INTRODUCTION — The effects of diabetes on bone are complex. While most studies agree that fracture risk is increased in diabetes, bone mineral density (BMD) may not reflect bone fragility, particularly in type 2 diabetes. The extent to which the metabolic abnormalities of diabetes potentially affect bone metabolism, structure, quality, and mineral density is still debated. This topic will review the effects of type 1 and type 2 diabetes on bone (table 1). The musculoskeletal complications of diabetes are discussed separately. (See "Overview of the musculoskeletal complications of diabetes mellitus".)
INCREASED BONE FRAGILITY
Bone fracture — The majority of epidemiologic studies have demonstrated bone fragility and an increased risk of fractures in patients with diabetes (table 1). As examples:
●In meta-analyses of observational studies in patients with type 1 diabetes, there was an increased risk of hip, lumbar spine, and all fractures in patients with type 1 diabetes [1,2]. In one meta-analysis, fractures occurred in 4.8 percent of adults aged 18 to 50 years with type 1 diabetes versus 2 percent without (pooled relative risk [RR] for all fracture 1.88, 95% CI 1.52-2.32) [2].
●In meta-analyses of observational studies in patients with and without type 2 diabetes, there was an increased risk of hip, vertebral, foot, and overall fracture in patients with type 2 diabetes (RRs ranging from 1.16 to 1.37) [3-5].
However, in a subsequent analysis of data from a prospective cohort study (men aged ≥65 years), the prevalence and incidence of vertebral fractures were not higher in men with or without type 2 diabetes [6].
●In an analysis of a Danish National Patient Register, there was an increased risk of subtrochanteric and femoral shaft fractures in patients with type 1 diabetes compared with age-matched controls without diabetes (52.14 versus 25.18 events per 100,000 person, hazard ratio [HR] 2.07, 95% CI 1.68-2.56) [7]. There did not appear to be an increased risk in patients with type 2 diabetes compared with controls.
In some population-based studies, there was an association between risk of fractures (proximal humerus, vertebral, and hip) and longer diabetes duration, poor glycemic management, diabetic retinopathy, advanced cortical cataract, neuropathy, and insulin treatment [8-12].
In a retrospective, population-based cohort study of almost three million veterans (900,402 with diabetes), the risk of any clinical fracture (RR 1.22, 95% CI 1.21-1.23) and hip fracture (RR 1.21, 95% CI 1.19-1.23) was increased in veterans with diabetes [13]. Peripheral neuropathy, cardiovascular disease, and congestive heart failure were associated with an increased risk of fracture.
Prolonged fracture healing has been described in both type 1 and type 2 diabetes [14,15]. In a systematic review of studies evaluating complications of fracture healing, patients with diabetes and surgically treated lower extremity fractures had increased rates of malunion, infection, and reoperation compared with patients without diabetes [15].
The pathophysiology of bone fragility in diabetes is complex and involves alterations in bone metabolism and structure [16,17].
Bone metabolism — Low bone turnover, with a reduction in unmineralized bone matrix, and increased collagen glycation may contribute to increased fragility of diabetic bone. In histomorphometric and biochemical studies in patients with diabetes, bone turnover is low with a reduction in both bone formation and, to a lesser degree, bone resorption [16-19]. In a systematic review and meta-analysis of 66 studies evaluating bone metabolism in patients with diabetes, markers of both bone formation (osteocalcin) and resorption (C-telopeptide) were decreased in patients with type 1 and type 2 diabetes compared with controls [18]. (See "Bone physiology and biochemical markers of bone turnover".)
Bone turnover may be affected by the late complications of diabetes (eg, renal failure, which may be associated with adynamic bone disease) [20-22]. However, decreased bone formation can be demonstrated in patients with type 1 diabetes before the onset of clinical renal disease, when estimated glomerular filtration rate is >60 mL/min/1.73 m2 [23-25].
Bone structure and quality
●Bone density – Compared with the reference population, bone mineral density (BMD), as measured by dual-energy x-ray absorptiometry (DXA), is usually lower in patients with type 1 diabetes and normal or increased in patients with type 2 diabetes [16,17,26]. As examples:
•In a study of 60 adolescents with type 1 diabetes, total body and lumbar spine BMD Z-scores were significantly lower compared with the age- and sex-matched reference population [27]. The onset of diabetes in adolescence may result in a decreased peak bone mass and a decrease in BMD due to a failure to acquire endosteal bone during growth [28].
•In a study of 65 adults (mean age 62.6 years) with longstanding (over 50 years) well-controlled type 1 diabetes from a specialist center, Z-scores at the lumbar spine, total hip, femoral neck, and radius were normal [29].
•In a study of older, well-functioning patients with type 2 diabetes, hip and total body BMD was higher in Black and White adults with diabetes compared with their appropriate controls [30].
