statins; statin-treated patients with hyperlipidemia may also have greater body mass, which may have a protective effect against osteoporosis.

There is also conflicting evidence regarding whether statins may have a dose-dependent effect. Leutner et al. reviewed claims data from Austria over a year to assess the relationship between statin types and doses with osteoporosis. Low-dose statin were associated with lower incidence of osteoporosis (OR 0.7 in simvastatin, 95% CI 0.56–0.86, p < 0.01; OR 0.39 in lovastatin, 95% CI 0.18–0.84, p < 0.05; OR 0.68 in pravastatin, 95% CI 0.52–0.89, p < 0.01; OR 0.69 in rosuvastatin, 95% CI 0.55–0.87, p < 0.01), whereas high-dose statins correlated with higher incidence of osteoporosis (OR 1.64, 95% CI 1.31–2.07 in > 40–60 mg simvastatin; OR 3.3, 95% CI 2.36–4.62 in > 60–80 mg of simvastatin, with a similar trend seen in atorvastatin and rosuvastatin).⁷⁴ Conversely, a case-control study in Taiwan involving 7464 elderly subjects diagnosed with hip fracture between 2000 and 2013, and controls discovered an inverse relationship between statin dose and hip fracture risk.⁶¹ A longitudinal cohort study based on Taiwanese National Health Insurance claim data investigated the link between various statins and new-onset osteoporotic fractures (NOFs). This study followed over 170,000 patients with hyperlipidemia and identified 44,405 patients who had NOFs. The risk of NOF was lower in those treated with atorvastatin and rosuvastatin when compared with simvastatin, with the authors concluding that statin potency may have a relationship to the degree of bone health benefit.⁷⁵ The same group conducted a retrospective population-based cohort study of patients receiving statin therapy and found lower rates of new-onset osteoporosis in statin-treated subjects; additionally, the risk of new-onset osteoporosis was lower with escalating doses of statin and high-potency statins.⁷⁶

Statins and their effect on osteoporosis remain an active area of research. Xiong et al. recently outlined their protocol for conducting a systematic review and network meta-analysis to study the effects of different statins at varying dosages on osteoporosis. They hope to shed light on whether there is a benefit (in fracture reduction and BMD improvement) to treating osteoporosis with different statin regimens by analyzing RCTs in which statins were used for osteoporosis treatment.⁷⁷

Warfarin

Warfarin serves as an oral anticoagulant by inhibiting the vitamin K-induced γ-carboxylation of glutamic acid (Glu) residues on clotting factors II, VII, IX, and X. Warfarin’s effects may extend to bone metabolism because vitamin K is required as a cofactor for the γ-carboxylation of Glu residues to gamma-carboxyglutamate (Gla) residues, which induces the synthesis of bone matrix proteins, such as osteocalcin, matrix Gla protein, and protein S.⁷⁸ Warfarin use raises circulating levels of nonfunctional undercarboxylated proteins, such as osteocalcin,^79,80 but whether such changes in the synthesis of bone matrix proteins affect fracture risk or BMD is debatable. Some animal studies found no change in BMD, bone turnover, and bone strength with warfarin therapy,^80,81 while others found decline in measured bone strength, trabecular bone volume, decreased bone formation, and increased bone resorption with warfarin treatment.^82,83

Warfarin embryopathy, which encompasses the bone deformities caused by fetal exposure to warfarin, is well known. However, the clinical data on warfarin’s effect on the adult skeleton have been mixed. In a case-control study conducted by Philip et al.,⁸⁴ warfarin use was linked to lower BMD. Beyond an association with lower BMD, vitamin K antagonist (VKA) therapy has been correlated with an increase fracture risk, in a population-based retrospective cohort study⁸⁵ and case-control study⁸⁶—in Gage et al.’s⁸⁷ retrospective cohort study comparing 4461 Medicare beneficiaries prescribed warfarin to 7587 who were not prescribed warfarin, the odds ratio of fracture was 1.63 (95% CI 1.26–2.10) in men treated with warfarin for more than 1 year. In contrast, in a prospective observational study of postmenopausal women, those who self-reported warfarin use had no difference in BMD at the hip and heel after 2 years, nor any difference in fractures during 3.5 years of follow-up, when compared to warfarin non-users.⁸⁸ Similarly, other studies in elderly patients found that warfarin use was not associated with a decline in BMD⁸⁹ or an increased risk of fracture.^89–91

Clinical studies have been limited by difference in warfarin treatment duration, populations studied, and the sites at which BMD and fractures were assessed and reported. A larger scale analysis of the existing data did not reveal a strong association between warfarin use and decline in BMD or increased fracture risk. Previously, data from a meta-analysis of nine cross-sectional studies by Caraballo et al.⁹² found an association between VKA use and decline in BMD at the ultra-distal radius site, but not at the lumbar spine, femoral neck, femoral trochanter, or distal radius. Veronese et al. performed a meta-analysis of fracture risk and BMD in patients treated with VKAs. They discovered that when medical controls were used to eliminate confounding medical illness that could contribute to fracture risk, the higher fracture risk and lower BMD correlated with vitamin K antagonism were no longer apparent.⁹³ A meta-analysis of 22 observational studies and one randomized controlled study involving over 1 million subjects showed VKD use did not increase the risk of overall fracture when compared to controls, but the fracture risk increased in women and those above the age of 65 years.⁹³

