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1st International Meeting of Diabetes and Bone

1st International Meeting of Diabetes and Bone
  • Endocrinology and metabolism
  • Diabetes

Resource type


Fracture risk and bone fragility in people with diabetes

Specialists in Endocrinology, Diabetes, Rheumatology, Internal Medicine and Primary Care attended this innovative meeting to discuss two key global health problems: diabetes and osteoporosis.

The conditions are often found concurrently, with bone assessment and fracture management requiring specialist skills, in affected patients.

Diabetes – in particular, type 2 diabetes mellitus (T2DM) – is of global concern. T2DM affects nearly half a billion people and the number of new diagnoses continues to increase at an alarming rate. Having a history of diabetes is known to increase fracture risk.

Osteoporosis is also being identified in more people than ever before, particularly in countries with ageing populations. Despite the widespread availability of drug treatments for osteoporosis (which have helped to reduce fracture burden by 50-60%), osteoporotic fracture morbidity is often accompanied by a loss of independence. In addition, the mortaility after hip fracture remains high, at ~50% in the first year.

This report highlights important subjects that were discussed at a recent two-day meeting on diabetes and osteoporosis, the learning objectives of which were to:

  • Assess fracture risk in diabetic patients
  • Utilise the latest pathophysiology of bone fragility in diabetes
  • Utilise the latest diagnostic tools and treatment options for diabetes-related fractures


Bone histomorphometry and biochemical markers in Diabetes

Biochemical markers generally support histomorphometric evidence of low bone turnover in people with diabetes, said Dr David W Dempster (Columbia University, New York, USA). Specific markers (e.g. serum osteocalcin [OC] and C-terminal cross-linked telopeptide [s-CTX]) may help to predict fracture risk in people with T2DM, independently of bone mineral density (BMD). Data from large cohorts are needed, to determine whether these analyses should be incorporated in routine diabetes care.

Bone histomorphometry in T2DM patients reveals reduced cortical thickness, reduced cancellous bone volume and impaired structure, reduced bone formation and turnover, and a reduction in circulating osteogenic cells.

In contrast, histomorphometry reveals little difference between type 1 diabetes (T1DM) patients and controls, although there may be subtle alterations in cancellous bone structure and bone formation dynamics in patients who experience fractures.

Although bone mineral density (BMD) is often below normal in T1DM, BMD is normal or elevated in T2DM. This suggests that other factors (such as enhanced fall risk or poor bone quality), may be at play.

Dr Dempster described biochemical markers that may be associated with fracture risk in T2DM:

  • Reduced IGF-1 – associated with vertebral fractures in diabetes, independent of BMD [1]
  • Increased sclerostin – may suggest skeletal fragility in T2DM as it is linked with an increased vertebral fracture risk and might reflect accumulation of older bone [2]
  • Increased accumulation of AGEs – observed over time and with repeated hyperglycaemia. Importantly, AGEs cause a deterioration in several biomechanical properties (e.g. decreased bone strength independent of BMD, increased brittleness of bone matrix, slow bone turnover)
  • Low parathyroid hormone (PTH) level –this is a marker of bone dysfunction


Bone formation is monitored by measuring serum osteocalcin (OC), type 1 procollagen amino-terminal-propeptide (P1NP) and bone alkaline phosphatase (BAP) levels. Bone resorption is assessed by s-CTX.

A combination of reduced PTH and OC levels may predict vertebral fracture risk, independent of lumbar spine BMD, explained Dr Dempster. He also presented a hypothesis for factors that may be responsible for heightened fracture risk in people with T2DM (Figure 1)

fig 1


1. Ardawi. Bone. Oct 2013;56(2):355-362.

2. Yamamoto et al  JCEM Oct 2013;98(10):4030-4037.


Central role of adipose tissue in metabolic disorders

A growing bank of data indicate that obesity increases the risk of several types of fracture, rather than offering a protective effect, as previously thought.

Evidence presented by Dr Marco Giorgio Baroni (University Sapienza, Rome, Italy) strongly implicates the role of excessive adipose tissue (particularly visceral fat) in producing inflammatory cytokines. Through a complex array of reactions these stimulate bone resorption and, ultimately, increase bone fragility (Figure 2).

Figure 2: Relationship between visceral fat and trabecular BMD

  • Adipose tissue formation: inflammatory cytokines (interleukin 6, tumour necrosis factor-α)
  • Growth hormone/insulin-like growth factor-1 axis (IGF-1, a differentiation factor for osteoblasts)
  • Increased free fatty acids (FFA), stimulates resorption
  • Increased leptin, inhibits bone formation
  • Peroxisome proliferator-activated receptor-gamma (PPARg) activation, inhibits bone formation and stimulates resorption


If the evidence is proven, the public health implications of obesity and overweight on increased fracture risk are likely to be substantial.

