Hypertension and bone health -
A part of the work was presented at the 70th Scientific Sessions of the American Heart Association, held in Orlando, FL in November, Recent studies have reported the abnormalities in calcium metabolism at the systemic level in human hypertension as well as in experimental hypertension.
Because bone is the largest store of calcium in the body, the bone calcium content and mineralization may represent the entire calcium balance. The present study was undertaken to investigate the bone mineral density BMD in women with essential hypertension by means of the dual-energy X-ray absorptiometric DXA method.
The DXA analysis showed a significant decrease in BMD in female hypertensive subjects compared with normotensive subjects. In addition, the BMD was inversely correlated with systolic blood pressure in women.
The h urinary calcium excretion was significantly greater in female hypertensive subjects than in female normotensive subjects. Furthermore, the greater the urinary calcium excretion, the lower the BMD in women.
The values of serum total calcium, total magnesium, ionized calcium, and 1, 25 OH 2 vitamin D were not different between hypertensive and normotensive subjects. The results of the present study demonstrated that DXA provided an index of whole calcium balance, and suggest that high blood pressure might be associated with reduced BMD in female hypertension.
Am J Hypertens ;— © American Journal of Hypertension, Ltd. It has been shown that abnormalities in calcium metabolism might play a key role in the pathophysiology in hypertension.
Increased calcium excretion and secondary activation of the parathyroid glands were reported in patients with essential hypertension. In animal studies, hypercalciuria with high blood pressure increased the risk of bone mineral loss. However, it is still unclear whether hypertension might be associated with reduced BMD in humans.
It is well recognized that osteoporosis is more likely to develop in women than in men. Thirty-one Japanese women with untreated essential hypertension were studied and compared with 14 normotensive control women.
Consent was obtained from all participants after they were informed about the nature and objective of the study. They had no other diseases such as hematologic or hepatic disorders and were not taking hormone replacement therapy before the study. The characteristics and laboratory findings in both hypertensive and normotensive women are shown in Table 1.
The BMD of lumbar spine L 2 —L 4 was measured in lateral view by means of the dual-energy X-ray absorptiometry DXA QDR , Hologic, Waltham, MA. From a sample of 15 female hypertensive subjects and 11 female normotensive subjects, the h urine collection was obtained for determination of calcium excretion.
Values are expressed as means ± SEM. Statistical analyses were performed by the Student's t test. A P value less than. Table 1 demonstrated the background of hypertensive and normotensive women.
There were no differences in serum total calcium, total magnesium, ionized calcium, and 1, 25 OH 2 vitamin D between hypertensive and normotensive subjects.
The DXA analysis revealed a significant decrease in BMD in female hypertensive HT subjects compared with female normotensive NT subjects female HT 0. In addition, the BMD was inversely correlated with systolic blood pressure in women Fig. The results of the present study with DXA method demonstrated that BMD in lumbar spine was significantly decreased in female hypertensive subjects compared with female normotensive controls.
The difference in mean age between hypertensive and normotensive groups, although it was not statistically significant, might partially account for the lower BMD in hypertensive patients. We also described that BMD was inversely correlated with systolic blood pressure in women, which suggests that high blood pressure might be associated with the decrease in BMD in women.
The finding might be consistent with a previous report of Cappuccio et al 11 showing that the rate of bone loss at the femoral neck was increased with blood pressure in white women.
Although our analysis was restricted to a small population of Japanese women and the findings may not be generalized to men and other ethnic groups, it would be possible that hypertension could be a risk factor for reduced BMD in women.
There has been much evidence showing that hypertension might be linked to the abnormalities in calcium metabolism, including an increased calcium excretion linked to salt intake.
The results might suggest that the increased urinary calcium could lead to a decrease in BMD in female hypertension. The precise mechanisms responsible for the decreased BMD in female hypertension are still unclear. In women, the loss of endogenous estrogen might contribute to the rapid decrease in BMD at perimenopause and after menopause.
Lehrer et al 17 examined the relationship between estrogen receptor variants and hypertension in women, and reported that the presence of the estrogen receptor B-variant allele might have increased the prevalence of hypertension in women.
Both quantitative and qualitative alterations in estrogen effect may partially explain the rapid decrease in BMD in female hypertensive subjects. Further studies are necessary to assess more thoroughly the role of estrogen in the regulation of calcium metabolism in female hypertension.
In summary, the results of the present study with DXA method demonstrated that the BMD in the lumbar spine was decreased in female hypertensive subjects compared with normotensive controls. The data also showed that the BMD was inversely correlated with systolic blood pressure and the h urinary calcium excretion in women.
The finding might propose the hypothesis that high blood pressure might be associated with reduced BMD in female hypertensive subjects. Hatton DC , Young EW , Bukoski RD , McCarron DA : Calcium metabolism in experimental genetic hypertension , in Laragh J.
and Brenner B. Hypertension: Pathophysiology, Diagnosis, and Management. Raven Press : New York , Google Scholar. Google Preview. MacGregor GA , Cappuccio FP : The kidney and essential hypertension: A link to osteoporosis?
J Hypertens ; 11 : — Strazzullo P , Nunziata V , Cirillo M , Giannattasio R , Ferrara LA , Mattioli PL , Mancini M : Abnormalities of calcium metabolism in essential hypertension. Clin Sci ; 65 : — Thanks for your great article😁.
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Is it too high? Some doctors disagree… Healthcare practitioners may be a bit divided when it comes to diagnosing high blood pressure, depending on the guidelines they choose to follow.
But get it checked anyway. What causes your blood pressure to skyrocket? The Hypertension-Osteoporosis Link Nothing in your body happens in a vacuum. Blood Pressure Medication Can Help Your Bones Too! Natural Ways to Prevent Hypertension Eat Food High In Riboflavin Riboflavin is a super-important B vitamin that helps your body do all kinds of cool stuff, such as: Harnessing fat for fuel Helping your body absorb vital minerals like iron and zinc Breaking down cholesterol Allowing your body to get all the goodness from fat-soluble vitamins A, D, E, and K Riboflavin does it all!
Skip happy hour Alcohol can raise blood pressure and may even reduce the effectiveness of blood pressure medications. Ditch the smokes Lighting up a cigarette might give you a quick hit of energy, but it can have a long-lasting impact on your blood pressure and heart rate.
FAQs What are the warning signs of hypertension? What are the 3 main causes of hypertension? Can high blood pressure affect your bones?
Can blood pressure meds cause bone loss? Which antihypertensive is good for osteoporosis? Category: Osteoporosis. Article Comments. Add New Comment Cancel reply Your email address will not be published. Georgia Clark May 20, , am I am so thankful for this article you sent me,.
Linda Sanders May 20, , pm thank you for this information, it has given me clear understanding of blood pressure, bones and osteoporosis. Kathleen Francis May 20, , pm Interesting facts about high blood pressure and bone loss help me to understand clearly about how to prevent them before serious consequences can happen.
Scherry May 21, , pm This article has been very informative and helpful! Littlejohns TJ, Holliday J, Gibson LM et al The UK Biobank imaging enhancement of , participants: rationale, data collection, management and future directions. Nat Commun Sudlow C, Gallacher J, Allen N et al UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.
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Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway. You can also search for this author in PubMed Google Scholar. Correspondence to D. Dexter Canoy received support from the National Institute of Health Research NIHR Oxford Biomedical Research Centre BRC and the British Heart Foundation outside the submitted work.
Professor Cyrus Cooper has received lecture fees and honoraria from Amgen, Danone, Eli Lilly, GSK, Kyowa Kirin, Medtronic, Merck, Nestlé, Novartis, Pfizer, Roche, Servier, Shire, Takeda and UCB outside of the submitted work. Haakon E. Meyer and Bjørn Olav Åsvold declare no conflict of interest.
