Gordon L. Klein

This review examines the relationship between cholesterol and bone resorption. It seeks to elucidate the dependence of bone turnover on cholesterol metabolism by highlighting the common inhibitory effect of both statins and nitrogen-containing bisphosphonates on cholesterol biosynthesis and bone resorption as well as on bone density. Moreover, this paper also discusses the epidemiologic studies of the effects of nitrogen-containing bisphosphonates on all-cause and cardiovascular mortality using the latest publications to reinforce the relationship between bone resorption and cardiovascular disease. This review will also discuss the role of lipoproteins in supplying cholesterol to both osteoclasts and osteoblasts and the effects of doing so on both of these bone cells and their precursors. As inflammation is a major factor in both bone resorption and cardiovascular calcification, this article will also discuss the role of cholesterol in triggering inflammatory responses. Finally, this paper will raise questions unanswered to date that bear on the relationship between lipid metabolism, bone resorption, and cardiovascular disease.

This review examines the relationships between cholesterol and bone resorption. It seeks to elucidate the dependence of bone turnover on cholesterol metabolism by highlighting the common inhibitory effect of both statins and nitrogen-containing bisphosphonates on cholesterol biosynthesis and bone resorption as well as on bone density. Moreover, this paper also discusses the epidemiologic studies of the effects of nitrogen-containing bisphosphonates on all-cause and cardiovascular mortality using the latest publications to reinforce the relationships between bone resorption and cardiovascular disease. The review will also discuss the role of lipoproteins in supplying cholesterol to both osteoclasts and osteoblasts and the effects of doing so on both these bone cells and their precursors. As inflammation is a major factor in both bone resorption and cardiovascular calcification, this article will also discuss the role of cholesterol in triggering inflammatory responses. Finally, the paper will raise questions unanswered to date that bear on the relationship between lipid metabolism, bone resorption and cardiovascular disease.

Bone releases calcium and phosphate in response to pro-inflammatory cytokine-mediated inflammation. The body develops impaired urinary excretion of phosphate with age and chronic inflammation given the reduction of the kidney protein Klotho, which is essential to phosphate excretion. Phosphate may also play a role in the development of the resistance of the parathyroid calcium-sensing receptor (CaSR) to circulating calcium thus contributing to calcium retention in the circulation. Phosphate can contribute to vascular smooth muscle dedifferentiation with manifestation of osteoblastogenesis and ultimately endovascular calcium phosphate precipitation. Thus phosphate, along with calcium, contributes to the calcification and inflammation of atherosclerotic plaques and the origin of these elements is likely the bone, which serves as storage for the majority of the body’s supply of extracellular calcium and phosphate. Early cardiac evaluation of patients with chronic inflammation and attempts at up-regulating the parathyroid CaSR with calcimimetics or introducing earlier anti-resorptive treatment with bone active pharmacologic agents may serve to delay onset or reduce the quantity of atherosclerotic plaque calcification in these patients.

This review describes the relationship between lipids and the immune system in the pathogenesis of atherosclerosis. It offers insights into how the immune system and lipids interact to generate atheromatous plaques. As these lesions become chronic, they can become calcified. Additional insight is provided by another recent review {1} which adds to this pathophysiology by suggesting that calcium from bone resorption cannot be excreted in the urine and continues to exacerbate the chronic inflammatory response, possibly leading to the calcification of atheromatous plaques.

Several epidemiologic studies associate bone-resorbing chronic inflammatory conditions with increased risk of atherosclerotic heart disease. These include post-menopausal osteoporosis, spinal cord injury, rheumatoid arthritis, and osteoarthritis. Additional studies have noted that the use of anti-resorptive agents following hip fracture, during rheumatoid arthritis, and prior to intensive care management have resulted in reduced overall mortality and mortality from cardiovascular disorders. The careful study of burn patients has allowed us to detect that children and adolescents have a mechanism that protects them from the entry of calcium into the circulation following inflammatory bone resorption. That is, they respond to pro-inflammatory cytokines by up-regulating the parathyroid calcium-sensing receptor (CaSR) with consequent development of hypocalcemic hypoparathyroidism and hypercalciuria. As extracellular calcium appears to exacerbate and/or prolong the inflammatory response, this responsiveness of the CaSR to inflammatory cytokines may be the factor that reduces cardiovascular morbidity and mortality. In adults with chronic inflammatory conditions, the ability of the CaSR to respond to pro-inflammatory cytokines is lost, suggesting that the calcium that enters the circulation following inflammatory bone resorption may persist in the circulation, entering the small coronary blood vessels and favoring the formation of coronary artery calcification, inflammation, and consequent cardiovascular disease.

The objective of this work was to estimate the incidence rate of cardiovascular disease (CVD) events (myocardial infarction, stroke or CVD-death) at 1 year

Burn injury serves as an example of a condition with a robust systemic inflammatory response. The elevation of circulating interleukins (IL)-1β and -6 in children and adolescents with severe burn injury upregulates the parathyroid calcium-sensing receptor (CaSR), resulting in hypocalcemic hypoparathyroidism accompanied by urinary calcium wasting. This effect protects the body from the hypercalcemia that results from bone resorption, liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR upregulation in response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation, allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis, and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population.

Editorial: Osteoporosis and the Role of Muscle

Burn injury serves as an example of a condition with a robust inflammatory response. The elevation of circulating interleukins (IL)- 1 beta and -6 in children with severe burn injury up-regulate the parathyroid calcium sensing receptor (CaSR) resulting in hypocalcemic hypoparathyroidism with urinary calcium wasting. This effect protects the body from the hypercalcemia resulting from bone resorption liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation and allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, , such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population.