Obesity has a multifactorial aetiology, with environmental and genetic factors being important (Figure 3). The multisystemic effects of obesity are linked to an imbalance in homeostatic and proinflammatory immune responses. Obesity triggers inflammatory pathways in the brain and adipose tissue that dysregulate the physiological responses that maintain insulin and leptin sensitivity.

Over time, ectopic lipid accumulation in muscle, liver, and blood vessels activates tissue leukocytes, contributes to organ-specific disease, and exacerbates systemic insulin resistance. Cellular- and cytokine-mediated inflammation in pancreatic islets accelerates the progression toward diabetes.   

Figure 3: Factors implicated in obesity development

fig 3


Implications for osteoporosis treatment in diabetic patients

Diabetic patients on insulin have nearly double the risk of fractures compared with those not on insulin. Increased fracture risk is associated with lower total hip BMD, recent falls and sulfonylurea use. These were the conclusions of a presentation outlining the relationship between diabetes, drugs and osteoporosis, given by Dr Nicola Napoli, University Campus Bio-Medico di Roma, Rome, Italy.

Lifestyle intervention (involving exercise, diet support and weekly group behavioural therapy) should always include physical activity, and should always be the first step in the treatment process. When pharmaceutical interventions are necessary, GLP-1/ DPP4 inhibitors,[1] insulin sensitizers (metformin/glitazones) and sulphonlyureas [2] should be considered ahead of basal or basal/bolus insulin regimens. Data suggest that DPP4 inhibitors could have a protective effect on bone.

Exercise added to weight loss therapy preserves muscle mass, increases strength, balance and gait speed. Exercise intervention may indeed be the primary focus, because (unlike diet or diet plus exercise), research indicates that exercise-only interventions improve BMD in people with diabetes.

Of the pharmaceutical interventions available for T2DM, studies show that glucagon-like peptide (GLP)-1 treatment controls weight. More specifically, in a rat model, exendin-4 (a GLP-1 receptor agonist) prevented osteopenia by promoting bone formation and suppressing bone resorption.

Despite improvements in the assessment of fracture risk in diabetics, knowledge of risk reduction is more limited. Dr Napoli spoke of the paucity of randomized data supporting the use of antiresorptives in diabetics. He cautioned that the most commonly prescribed antiosteporotics (e.g bisphosphonates, denosumab, raloxifene) may be less effective in diabetics because bone formation rates may be reduced relative to bone resorption. Consequently, these agents may further decrease bone strength.

He added that there are extremely limited data on the role of anabolic drugs in people with diabetes, although these agents increase bone formation in nondiabetics.


1. Monami M, et al. Diab Care 2011;34:2474-6

2. Vestergaard P, et al. Diabetologia. 2005 Jul;48(7):1292-9.


Individualising T2DM therapy

Several pathophysiological mechanisms (alone or in combination) cause hyperglycaemia, but now almost 40 compounds are available to interfere with these mechanisms and improve diabetic control. Professor Paolo Pozzilli (University Campus Bio-Medico, Rome, Italy; St. Bartholomew’s and The London School of Medicine, Queen Mary University of London, UK) outlined the range compounds, including GLP-1 analogues, DIPP4 and SGLT2 inhibitors.

These expanding therapeutic opportunities have facilitated personalised treatment for diabetes. Algorithms (such as ABCDE and SMART; Figure 4) take account of key factors including age, weight, complications, disease duration and economic considerations (for ABCDE) and safety, multifactorial issues, risk reduction and therapeutic choice (for SMART). Professor Pozzilli said that algorithms can be applied to great effect, including when one needs to factor in the patient’s risk of bone disease.

Figure 4. Algorithms that are useful in the personalized management of type 2 diabetes

fig 4

fig 4a


Bariatric surgery, insulin resistance and beta-cell dysfunction

A growing bank of literature shows that certain bariatric surgery procedures can induce remission of type 2 diabetes and improve β-cell function, for many patients. Conducting surgery early after the development of T2DM, having a relatively low fasting plasma glucose level before surgery and the choice of surgical procedure all predict higher rates of diabetes remission postsurgery (independently of BMI).

In addition, lower baseline HbA1c, waist-circumference and HOMA-IR predict greater improvement in glycaemic control than BMI, postsurgery. Dr Geltrude Mingrone (Catholic University, Rome, Italy) stressed the need for new criteria, to better define diabetic patients who are suitable candidates for bariatric surgery.