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Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF. Abstract Blood pressure and bone metabolism appear to share commonalities in their physiologic regulation. Hypertension, Antihypertensive Drugs, and Bone Mineral Density Article 21 August Hypertension, Antihypertensive Drugs and the Risk of Fractures Article 12 August Bone mineral density changes among women initiating blood pressure lowering drugs: a SWAN cohort study Article 08 October Use our pre-submission checklist Avoid common mistakes on your manuscript.
Introduction For some years, a close link between cardiovascular and bone health has been hypothesised [ 1 , 2 , 3 , 4 , 5 ], given that there are similarities in the biological risk factors, lifestyle determinants and demographic profile associated with cardiovascular disease CVD and bone health conditions [ 1 , 3 , 6 , 7 , 8 , 9 , 10 ].
High population burden of osteoporosis and fractures Osteoporosis is a systemic skeletal disease characterised by low bone mass and deterioration of the microarchitecture of bone tissue, which increases fragility of the bone and susceptibility to fractures [ 40 , 41 ].
Blood pressure may influence bone health Elevated BP, or hypertension, is the leading cause of cardiovascular disease morbidity and mortality in many regions worldwide [ 48 ]. Raised blood pressure, blood pressure reduction and bone health outcomes While raised BP is an established risk factor of CVD, there are suggestions that it also affects long-term bone health.
Table 1 Randomised clinical blood pressure—lowering treatment trials with long-term follow-up and have reported on the risk of fracture as an outcome Full size table. Table 2 Blood pressure—lowering drugs and hypothesised effects and mechanisms on bone health and fracture risk adapted and modified from Ghosh and Majumdar [ 59 ] Full size table.
Advancing research into blood pressure and bone health in the population: current opportunities Developments in population-based research in recent years have opened up opportunities to address fundamental questions on the role of elevated BP in the aetiology of osteoporosis and fractures.
Big data from large-scale cohort studies and healthcare databases Routinely collected healthcare data have become increasingly an important resource to generate and test hypotheses in clinical research.
Methodological and analytical innovations Epidemiological investigations Designing studies and analysing data to examine associations between an exposure e.
Mendelian randomisation studies Naturally randomised genetic variants associated with specific phenotypes are increasingly being applied in epidemiologic analysis to investigate unconfounded associations between an exposure and an outcome of interest [ , ].
Individual participant-level data meta-analysis As mentioned earlier, there were very few RCTs that reported on the effects of BP-lowering treatment and effects of antihypertensive drug class on risk of fractures.
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Hypertension is a chronic-low grade inflammatory healt, which Hypertemsion known to be healfh with increased bone loss. Excessive activity of anx local xnd system RAS helth Hypertension and bone health leads to Anti-oxidants bone resorption. As inflammatory Hypertension and bone health may activate RAS components, we hypothesized Hypertension and bone health the heealth proinflammatory cytokine levels in hypertension activate bone RAS and thus lead to increased bone resorption. SSHTN led to the reduction of distal femur trabecular number and bone volume fraction, while trabecular separation of femoral bone showed a significant increase, with no change in cortical thickness. Histomorphometric examination showed a significant reduction in trabecular bone volume fraction with an increased number of multinucleated tartrate-resistant acid phosphatase TRAP -positive cells and increased osteoclast surface fraction in the trabecular distal femur of hypertensive mice. TNF-α and angiotensin II type 1 receptor AGTR1 mRNA and protein expression were also upregulated in SSHTN mice.Hypertension and bone health -
These changes involving the weakening of bones can increase the risk of fractures. Several observational studies have shown that individuals with high blood pressure or hypertension are at higher risk of fractures due to osteoporosis. In addition, there is also evidence suggesting that certain drugs for high blood pressure can also increase bone strength and reduce the risk of osteoporotic fractures.
Researchers think an increase in inflammation could be one of the mechanisms that could mediate the association between hypertension and osteoporosis. Previous studies have shown that inflammation contributes to the development of high blood pressure.
This involves the accumulation of activated immune cells in the bone marrow that secrete pro-inflammatory proteins. These activated immune cells and the pro-inflammatory proteins secreted by immune cells can influence the survival and activity of cells involved in maintaining the balance between the synthesis and breakdown of bone tissue.
Studies suggest that an inflammatory environment in the bone marrow can modulate the bone remodeling process and cause bone loss. A gradual decline in bone density and strength typically occurs with aging. The typical aging process is also associated with chronic, low-grade inflammation, and this increase in inflammation could lead to bone loss.
Whether hypertension in young animals results in bone loss similar to that observed during the aging process and how aging, hypertension, and inflammation interact to influence bone loss is not well understood. To address these issues, researchers at Vanderbilt University compared the effects of hypertension on bone loss and inflammation in young and older mice.
For the study, researchers used the hormone angiotensin II to induce high blood pressure in the animals. Angiotensin II is a vital hormone in regulating blood pressure, and dysregulation of the system involving angiotensin II is observed in individuals with hypertension.
The study involved two groups of younger mice ages 4 months equivalent to a human age of about 25 years old and two groups of older mice ages 16 months a human age equivalent to around 52 years old. The young and old mice received infusions of either angiotensin II or a placebo vehicle for six weeks.
Six weeks after treatment, the researchers obtained lumbar vertebrae from the young and the old mice to assess bone health. The induction of high blood pressure in young mice using angiotensin II resulted in a reduction in bone volume, structural integrity, and strength compared with vehicle-treated young mice.
Similar to the young mice with high blood pressure, a decline in bone health was also observed in older mice with healthy blood pressure levels. Moreover, angiotensin II-treated older mice did not show elevated levels of bone loss than vehicle-treated older animals.
In sum, young mice with high blood pressure showed levels of bone loss similar to older mice, regardless of whether they had typical or high blood pressure.
Daichi Shimbo , a cardiologist at Columbia University in New York City, told MNT :. There is some evidence in humans linking hypertension to osteoporosis, so these data in mice are important.
Also, given that the findings were seen primarily in younger versus older mice, that suggests that it would be important to detect hypertension as early as possible in humans i.
The researchers then examined the impact of high blood pressure on the inflammatory response in the bone marrow. The induction of high blood pressure in young mice using angiotensin II resulted in the accumulation of activated immune cells in the bone marrow.
Such an immune response activation was absent in the vehicle-treated mice with healthy blood pressure. Moreover, researchers observed an elevated inflammatory response in the bone marrow in both angiotensin-II and vehicle-treated old mice.
These results suggest that aging is associated with higher levels of inflammation, independent of high blood pressure.
Such an increase in inflammation associated with aging could be sufficient to cause bone loss, independent of blood pressure levels. In contrast, hypertension resulted in elevated levels of immune response in younger animals, which may subsequently mediate loss in bone volume and strength.
The researchers found that certain pro-inflammatory factors were elevated in the bone marrow, and understanding how these factors mediate the effects of high blood pressure on bone loss could help develop therapies to prevent osteoporosis in young adults.
The authors caution that these findings do not establish a causal role for inflammation in mediating the effects of hypertension on bone loss in young animals. MR estimates for instrumental variables were meta-analyzed by computing an inverse variance weighted IVW analysis for the primary analysis To assess the potential violation of these assumptions, MR-Egger analysis was used to assess the directional pleiotropy based on the intercept The presence of pleiotropy was also assessed by the MR pleiotropy residual sum and outlier test MR-PRESSO , during which outlying SNPs were excluded and the effect estimates were reassessed The ethical approval and informed consent for each study included in the study can be found in the original publications.
All of the analyses were conducted in R V. The funders of this study had an important role in study design, data collection, data analysis, data interpretation, and writing of the report.
All authors had full access to all data in the study and had final responsibility for the decision to submit for publication. We evaluated the causal effect of blood pressure including SBP Figure 1 , DBP Figure 2 , and PP Figure 3 on FA-BMD, FN-BMD, and LS-BMD in the MR analysis Table 1.
High PP was significantly associated with improved FA-BMD beta-estimate: 0. However, PP showed no remarkable influence on FN-BMD or LS-BMD based on the results of IVW, weighted-median, and MR-Egger analyses. Figure 1 Mendelian randomization estimates for the associations between SBP and outcomes.