The effects of warfarin on bone metabolism, while demonstrated in vivo, have not translated to clear and consistent clinical evidence for increased fracture risk or decreased BMD. Even in the absence of compelling data to support warfarin avoidance in patients with metabolic bone disease, such as osteoporosis, warfarin’s effects may still be important to consider when choosing anticoagulant. In their meta-analysis of studies of fracture in warfarin and non-VKA oral anticoagulants, Huang et al.⁹⁴ discovered that the warfarin-treated group had a higher risk of fracture than the other anticoagulant groups. These findings have been echoed in other meta-analyses,⁹⁵ including a meta-analysis assessing fractures among subjects treated with VKA and various direct oral anticoagulants (DOACs), which found that the risk of osteoporotic fracture was greatest in groups treated with VKA versus DOACs.⁹⁶ Hence, when prescription of other anticoagulants is an option, the evidence surrounding warfarin’s effects on bone health—albeit conflicting—may need to be weighed when making anticoagulant choices. Whether the VKAs, such as warfarin, truly are associated with reduced BMD and increased fracture risk, and whether different anticoagulants are detrimental to bone or may offer protective effects remain an area of uncertainty and potential future research.

Spironolactone

Spironolactone is an aldosterone receptor antagonist that modulates the renin–angiotensin–aldosterone system. Animal studies have shown that hyperaldosteronism, a consequence of heart failure, promotes a pro-inflammatory state⁹⁷ in which there is also increased excretion of calcium and magnesium, a rise in PTH, and a decline in BMD and bone strength.^98,99 Furthermore, spironolactone can mitigate the negative effect of hyperaldosteronism in animals by improving hypercalciuria and hypermagnesuria while also increasing BMD and bone strength.^98,99 Similarly, in animals, spironolactone can reduce the hypercalciuric and hypermagnesemic effects of hyperaldosteronism and furosemide therapy, and the decline in femur BMD.¹⁰⁰

Human case-control, retrospective cross-sectional, and prospective studies of subjects with primary hyperaldosteronism have revealed a similar presentation with hypercalciuria, hyperparathyroidism, low BMD,¹⁰¹ low trabecular bone score,¹⁰² and increased vertebral fracture risk.^103,104 While studies of surgical and medical treatment of primary hyperaldosteronism have shown that treatment of primary hyperaldosteronism improves adverse bone effects,¹⁰⁵ Adolf et al.’s study of postmenopausal women with primary hyperaldosteronism suggested that medical therapy with spironolactone may offer a unique additional benefit. In this observational longitudinal cohort study of 36 postmenopausal women with primary hyperaldosteronism, those treated with spironolactone had a greater reduction in bone turnover markers than their peers who underwent adrenalectomy;¹⁰⁶ however, it is important to note that those with unilateral primary hyperaldosteronism (who were more likely to undergo adrenalectomy) had significantly higher aldosterone levels at baseline compared to those with bilateral disease and this may have been a factor contributing to differences in bone turnover markers. There has been evidence suggesting a bone-sparing effect of spironolactone, with spironolactone preserving BMD in women with polycystic ovary syndrome (treated with GnRH agonists,¹⁰⁷ but also contrary evidence of adverse BMD effects of spironolactone in women with androgen excess).¹⁰⁸ Carbone et al.¹⁰⁹ discovered a lower fracture risk in male congestive heart failure (CHF) patients treated with spironolactone in their medical record review of 4735 male US veterans with CHF, with an odds ratio of 0.575 (95% CI 0.346–0.955) for total fracture in those receiving spironolactone. While further study is needed, preliminary evidence suggests that spironolactone may modulate the interaction between the renin–angiotensin–aldosterone system and skeletal systems by influencing calcium regulation, PTH, and inflammatory pathways.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), such as spironolactone, affect parts of the renin–angiotensin–aldosterone axis and are widely used in the treatment of hypertension, heart failure, and have a role in cardiac and renal protection. Renin–angiotensin system (RAS) activation has been linked to a pro-inflammatory and pro-atherogenic effect on vessel walls.¹¹⁰ The effect of RAS activation likely extends to bone. Angiotensin II has been shown in vitro to cause osteoblast population expansion.¹¹¹ Angiotensin II stimulates osteoclastic activation, possibly via its effects on osteoblasts¹¹² and ACE inhibitor treatment reduces this stimulatory effect on osteoclasts.¹¹³ Animal studies showed that treatment with an ACE inhibitor prevents the ovariectomy-induced decline in BMD and increase in markers of bone resorption.¹¹² Similarly, angiotensin II type 2 receptor blocker treatment resulted in enhanced bone formation, reduced bone resorption, and increased bone mass in animals.¹¹⁴

Clinical studies have suggested higher BMD in ACE inhibitor-treated subjects: a cross-sectional study of 3887 elderly Chinese subjects noted higher femoral neck BMD in women and higher femoral neck, total hip and lumbar spine BMD in men treated with ACE inhibitors, even after controlling for factors that could impact BMD, such as age, weight, other medications used, and various comorbid conditions, including diabetes, heart disease, and tobaccos use.¹¹⁵ While the use of ACE inhibitors¹¹⁶ and ARBs has been correlated with reduced fracture risk¹¹⁷ in large case-control and prospective studies, not all studies have drawn such positive correlations. A population-based longitudinal cohort study of 1144 elderly Chinese subjects with hypertension showed an increased risk of new onset osteoporotic fracture in those treated with ACE inhibitors (HR 1.64, 95% CI 1.01–2.66), while ARB therapy showed no association with fracture.¹¹⁸ Kwok et al.¹¹⁹ observed greater loss of BMD at the total hip and trochanter in ACE inhibitor-treated subjects over 4 years of follow-up in their prospective cohort study of elderly men treated with ACE inhibitors and ARB, whereas no significant bone loss was observed with ARB treatment. It is worth noting that the different modes of RAS inhibition between ACE inhibitors and ARB, and the duration of exposure to these medications may contribute to the differences in drug effects between studies: Kwok et al.,¹¹⁷ in the same aforementioned elderly male population found that while both ACE inhibitors and ARB were associated with lower non-vertebral fracture risk, a longer duration of ARB treatment showed a greater reduction in non-vertebral fractures risk. A meta-analysis of studies assessing fracture outcomes in various antihypertensives included one study of ACE inhibitors, which found that RAS blockade reduced the risk of any fracture when compared to controls.¹²⁰ Kunutsor et al.¹²¹ specifically focused on the effect of RAS inhibition by ACE inhibitors and ARB and its effect on fracture risk in their population-based prospective cohort and their meta-analysis of 11 prospective cohort studies: data from meta-analysis indicated that the use of RAS blockers was associated with reduced hip fracture risk. While some studies suggest a beneficial effect on bone health with RAS blockade, the quality and depth of data in this area is limited.

