Diabetes and bone health: the relationship between diabetes and osteoporosis-associated fractures

It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. The relationship between diabetes and bone disease is less well defined but recent data seem to suggest that diabetes and the complications associated with it can be detrimental to bone health. Furthermore, it appears that thiazolidinediones, medications used in the treatment of diabetes, can also cause bone loss and increase the risk of fracture. This article will review the relationship between diabetes and bone health.     

Diabetes and skeletal health

Osteoporosis and diabetes affect a large proportion of the elderly population. The prevalence of diabetes and osteoporosis is increasing. Compared with individuals without diabetes, both men and women with diabetes have a higher risk of fractures, particularly at the hip, with consequent significant morbidity and mortality. Type 1 diabetes is associated with decreased bone mass and although bone mass data for Type 2 diabetes may or may not be decreased, there is evidence of altered bone quality in diabetes. The mechanisms involved include effects of insulin, insulin-like growth factor 1, cytokines, advanced glycation end products, and altered calcium homeostasis. In addition, a drug-induced increase in the incidence of fractures has been noted with the use of thiazolidinediones (TZDs). TZDs improve insulin sensitivity and have multitude other beneficial effects. Osteoblasts and adipocytes are derived from a common multipotential mesenchymal stem cell progenitor, with activation of peroxisome proliferator-activated receptor γ2 by both currently available TZDs (i.e. rosiglitazone and pioglitazone) stimulating adipogenesis and inhibiting osteoblastogenesis. The use of both rosiglitazone and pioglitazone is associated with an increased fracture risk, with changes in bone turnover markers and decreased bone mineral density.     

炎性反应与骨骼健康

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Food groups and bone health

Studies aimed at determining the relationship between key nutrients (especially calcium) and bone health have examined directly the effect of a specific nutrient (or, in some cases, various nutrients) commonly consumed in the human diet. Consideration of the foods man actually consumes rather than the nutrients contained within them is an alternative strategy that has been adopted in other disciplines examining the relationship between diet and disease. Two studies indicate that a high fruit and vegetable, intake is protective for the skeleton, whereas high candy consumption is associated with lower bone mass, irrespective of gender. These data also suggest that a high intake of fatty, sugary foods is detrimental to bone health around the time of menopause. Because milk and milk products provide greater than 50% of the total calcium in the Western diet as well as a number of other key nutrients including phosphorus, magnesium, and zinc, they have a fundamental role in bone health determination. Milk supplementation also improves the nutritional quality of postmenopausal women's diets to a greater extent than calcium. Data for alcohol consumption are also intriguing. Recently, a positive association was noted between tea drinking and bone mass in postmenopausal women and may point to the influence of flavonoids contained in tea on bone health.     

Diabetes,bone and glucose-lowering agents: basic biology

Skeletal fragility often accompanies diabetes and does not appear to correlate with low bone mass or trauma severity in individuals with diabetes. Instead (and in contrast to those with osteoporotic bone disease), bone remodelling and bone turnover are compromised in both type 1 and type 2 diabetes, contributing to defective bone material quality. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Ann Schwartz (DOI:  10.1007/s00125-017-4283-6). This review presents basic science evidence that, alongside other organs, bone is affected in diabetes via impairments in glucose metabolism, toxic effects of glucose oxidative derivatives (advance glycation end-products [AGEs]), and via impairments in bone microvascular function and muscle endocrine function. The cellular and molecular basis for the effects of diabetes on bone are discussed, as is the impact of diabetes on the stem cell niche and fracture healing. Furthermore, the safety of clinically approved glucose-lowering therapies and the possibility of developing a single therapy that would be beneficial for both insulin sensitisation and diabetes bone syndrome are outlined.     

Diabetes,bone and glucose-lowering agents: clinical outcomes

Older adults with diabetes are at higher risk of fracture and of complications resulting from a fracture. Hence, fracture risk reduction is an important goal in diabetes management. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Beata Lecka-Czernik (DOI  10.1007/s00125-017-4269-4). Specifically, this review discusses the challenges of accurate fracture risk assessment in diabetes. Standard tools for risk assessment can be used to predict fracture but clinicians need to be aware of the tendency for the bone mineral density T-score and the fracture risk assessment tool (FRAX) to underestimate risk in those with diabetes. Diabetes duration, complications and poor glycaemic control are useful clinical markers of increased fracture risk. Glucose-lowering agents may also affect fracture risk, independent of their effects on glycaemic control, as seen with the negative skeletal effects of the thiazolidinediones; in this review, the potential effects of glucose-lowering medications on fracture risk are discussed. Finally, the current understanding of effective fracture prevention in older adults with diabetes is reviewed.     

Transdermal hormone therapy and bone health

The clinical aftermath of the reporting of the initial findings of the Women’s Health Initiative (WHI) in 2002 was a profound reduction in the use of hormone therapies by menopausal women. This reduction led to a well documented increase in vasomotor symptoms and vaginal atrophy among those women who discontinued their hormone regimens. However, another adverse impact among these women, as well as many other menopausal women, is the well recognized increased likelihood of osteoporosis resulting from the decline in circulating estradiol levels associated with natural and surgical menopause. Although the use of non-hormonal drugs such as bisphosphonates has been shown to reduce the risk of fracture in women with osteoporosis, bisphosphonates have not been shown to reduce the risk of fracture in non-osteoporotic women. Indeed, only oral estrogen (as demonstrated in the WHI studies) has been shown to reduce the risk of fracture in osteoporotic and non-osteoporotic women. As non-oral hormone therapies have been shown to be as effective in treating vasomotor symptoms and vulvovaginal atrophy and to have a different (and perhaps more beneficial) physiological effect than oral regimens, it behooves us to assess the impact of non-oral hormone regimens on bone mineral density and fracture risk. Although there are no clinical trials that primarily assess the impact of non-oral regimens on fracture risk in menopausal women, numerous studies are consistent in demonstrating the positive impact of non-oral regimens in maintaining and increasing bone mineral density among users, even for those women using estrogen doses that are considered to be “too low” to have a beneficial impact on other menopausal symptoms.     