FA-BMD, forearm BMD; FN-BMD, femoral neck BMD; LS-BMD, lumbar spine BMD; CI, confidence interval. Figure 2 Mendelian randomization estimates for the associations between DBP and outcomes. Figure 3 Mendelian randomization estimates for the associations between PP and outcomes.
These results were also confirmed by the weighted-median analysis and MR-Egger analysis. SBP, DBP, and PP showed null association with fall in the IVW odds ratio [OR]: 1. Consistently, there was also no relationship between BP and fracture in the IVW analysis OR: 1.
These results were all confirmed by the weighted-median analysis and MR-Egger analysis. The estimates from the weighted-median approach and MR-Egger analysis were all consistent with those of IVW models Table 1.
Among the instrument variables, MR-PRESSO method only identified one outlier rs for the association between DBP and fall, and one outlier rs for the association between PP and fall. After excluding these outliers, DBP and PP still revealed no causal effect on the incidence of fall OR: 1.
Table 2 Mendelian randomization estimates between blood pressure and outcomes after excluding outliers detected by MR-PRESSO. In this two-sample MR analysis, we found the casual effect between high PP and improved FA-BMD beta-estimate: 0. This positive finding was also confirmed by weighted median, MR-egger, and MR-PRESSO analyses.
However, no causal association was seen between BP and other outcomes i. Hypertension has important association with alterations in calcium metabolism, including increased calcium loss, compensatory activation of parathyroid gland, and increased movement of calcium from the bones Long-lasting impairment effect of hypertension on calcium homeostasis may result in age-related excessive reduction of BMD and fracture Previous studies explored the association between BP and BMD, but reported conflicting results 14 — In one cross-sectional study involving postmenopausal Turkish women, hypertension was found to be significant predictors of osteopenia in a multivariate analysis OR: 2.
A retrospective analysis of postmenopausal women with a mean age of These studies did not involve male patients and were indeed contradictory.
These inconsistent results may result from small patient sample, confounding factors, and the limitation of study design. Our two-sample MR analysis involved 53, European individuals for the association with BMD, , European individuals for fall susceptibility, and up to 1.
The association between PP and BMD was explored after adjusting for sex, age, age 2 , and weight In addition, we found no obvious MR association between BP and other outcomes i. It is very interesting to confirm that genetically high PP shows strong MR association with improved BMD.
PP is defined as SBP minus DBP. High PP largely results from large-artery stiffness, while decreased PP is caused by low stroke volume, such as congestive heart failure and aortic valve stenosis Vascular smooth muscle cells VSMC have important roles in regulating arterial stiffness by overproducing various extracellular matrix components e.
However, patients with high PP have vascular calcification and increased arterial stiffness, which increase the expression of bone markers such as alkaline phosphatase ALP and type 1 collagen.
These factors also improve the osteogenic differentiation and mineralization for bone formation and increased BMD Forearm BMD represents the BMD of combined trabecular and cortical bone structures, indicating the better improvement of BMD than other sites of BMD after effective anti-osteoporosis treatments, which may account for the positive MR association only between PP and forearm BMD In addition, 1, men and 1, women aged 50 years and older were included in the Dubbo Osteoporosis Epidemiology Study, and hypertension may be an independent risk factor for fragility fracture hazard ratio, 1.
However, our two-sample MR analysis confirmed null association between BP and fracture. To the best of our knowledge, this is the first two-sample MR study to find the positively casual association between PP and FA-BMD. The summary statistics of outcome phenotypes are retrieved from GWAS or genome-wide meta-analysis with huge sample size.
This two-sample MR method allows for the estimation of the causal effects of BP on all outcomes while at the same time minimizing reverse causation bias and confounding factors. The intercepts for the MR-Egger analysis, except for the association between DBP and FN-BMD, indicate that there is no directional pleiotropy to influence other causal associations.
Several limitations should be taken into consideration. Firstly, there is some heterogeneity between DBP or PP and fall, which may be caused by the selection of some instrumental variables. Secondly, this MR study reveals the potential causal effect of PP on FA-BMD, but null association is observed between BP and FN-BMD or LS-BMD.
The factors of this inconsistency remain elusive. Thirdly, it is not feasible to perform the MR analysis based on different age stratums because of the limitation of GWAS summary statistics.
Fourthly, the MR analysis is restricted in the European-ancestry population, which may limit the generalizability of our finding to other populations. This two-sample MR reveals the potential causal effect of high PP on improved FA-BMD, suggesting the protective role of high PP for osteoporosis.
BH, ZQ, and QL conducted study design. BH, LFY and MZZ conducted data collection and statistical analysis. BH, ZQ, QL, and YO conducted data interpretation, manuscript preparation, and literature search.
BH and QL conducted funds collection. All authors contributed to the article and approved the submitted version. This study was funded by Natural Science Foundation of Chongqing cstcjcyj-msxmX , National Natural Science Foundation of China , Foundation of The First Affiliated Hospital of Chongqing Medical University PYJJ , and Chongqing Yuzhong Nature Science Foundation of China Grant No.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The authors acknowledged the GEnetic Factors for OSteoporosis Consortium and the UK Biobank for contributing the data used in this work. We thanked all the genetics consortiums for making the GWAS summary data publicly available.
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We boje know blood pressure can Hypertensioj heart health, but how does it influence Hypertension and bone health structure? This vital bonee is Hypertension and bone health force your healhh blood puts on Hypertension and bone health Organic immune boosters vessel walls. So, make sure to ask your doctor Herbal appetite management check halth blood pressure at your next visit. Hypertension and bone health is a serious condition, as it can lead to a variety of health risks, including heart disease, heart attack, and stroke. Healthcare practitioners may be a bit divided when it comes to diagnosing high blood pressure, depending on the guidelines they choose to follow. You know, like spending too much time on the couch, stress eating, indulging in too many happy hour drinks, and eating a lot of salty snacks. The problem is that while hypertension may not be top of mind for you, when this condition goes unchecked it can cause a host of serious problems like organ damage and potentially compromising cardiovascular health. Halth Musculoskeletal Disorders volume 22Article ane Cite this article. Metrics details. Hypertension and bone health and cardiovascular disease CVD are age-related diseases. It is reported that patients with CVD have a higher risk of bone loss. This retrospective study sought to reveal the association between osteoporosis and CVD in Chinese women.Blood pressure and bone metabolism appear to znd commonalities in their physiologic regulation. Specific antihypertensive drug classes may also influence hdalth mineral density.
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Jonathan K. Debra A. Butt, Bonf Alharty, … Angela M. Solomon, Hyperteension. Ruppert, … J. For some hezlth, a close link between cardiovascular and Hypertenion health has been hypothesised [ 123 healtn, 45 ], given that there are bonne in Artichoke salad recipes biological heath factors, lifestyle determinants and demographic profile associated with cardiovascular disease Hypeertension and bone health conditions [ 136ad8 snd, 910 ].
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These findings were largely based on observational studies and ans confounding could be an issue, so the likely causal role of BP or use of antihypertensive Hypertesnion on bone health outcomes remains to be established. Time trends suggest healht age-adjusted mean BP and incidences of osteoporosis and fractures have Hypertensoon improving in some Hypertemsion [ 3536 ], but the global burden of these conditions remains high [ 37 Abdominal obesity and WHR, 3839 ] perhaps because Liver detox for toxin elimination a demographic shift towards an ageing population.
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In recent years, large-scale population-based cohorts with detailed clinical assessments, biological measures Hypertenion genetic heealth are being Hypertension and bone health wnd epidemiologic and clinical investigations.
Novel study hhealth and innovative analytical approaches have been developed, and collaborative healtn that anv sharing of biomedical data of study cohorts Hypeetension become a common practice. These research developments provide Hypertension and bone health opportunity to revisit bne linking cardiovascular Hypertenison bone health, and explore ways Hypertnsion answer bne that characterise and anv the causal role of raised BP on Boone health boje in the Hypertension and bone health.