Calcium channel blockers

Osteoblasts express various types of calcium channels.¹²² Some calcium channel blockers have been shown in vitro to stimulate osteoblast differentiation and function,^123,124 while in vivo, calcium channel blockers promoted the differentiation of bone marrow stromal cells into osteoblasts and improved trabecular thickness and number, and BMD when compared to controls.¹²⁵ While other animal studies citing bone benefits calcium channel blockers treatment,¹²⁶ not all studies have consistently shown benefit—and benefit may be specific to particular subtypes of calcium channel blockers.¹²⁷

In human studies, some data have suggested that nifedipine reduced PTH and osteocalcin levels in postmenopausal osteoporotic women,¹²⁸ whereas other data suggested that nifedipine, when compared to verapamil, may promote PTH secretion that did not persist at the 4-week follow-up.¹²⁹ A study of patients treated with nifedipine for CAD or hypertension showed increased serum calcium and phosphate levels over the 24-month period of treatment, but no changes in bone turnover markers or significant changes in BMD.¹³⁰ An 8-week course of amlodipine treatment (with or without hormone replacement therapy) in 20 postmenopausal women had no significant effects on bone turnover markers, nor changes in serum and urine calcium and phosphorus.¹³¹

In studies that have evaluated the effect of bone density and fracture risk, calcium channel blockers have shown variable outcomes: either no effects, benefit, or detriment. A study that compared over 30,000 fracture cases to over 120,000 matched controls from the UK-based General Practice Research Database (GPRD) found no difference in fracture risk for subjects taking calcium channel blockers.¹³² Similarly, an observational study of medication adherence found no effect on fracture risk in calcium channel blocker-treated patients.¹³³ A large cross-sectional study of more than 3000 Chinese men and women found that using calcium channel blockers was associated with higher BMD at the lumbar spine in women (higher by 0.017 g/cm², p = 0.026), but no significant difference in BMD at other sites or in men.¹¹⁵ A case-control study of patients in a national register (124,655 cases with fracture and 373,962 age- and gender-matched controls) found that using calcium channel blockers (among other antihypertensives) lowered the risk of any fracture by 6% (OR 0.94, 95% CI 0.91–0.96).¹¹⁶ Similarly, large population-based cohort studies in Denmark,¹³⁴ Norway,²⁸ and Taiwan, China¹¹⁸ showed patients treated with calcium channel blockers had reduced incidence of fragility fracture, hip fracture, and new onset of osteoporotic fracture, respectively. However, increased fracture risk has also been reported with calcium channel blocker use.¹³⁵ An analysis of a South Korean claims database revealed fracture outcomes in 528,522 subjects over a mean follow-up of 1.9 years who were either initiated on a single-drug antihypertensive or were not on therapy. Those treated with calcium channel blockers showed significantly increased risk of fractures (HR 1.23, 95% CI 1.19–1.28, p < 0.05) compared with non-users when other clinical factors including osteoporosis were controlled.¹³⁶ In summary, the data on calcium channel blockers are contradictory; however, the balance of studies demonstrating neutral or beneficial effects on bone is greater.

Sodium-glucose cotransporter 2 inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel glucose-lowering agents that inhibit glucose reuptake at the renal proximal tubule, where most glucose is reabsorbed resulting in increased urinary glucose excretion. SGLT2 inhibitors have exhibited cardiovascular and renal benefits in type 2 diabetes patients^137–140 and patients with heart failure.^141–144 Canagliflozin, dapagliflozin and empagliflozin are Food and Drug Administration-approved medications in this class. The data and safety committee,¹⁴⁵ which published the higher fracture incidence in the canagliflozin group of the CANagliflozin cardioVascular Assessment Study (CANVAS) in 2013, sparked concern about the effect of SGLT2 inhibitors on bone health and fracture. Watts et al.¹⁴⁶ analyzed data from CANVAS and eight pooled non-CANVAS studies and reported the increased incidence of fractures with canagliflozin (4.0%) versus placebo (2.6%) in CANVAS study, while the fracture risk was not observed in canagliflozin treatment in non-CANVAS studies. A subsequent study by Neal et al.,¹⁴⁷ which included 10,142 participants with type 2 diabetes and high cardiovascular risk from the pooled data of CANVAS and CANVAS-R trials to assess cardiovascular, renal, and safety outcome found an increased rate of all fractures (15.4 versus 11.9 per 1000 patient-years; HR 1.26, 95% CI 1.04–1.52) in CANVAS but not in CANVAS-Renal (HR 0.76, 95% CI 0.52–1.12). While there was no definite explanation for the difference in fracture risk observed in CANVAS versus CANVAS-R studies,¹⁴⁸ it is noteworthy that the data on fall risk or event during the trial were limited. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, a RCT of type 2 diabetes with kidney disease found no increased fracture risk in canagliflozin group.¹⁴⁹ As a result, the finding of fracture risk in CANVAS likely appeared to be a chance observation, though the possibility remained whether this medication may have exerted its fracture risk through other mechanisms, such as increased risk of falls due to limited data.¹⁴⁸

