Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies

Hamerman, David

doi:10.1093/qjmed/hci077

Cited by 115 publications

(95 citation statements)

References 240 publications

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“…There are many potential culprits for this accelerated post-menopausal bone loss with a bone-vascular connect, aggravated by sex-hormone depletion, being a plausible possibility. Bone and vasculature are so closely connected that, at a cellular level, well over a hundred potential mechanisms exist whereby arteries can interact with bone and visa versa [25,26]. Broadly speaking, an arterial disorder may be affecting bone; a bone disorder may be affecting arteries or both tissues may be influenced by common extraneous factor or factors.…”

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confidence: 99%

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confidence: 99%

“…These proteins are present in the arterial intima and aortic valve where they are synthesized by vascular cells and regulate vascular calcification and ossification [26]. These same proteins help regulate osteoblast:osteoclast activity, bind growth factors, and assist in apatite deposition in bone [26]. While bone-modulating factors released from calcifying arteries may be influencing bone downstream, it is also conceivable that the reverse is true and mediators over spilling from bone may be secondarily affecting arteries.…”

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confidence: 99%

“…This is understandable given that osteoclasts derive from the macrophage cell line in the bone marrow while in the arterial wall, macrophages are key to the development and progression of atherosclerosis [26]. For example, subendothelial accumulation of oxidized lipids, seen from the very earliest stage of plaque formation, induces osteoblast differentiation in arteries while these same oxidized lipids inhibit osteoblast formation in bone [9].…”

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Hard arteries, weak bones

2011

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Given the close association between bone and blood, it is not that surprising how the two common diseases of artery and bone, namely atherosclerosis and osteoporosis, may in part share a common pathogenesis. Although atherosclerosis and osteoporosis are both clearly more prevalent in later years, there is nonetheless increasing evidence of a bone-vascular connect independently linking osteoporosis with atherosclerosis beyond the occurrence of shared risk factors such as age, gender, smoking, lifestyle factors, alcohol, and diabetes.Several studies have shown how atherosclerosis is more common in both men and women with osteoporosis or low bone mass ('osteopenia'). Regarding cerebrovascular disease, a study of over 9,500 women aged more than 65 years, showed how low areal bone mineral density (BMDa) at baseline increased the relative risk of stroke by 1.7 with low BMDa at baseline proving to be an even stronger predictor of subsequent stroke than systolic blood pressure [1]. In over 4,300 middle-aged to elderly men and women followed-up for an average 5.6 years, relative risk of both stroke and death from any cause was almost twice as high in those with osteoporosis at baseline even after adjusting for confounding variables such as age, smoking, diabetes, and hypertension [2]. In post-menopausal women, the decrease in lumbar BMDa is associated with an increase in carotid intimal thickness (p<0.01) [3].Regarding cardiovascular disease, low BMDa independently predicts coronary artery disease in women undergoing coronary angiography better than traditional risk factors such as age, hypertension, diabetes, smoking, family history, or dyslipidemia [4]. In a study of over 2,500 postmenopausal women followed-up for more than 4 years, not only did women with osteoporosis have a 3.9-fold increased risk for cardiovascular events compared to women with low bone mass, it was also seen that the more severe the impairment of bone strength, as evidenced by the frequency and severity of vertebral fracture, the greater the risk of a subsequent cardiovascular event [5].For peripheral vascular disease, a study of almost 6,000 elderly male subjects, followed-up for more than 5 years, showed how BMD loss was almost twice as pronounced in those with peripheral arterial disease as those with no peripheral arterial disease while the relative risk of nonspinal fracture was also increased by 1.47 [6]. Although low-energy fractures are a more reliable indicator of osteoporosis than BMD, when addressing the link between osteoporosis and atherosclerosis, BMD or other structural bone parameters may be more apt as vascular disease per se will increase the risk of fall and thereby the likelihood of fracture.Osteoporosis is linked to atherosclerosis and probably even more so to the occurrence of vascular calcification, which is a very frequent accompaniment of atherosclerosis. For example, in both sexes, lower lumbar vertebral trabecular BMD is more strongly associated with increasing calcification and severity of carotid atherosclerotic plaque

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Hard arteries, weak bones

2011

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“…Recently, great interest is being taken in BPs, also in view of the emerging relationship between osteoporosis and cardiovascular disease (CD). 11,12 In this paper we report synthesis, physico-chemical characterisation and pharmacological profile of a new series of N-BPs bearing the nitrogen-containing furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in the lateral chain. Since it is known that furoxans can produce NO under the action of thiol cofactors, 13 furoxan bisphosphonates herein described represent a new class of NO-donor bisphosphonates (NO-BPs).…”

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Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

Lolli

Rolando

Tosco

et al. 2010

Bioorganic & Medicinal Chemistry

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a new series of bisphosphonates bearing either the nitrogen containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pK a values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10 M concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.

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Impaired arterial function associated with thinning of cortical bone in rheumatoid arthritis

Roldán¹,

Escalante²,

Rincón³

2008

Arthritis & Rheumatism

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Objective. To evaluate the association between peripheral arterial function and cortical bone thickness in rheumatoid arthritis (RA). Methods. In a cross-sectional study, we measured the combined cortical thickness (CCT) of the second metacarpal bone from hand radiographs, and the ankle-to-arm systolic blood pressure ratio, also known as ankle-brachial index (ABI), in RA patients. We evaluated the association between the 2 using multinomial logistic regression. Results. We obtained CCT and ABI measurements in 588 RA patients. The mean ؎ SD CCT was 3.62 ؎ 1.16 mm. The proportion of patients with >1 ABI value <0.9, indicating obstructed lower limb arteries, increased from 18 (9.2%) of 191 patients in the highest CCT tertile to 25 (12.5%) of 200 in the middle CCT tertile to 38 (19.2%) of 198 in the lowest CCT tertile (P for trend 0.005). We noted a similar pattern for ABI values >1.3, indicative of arterial incompressibility (frequencies in high, middle, and low CCT tertiles were 4.7%, 9.5%, and 19.9%, respectively; P for trend <0.001). These trends remained significant after multivariable adjustment for potential confounders. After adjustment for the manifestations of RA and cumulative glucocorticoid dose, the association between CCT and arterial obstruction remained significant, but that with arterial incompressibility weakened considerably. Conclusion. There is an association between metacarpal cortical bone thinning and obstruction or incompressibility of the peripheral arteries in RA. The association with incompressibility may be mediated by systemic inflammation and/or glucocorticoids, but that with obstruction is independent of a wide array of potential confounders. Clinicians should be alert to the possibility of impaired arterial function RA patients with thinned metacarpal cortical bone.

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Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies

Cited by 115 publications

References 240 publications

Hard arteries, weak bones

Hard arteries, weak bones

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

Impaired arterial function associated with thinning of cortical bone in rheumatoid arthritis

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