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Hypertemsion Hypertension and bone health, or hypertension, is the leading Hypergension of cardiovascular gone morbidity Hypertensin mortality in many Hypettension worldwide [ 48 ].
Over 1. Improve metabolic health naturally are public health preventive measures heath reduce this anr [ 51 ]. Moreover, haelth medications are effective, affordable and gealth safe, and therefore widely heallth for managing hypertension in many populations globally.
Nevertheless, fewer Antifungal remedies for scalp 1 Hypertfnsion 5 people with hypertension globally have their Hypertension and bone health andd under control Hypertemsion 48 ].
In England, nearly a hone of all adults have hypertension. However, Hyperttension continuing Hypergension for Anti-arthritic lifestyle choices use of effective drugs to control and manage snd BP are showing an impact on encouraging trends towards more people with hypertension in England who are receiving treatment and whose raised BP are getting controlled.
While raised BP is an established risk factor of CVD, there are suggestions that it also affects long-term bone health. While the underlying mechanisms are not fully understood, elevated BP has been thought to alter calcium metabolism leading to increased calcium loss [ 1516 ].
Increased sympathetic nervous system activity, enhanced inflammation response and alteration of parathyroid hormone regulation are pathways that have also been suggested to be involved [ 167813 ]. This relation between raised BP and low bone mineral density could lead to enhanced bone fragility which may increase the risk of fracture, not least in some susceptible individuals such as among the elderly.
There is also a suggestion that hypertension affects balance and mobility [ 52 ] thereby increasing the likelihood of falls and, consequently, fractures.
Few studies have examined the association between BP and BMD. In one small study, hypertensive women were shown to have lower BMD and higher h urinary calcium excretion than normotensive women [ 17 ].
A meta-analysis of observational studies observed a heterogeneity in the association between BP and BMD depending on the anatomical location of the bone and ethnicity, although the study largely included cross-sectional studies [ 53 ].
In a prospective investigation based on repeated BMD measurements among elderly women, elevated BP was associated with increased bone loss in the femoral neck after 3 years of follow-up, independently of hormone replacement therapy and use of BP-lowering drugs [ 14 ].
It is uncertain if a similar observation can be seen in elderly men. Limited data exist for investigating the impact of elevated BP on outcomes involving bone fractures. In another study, mean arterial pressure or hypertension was not shown to predict incident hip fracture, but the study was based only on events in men and in women, and did not account for the use of antihypertensive treatment [ 54 ].
There are also other possible pathways by which elevated BP, or rather, its pharmacologic reduction, can influence bone health. Susceptible individuals may develop syncope or hypotension soon after initiating antihypertensive treatment, leading to injurious falls [ 12 ] and, consequently, to fractures [ 55 ].
Indeed, a history of a fall is a well-established predictor of future fractures [ 10 ]. Three randomised clinical trials RCTs with relatively long follow-up have separately reported on the effect of BP reduction on fracture outcomes Table 1but these trials only involved less than fracture events collectively [ 565758 ].
One trial [ 56 ] reported no difference in the risk of any fracture between comparison groups, while the other two trials [ 5758 ] showed suggestive reduction in fracture risk in the active BP-lowering treatment arm, but the confidence interval of the risk estimate included the null value. To our knowledge, no randomised trials have examined the effects of pharmacologic lowering of BP on BMD or osteoporosis outcomes.
Other than the unintended effects of antihypertensive medications in lowering BP on falls, others have shown class-specific effects of antihypertensive drugs by affecting different pathways involved in bone remodelling Table 2.
Thiazide diuretics are widely prescribed drugs to manage elevated BP, and this drug can also modulate calcium homeostasis [ 59 ]. In contrast, loop diuretics are associated with increased urinary calcium excretion and increase parathyroid hormone levels and bone-specific alkaline phosphatase, which could be indicative of accelerated bone remodelling [ 6465 ].
β-Blockers have been suggested to inhibit osteoclastic activity thereby decreasing bone resorption [ 2566 ]. Selective β-blockers particularly inhibit signalling pathways via β 1 -adrenergic receptors that are expressed in human bones [ 67 ].
The renin—angiotensin—aldosterone system not only has systemic effects but also local effects in several tissues including the bone which might explain some of the effects of angiotensin-converting enzyme inhibitors ACEI heqlth improving bone mineral density, albeit similar effects are not seen for angiotensin-II receptor blockers ARB [ 5968 ].
There are, therefore, several plausible pathways by which antihypertensive drug classes—collectively or individually—can have an impact on important bone health outcomes. Several observational studies have examined associations of specific BP-lowering drug classes with bone loss or fracture risk [ 59 ].
While some findings are inconsistent, many have suggested protective effects on BMD and reduction in fracture risk for thiazide diuretic [ 69707172 ], β-blocker [ 26jealth ] and ACEI [ 687374 ].
Loop diuretics have been reported to increase the risk of fracture [ 27707576 ], with no or little evidence of any impact of the use of ARB and calcium channel blocker CCB on bone fractures [ 3270737476 ]. Evidence from RCTs also remains limited.
To date, only one long-term trial has investigated the effects of specific antihypertensive drug class on fracture risk [ 77 ]. So far, we see that much of the existing findings on BP level or BP-lowering drug classes on bone health outcomes have been based on observational studies, with only a handful using a prospective study design.
Since both hypertension and osteoporosis and fractures are influenced by similar factors as age, body size, physical activity level and co-existing chronic conditions, these factors need to be considered and will pose analytical challenges when establishing the causal relation between raised blood pressure and bone health outcomes using data from observational studies.
As exposure to these drugs in these studies is mainly based on self-reports, details on timing of prescription as well as the dose and duration of drug treatment are often missing, which limits characterisation of exposure to these drugs.
Given how common hypertension is and how widely antihypertensive drugs are being prescribed, even small effects of these exposures could be relevant at the population level.
It is therefore crucial to determine the causal relation between BP and BP-lowering drugs with bone health, as it will improve our understanding of the additional implications of BP control in the promotion of optimal bone health. Since the prevalence of raised BP and use of antihypertensive medications increase with age, and those at risk to suffer from metabolic bone disorders and fractures are also more likely to be older, understanding the nature of the associations is important for maximising the benefits and reducing the risks associated with BP control and treatment.
Developments in population-based research in wnd years have opened up opportunities to address fundamental questions on the role of elevated BP in the aetiology of osteoporosis and fractures.
Access to databases providing detailed health data for large numbers of people allows us to investigate associations between BP and bone health outcomes prospectively and with sufficient statistical power.
Further, advances in study designs and innovative analytical techniques have drawn us towards making causal inference with more credence. There is also an increasing trend among research communities across disciplines towards working collaboratively and sharing research data and expertise, which have opened up new ways to re-examine old, unanswered questions using novel ideas and perspectives.
Routinely collected healthcare data have become increasingly an important resource to generate and test hypotheses in clinical research. Anonymised data are extracted from electronic health records EHRssuch as the United Kingdom UK Clinical Practice Research Database [ 78 ].
These EHRs provide rich datasets that include time-stamped information on clinical measures, diagnoses and prescriptions and are linked to various national databases that further enrich the datasets to incorporate information on hospitalisations and vital status.
These linkages at individual level allow investigations Hyperrtension the prospective associations of hypertension and antihypertensive drug use on bone health outcomes including osteoporosis and fractures. As drug dose and duration can be estimated from these medical records, detailed characterisation of drug exposure is possible to conduct in this context.
Similar possibilities exist in other countries using their national healthcare or prescription databases [ 808182 ].
By linking prescriptions with other administrative health records, it is possible to create anonymised records of prescriptions and relevant health data at individual level. In addition, several cohorts involving large numbers of participants have collected detailed information on personal characteristics, medical history, lifestyle factors, biological samples, genetic data and clinical measures such as bone densitometry and heel bone ultrasound.
For example, in the UK Biobank, these data have been collected for nearly 0. Similar detailed phenotypic and genetic data have been collected in other cohorts, such as the population-based Trøndelag Health Study with genetic information combined with phenotypic data that include BMD measurements and prospectively recorded fracture information [ 86 ].