Premenopausal bone health assessment

The World Health Organization criteria for classification of bone mineral density (BMD) cannot be applied to premenopausal women because the relationship between BMD and fracture risk is not the same as in postmenopausal women. Approximately 2.5% of premenopausal women have BMD that is more than 2.0 standard deviations below the mean BMD of an age-, gender-, and ethnicity-matched reference population. Most premenopausal women with low BMD have low peak bone mass and low 5-to 10-year probability of fracture. The management of these patients involves nonpharmacologic lifestyle measures and reassurances that fracture risk is low. A minority of premenopausal women with low BMD have significant elevation of fracture risk, usually a result of contributing diseases, conditions, or medications that may be identified and treated. Premenopausal women with fractures are at increased risk for postmenopausal osteoporosis and fractures later in life.     

Calcium and bone health in Asians

A low dietary calcium intake is prevalent among Asian populations. The results of epidemiological studies showed that low dietary calcium intakes may be associated with lower bone mass, and increased fracture risk. The finding from randomised controlled clinical trials consistently show that calcium supplementation may be associated with higher bone mineral density in populations with low calcium intake. A Recommended Dietary Allowance of 1,000 mg or above is appropriate in Asians.     

Diabetes complications and adverse health outcomes after coronary revascularization

Aims

To examine effects of diabetes complications on health outcomes following coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI), comparing outcomes for patients with diabetes complications to those without diabetes complications.

Methods

Retrospective analysis of discharge data for 61,566 patients with diabetes age 45 or older who had CABG or PCI in 2007 in United States community hospitals, using data from the Nationwide Inpatient Sample. Analysis included propensity score-adjusted logistic regression.

Results

Of all patients, 21.2% of the weighted sample had diabetes complications. Older patients, Blacks and Hispanics, and those with greater illness severity were more likely to have diabetes complications. Unadjusted rates of in-hospital mortality, postoperative stroke, and renal failure were higher for patients with diabetes complications (rate ratios 2.2, 1.8, and 9.8, respectively; all p < 0.0001). In adjusted results, having diabetes complications was associated with higher odds of in-hospital mortality (odds ratio, OR 1.62, 95% confidence interval, CI 1.37–1.91) and renal failure (OR 3.03, CI 1.71–5.39). Compared to CABG, PCI was associated with extra risk of postoperative renal failure for those with diabetes complications.

Conclusion

Among patients with diabetes having revascularization, those with diabetes complications have higher risks of in-hospital death and renal failure irrespective of having CABG or PCI.     

Diabetes and bone fracture: risk factors for old and young

Diabetes mellitus may affect bone turnover in a number of ways, thus leading to impaired bone quality and a consequent increase in fracture risk. These factors are summarised in this commentary.     

Hormones and bone health in postmenopausal women

Although it has been known for some time that estrogen deficiency is a major pathogenetic factor for osteoporosis related fractures among postmenopausal women, the capability of estrogen (with or without a progestin) to prevent fractures has often been questioned. The publication of the data from the two hormone clinical trials of the Women’s Health Initiative lays that discussion to rest. In both studies what have been considered a standard dose of conjugated estrogen with or without medroxyprogesterone acetate significantly reduced the risk of all fractures, including clinical vertebral fractures and hip fracture, in a population of postmenopausal women, average age 63 yr, not selected for osteoporosis by BMD. These results are particularly impressive given the difficulty of finding a fracture benefit in lower risk populations with other anti-resorptive agents. Surrogate data on lower doses of hormone therapy suggest a fracture benefit would be seen if studies were to be done. The other outcomes in WHI make it important to define appropriate clinical guidelines for use of hormone therapy for prevention of fractures in postmenopausal women.     

Exercise and the preservation of bone health

Exercise is generally accepted as having favorable effects on bone health and, subsequently, a reduction in fracture risk. In the absence of large randomized controlled trials of the potential benefits of exercise on fracture risk, support for this belief comes from cross-sectional studies and interventional studies using surrogate endpoints such as bone mineral density and falls. In this review, we discuss the characteristics of exercise programs that provide an osteogenic stimulus. The goals and benefits of exercise on bone across the age spectrum are discussed. Where there is a paucity of human data, animal studies examining the roles of variables such as exercise intensity, frequency, duration, and mode in shaping the response of bone to exercise are discussed. The effects of disuse and the limited response of bone to remobilization are described. The rapid and dramatic decrease in bone mineral density observed in the early period after heart or lung transplantation is discussed, as are the available data on the benefits of exercise on bone in this population. For cardiopulmonary rehabilitation programs to improve bone health, they should include not just weight-supported activities (eg, cycling) but also weight-bearing activities (eg, walking, resistance exercise). Although the optimal exercise routine for bone health is unknown, components of an osteogenic program are discussed.