Diabetic Bone Disease
This is an excellent book. I decided to include in this post the entire book description included on goodreads, even if it’s somewhat long, because I thought the description gave a good overview of the topics covered in this book:
“Providing the most up-to-date research and current clinical knowledge of diabetic bone disease and the challenges still facing the research and clinical care communities, this book unites insights from endocrinology and orthopedics to create a truly unique text. The first part covers clinical and pre-clinical applications and research. The first two chapters present the clinical and epidemiological data about diabetic bone disease, evaluated and reviewed for type 1 and type 2, respectively. This is followed by discussions of how the propensity to fracture in diabetic bone disease can impact fracture risk assessments and how it can be adjusted for using current clinically relevant fracture risk models. A comprehensive overview of orthopedic complications observed in diabetes is next, as well as a focus on the consequences of diabetes on periodontal disease. Other topics include the utility of skeletal biomarkers in assessing diabetic bone disease, how drugs used to treat diabetes may also have skeletal consequences, and the possibility that diabetes may fundamentally impact early progenitor cells of various bone lineages and thus globally impact bone. The second part covers biomechanics and bone quality in diabetes: how diabetes ultimately may impact the architecture, integrity, and quality of bone. Utilizing the expertise of top researcher and clinicians in diabetic bone disease in one comprehensive text, this volume will be a useful and thought-provoking resource for endocrinologists and orthopedic surgeons alike.”
I would note that the book is also a useful and thought-provoking resource if you’re just a random diabetic who happens to know enough about medicine and related topics to make sense of a book like this one – i.e. if you’re someone like me. A few related observations from the book’s preface:
“Historically, most attention has been focused on four major complications known to afflict many individuals with T1DM and T2DM: retinopathy, neuropathy, nephropathy, and cardiovascular disease. However, epidemiological data now show that other tissues and organs may be significantly impacted by the diabetic state—and the skeletal system is now emerging as a primary target of diabetes-mediated damage (i.e., diabetic bone disease).
Studies have demonstrated that osteopenia and osteoporosis may be frequent complications of T1D, both in children and adults, and that T1D is associated with decreased bone density and increased fracture risk. In contrast to T1D, T2D has typically not been associated with osteopenia or osteoporosis and, in fact, has been more often associated with increased BMD [bone mineral density]. However, newer data show that bone quality and bone microarchitecture may be compromised in both conditions, suggesting that underlying mechanisms related to increased risk to fracture may be contributory to both forms of diabetes.
In this volume, we provide the reader with up-to-date information about what is currently known about diabetic bone disease and what are the challenges still facing the research and clinical care communities.”
This was a topic about which I knew next to nothing, and one of emotional responses I had early on to some of the coverage in the book was to think along the lines of: ‘Ah, type 1 diabetes, the gift that keeps on giving…’ or perhaps: ‘How was I not told this???’ It reminded me a bit of how I felt back when I realized some years ago that my diabetes was probably also messing with my lungs, without me knowing about it and despite nobody having told me anything about that (for details on that topic, see e.g. this paper). As far as I can remember, bone health has never come up during conversations I have had over the years in the past with endocrinologists or diabetes nurses, nor has it ever been discussed in detail in publications I’ve read on diabetes-related topics; the closest I’ve got has probably been remarks about individuals developing diabetics during childhood being slightly shorter than non-diabetics on average, due to (non-specific) disease-related adverse effects on growth during childhood. Relevant mechanisms have not been discussed in any detail, and actually what I had read on the topic of diabetes and growth had basically lead me to believe that a slight growth disadvantage was really all there was to this topic, as a potential interaction between diabetes status and osteoporosis risk was never touched upon in these publications. To give a great illustrative example, Sperling et al.‘s comprehensive textbook (~600 pages) about type 1 diabetes includes exactly 3 hits for osteoporosis in the text, all of which relate to very specific subtopics and none of which even remotely relate to the highly increased risk of fractures which type 1 diabetes in particular confers – the authors of that text clearly had no idea that type 1 diabetes dramatically increases the risk of fractures and poor bone health; there are zero indications to the contrary. It’s probably not uncommon to see important information in textbooks which people forget about in clinical practice (perhaps because the people working in clinical practice read different textbooks, in which this information was not included…), but it’s certainly less common to see important information not included in textbooks because the textbook authors simply don’t know about them. It seems highly likely to me that a lot of health care providers involved in diabetes care currently do not know anything about the topics discussed in this publication; I hope this state of affairs will change in the future.