Indicators of bone health as well as diagnoses of osteoporosis and fractures are collected in these cohort studies. Data from EHR and well-characterised cohort studies have detailed health information that allows analyses that account for the potential effects of confounding factors.
With large numbers of participants and long follow-up, health outcomes will accrue in sufficient numbers and allow conducting stratified analysis to investigate associations in important subgroups, such as by age and sex.
Trials investigating the effects of antihypertensive drugs involving large numbers of participants with relatively long follow-up have been conducted for many years.
Findings from these RCTs, particularly by pooling evidence from across these trials, have helped establish the causal role of elevated BP in the aetiology of cardiovascular disease and clearly demonstrated the efficacy of antihypertensive drugs in reducing cardiovascular disease risk [ 87 ].
In recent years, collaborative efforts of trialists have allowed pooling of evidence based on individual-level data, which further provided evidence into the efficacy of BP-lowering treatment across important patient subgroups and clinical characteristics [ 88 ].
While bone health conditions are not the primary outcomes of these trials, adverse events and other unintended consequences of antihypertensive drug treatments are commonly collected, which may include information on hypotension, Hypertenison and fractures.
org is one such collaboration which recently has been investigating the efficacy and safety of antihypertensive drug treatment [ 89 ].
As many of the trials in the collaboration have collected safety data, it could be an important resource to provide randomised evidence for the effects of BP reduction and specific effects of antihypertensive drug classes on fracture risk.
Designing studies and analysing data to examine associations between an exposure e. raised BP or specific classes of BP-lowering drugs and an outcome e. low BMD or fracture in cohort studies require careful consideration as associations based on observational data are prone to biases, confounding and reverse causation.
As bone health outcomes are likely to affect the elderly, analysis should account for yHpertension risk such as from other causes of death. While using relevant study designs may help establish temporality of the association of the exposure with the HHypertension and confounding factors could be adjusted for by employing appropriate statistical methods, residual confounding remains a possibility due to unmeasured or imprecisely measured confounders.
: Hypertension and bone health| High blood pressure linked to bone loss and aging, mouse study finds | According to the criterion, the osteoporosis group had subjects, and the non-osteoporosis group had subjects. Åsvold Authors D. Am J Epidemiol — Article PubMed PubMed Central Google Scholar Haneuse S, Arterburn D, Daniels MJ Assessing missing data assumptions in EHR-based studies: a complex and underappreciated task. Performed the experiments: Peng Liu. Increased calcium excretion and secondary activation of the parathyroid glands were reported in patients with essential hypertension. |
| Top bar navigation | MR estimates for instrumental variables were meta-analyzed by computing an inverse variance weighted IVW analysis for the primary analysis To assess the potential violation of these assumptions, MR-Egger analysis was used to assess the directional pleiotropy based on the intercept The presence of pleiotropy was also assessed by the MR pleiotropy residual sum and outlier test MR-PRESSO , during which outlying SNPs were excluded and the effect estimates were reassessed The ethical approval and informed consent for each study included in the study can be found in the original publications. All of the analyses were conducted in R V. The funders of this study had an important role in study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication. We evaluated the causal effect of blood pressure including SBP Figure 1 , DBP Figure 2 , and PP Figure 3 on FA-BMD, FN-BMD, and LS-BMD in the MR analysis Table 1. High PP was significantly associated with improved FA-BMD beta-estimate: 0. However, PP showed no remarkable influence on FN-BMD or LS-BMD based on the results of IVW, weighted-median, and MR-Egger analyses. Figure 1 Mendelian randomization estimates for the associations between SBP and outcomes. FA-BMD, forearm BMD; FN-BMD, femoral neck BMD; LS-BMD, lumbar spine BMD; CI, confidence interval. Figure 2 Mendelian randomization estimates for the associations between DBP and outcomes. Figure 3 Mendelian randomization estimates for the associations between PP and outcomes. These results were also confirmed by the weighted-median analysis and MR-Egger analysis. SBP, DBP, and PP showed null association with fall in the IVW odds ratio [OR]: 1. Consistently, there was also no relationship between BP and fracture in the IVW analysis OR: 1. These results were all confirmed by the weighted-median analysis and MR-Egger analysis. The estimates from the weighted-median approach and MR-Egger analysis were all consistent with those of IVW models Table 1. Among the instrument variables, MR-PRESSO method only identified one outlier rs for the association between DBP and fall, and one outlier rs for the association between PP and fall. After excluding these outliers, DBP and PP still revealed no causal effect on the incidence of fall OR: 1. Table 2 Mendelian randomization estimates between blood pressure and outcomes after excluding outliers detected by MR-PRESSO. In this two-sample MR analysis, we found the casual effect between high PP and improved FA-BMD beta-estimate: 0. This positive finding was also confirmed by weighted median, MR-egger, and MR-PRESSO analyses. However, no causal association was seen between BP and other outcomes i. Hypertension has important association with alterations in calcium metabolism, including increased calcium loss, compensatory activation of parathyroid gland, and increased movement of calcium from the bones Long-lasting impairment effect of hypertension on calcium homeostasis may result in age-related excessive reduction of BMD and fracture Previous studies explored the association between BP and BMD, but reported conflicting results 14 — In one cross-sectional study involving postmenopausal Turkish women, hypertension was found to be significant predictors of osteopenia in a multivariate analysis OR: 2. A retrospective analysis of postmenopausal women with a mean age of These studies did not involve male patients and were indeed contradictory. These inconsistent results may result from small patient sample, confounding factors, and the limitation of study design. Our two-sample MR analysis involved 53, European individuals for the association with BMD, , European individuals for fall susceptibility, and up to 1. The association between PP and BMD was explored after adjusting for sex, age, age 2 , and weight In addition, we found no obvious MR association between BP and other outcomes i. It is very interesting to confirm that genetically high PP shows strong MR association with improved BMD. PP is defined as SBP minus DBP. High PP largely results from large-artery stiffness, while decreased PP is caused by low stroke volume, such as congestive heart failure and aortic valve stenosis Vascular smooth muscle cells VSMC have important roles in regulating arterial stiffness by overproducing various extracellular matrix components e. However, patients with high PP have vascular calcification and increased arterial stiffness, which increase the expression of bone markers such as alkaline phosphatase ALP and type 1 collagen. These factors also improve the osteogenic differentiation and mineralization for bone formation and increased BMD Forearm BMD represents the BMD of combined trabecular and cortical bone structures, indicating the better improvement of BMD than other sites of BMD after effective anti-osteoporosis treatments, which may account for the positive MR association only between PP and forearm BMD In addition, 1, men and 1, women aged 50 years and older were included in the Dubbo Osteoporosis Epidemiology Study, and hypertension may be an independent risk factor for fragility fracture hazard ratio, 1. However, our two-sample MR analysis confirmed null association between BP and fracture. To the best of our knowledge, this is the first two-sample MR study to find the positively casual association between PP and FA-BMD. The summary statistics of outcome phenotypes are retrieved from GWAS or genome-wide meta-analysis with huge sample size. This two-sample MR method allows for the estimation of the causal effects of BP on all outcomes while at the same time minimizing reverse causation bias and confounding factors. The intercepts for the MR-Egger analysis, except for the association between DBP and FN-BMD, indicate that there is no directional pleiotropy to influence other causal associations. Several limitations should be taken into consideration. Firstly, there is some heterogeneity between DBP or PP and fall, which may be caused by the selection of some instrumental variables. Secondly, this MR study reveals the potential causal effect of PP on FA-BMD, but null association is observed between BP and FN-BMD or LS-BMD. The factors of this inconsistency remain elusive. Thirdly, it is not feasible to perform the MR analysis based on different age stratums because of the limitation of GWAS summary statistics. Fourthly, the MR analysis is restricted in the European-ancestry population, which may limit the generalizability of our finding to other populations. This two-sample MR reveals the potential causal effect of high PP on improved FA-BMD, suggesting the protective role of high PP for osteoporosis. BH, ZQ, and QL conducted study design. BH, LFY and MZZ conducted data collection and statistical analysis. BH, ZQ, QL, and YO conducted data interpretation, manuscript preparation, and literature search. BH and QL conducted funds collection. All authors contributed to the article and approved the submitted version. This study was funded by Natural Science Foundation of Chongqing cstcjcyj-msxmX , National Natural Science Foundation of China , Foundation of The First Affiliated Hospital of Chongqing Medical University PYJJ , and Chongqing Yuzhong Nature Science Foundation of China Grant No. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. The authors acknowledged the GEnetic Factors for OSteoporosis Consortium and the UK Biobank for contributing the data used in this work. We thanked all the genetics consortiums for making the GWAS summary data publicly available. Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, et al. An Atlas of Genetic Influences on Osteoporosis in Humans and Mice. Nat Genet 51 2 — doi: PubMed Abstract CrossRef Full Text Google Scholar. Liu J, Curtis EM, Cooper C, Harvey NC. State of the Art in Osteoporosis Risk Assessment and Treatment. J Endocrinol Invest 42 10 — Leder BZ, Mitlak B, Hu MY, Hattersley G, Bockman RS. Effect of Abaloparatide vs Alendronate on Fracture Risk Reduction in Postmenopausal Women With Osteoporosis. J Clin Endocrinol Metab 3 — CrossRef Full Text Google Scholar. Reid IR. A Broader Strategy for Osteoporosis Interventions, Nature Reviews. Endocrinology 16 6 —9. Khosla S, Hofbauer LC. Osteoporosis Treatment: Recent Developments and Ongoing Challenges. Lancet Diabetes Endocrinol 5 11 — Compston JE, McClung MR, Leslie WD. Lancet London England — Richards JB, Zheng HF, Spector TD. Genetics of Osteoporosis From Genome-Wide Association Studies: Advances and Challenges, Nature Reviews. Genetics 13 8 — Trajanoska K, Rivadeneira F. The Genetic Architecture of Osteoporosis and Fracture Risk. Bone — Yang TL, Shen H, Liu A, Dong SS, Zhang L, Deng FY, et al. A Road Map for Understanding Molecular and Genetic Determinants of Osteoporosis, Nature Reviews. Endocrinology 16 2 — Muñoz M, Pong-Wong R, Canela-Xandri O, Rawlik K, Haley CS, Tenesa A. Evaluating the Contribution of Genetics and Familial Shared Environment to Common Disease Using the UK Biobank. Nat Genet 48 9 —3. Poulter NR, Prabhakaran D, Caulfield M. Forouzanfar MH, Alexander L, Anderson HR, Bachman VF, Biryukov S, Brauer M, et al. Global, Regional, and National Comparative Risk Assessment of 79 Behavioural, Environmental and Occupational, and Metabolic Risks or Clusters of Risks in Countries, A Systematic Analysis for the Global Burden of Disease Study Karmali KN, Lloyd-Jones DM, van der Leeuw J, Goff DC Jr. Blood Pressure-Lowering Treatment Strategies Based on Cardiovascular Risk Versus Blood Pressure: A Meta-Analysis of Individual Participant Data. PloS Med 15 3 :e Cakmak HA, Cakmak BD, Yumru AE, Aslan S, Enhos A, Kalkan AK, et al. The Relationships Between Blood Pressure, Blood Glucose, and Bone Mineral Density in Postmenopausal Turkish Women. Ther Clin Risk Manage —8. Kaplan S, Smith SR, Zuckerman IH. Blood Pressure and Bone Mineral Density in Premenopausal and Postmenopausal Women. Yazici S, Yazici M, Korkmaz U, Engin Erkan M, Erdem Baki A, Erden I, et al. Relationship Between Blood Pressure Levels and Bone Mineral Density in Postmenopausal Turkish Women. Arch Med Sci: AMS 7 2 — Burgess S, Dudbridge F, Thompson SG. Combining Information on Multiple Instrumental Variables in Mendelian Randomization: Comparison of Allele Score and Summarized Data Methods. Stat Med 35 11 — Dalbeth N, Topless R, Flynn T, Cadzow M, Bolland MJ, Merriman TR. Mendelian Randomization Analysis to Examine for a Causal Effect of Urate on Bone Mineral Density. J Bone Mineral Research: Off J Am Soc Bone Mineral Res 30 6 — Davey Smith G, Ebrahim S. What can Mendelian Randomisation Tell Us About Modifiable Behavioural and Environmental Exposures? BMJ Clinical Res ed —9. Davies NM, Holmes MV, Davey Smith G. Spontaneously hypertensive rats SHR —a hypertensive animal model developed by selective breeding Wistar-Kyoto individuals carrying sporadic gene mutations linked to blood pressure control 11 —were used in the present study. This SHR model has been widely used as a model of essential hypertension with the onset of high blood pressure at 4—6 weeks and cardiovascular complications at 24 weeks of age Therefore, these rats should allow us to address any changes in the skeleton as outcomes of genetic-induced high blood pressure with controlled environmental variables. However, there are conflicting reports on skeletal changes in the hypertensive animal models. For example, loss of trabecular thickness and impaired bone healing at proximal tibia were observed in week-old male SHR In addition, male SHR displayed trabecular loss and delayed healing at the dental socket of mandibles In contrast, improved trabecular BMD and microarchitecture were reported in month-old male SHR Bone is a dynamic tissue and constantly being remodeled to maintain optimal mass and integrity throughout life, in which bone resorption and formation are kept in balance. Bone forming cells, osteoblasts, are differentiated from mesenchymal stem cells under the control of transcription factors, runt -related transcription factor Runx 2 and osterix Later, it produces collagen and other proteins including alkaline phosphatase ALP and osteocalcin, that are necessary for bone matrix synthesis and mineralization. In addition, these cells also secrete soluble factors, such as receptor of nuclear factor- κB ligand RANKL , osteoprotegerin OPG , macrophage colony stimulating factor M-CSF and interleukin IL -6, to direct differentiation of bone-resorbing cells, osteoclasts 17 , Whether these factors produced by osteoblasts are altered due to high blood pressure requires further investigation. Overall, complete characterization of these skeletal changes with underlying cellular mechanisms would be benefit for establishing the use of this in vivo pre-clinical model for development of dual therapy targeting hypertension and osteoporosis. Upon arrival at the Central Animal Facility, Faculty of Science, Mahidol University MUSC-CAF , animals were acclimatized for 5 days and general health status was checked daily by a veterinarian. At the age of 18 weeks old, blood pressure of all animals was monitored using non-invasive tail-cuff method CODA ® tail-cuff blood pressure system, Kent Scientific Corporation, USA. All rats were divided into two groups, i. They were fed with standard diet containing 1. The experimental protocol was approved by the Institutional Animal Care and Use Committee IACUC , Faculty of Science, Mahidol University and all experiments were performed in accordance with relevant guidelines and regulations. Fresh frozen femoral heads from SHR and WT controls were collected and used in the present study. Each sample was placed in a cylindrical sample holder filled with cottons soaked in formaldehyde solution to prevent displacement and dehydration during tomographic scanning. SRXTM experiments were performed at the XTM beamline BL1. The synchrotron radiation was generated from 2. The sample projections were obtained from the detection system, which was equipped with µm-thick YAG:Ce scintillator, the white-beam microscope Optique Peter, France and the pco. edge 5. All tomographic scans were acquired at a pixel size of 1. In order to resolve fine details of femoral head, a tomographic volume was reconstructed from enlarged composite projections acquired from two scans. The first scan was taken over °. Then, the other ° scan was taken on vertical axis of rotation that shifted horizontally and parallel to the camera Subsequently, the X-ray projections were normalized by flat-field correction, stitched, and reconstructed using Octopus software as described previously All 3D representation of tomographic volume typically slices was rendered using Drishti software Micro-computed tomography µCT; model , SkyScan, Aartselaar, Belgium was used to examine trabecular and cortical bone volume as previously described The scanning angular rotation was ° with angular increment in 0. The volume of interest VOI was between 1. Images were reconstructed and analyzed by a computer cluster running SkyScan CT-analyzer software package version 1. The OsteoMeasure histomorphometric system version 4. The resin-embedded specimens were first adjusted to obtain the same orientation. Then, they were cut longitudinally to obtain 7-mm thick sections by using a rotary microtome equipped with a tungsten carbide blade model