Other studies of different SGLT2 inhibitors on cardiovascular outcome found no evidence of increased fracture between treatments and placebo groups. The finding from Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial, which randomly assigned patients with type 2 diabetes who had or were at risk for CVD to dapagliflozin or placebo, found no difference in fracture risk between dapagliflozin and placebo (5.3% versus 5.1%, HR 1.04, 95% CI 0.91–1.18, p = 0.59).¹⁵⁰ Similarly, fracture rates were similar between empagliflozin (3.8% versus 3.9%) compared to placebo group in the EMPA-REG OUTCOME which was a randomized, double-blind, placebo-controlled trial of empagliflozin on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events.¹⁵¹ Subsequent several meta-analyses of RCTs failed to demonstrate increased risk of fracture with SGLT2 inhibitors among type 2 diabetes with and without diabetic kidney disease^{137–140,152,153} and in population-based cohort studies.^141,154

Although the effect of SGLT2 inhibitors on fracture risk remains controversial, the potential mechanism of SGLT2 inhibitors on bone metabolism is thought to be through changes in calcium and phosphate metabolism. Data suggest that SGLT2 inhibitors increase tubular phosphate reabsorption and lead to secondary hyperparathyroidism and increased fibroblast growth factor-23, resulting in enhanced bone resorption.¹⁴² Canagliflozin was found to increase bone resorption markers at 6 and 12 months of treatment, which was not observed for other SGLT2 inhibitors (dapagliflozin, ertugliflozin).^143,144,155 A small reduction in bone density at the total femur was observed in the canagliflozin group compared to placebo in a double-blind, placebo-controlled, 2-year trial of over 700 patients with type 2 diabetes.¹⁴³

To date, there has been limited data of SGLT2 inhibitors on fracture risk. The majority of the evidence came from the CANVAS study, while other studies found no increased fracture risk associated with SGLT2 inhibitors. Because this is a relatively new anti-diabetic agent, and most of the clinical trials and observational cohort studies had relatively short treatment duration (between 1–3 years), fracture risk or bone density was not the primary endpoint of the cardiovascular safety trial, and the assessment of fracture risk, which could take a longer period that might not be apparent during the study period. On the bone effect of SGLT2 inhibitors, cautious data interpretation and post-market long-term safety data research are required.

Metformin

Metformin is considered the first-line pharmacological therapy in the management of type 2 diabetes (American Diabetes Association 2022).¹⁵⁶ Its glucose-lowering effect is thought to be due to the activation of the 5’-adenosine monophosphate kinase (AMPK) pathway.¹⁵⁷ Cellular studies have shown that metformin is a potent stimulator of AMPK activation in osteoblasts, resulting in their differentiation and mineralization, and stimulates type 1 collagen production suggesting a direct osteogenic effect.¹⁵⁸ Metformin has an inhibitory effect on osteoclastogenesis, as evidenced by an increase in osteoprotegerin and a decrease in RANKL expression in osteoblast cell culture exposed to metformin, and a decrease in the number of osteoclasts in ovariectomized rats treated with metformin compared to sham-treated rats.^57,159

Metformin’s effect on bone turnover markers has been found to be inconsistent in clinical studies: in a group of 40 postmenopausal women with type 2 diabetes and osteoporosis treated with metformin for 12 weeks, serum osteocalcin, alkaline phosphatase levels, and urine deoxypyridinoline levels were not changed compared to baseline.¹⁶⁰ A subset of young women with polycystic ovarian syndrome from a prospective multicenter placebo-controlled randomized trial showed a 25.7% decline in bone formation marker, procollagen type I amino-terminal propeptide (P1NP), and 31.1% decline in bone resorption marker, carboxy-terminal cross-linking telopeptide of type I collagen (CTX; p < 0.001 for both) in non-obese women after 12 weeks of metformin treatment, but not obese women.¹⁶¹

Several cross-sectional studies looked at bone density and metformin treatment. A retrospective study from China revealed higher T-scores at the lumbar spine, total femur, and femur neck independent of sex, age, BMI, and estimated glomerular filtration rate (eGFR) in middle aged and elderly patients with type 2 diabetes¹⁶² Metformin use was associated with a lower risk of osteoporosis with and without vertebral fracture over a 5-year median follow-up (HR: 0.592, 95% CI: 0.550–0.638).¹⁶³ In contrast, a substudy of the Copenhagen Insulin and Metformin Therapy multicenter randomized placebo controlled trial in patients with type 2 diabetes¹⁶⁴ 18 months of metformin treatment failed to demonstrate a decrease in bone density as measured by BMD and trabecular bone score (TBS) after adjustment of multiple variables, such as type 2 diabetes duration, glycemic control, and BMI. Metformin’s effect on bone health was also investigated in the Diabetes Prevention Program Outcome Study (DPPOS), which included a cohort of patients at high risk of type 2 diabetes.¹⁶⁵ After 12 years of follow-up, metformin was associated with non-significant increase in BMD compared to placebo after adjusting for clinical parameters. An increase in BMD was noted only at the femur neck (+ 0.027 g/cm², 95% CI: 0.0007–0.047, p = 0.009) and when combined analysis of men and women. Regarding the association between fracture risk and metformin,¹⁶⁶ a recent systematic review and network meta-analysis that included a total of 117 RCTs of nine types of anti-diabetic drugs found inconsistent fracture outcome in metformin treatment when compared to other anti-diabetic medications or placebo (RR 0.81; 95% CI 0.14–4.56) with moderate quality of evidence. A systematic review and meta-analysis¹⁶⁷ of six studies comparing metformin users to non-users found a significant inverse relationship between metformin use and risk of fracture (RR 0.82; 95% CI 0.72–0.93). Similarly, metformin use was associated with a lower risk of fracture in a meta-analysis of 12 observational studies (RR 0.86, 95% CI 0.75–0.99).¹⁶⁸ A population-based study in South Korea¹⁶⁹ included a cohort of 37,378 propensity score-matched cohort with type 2 diabetes, half of whom were on metformin for at least one year. There was no significant association between metformin exposure and hip fracture (HR 0.78; 95% CI 0.36–1.69).