Some types of bariatric surgery induce diabetes remission, possibly by improving hepatic and/or peripheral insulin resistance, together with full restoration of insulin secretion, added Dr Mingrone.

For example, duodenum and proximal jejunum bypass is associated with a notable improvement of whole-body insulin sensitivity in both diabetic and nondiabetic individuals.

After biliopancreatic diversion (BPD) surgery, insulin sensitivity can be fully normalized, independently of the presurgical degree of derangement of glucose metabolism. A less impressive but still significant improvement is observed after Roux-en-Y gastric bypass (RYGB).

 Lower cumulative incidence rates for micro- and macrovascular diabetes complications are consistently reported in studies, in bariatric surgery compared with control groups, even after multivariable adjustments (Figure 5).

Figure 5: Cumulative incidence of micro- and macrovascular diabetes-related complications in surgery and control groups

fig 5

Bariatric surgery shows the central role played by the small intestine in glucose homeostasis. The duodenum and jejunum respond to a dietary carbohydrates and/or fat by increasing the secretion of incretin, GLP1 and gastric inhibitory polypeptide (GIP) , which in turn stimulate insulin secretion.


Sirtuin1 - a link between osteoporosis and diabetes

Sirtuins are a class of proteins purported to have anti-ageing properties. Sirtuin1 (Sirt1) has been widely studied and is implicated in age-associated diseases and metabolism; it appears to play a role in diabetes and osteoporosis, therefore increasing levels of Sirt1 may be a therapeutic target for both conditions. However, published evidence for natural Sirt1 activators, such as resveratrol, is not strong enough to justify its administration in patients, although interestingly, the anti-diabetic drug metformin activates Sirt1 and improves bone mass

Dr Rivka Dresner-Pollak, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, described how Sirt1 mediates the beneficial effects of calorie restriction. Calorie restriction (which is physiologically different compared with weight loss) has been shown to extend lifespan in various animal models.

A decrease in Sirt1 is observed with ageing and obesity, and correlates with diabetes and bone mass in animal models and early phase human studies:

  • Consistently, overexpression of Sirt1 in mice protects against bone loss and prevents diabetes
  • Reduced levels of Sirt1 were observed at the femoral neck in women who sustained hip fracture


Sirt1 genetic variations may be associated with BMI, obesity and diabetes risk. Two single-nucleotide polymorphisms (SNPs) appear to confer protection from obesity, whereas another two SNPs are associated with a decrease in acute insulin response and a sex-specific increase in risk of T2DM.

Pharmacologic Sirt1 activation (STACs) improves bone mass and metabolic parameters in mice, and improves lipid profile in humans. It may therefore represent a novel strategy to design therapeutics for diabetes and osteoporosis, said Dr Dresner-Pollak. The roles of other sirtuins remain to be investigated, she added.


Post-transplant bone disease, immunosuppressants and diabetes

Following organ, bone marrow or stem cell transplantation, rapid and severe bone loss is observed and rates of fracture incidence increase, due to the use of immunosuppressant therapy. Dr Solomon Epstein (Mt Sinai School of Medicine New York, USA) said that the fracture risk in recipients is five tmes that seen in the general population. With hip fracture risk increased by ~34%. In transplant recipients, BMD can be near normal or normal, and the incidence of osteoporosis is significantly higher than in the general population.

The clinical picture shows an extremely high incidence of fractures at all sites,especially in people with concomitant diabetes. This may be due to cofactors such as combined renal/pancreatic transplantation, pre-existing bone disease, time interval before transplantation, and immunosuppressive drug regimen

Calcineurin inhibitors (e.g. cyclosporine and tacrolimus) are immunosuppressants that have substantially reduced the incidence of organ rejection and enhanced patient survival following transplantation. However, these agents are associated with the promotion of rapid and severe bone loss.

The mechanism accounting for this action is complex and unclear, with in vitro and in vivo studies producing conflicting results, explained Dr Epstein.

The management of patients with post-transplant bone disease centers on a rapid reduction in glucocorticoid dosage and instigation of antiresorptives (such as bisphosphonates plus calcium and vitamin D or analogues).

Other immune-modifying drugs (such as azathioprine, mycophenolate mofetil and sirolimus) are not thought to promote bone loss.


Animal models of diabetic bone disease


Using multiple types of mouse model, then confirming the observed changes in bone phenotype in human studies, is a relevant strategy for ongoing investigation of diabetic bone disease. Mechanisms mediating diabetic bone changes are important to understand, said Dr Laura McCabe (Michigan State University East Lansing, MI, USA). Such mechanisms differ from mechanisms of other types of bone loss (such as menopausal) and therefore will likely require different therapeutic approaches.