RM; Leica, Nussloch, Germany. Three-point bending technique was used to evaluate the flexional stiffness and strength of femur model , Instron, Norwood, MA, USA. The femoral length and thickness at mid-shaft were recorded before each mechanical test. Load-displacement curves of each specimen were constructed by Instron software Norwood, MA, USA. The recorded parameters were ultimate load, yield load and stiffness, which could represent bone strength. Right tibiae and fibulas were collected and extraneous soft connective tissue was removed from the outer surface using a scalpel blade. Intact bones were rinsed with phosphate-buffered saline PBS, pH 7. Growth medium was changed at day 3 and 6 prior to further experiments. Then, 1-µg total RNA was reverse-transcribed to cDNA with iScript cDNA synthesis kit Bio-rad, Hercules, CA, USA using conventional thermal cycler modelMyCycler, Bio-rad. Rat PCR primers used in this study are shown in Table 1. The primers have been validated for specificity and efficiency by conventional RT-PCR, as previously described 24 , Conventional PCR was performed with GoTaq Green Master Mix Promega, Madison, WI, USA. Relative expression were calculated from the threshold cycles C t based on the standard ΔC t method. All data were analyzed by GraphPad Prism 5 GraphPad, San Diego, CA, USA. Longitudinal assessment of blood pressure parameters in SHR revealed progressive elevation of systolic and diastolic pressure reaching statistical significance at five to six weeks old in both sexes. In this study, we assessed systolic and diastolic pressure of our SHR rats at 18 weeks old and also found that both parameters were significantly elevated Table 2. The ranges of systolic and diastolic pressure were consistent with the previous report 11 , 26 , Having confirmed the hypertensive phenotypes in these SHR, we first performed a high-resolution screening for the changes on bone parameters associated with elevated blood pressures using SRXTM. This technique allowed us to visualize changes in bone structure of these rats in details, superior to those obtained from conventional µCT Head of femur was chosen as a representative site of fractures as well as hypertension-associated necrosis often observed in the elderly The 3D structure of femoral heads revealed a marked decrease in bone mass near the epiphysis of SHR. A disarray of the subchondral trabeculae was conspicuous in SHR compared to the WT controls. In addition, the porosity was apparently greater in hypertensive rats than WT rats Fig. The Synchrotron radiation X-ray tomographic microscopy SRXTM imaging of femoral heads of femur. The cross-sectional structure of femoral head A , the microstructural changes of femoral head in week WT controls B and SHR C. We then quantified the changes in cortical and trabecular bones using volumetric µCT. Femurs and tibia from week-old female SHR and WT controls were assessed. The total length of each sample was measured and found that both femur and tibia from SHR exhibited a significant decrease in total length Fig. For the volumetric measurement of cortical and trabecular bone density, we found that cortical as well as trabecular BMD in the femora of SHR was significantly decreased as compared to WT controls. However, in the tibia, there was no difference in both cortical and trabecular BMD of SHR compared to WT controls Fig. Microstructural parameters of femurs and tibiae of WT controls and SHR. We further examined additional parameters of these long bones across cross-sectional planes. Cortical thickness of these two bones was significantly reduced in female SHR compared to WT controls Fig. In addition, periosteal perimeter and cortical bone area of femur and tibia from SHR were decreased Fig. Taken together, long bones from SHR exhibited decreases in length and width and a reduction in cortical and trabecular BMD compared to the WT controls. We then asked whether those bone defects characterized by µCT analyses compromised the strength in SHR. Three-point bending test was used on femurs from week-old female SHR and WT controls. Long bones from SHR showed a marked reduction in ability to withstand maximum load compared to respective controls Fig. Similarly, ability of SHR femurs to withstand the yield load prior to the irreversible deformities was significantly decreased Fig. Next, bone stiffness was assessed to further demonstrate the mechanical impairment. Therefore, our data demonstrated that reduction in bone mass and density in SHR led to impairment of bone strength. Mechanical property analysis of left femurs of WT controls and SHR. We then investigated the possible mechanisms that linked to decreased bone mass and bone strength in SHR. Primary osteoblasts were isolated from week-old female SHR and WT controls and mRNA expression of markers associated with bone formation and resorption was assessed. First, we examined the expression of genes that promote osteoblast differentiation. There was no significant difference in transcript levels of Runx2 and osterix in osteoblasts from SHR and WT controls Fig. Next, the expression of genes involving in bone formation was investigated. Expression of ALP was markedly decreased in the cells from SHR compared to WT controls Fig. Osteoblasts from SHR expressed slightly higher but significant levels of osteocalcin and collagen type I transcripts compared to those from WT controls Fig. This discrepancy in regulation of bone formation and mineralization suggested that other regulatory markers of bone remodeling play critical roles in the bone phenotypes of SHR. mRNA expression of bone formation markers, i. Since osteoblasts are able to regulate osteoclast differentiation and activity via soluble factors and cytokines, we then examined the expression of these osteoblastic genes. We found that expression of RANKL was significantly upregulated in SHR Fig. Expression of OPG was also reduced without reaching statistical significance in these rats Fig. Furthermore, expression of other osteoclastogenic factors, M-CSF and IL-6, was significantly increased in SHR Fig. Together, these data suggested that dysregulation of bone remodeling process, i. The mRNA expression levels of osteoblast-derived osteoclastogenic factors in primary osteoblasts of SHR and normotensive rats WT. Since the upregulation of RANKL, M-CSF and IL-6 expression Fig. As shown in Fig. However, the number of osteoclasts of SHR was not different from that of normotensive WT rat Fig. Interestingly, the active erosion surface was significantly enlarged in SHR Fig. Tb, bone trabeculae; Ma, marrow cavity. B Osteoclast number normalized by tissue area Oc. Numbers in parentheses are numbers of animals per group. In this study, we have demonstrated that high blood pressure in SHR caused marked reduction of bone mineral density at both cortical and trabecular sites as decrease in cross-sectional area of the long bones. Importantly, these changes led to substantial decreases in strength to withstand external forces as indicated by three-point bending tests. Further, we found that these rats manifested the increased bone resorption markers concomitantly with decreased bone formation makers. These data have suggested that high blood pressure led to compromised bone structure and mechanics, which might, in turn, result in a greater incidence of fracture. Previous studies were often carried out using male SHR particularly when characterizing bone phenotypes. Less is known about bone phenotypes in female SHR although the incidence of bone loss and fracture are in fact greater in women. Interestingly, strong correlation between hypertension and bone loss was found selectively in female subjects with a significant increase in overall cumulative incidence of fracture To examine early changes in the skeleton due to hypertension, we thus used young adult female rats at the age of 18 weeks. These rats fully developed hypertension without reproductive senescence 31 ; therefore, we were able to avoid the interference owing to age-dependent changes in gonadal steroids. Here, our data indicated that female SHR were susceptible to fracture due to compromised bone mass, mimicking those found later on in aging population, particularly in the postmenopausal group. Consistent with our study, ovariectomized adult female SHR displayed accelerating loss of cortical and trabecular bones compared to controls Further, it would be interesting to examine mechanical properties of bone in these ovariectomized and aged SHR. Due to the limitations of the imaging resolution in µCT technique, it has still not been possible to fully characterize bone micro-architecture, i. Therefore, in this study, synchrotron imaging techniques have been developed to overcome this limitation in spatial resolution We utilized two techniques, SRXTM and conventional µCT to comprehensively examine long bones of the hind limb, particularly at the changes in bone mass, density and microarchitecture. High-resolution images from SRXTM indicated an increase in porosity of the femoral head from SHR, which was similar to those observed in osteoporotic patients 33 , This decrease in trabecular bone connectivity is likely to associate with tendency to fracture especially at the femoral neck, a