As also noted in the comments above, the relationship between diabetes and bone health is complicated and interacts with type; type 1 seems to be much worse for the bones than is type 2, and the relationship between in particular type 2 diabetes and bone health is not at all simple. Type 2 diabetics tend to have both some elevated non-diabetes-related risk factors for fractures (in one chapter the authors thus list in that category obesity, reduced muscle quality, poor balance, and falls – e.g. but not only hypoglycemia-related) and some diabetes-specific risk factors ((/very) poor glycemic control probably increases risk (but see also below), duration of disease increases risk, medications – e.g. the thiazolidinedione drug class used to treat type 2 diabetes), but these don’t fully account for the increased risk.
Most of the standard metrics used to assess fracture risk, such as FRAX, do not take diabetes status into account, which is a problem – “studies indicate that FRAX systematically underestimates fracture risk in patients with T2DM” (this problem is not just related to FRAX, thus elsewhere in the publication it is noted more generally that: “fracture prediction tools underestimate fracture risk in diabetes”). The only one of the widely used risk assessment tools which does take diabetes status into account is the QFracture tool, but this tool “has not been specifically evaluated with regard to calibration in individuals with diabetes”; so there is a lot of uncertainty here. This state of affairs is of course hardly ideal, especially not considering how the number of type 2 diabetics is projected to increase over time in the years to come. It is worth keeping in mind that the total population prevalence of type 2 can be deceiving people here into thinking this is less of a problem than it really is, as most people at increased risk of fractures are old people, and type 2 incidence/prevalence increases with age: “Type 2 diabetes affects over 25 % of older adults in the United States, including diagnosed and undiagnosed cases .” The hip fracture estimates included in Vestergaard’s meta-review discussed below indicate a relative risk of hip-fracture of ~1.4 in the type 2 diabetic sub-population, and if you multiply that number by the 25% prevalence among elderly people in the US, that’s more than a third of all fractures in older adults. That’s a lot of people, and a lot of risk not well accounted for.
A problem related to the above observations in the context of type 2 diabetes (and most of the research that has been done in this area has been done on type 2 diabetes, for reasons which should be obvious (“type 1 diabetes mellitus (T1D) accounts for dual-energy X-ray absorptiometry (DXA), a standard way to measure bone mineral density also used to diagnose osteoporosis, does not ‘pick up on’ the excess risk associated with T2DM; in type 2 individuals risk is elevated even when taking DXA measurements into account (this fact may actually be one argument why the QFracture tool may not be bad at all to apply to people in this patient subgroup; QFracture does not include DXA numbers, and if a substantial proportion of the risk is unrelated to the DXA estimates in type 2 anyway then maybe they’re not that important to include). The arguably poor performance of DXA in the context of fracture risk in type 2 diabetes have lead to the development of other tools which might be better at assessing risk in this patient population, and the authors of some of the later chapters of the book talk in some detail about these tools and the results derived from related studies using these tools. It should perhaps be noted in the context of DXA and bone mineral density numbers that one of the clear differences between type 1 and type 2 here is that bone mineral density tends to be decreased in type 1 diabetes, whereas it’s usually if anything increased in type 2 (but the increased, or at least not lowered, bone mineral density in type 2 does not translate into a lower risk of fracture; risk is still elevated, which is what is surprising and not easy to fully account for).
An interesting aspect of the coverage was that the relationship between glycemic control and bone health seems to not be completely clear; to me the coverage of this topic throughout the various chapters (many chapters cover closely related topics and there’s some coverage overlap, but I didn’t mind this at all) reminded much more of the typical coverage you see in publications discussing how the risk of macrovascular complications relate to glycemic control (…’it’s complicated’) than it reminded me of how the risk of microvascular complications relate to glycemic control (…’hyperglycemia increases risk and there’s a dose-response relationship between complication risk and the level of hyperglycemia’). One problem is that low Hba1c may increase the fall risk because of an increased risk of hypoglycemic episodes, increasing risk at the lower end of the spectrum.