Utilising genetic and pharmacologic manipulation in mouse diabetic models will identify mediators of diabetic bone pathology (including IGF-1, Wnt and immune signalling). This, in turn, will determine their potential to serve as therapeutic targets, added Dr McCabe.

Spontaneous and pharmacologically induced T1DM rodent models display bone loss with similar characteristics to those seen in humans. They also exhibit altered bone matrix properties, including type I collagen glycation.

However, current T2D rodent models have several problems including the inability to recapitulate the bone changes seen in diabetic patients, added Dr McCabe.


Pathophysiology of diabetic bone disease

Although BMD is typically normal or elevated in people with T2DM, diabetic bone is more fragile than nondiabetic bone at a given BMD, explained Dr Ann Schwartz (University of California at San Francisco, USA). The reasons for this greater fragility are little understood. Potential contributing factors in diabetics (such as reduced bone formation, increased cortical porosity, bone vascularisation, material properties and susceptibility to microindentation, and advanced glycation end-products [AGEs]) are the focus of current research.


Diabetes and fracture: a global problem

The heightened risk of fracture associated with T2DM is influenced by increased risk of falls, potentially altered fracture threshold, altered geometry with lower bone area and reduced femoral neck bending strength.

Dr Bo Abrahamsen, University of Southern Denmark & Research Centre for Ageing and Osteoporosis, Glostrup, Copenhagen) explained that fall risk is particularly high in older patients with T2DM or those who experience hypoglycaemic events, vestibular dysfunction, other diabetes complications or poor glycaemic control.

Fracture risk is significantly higher at nonvertebral sites, especially the hip or wrist, and appears to develop over time, as patients begin to requiring medical therapy to achieve diabetic control. Fracture risk is not increased in those with newly diagnosed diabetes or impaired glucose tolerance, added Dr Abrahamsen.


Hypovitaminosis D and diabetes

Data show a clear link between vitamin D deficiency, glucose intolerance, and T2DM, said Dr Renate T de Jongh (VU Medical Center Amsterdam, The Netherlands). Although some data suggest a potential therapeutic role for vitamin D supplementation in people with diabetes, evidence from large-scale clinical trials is needed.

Hypovitaminosis D is associated with a higher risk of developing T1DM in genetically susceptible individuals. Basic science and animal models of T1DM and T2DM consistently indicate that Vitamin D helps to prevent diabetes or slow its development. However, upcoming results from large, prospective, ongoing trials of vitamin D supplementation should provide more information on the exact mechanism between vitamin D and diabetes. Higher dosages may be needed than those currently available, although the potential for vitamin D toxicity is of concern.


Osteoblasts in diabetic patients, lazy or insulin resistant?

Research is challenging the dogma that skeletal tissues are simple consumers of glucose to fuel the process of bone remodelling. Instead, bone appears to be an integral part of an endocrine system that regulates insulin production and sensitivity. This was the view expressed by Dr Roberto Civitelli, Washington University School of Medicine, St. Louis, USA.

Osteocalcin levels appear to be consistently lower in diabetics than in nondiabetics, but glycaemic control may itself decrease bone turnover. Dr Civitelli presented findings from animal and in vitro studies that, he acknowledged, remain to be fully translated to humans and are not yet clear. While one study showed correlations between uncarboxylated-OC and fat mass, another failed to show any changes in bone turnover between diabetic and nondiabetic individuals when insulin levels were changed. Dr Civitelli commented that we are just beginning to understand the relationship between bone and energy metabolism.


Gut endocrine system and bone turnover

Bone turnover is responsive to feeding and fasting. Gut hormones help to regulate bone mass by affecting both resorption and formation processes, as part of a gut–bone axis.

Dr Laurie Baggio (Mount Sinai Hospital; Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada) outlined the impact of gastrointestinal horomones and adipokines on regulating bone homoeostasis.

Dr Baggio discussed the mechanisms by which gut hormones (ghrelin, gastric inhibitory polypeptide [GIP], glucagon-like peptide [GLP]-2, neuropeptide-Y, peptide-YY), and the adipokines leptin and serotonin, mediate their effects on bone metabolism.

The gut endocrine system is a complex network of specialized cells that produce and secrete numerous peptide hormones (which are local neurotransmitters), or classic endocrine hormones (which regulate nutrient or energy intake, digestion, absorption, disposal or storage). The majority of gut hormones are secreted at low basal levels in the fasting state and their levels rise rapidly in response to energy intake.