In some individuals with diabetes, therefore, BMD does not appear to reflect fracture risk. Poor bone quality likely contributes to bone fragility and increased risk of fracture independent of measured BMD.
●Increased cortical porosity – Research using high-resolution peripheral quantitative computed tomography (HR-pQCT) has suggested that a deficit in cortical bone, resulting in increased cortical porosity, may contribute to fracture risk in type 2 diabetes, explaining in part the reduction in bone strength, which is not detected by DXA [31,32].
●Bone microarchitecture – Trabecular bone score (TBS) is an index of bone microarchitecture derived from lumbar spine DXA, and it serves as an indirect measurement of trabecular bone quality [33]. Adults with diabetes have a lower TBS than individuals with normal glycemia [33-35]. In addition, TBS is a significant predictor of fracture risk independent of bone density [34,36].
PATHOGENESIS — The mechanism for increased bone fragility in diabetes is poorly understood, but it is likely multifactorial and in broad terms, can be attributed to metabolic abnormalities, diabetes microvascular complications, and diabetes treatment (table 1).
Hyperglycemia — In chronic hyperglycemia, some of the excess glucose combines with free amino acids on circulating or tissue proteins. This nonenzymatic process initially forms reversible early glycation products and, later, irreversible advanced glycation end products (AGEs). The accumulation of AGEs in bone matrix as a result of hyperglycemia alters collagen structure, impacts osteoblasts and osteoclast function, increases bone marrow adiposity and release of inflammatory cytokines, and alters osteocyte number and function, all of which contribute to reduced bone quality [17,37,38]. Osteocytes secrete bone-specific proteins, including sclerostin, which inhibit bone formation. Osteocyte death is followed by hypermineralization of bone and later by filling of canaliculi with mineralized connective tissue, potentially resulting in increased brittleness of bone. (See "Pathogenesis of osteoporosis", section on 'Decreased osteocyte viability'.)
AGEs also contribute to the development of microvascular complications. (See 'Microvascular disease' below.)
Microvascular disease — Microvascular disease may affect the bone microvasculature and the bone marrow microenvironment where bone progenitor cells reside, with shifts in production to adipocytes and away from osteoblasts, resulting in an increase in bone marrow adiposity [39]. In some studies, marrow adiposity was associated with glycated hemoglobin (A1C) level or fractures [17,40-42].
In a study using high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate patients with type 2 diabetes (with and without microvascular complications) with controls, only the group with microvascular complications had cortical bone deficits [43]. A similar study on patients with type 1 diabetes showed that the presence of microvascular complications was associated with deficits in both cortical and trabecular bone [44]. Another HR-pQCT study suggested that microvascular disease may play a role in increased cortical porosity in patients with type 2 diabetes [45].
In addition, microvascular complications, such as sensory neuropathy and retinopathy with visual impairment, increase the risk of falling. An increased risk of falling and fall-related fractures has been reported in older women with diabetes [46,47]. Neuropathy may also cause localized bone loss, which may increase the risk of fracture at the foot and ankle.
Diabetes therapy — Fracture risk may also be related to therapy. Thiazolidinediones and the sodium-glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, have been reported to increase the risk of fractures. The adverse effects of these drugs are reviewed separately. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Skeletal fractures' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Skeletal fragility'.)
Insulin has anabolic effects, but its use in patients with type 2 diabetes marks longstanding or severe diabetes, which confounds studies evaluating the effects of insulin on fracture. The anabolic effects of insulin may be mediated through the insulin-like growth factor 1 (IGF-1) pathway, and in type 1 diabetes, low levels of insulin and IGF-1 may impair osteoblast function [48].
APPROACH TO EVALUATION AND MANAGEMENT
Clinical evaluation — The evaluation of fracture risk in patients with diabetes mellitus is similar to patients without diabetes, with several caveats, and includes assessment of:
●Clinical risk factors for fracture (table 2).
●Bone mineral density (BMD), with cautious interpretation. The use of BMD to predict fracture risk in patients with diabetes (particularly type 2) is problematic because the risk of fracture may be higher than that predicted by BMD T-score [49-51]. (See 'Bone structure and quality' above.)
●Fracture probability using a risk assessment tool, such as FRAX. For a given FRAX score, however, the risk of fracture may be higher in patients with compared with those without diabetes [52,53]. The FRAX algorithm does not include diabetes as a risk factor. More research is required in collecting new population cohorts worldwide before this risk factor can be included. Tools that may enhance estimation of fracture risk in patients with diabetes include the trabecular bone score (TBS), which is derived from lumbar spine dual-energy x-ray absorptiometry (DXA) images, and TBS-adjusted FRAX [50].