common fracture site with long-term health consequences. Indeed, hypertensive patients had higher risk of the femoral neck fracture compared to their cohorts 6. Furthermore, avascular necrosis of the femoral head is another common complication associated with hypertension, thereby aggravating poor bone quality. Nevertheless, our SRXTM and µCT images from SHR at the age of 18 weeks without extremely high systolic pressure showed intact femoral heads without irregular contour, a sign of avascular necrosis. However, it is still possible that long-term moderate hypertension seen in our SHR model might eventually lead to progressive necrosis of the femoral head. Collectively, these findings point to increases in porosity and fracture tendency owing to poor bone quality in the long bones from this SHR model. Our study has demonstrated for the first time that long-standing hypertension resulted in marked reduction in resistance to external forces. Here, we found that ability of bone to withstand loads was dramatically decreased in SHR group reflecting a decrease in bone strength and increase tendency to fracture. Bone strength is determined by the degree of mineralization, cortical and trabecular architecture, and rate of bone remodeling Aberrant regulation of bone quality—i. Therefore, bone fragility in SHR model could probably link to mineralization defects or misconfiguration of collagen alignment. It would be interesting to further examine whether these structural defects exist in SHR skeleton. Defects of collagen alignment and other defects related to connective tissue microstructures in bone and blood vessel may underlie the common etiologies of bone fragility and cardiovascular dysfunction found in SHR Maintenance of the bone mass reflects the balance of osteoblast-mediated bone formation and osteoclast-mediated resorption. The exact underlying mechanism by which hypertension induces bone loss remains unclear. In this regard, we hypothesized that high blood pressure compromised the integrity of bone tissue via dysregulation of bone cell functions at the cellular and molecular levels. At early osteoblast development from mesenchymal cells to osteoblastic lineage, Runx2 and osterix are salient transcription factors for both osteoblast proliferation and differentiation under normal conditions and perhaps hypertensive condition as well. Once osteoblast proliferation declines, the expression of an early marker of matrix maturation phase, particularly ALP, is gradually increased. Finally, bone matrix is mineralized concurrently with an increase in the expression level of osteocalcin, which is the major non-collagenous protein in bone matrix essential for calcium biding, stabilization of hydroxyapatite in the matrix, and regulation of bone formation Since our results showed an absence of changes in Runx2 and osterix expression in hypertensive rats whereas a decrease in ALP expression together with increases in osteocalcin and collagen type I expression were found, it was suggested that the pre-osteoblasts from SHR group had similar potential to proliferate and start to differentiate into mature osteoblasts. Nevertheless, when the process of differentiation commenced, the SHR osteoblasts might have less ability to fully differentiate or slowdown in the process of differentiation, as suggested by downregulation of ALP, a marker of early differentiated cells. Thereafter, once the osteoblasts fully differentiated, they might resume their function and were thus able to express osteocalcin and collagen type I, the upregulation of which in SHR probably a sign of compensation to help overcome hypertensive osteopathy. It is also possible that some other hypertension-induced impairments of osteoblastic functions, e. Moreover, despite being an important osteoblast differentiation marker, it is difficult to predict the long-term consequence of osteocalcin overexpression. Indeed, the expression of osteocalcin has been known to be more variable dependent on various factors, including prolonged exposure to catecholamines and high blood glucose 44 , For example, epinephrine and norepinephrine have been reported to upregulate the osteocalcin expression in osteoblasts of male ICR mice Further investigation is thus required to evaluate the outcome of osteocalcin production from osteoblasts in SHR. Normally, mature osteoclasts are multinucleated cells of hematopoietic origin with a unique in their ability to resorb bone matrix. Osteoclastogenesis is principally stimulated by two essential cytokines expressed by osteoblasts, i. The biological activity of RANKL is counterbalanced by the osteoblast-derived decoy receptor, osteoprotegerin OPG. In addition, pro-inflammatory cytokines, especially interleukin-6 IL-6 , are potent inducers of osteoclast activity Increased circulating levels of M-CSF and IL-6 during hypertension have been reported in both humans and rodents 48 , 49 , consistent with the present PCR study. In addition, an increase in active erosion surface in SHR without change in osteoclast number suggested that hypertension accelerated the activity of differentiated osteoclasts to resorb bone rather than inducing pre-osteoclast proliferation. Regarding the osteoblast-mediated bone formation, hypertension might predominantly affect ALP expression, thereby posing a difficulty for osteoblasts to obtain inorganic phosphate for matrix mineralization. This postulation is supported by the fact that ALP is responsible to cleave the phosphate group from phosphorylated proteins in order to supply inorganic phosphate for hydroxyapatite formation. The collagen fibril malalignment as reported previously probably contributes to mineralization defect despite having a sign of collagen type I overexpression It is also possible that changes in osteoblastic gene expression were cell-autonomous without the presence of high blood pressure. Specifically, genetic predisposition of hypertension might be sufficient to induce osteogenic defect since reduction of osteogenic markers was observed in differentiated bone marrow mesenchymal stem cells from 4-week-old prehypertensive SHR In conclusions, we have demonstrated the effects of high blood pressure on the skeleton of adult female rats using integrative biophysical and molecular approaches. These hypertensive rats have low bone density, presumably due to dysregulation of bone remodeling together with compromised bone architecture susceptible to fracture. Establishment of this hypertensive-induced osteoporosis and fracture model would be valuable for development of new therapeutic regimens for dual treatment of high blood pressure and hypertension-associated osteoporosis. Bromfield, S. High blood pressure: the leading global burden of disease risk factor and the need for worldwide prevention programs. Article PubMed PubMed Central Google Scholar. Hernlund, E. et al. 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Links between hypertension and osteoporosis: benidipine ameliorates osteoporosis in ovariectomized hypertensive rats through promotion of osteoblast proliferation and inhibition of osteoclast differentiation. Curr Cardiovasc Risk Rep 6 , — Article Google Scholar. Tsuda, K. Bone mineral density in women with essential hypertension. Am J Hypertens 14 , — Varenna, M. The association between osteoporosis and hypertension: the role of a low dairy intake. Okamoto, K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27 , — Zicha, J. Ontogenetic aspects of hypertension development: analysis in the rat. Bastos, M. Trabecular bone area and bone healing in spontaneously hypertensive rats: a histometric study. Braz Oral Res 24 , — Manrique, N. Hypertension modifies OPG, RANK, and RANKL expression during the dental socket bone healing process in spontaneously hypertensive rats. Lee, T. Improved trabecular bone structure of month-old male spontaneously hypertensive rats. Komori, T. Regulation of osteoblast differentiation by transcription factors. Kearns, A. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Yamashita, T. New roles of osteoblasts involved in osteoclast differentiation. Kyrieleis, A. Image stitching strategies for tomographic imaging of large objects at high resolution at synchrotron sources. Nucl Instrum Methods Phys Res A , — Article ADS CAS Google Scholar. Vlassenbroeck, J. Limaye, A. Drishti: a volume exploration and presentation tool. In: Proceedings SPIE , Developments in X - Ray Tomography VIII , X Charoenphandhu, N. Enhanced trabecular bone resorption and microstructural bone changes in rats after removal of the cecum. |
| High blood pressure may accelerate bone aging | gov or. Another study followed men and women for 5. The cross-sectional structure of femoral head A , the microstructural changes of femoral head in week WT controls B and SHR C. Lancet — Article CAS PubMed Google Scholar McCarron DA Low serum concentrations of ionized calcium in patients with hypertension. CAS PubMed PubMed Central Google Scholar Lello S, Capozzi A, Scambia G. J Hypertens —; discussion Article CAS PubMed Google Scholar Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV Association between hypertension and fragility fracture: a longitudinal study. |
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