Optimizing clinical trial design for bone studies in diabetes

Dr H Bone, Michigan Bone and Mineral Clinic, USA, discussed optimum clinical trial design for studies that evaluate skeletal benefits and risks in people with diabetes, stating that there are many overlapping questions about bone fragility (Figure 6). In future it will be essential to distinguish osteoporosis from other causes of increased fracture risk. Well-matched controls are critical, in interventional and exploratory studies; questions and targets that are specific, and answerable, are also needed. Isolation and quantification of these and other factors is critical to the identification of diabetes-specific interventions

Dr Bone called for  baseline data on diabetes to be incorporated into osteoporosis trials, and conversely, for baseline bone data to be incorporated into diabetes trials. While we await for better-designed studies to be developed, he added that clinical trial data bases may be a rich source of information for “big data” analyses.

Figure 6: Each of the factors contributes independently to bone strength, but likely work together in an integrated way to maintain overall bone quality (presented by Dr H Bone)

fig 6


Trabecular bone score and disease assessment

Advances in techniques to assess bone disease, such as HR-pQCT, pMRI and trabecular bone score (TBS) may indicate aspects of bone strength that are not captured by standard DXA scans.

These newer approaches reveal that, in diabetics with preserved BMD, cortical bone porosity at peripheral site is increased, and trabecular bone microstructure at both peripheral (pMRI) and axial site (TBS) are compromised. Such findings may account for high fracture risk seen in diabetics, said Prof. Didier Hans (Center for Bone diseases, DAL, Lausanne University Hospital, Switzerland).

Abnormal trabecular microarchitecture may help explain the paradox of increased fractures seen in people with T2DM who have a high BMD. Elevated TBS values correlate with better skeletal microstructure; low TBS values correlate with weaker skeletal microstructure. In T2DM, TBS are often lower and are associated with poor glycaemic control.

Clinical evidence for the role of the TBS value is growing.[1] TBS gives lower values in post-menopausal women and in men with previous fragility fractures than their non-fractured counterparts. TBS is complementary to data available by lumbar spine DXA measurements; TBS results are lower in women with a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; TBS predicts fracture risk and lumbar spine BMD measurements in postmenopausal women; efficacious therapies for osteoporosis differ in the extent to which they influence the TBS. TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality.

TBS is more sensitive than BMD in predicting diabetes-related fracture risk;[2] it may also be related to the level of diabetic control. Spinal TBS is sensitive to skeletal deterioration in postmenopausal women and diabetic men, whereas BMD is paradoxically greater in these groups.

Spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD. Combining lumbar spine TBS with BMD incrementally improves fracture prediction. Larger studies with longitudinal follow up are needed to validate these observations.


1. Silva et al. J Bone Miner Res. 2014 Jan 20

2. Leslie WD  et al. JCEM 2013.


Expanding the anabolic window with teriparatide

Agents with antiresorptive properties may improve bone strength by stabilising or increasing BMD, maintaining the trabecular architecture and increasing mineralisation density of the bone matrix.Teriparatide is a recombinant form of parathyroid hormone that is an effective anabolic agent, which stimulates bone formation and remodelling. Clinical trial data show that teriparatide significantly reduced in vertebral fractures (by 65%) and non-vertebral fractures (by 53%) fractures.[1] Dr Nicola Napoli presented a review of teriparatide to delegates in an additional presentation following the study day.

Teriparatide is equally effective in women with mild or severe previous fragility fractures,[2] and in women with 1, 2 or more previous fragility fractures.[2] Treatment may also reduce back pain.[3]

Teriparatide is also suitable for patients with glucocorticoid-induced osteoporosis who have moderately low to severely low BMD and/or fractures.

Dr Napoli described the DANCE study,[4] which is assessing the effect of teriparatide treatment in people with osteoporosis and T2DM. This trial reported substantial increases in bone mineral density and substantial reductions in the rate of nonvertebral fragility fractures after 18 months’ treatment, compared with baseline findings. DANCE is a prospective observational trial, involving over 4100 participants.

In patients with severe osteoporosis (defined as T scores -3.0 to -4.0 range or lower, with or without fractures), teriparatide should be considered as a first-line therapy to rebuild bone scaffold. Teriparatide treatment can be considered for those intolerant to or who failed on other agents, and is suitable for men and women.


1. Neer RM, et al. N Engl J Med. 2001;344:1434-41

2. Gallagher JC et al. J Clin Endocrinol Metab. 2005 Mar;90(3):1583-7. 

3. Miller RG. Geriatrics. 2006 Jan;61(1):24-30.

4. Silverman et al. Osteoporos Int 2013;24(8):2309-17

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International conference
Rome, Italy
Nov 7 - 8, 2014
Target audience
Endocrinologists, diabetologists, rheumatologists, physicians
by Excemed
Cardiometabolic, Endocrinology and metabolism