In summary, metformin demonstrated positive osteogenic benefits and antiresorptive effects at the cellular level. Clinical studies have shown that metformin treatment can improve bone density and reduce fracture risk, but results have been inconsistent.

Anti-osteoporosis medications and cardiovascular effects

Bisphosphonates

Bisphosphonates are a well-known anti-osteoporosis drug class that is effective at increasing bone density and reducing the risks of vertebral, hip, and non-vertebral fractures in patients with osteoporosis.¹⁷⁰ They primarily inhibit bone resorption directly inhibiting osteoclasts. Bisphosphonates inhibit the enzyme farnesyl pyrophosphate synthase in the mevalonate pathway which is a downstream step of HMG-CoA reductase, part of cholesterol synthesis. Inhibition of farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates (second, third generation) selectively blocks prenylation of signaling proteins in the bone resulting in osteoclast apoptosis.¹⁷¹ In addition to skeletal benefits of bisphosphonates, there has been a lot of interest in potential non-skeletal, especially cardiovascular benefits of this drug class because patients with osteoporosis frequently have coexisting chronic diseases, especially CVD.^172–174 The two main issues highlighted in this section are the bisphosphonates’ potential cardioprotective effects and risk of atrial fibrillation.

Potential mortality and cardiovascular benefit of bisphosphonates

The benefit of bisphosphonates on cardiovascular benefit received attention after unexpected results from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)¹⁷² which was a multicenter, double-blind, placebo-controlled trial, including patients with recent hip fracture who received annual zoledronic acid versus placebo, with the first dose being given within 90 days of hip fracture with median follow-up of 1.9 years. The study demonstrated not only the reduction of the rates of new clinical fracture but also a significant relative risk reduction in mortality following hip fracture by 28% (HR 0.72, 95% CI 0.56–0.93, p = 0.01) and the survival benefit was seen at 16 months. Subsequently, a retrospective post hoc analysis of the HORIZON-RFT attempted to evaluate the potential mediator of mortality reduction and confirmed that mortality reduction was 25% in patients receiving zoledronic acid after adjusting for risk factors (age, sex, cognitive impairment, BMI, diabetes, coronary artery disease (CAD), CHF, hypercholesterolemia, femoral neck T-score, residence before and after hip fracture, time to dosing following hip fracture), and the benefit was similar across all age groups.¹⁷⁵ Patients receiving zoledronic acid were less likely to die from cardiac arrhythmia (interaction p = 0.02) and pneumonia (interaction p = 0.04) compared to placebo,¹⁷⁵ indicating that bisphosphonates may have a protective cardiovascular benefit, though the mechanism of mortality reduction from HORIZON-RFT remained unknown. Reid et al. published the findings of the Fracture Prevention with Zoledronate in Older Women with Osteopenia trial, which involved zoledronic acid infusions every 18 months for 6 years duration in women with osteopenia. This study also found that zoledronic acid may lower mortality (HR 0.65, 95% CI 0.40–1.06).¹⁷⁶ A detailed analysis of the adverse events data revealed a trend toward a reduction of myocardial infarction (HR 0.60, 95% CI 0.36–1.00) and composite cardiovascular endpoints (sudden death, myocardial infarction, coronary artery revascularization, or stroke) (HR 0.76, 95% CI 0.53–1.08) in zoledronic acid group.¹⁷⁷ In contrast, the HORIZON Pivotal Fracture trial (HORIZON-PFT), which examined yearly infusion of zoledronic acid for 3 years in postmenopausal women with osteoporosis did not show the benefit on mortality and CVD.¹⁷⁸ The mortality (3.4% in zoledronic acid versus 2.9% in placebo, p = 0.27) and the myocardial infarction (1.0% in zoledronic acid versus 1.2% in placebo, p = 0.44) were not significantly different between treatment groups. It should be noted that clinical trial data should be interpreted with caution because mortality and cardiovascular events were not the primary endpoints of the studies. Furthermore, each study’s participants may represent a different patient population. The recurrent HORIZON study, for example, included patients who were likely to be frail due to pre-existing hip fractures, whereas other studies included patients who did not have hip fractures.