The book has a lot of stuff about the specifics of what might be going on at the cellular level and so on, but I won’t talk much about that here even if I found it interesting (it would take a lot of time to go over the details here); one key point to take take away from that part of the coverage should however be mentioned here, and that is that that stuff thoroughly convinced me that there’s no way the increased fracture risks observed in the various epidemiological studies presented at the beginning of the publication are flukes. There are good reasons to think that diabetes may be bad for the bones, quite aside from the reason that they seem to break their bones more often than other people do.
I have included some data and key observations from the book below. As the post is rather long I decided to highlight/bold a few of the most important observations (they’re not bolded in the book).
“In patients with T1D, an increased incidence of osteopenia and osteoporosis has been recognized for over three decades [10–14], occurring not only in adults, but in children as well [15–17]. Many more recent studies have since validated these early findings, demonstrating a reduced bone mineral density (BMD) in T1D [18–22]. Clinical factors associated with lower bone density include: male gender […]; longer duration of disease […]; younger age at diagnosis […]; lower endogenous insulin or C-peptide levels ; low body mass index (BMI) […]; and possibly the presence of chronic diabetes comorbidities or associated autoimmunity . Some studies also suggest that greater longitudinal decrements in BMD occur over time in males . […] In most studies, poor glycemic control does not seem to be strongly associated with a reduced BMD [18–20, 22, 23, 30, 31] […] T1D is […] associated with an increased risk for fracture, higher than the risk in type 2 diabetes (T2D)”
“among risk factors for hip fracture in >33,000 middle-aged adults in Sweden (~25–60 years), the strongest risk factor for both women […] and men […] was diabetes , suggesting that the presence of diabetes was a major risk determinant for this age group. Similar findings had been reported years before in middle-aged Norwegian women and men […] Together, [studies conducted during the last 15 years on type 1 diabetics] demonstrate an unequivocally increased fracture risk at the hip [compared to non-diabetic controls], with most demonstrating a six to ninefold increase in relative risk. […] type I DM patients have hip fractures at a younger age on average, with a mean of 43 for women and 41 for men in one study. Almost 7 % of people with type I DM can be expected to have sustained a hip fracture by age 65  […] Patients with DM and hip fracture are at a higher risk of mortality than patients without DM, with 1-year rates as high as 32 % vs. 13 % of nondiabetic patients […] Though only a very few studies have examined fracture risk at other skeletal sites [51, 54], an increased risk for vertebral fracture is also a consistent finding in studies that have quantified this. […] in one study, an approximate threefold increase in risk for all non-vertebral fractures was reported in men with T1D”.
“studies […] suggest that cumulative changes in bone architecture are beginning early in childhood, particularly in those diagnosed with T1D at very young ages . Compared with nondiabetic children, reductions in BMD [68, 74–78] and bone size, specifically total cross-sectional area (CSA) [73, 79] and cortical area [15, 80], are relatively consistent findings. […] As a whole, […] studies suggest that systemic markers of bone formation in T1D are generally indicative of a condition in which bone formation is reduced. […] Taken together, it would appear that T1D is characterized best as a state of inappropriately lowered bone turnover which exists in conjunction with relative osteoblast dysfunction  and, hence, low bone formation […] serum AGE concentrations are clearly elevated in T1D during childhood , even during preschool and prepubertal years […] skin AGEs […] are increased in children with both T1D and T2D, to the extent that “approximately 4–6 years of diabetes exposure in some children may be sufficient to increase skin AGEs to levels that would naturally accumulate only after ~25 years of chronological aging””.
“diabetic bone has a greater propensity for fracture than is predicted by BMD […] A role for the skeletal accumulation of advanced glycation end products […], chronic hyperglycemia , oxidative stress , and microarchitectural bone defects  have all been proposed, and it is expected that the pathological mechanisms leading to bone fragility in T1D are multifactorial […] Beyond fragility fractures, other skeletal complications also occur disproportionately in persons with T1D, including fracture-healing complications (nonunion, malunion) , Charcot osteoarthropathy , osteomyelitis, and diabetic foot syndrome.”