Fracture risk assessment, including a description of FRAX, TBS, and the clinical applications of fracture risk assessment, is reviewed in detail elsewhere. (See "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk' and "Osteoporotic fracture risk assessment", section on 'New and emerging technologies'.)
Treatment — Lifestyle measures should be adopted universally to improve glucose management, as well as general heath in patients with diabetes.
●Glycemic management – Prevention of chronic hyperglycemia to reduce advanced glycation end products (AGEs), glycation of collagen, and microvascular complications may be important for skeletal health. Glycemic targets should be individualized, balancing the demonstrated benefits with regard to prevention and delay in microvascular complications with the risk of hypoglycemia. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Blood glucose monitoring and target A1C'.)
Thiazolidinediones and sodium-glucose co-transporter 2 (SGLT2) inhibitors (particularly canagliflozin) have been associated with an increased risk of fracture. In patients at high risk for fracture (eg, low bone density, previous fracture), thiazolidinediones should not be used, except in the rare circumstance that other glucose-lowering agents cannot be used, and SGLT2 inhibitors should be used with caution. Although bone fractures have been reported to occur more frequently only in patients taking canagliflozin, based on putative mechanisms, other SGLT2 inhibitors may also reduce bone mass and increase bone fractures. (See 'Diabetes therapy' above.)
●Lifestyle measures – The general recommendations regarding healthy lifestyle (exercise to improve muscle strength and reduce the risk of falls, calcium and vitamin D supplementation) are applicable to older adults with diabetes. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake'.)
In addition to lifestyle measures, patients at high risk for fracture should receive pharmacologic therapy. Similar to patients without diabetes, high risk in patients with diabetes includes a history of fragility fracture or osteoporosis based upon BMD measurement (T-score ≤-2.5). For patients with T-scores between -1.0 and -2.5, we treat patients with a 10-year probability of fracture that meets country-specific intervention thresholds, which are reviewed separately. If a patient with diabetes is just below the FRAX-based intervention threshold, some experts take into account the effect of diabetes on fracture risk and recommend treatment [54]. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection' and "Treatment of osteoporosis in men", section on 'Candidates for therapy' and "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool'.)
●Choice of pharmacologic therapy – In the absence of studies specifically targeting osteoporosis therapy in individuals with diabetes, treatment should follow general guidelines for the treatment of osteoporosis. (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
There are few studies specifically addressing the treatment of osteoporosis in individuals with diabetes. In a systematic review of nine studies (predominantly subgroup or post hoc analyses of trials evaluating alendronate, risedronate, raloxifene, and teriparatide for the treatment of osteoporosis), there were similar increases in bone density and reductions in vertebral (alendronate, raloxifene) or nonvertebral (teriparatide) fracture risk in patients with and without diabetes [55]. The majority of the patients in the trials had type 2 diabetes. In a post hoc analysis of the FREEDOM and FREEDOM extension studies comparing denosumab with placebo in patients with diabetes, denosumab significantly increased BMD and decreased vertebral fracture rate compared with placebo [56].
Serious adverse events from bisphosphonate treatment do not seem to be increased in patients with diabetes [57-59]. (See "Risks of bisphosphonate therapy in patients with osteoporosis".)
SUMMARY
●Bone turnover – Patients with diabetes typically have low bone turnover with reduction in bone formation and, to a lesser degree, bone resorption. The mechanism for the reduced bone turnover is likely multifactorial. In type 1 diabetes, low levels of insulin and insulin-like growth factor 1 (IGF-1) may impair osteoblast function. In both type 1 and type 2 diabetes, the accumulation of advanced glycation end products (AGEs) in collagen as a result of hyperglycemia also may contribute to reduced bone formation (table 1). (See 'Bone metabolism' above.)
●Bone mineral density – Bone mineral density (BMD), as measured by dual-energy x-ray absorptiometry (DXA), is lower in patients with type 1 diabetes and normal or increased in patients with type 2 diabetes, although cortical porosity may be increased. (See 'Bone structure and quality' above.)
●Fracture risk – Fracture risk is increased in both groups, possibly related to factors in addition to BMD, such as duration of diabetes, glycemic management, diabetic complications, bone quality, treatment, and risk of falling (table 1). (See 'Increased bone fragility' above.)
Thiazolidinediones and sodium-glucose co-transporter 2 (SGLT2) inhibitors (particularly canagliflozin) for the treatment of diabetes have been associated with an increased risk of fracture. In patients at high risk for fracture (eg, low bone density, previous fracture), thiazolidinediones should not be used, except in the rare circumstance that other glucose-lowering agents cannot be used, and SGLT2 inhibitors should be used with caution. (See 'Diabetes therapy' above.)
●Treatment – In the absence of studies specifically targeting osteoporosis in individuals with diabetes, treatment recommendations should follow general guidelines for the treatment of osteoporosis. (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