Several meta-analyses conducted to examine the potential association of bisphosphonates and cardiovascular events and mortality have resulted in uncertain findings. Kim et al.¹⁷⁹ did not find cardiovascular benefit including total cardiovascular events (14 trials; ORs 0.98, 95% CI 0.84–1.14; I² = 0.0%), atrial fibrillation (41 trials; 1.08, 95% CI 0.92–1.25; I² = 0.0%), myocardial infarction (10 trials; 0.96, 95% CI 0.69–1.34; I² = 0.0%), stroke (10 trials; 0.99, 95% CI 0.82–1.19; I² = 5.8%), and cardiovascular death (14 trials; 0.88, 95% CI 0.72–1.07; I² = 0.0%) with bisphosphonate treatment. Subsequently, Cummings et al. conducted a large meta-analysis of randomized clinical trials, including 21 clinical trials of bisphosphonates treatment and found no significant association between bisphosphonates and overall mortality rate (RR 0.95, 95% CI 0.86–1.04). Analysis including only clinical trials of zoledronic acid showed no association with overall mortality rate (RR 0.88, 95% CI 0.68–1.13).¹⁸⁰ Another large meta-analysis conducted by Kranenburg et al.¹⁷³ that included RCTs of a variety of bisphosphonates also found no difference in cardiovascular events in patients treated with bisphosphonates compared to placebo (pooled RR of 20 trials 1.03, 95% CI 0.91–1.17, I² = 16%), while lower risk of cardiovascular mortality by 19% was observed but did not reach statistical significance (pooled RR of 10 trials 0.81, 95% CI 0.64–1.02; I² = 0%). There was also a reduction in all-cause mortality of 10% (pooled RR of 48 trials 0.90; 95% CI 0.84–0.98; I² = 53%) but the majority of studies included in analysis of all-cause mortality were cancer patients. Importantly, the included studies were too short in duration to possibly observe beneficial cardiovascular effects and mortality.¹⁷³

Numerous observational studies have examined the association between bisphosphonates and overall cardiovascular mortality. The Canadian Multicenter Osteoporosis Study (CaMOS) population-based cohort included 6120 patients aged > 50 years who were followed up for 15 years and showed a significant 34% mortality reduction in those treated with nitrogen-containing bisphosphonates (alendronate and risedronate) compared to non-treated patients (pairwise HR 0.66, 95% CI 0.48–0.91). The association was not found in non-nitrogen-containing bisphosphonates (pairwise HR 0.89, 95% CI 0.66–1.20).¹⁸¹ Another study from the Swedish Hip Fracture Register that was a retrospective cohort study of hip fracture patients over a follow-up period of 3 years, the mortality rate was 15% lower in bisphosphonate-treated group (HR 0.85, 95% CI 0.79–0.91) and the lower mortality occurred days (~6 days) after treatment initiation raising the possibility of confounding factors, such as time of bisphosphonates initiation or previous fragility fracture.¹⁸² Other observational studies have found that oral bisphosphonates reduce mortality in frail older patients and critically ill patients.^183,184 It is interesting that the magnitude of mortality reduction observed in the majority of observational studies corresponded to the HORIZON-RFT study (post hip fracture trial).¹⁷²

In a retrospective study from Hong Kong that included patients with hip fracture, Sing et al.¹⁸⁵ found that alendronate was associated with a significantly lower risk of 1-year cardiovascular mortality (HR 0.33, 95% CI 0.17–0.65) and myocardial infarction (HR 0.55, 95% CI 0.34–0.89). The association remained for 10 years, albeit with diminished strength. In another study from Taiwan National Health Insurance database, Kang et al.^186,187 found a 65% lower rate of myocardial infarction (HR 0.35, 95% CI 0.14–0.84) and 21% lower rate of stroke (HR 0.79; 95% CI 0.66–0.99) over 2 years among patients who received at least 1 year of bisphosphonates compared to patients with osteoporotic fracture who did not receive bisphosphonates during the follow-up period. More recently, real-world data from the Danish national prescription registry revealed that oral bisphosphonates (96% of which were alendronate) reduced cardiovascular events by 33% (HR 0.67, 95% CI 0.58–0.78).¹⁸⁸ Similar results were observed with regard to the outcomes of atrial fibrillation, heart failure, and aneurysms.

Risk of atrial fibrillation of bisphosphonates

Greater incidence of atrial fibrillation was found as a serious adverse event among zoledronic acid recipients (1.3% versus 0.5%; p = 0.003) versus placebo in the HORIZON-PFT (p < 0.001).¹⁷⁸ However, overall atrial fibrillation adverse events were not different between groups. The majority of atrial fibrillation (94%) occurred more than 30 days following the infusion. Other non-arrhythmia cardiovascular adverse events were not significantly different between groups, but arrhythmia was more common in the zoledronic acid group than in the placebo group (6.9% versus 5.3%, p = 0.003).¹⁷⁸ Increased risk of atrial fibrillation adverse events were not observed in zoledronic acid group in other large clinical trials (the HORIZON-RFT that included older patients with hip fractures and the Fracture Prevention with Zoledronate in Older Women with Osteopenia).¹⁴⁷ In the results of the Fracture Intervention Trial, a randomized study of oral alendronate involving postmenopausal women for a 4-year period, atrial fibrillation as a serious adverse event occurred in 1.5% of the alendronate group and 1.0% of the placebo group (RR 1.51, 95% CI 0.97–2.40, p = 0.07) but the overall atrial fibrillation adverse events were similar.¹⁶³

Several real-world studies have been carried out to explore this relationship. A population-based case-control study using diagnostic code from medical records found that women who had ever used alendronate had a higher incidence of atrial fibrillation than those who had never used it (6.5% versus 4.1%, p = 0.03).¹⁶⁴ In another large retrospective cohort study that used the national Swedish and Denmark database, patients who were given zoledronic acid had a higher risk of atrial fibrillation that those who were not (HR 1.18, 95% CI 1.05–1.32).¹⁸⁹ In contrast, other two population cohort studies found no increased risk of atrial fibrillation in patients receiving oral bisphosphonates (etidronate and alendronate).^188,190 Kim et al. performed a meta-analysis on bisphosphonates and CVD endpoints. The risk of atrial fibrillation appears to be modestly higher with zoledronic acid (6 trials; 1.24, 95% CI 0.96–1.61; I² = 0.0%), but not with oral bisphosphonates (26 trials; 1.02, 95% CI 0.83–1.24; I² = 0.0%).¹⁵²