“In orthopaedics, patients with diabetes have a number of associated disorders, and these present a challenge as many have an increased hospital stay, higher risk of infection, and higher risk of complications after orthopaedic treatment. The orthopaedic-related problems in diabetes are varied, and the true causal links between diabetes and the disorders are largely unknown. […] The incidence of trigger finger [/stenosing tenosynovitis] is 7–20 % of patients with diabetes comparing to only about 1–2 % in nondiabetic patients […] The prevalence of [carpal tunnel syndrome, CTS] in patients with diabetes has been estimated at 11–30 % [130, 133, 153, 156], and is dependent on the duration of diabetes. […] Type I DM patients have a high prevalence of CTS with increasing duration of disease, up to 85 % after 54 years of DM. However the prevalence does not seem to be associated with glycemic control”
“Diabetes increases the severity and risk of periodontitis, the most common lytic disease of bone and a frequent complication of diabetes […] The risk of periodontitis is increased approximately 2–4 times in diabetic versus nondiabetic subjects [4, 47]. In one study, periodontitis was found in 60 % of T1DM patients compared to 15 % without diabetes . Patients with diabetes are at higher risk of severe periodontitis compared with nondiabetic subjects […] There is a direct link between persistent hyperglycemia, an exaggerated inflammatory response to periodontal pathogens and periodontal bone loss”.
“Because diabetic bone disease in type 1 diabetes represents a deficit in osteoblast function and bone formation, antiresorptive therapies for osteoporosis (e.g., bisphosphonates, denosumab) may be ineffective in this form of secondary osteoporosis […] Calcium and vitamin D supplementation […] is considered standard-of-care for osteoporosis treatment . Nonetheless, 1 year of calcitriol supplementation in young adults with recent-onset T1D did not significantly change circulating markers of bone turnover […] very little information from comparative effectiveness studies is available on the treatment of osteoporosis in T1D.”
Type 2 does not increase risk nearly as much as does type 1:
“In 2007 Vestergaard published a meta-analysis of hip fracture results that included eight studies and reported an age-adjusted summary relative risk for hip fracture of 1.38 (1.25–1.53), comparing those with and without T2D . This increase in fracture risk with T2D occurred in spite of higher bone density in those with T2D. […] Most [15–21], but not all [22, 23], subsequent studies have reported increased rates of hip fracture with T2D in age-adjusted models. […] Evidence that more frequent falls do not fully account for increased fracture risk with T2D […], combined with evidence from rodent models , has led to the conclusion that diabetic bone is more fragile for a given BMD. Understanding the aspects of bone that are affected by diabetes and that result in fragile bone has been an important focus of research on diabetes and skeletal health.”
“The effect of glycemic control on fracture risk, BMD, and falls remains poorly understood and controversial.”
“Diabetic patients with multiple complications appear to be at higher risk of fracture, but results are mixed for the association between specific complications and fracture.”
“Our current understanding of the pathogenesis of skeletal fragility in [type 2] diabetes suggests a working model […], whereby poor glucose control in patients with T2DM leads to increases in AGEs that have negative effects on osteoblasts, which in turn causes a reduction in bone formation. This defect in bone formation subsequently results in low bone turnover in T2DM patients, which prolongs the lifespan of type I collagen in bone, thereby leaving it particularly vulnerable to damage from increased AGEs. Ultimately, this creates a “vicious cycle” that may contribute to reduced bone quality and increased fracture risk in patients with T2DM.”
As for an overall assessment of the book, I gave the book five stars on goodreads, because it’s basically to a significant extent written the way I’d like Springer publications like this one to be written. The language in one chapter (out of 11) was slightly sub-optimal, but aside from that chapter every single chapter was in my opinion well written, some of them very well written. Frequent discussions of the results of meta-analyses were included in the book. The authors seemed in general to be aware of potential problems with specific interpretations and to me seemed cautious about drawing strong conclusions from the data they had at hand; in terms of the analytical level of the coverage the publication for example included comments about problems with confounding by indication in cross section analyses. There were a couple of places in one of the later chapters where it was slightly difficult for me to figure out ‘what was going on’, but the coverage included in the next chapter of the book clarified these issues; I was not willing to subtract a star because of that.
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