Both atrial fibrillation and osteoporosis are common in an aging population. The plausibility of an observed risk of atrial fibrillation in both zoledronic acid and alendronate clinical trials remains unclear. A number of mechanisms have been proposed. For example, potent bisphosphonates in particular may stimulate inflammatory cytokines¹⁶⁷ or exert the potent hypocalcemic effects of bisphosphonates.¹⁹¹

In conclusion, the effects of bisphosphonates on mortality and cardiovascular outcomes remain uncertain due to a lack of data, particularly from trials that focused cardiovascular outcomes as the primary endpoints. The majority of the data were analyzed from secondary outcomes of previous RCTs, and some data were from observational studies that may have included different populations (age, sex, ethnic diversity, frailty, and type of bisphosphonates), and the results are inconclusive to make a clear judgment on the cardiovascular benefit or harm of bisphosphonates.

Denosumab

Denosumab is a fully human monoclonal antibody and inhibitor of the RANKL that inhibits osteoclast function resulting in potent antiresorptive effects. The Fracture Reduction Evaluation of Denosumab in Osteoporosis (FREEDOM) study which was a double-blind, placebo-controlled trial of postmenopausal women with osteoporosis found no significant difference in cardiovascular events, stroke, coronary heart disease, peripheral vascular disease, and atrial fibrillation between treatment groups.¹⁹² Subsequent meta-analysis studies of RCTs found that denosumab treatment did not increase cardiovascular risks when compared to placebo or active comparators.^193,194 Seeto et al.¹⁹⁵ recently published another systematic review and meta-analysis of denosumab, demonstrating a 46% increase (RR 1.46, 95% CI 1.05–2.02) in cardiovascular adverse events in denosumab-treated compared with bisphosphonate-treated postmenopausal women, but not when compared to placebo. The authors concluded that the findings could indirectly support the possibility of cardiovascular benefit of bisphosphonates.¹⁹⁵ However, because the cardiovascular adverse events reported were not the primary outcomes of the trials, more comprehensive clinical trials are required to confirm the findings of the meta-analysis. Due to scarcity, data on the mortality rate of denosumab are limited. Overall, there is no clear evidence of increased cardiovascular risk associated with denosumab treatment, and cardiovascular risk does not need to be considered for the use of this medication.

PTH analogs

Teriparatide and abaloparatide are two agents that have anabolic effect on the bone. Teriparatide is a recombinant human PTH (1-34 amino acid). Abaloparatide is a parathyroid-related peptide hormone that binds to the RG conformation of PTH type 1 receptors. There was no difference in mortality or cardiovascular events between treatment groups in the Vertebral Fracture Treatment Comparisons in Osteoporotic Women trial, which was a RCT comparing teriparatide and risedronate.¹⁹⁶ The mortality rate and rate of myocardial infarction were similar in the pivotal study of abaloparatide, which compared abaloparatide to placebo in postmenopausal women for 18 months.¹⁹⁷ Meta-analysis by Ferrieres et al.¹⁹⁴ showed no significant difference between overall mortality (p = 0.77), CAD (p = 0.74), cardiac arrhythmia (p = 0.28), and stroke (p = 0.61) between parathyroid analog and placebo.

Romosozumab

Romosozumab is a human monoclonal antibody that inhibits sclerostin, is an antagonist to the Wnt-signaling pathway. Romosozumab has dual properties in anabolic and antiresorptive effects on bone. A separate review article in this issue discusses the detailed cardiovascular effects and safety data of romosozumab.

Vitamin D

Vitamin D receptors (VDRs) have been localized to various cells in the cardiovascular system. Vitamin D may therefore have direct cardiovascular effects, with in vitro and in vivo studies indicating that liganded VDR modulates blood pressure, suppresses development of atherosclerosis, and limits cardiac hypertrophy and fibrosis.¹⁹⁸ Furthermore, vitamin D may indirectly affect cardiovascular health. Vitamin D has been proposed as an RAS modulator.¹⁹⁹ Vitamin D has also been proposed to have an anti-diabetic effect,^200,201 potentially attenuating CVD through its glucose-lowering and insulin-sensitizing effects. The lipid-modulating benefits of vitamin D have been studied and the results have been inconsistent. While higher vitamin D level has been associated with an improved lipid profile in observational studies,^202,203 interventional studies have yielded inconsistent findings.^204,205

Observational studies have frequently, although not always,²⁰⁶ indicated an association between vitamin D deficiency and increased risk of CVD.^207–212 A study of 1739 Framingham Offspring Study participants found a graded increase in the risk of first cardiovascular events with greater degrees of vitamin D deficiency over 5.4 years of mean follow-up.²¹³ A meta-analysis of 25 prospective cohort studies of healthy individuals (with 10,099 cases of CVD) noted that while low vitamin D levels were correlated with an increased relative risk of CVD (RR 1.44, 95% CI 1.24–1.69), there was no significant relationship between vitamin D status and CVD incidence (RR 1.18, 95% CI 1–1.39).²¹⁴

RCTs have yielded variable results in the general population and in patients with pre-existing CVD. While some have shown cardiovascular benefit,²¹⁵ the majority of studies have found no difference in CVD events with interventions aimed at improving vitamin D levels.^216–220 Wu et al.²²¹ studied 90 patients in China who had stable CAD who were randomized to receive either 0.5 μg vitamin D3 daily or placebo. Those in the supplemented group had a significant increase in 25-hydroxyvitamin D levels, decrease in PTH, high-sensitivity C-reactive protein, renin, angiotensin II and aldosterone levels. Moreover, after 6 months of vitamin D supplementation, the vitamin D-supplemented group had a greater decline in the SYNTAX score, a semi-quantitative angiographic tool that has been shown to predict the severity of CAD. However, a double-blind placebo-controlled RCT of elderly patients (age 70 years or older) with isolated systolic hypertension and baseline 25-hydroxyvitamin D levels < 30 ng/mL found no improvement in blood pressure, arterial stiffness, or endothelial function (among other measures) with 100,000 IU of vitamin D.²²² The Effect of Vitamin D on All-Cause Mortality in Heart Failure (EVITA) study found that heart failure patients who took 4000 IU vitamin D daily for 3 years had no mortality benefit and, in fact, had a greater need for mechanical circulatory support implant (HR 1.96, 95% CI 1.04–3.66, p = 0.031).²²³

Meta-analyses, although limited by the fact that some included studies where CVD outcomes were not the primary endpoints, have shown no significant reduction in mortality and cardiovascular risk with vitamin D supplementation.^224–226 Recently, Pei et al.²²⁷ found no effect of vitamin D supplementation on mortality and incidence of cardiovascular events in a meta-analysis of 18 trials (70,278 participants). Another meta-analysis of RCTs evaluating mortality effect of vitamin D supplementation compared with placebo or no treatment found that, while vitamin D supplementation significantly reduced risk of cancer death, it had no effect on all-cause mortality or cardiovascular mortality.²²⁸

The heterogeneity of study groups, outcomes, variation in vitamin D regimens used, and different essays used to assess Vitamin D level have all been suggested as contributing factors to the inconclusive results of randomized trials evaluating vitamin D’s cardiovascular benefit.^229,230 It is also possible that the discrepancy between findings in observational studies (which favor cardiovascular benefit with improved vitamin D status) and the more inconclusive results from interventional RCTs (which have not consistently shown cardiovascular benefit) are due to the fact that optimal vitamin D levels are the result, rather than the cause, of good health. Improved vitamin D levels may be an indicator of otherwise good health—for instance, lower BMI, greater time outdoors, and better nutrition have all been linked to higher vitamin D levels.^231–233 Hence, it may be that these factors, rather than vitamin D itself reduce the burden of CVD.

Limitations

This review is aimed to provide an overview of the current evidence examining the impact of cardiovascular medications to bone health and also the cardiovascular safety of anti-osteoporosis medications. While original articles or rigorous meta-analyses were preferred as references, there is a general scarcity in large RCTs with BMD or fracture risk as primary outcomes. As a result, the data available come from safety data of large osteoporosis RCTs, moderately large studies, meta-analyses and cohort and database studies. The majority of data from clinical studies have been presented on the association of the events with either cardiovascular events or fracture risk thus, it would be impossible to draw a causal relationship or completely minimize all potential confounders. The interaction between the cardiovascular system and bone metabolism are strong and pose the knowledge gaps that require basic, translational, and clinical trials to explore the complexity of bone and cardiovascular connection.

Conclusion

This review highlights the association between osteoporosis and CVD, which have unifying pathophysiologic mechanisms through the aspect of medications’ effects. Medication used to treat CVD can influence bone health through their effects on these common pathophysiologic mechanisms, and anti-osteoporotic therapies may have an effect on cardiovascular health. While some data in this field can be conflicting, the main goal of this review is to draw attention to the similarities between cardiovascular and bone disorders. While there are no guidelines for screening for osteoporosis in those with CVD, nor for testing for the presence of CVD in those with metabolic bone disease, it remains important to remember these parallels so that the diagnosis of one disorder—such as osteoporosis—may prompt consideration that another condition, such as CVD may co-exist. At present there is no sufficient strong evidence to support the use of anti-osteoporosis medications for the primary purpose of prevention or management of CVD, nor is there adequate data to use cardiovascular medications primarily for skeletal disease. Existing data suggest that anti-osteoporosis medications, including PTH analogues, denosumab, and bisphosphonates, are deemed safe, with potential cardioprotective effects seen with bisphosphonates. A finding of increased cardiovascular risk with denosumab was only seen when compared to bisphosphonates, which may reflect the beneficial effect of bisphosphonates rather than adverse cardiac effects of denosumab. Some uncertainty remains on cardiovascular safety with romosozumab that requires further post market data. Furthermore, it is important to not only weigh the benefits and risks when considering medications but also account for the fracture risk if osteoporosis is left untreated, in particular, for patients with co-existence of heart or bone disease

Footnotes

Acknowledgements

The authors thank Dr Lisa S. Chow for her critical review and suggestion of this article.

Declarations

ORCID iD

Susanne Trost

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The interplay between bone and heart health as reflected in medication effects: A narrative review

Abstract

Keywords

Introduction

Cardiovascular medications and their effects on bone health

Loop diuretics

Thiazide diuretics

Beta-blockers

Statins

Warfarin

Spironolactone

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Calcium channel blockers

Sodium-glucose cotransporter 2 inhibitors

Metformin

Anti-osteoporosis medications and cardiovascular effects

Bisphosphonates

Potential mortality and cardiovascular benefit of bisphosphonates

Risk of atrial fibrillation of bisphosphonates

Denosumab

PTH analogs

Romosozumab

Vitamin D

Limitations

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References